Contents Section l: Musculoskeletal Connective Tissue, System, andIntegument o guys:c u l o s k e l e t a l C h a p t eE r lm . b r y o lM
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g yo:n n e c t i v e T i s s u e C h a p t eH r 2i $ . o l oC
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C h a p t eH r Si s. t o l oMguys: c l e
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Chapter4. Histology: lntegument ...
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Chapter 5.Anatomy: Musculoskeletal
. . . .33
Chapter 6.Physiology: Musculoskeletal
. . .67
a t. h o l o g y C h a p t ePr T Chapter 8.Pharmacology
.......81 . . 107
ll: Gastrointestinal Section System C h a p t e rEl .m b r y o l o g y Chapter2.Histology Chapter5.Anatomy.... Physiology Chaptera. Chapter5.Pathology.. Chapter 6. Pharmacology
....119 ......125 ...137 ..... 145 ....169 . . .211
ilitshical vii
Section lll: Endocrine System C h a p t le. rH i s t o l o g y
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Chapter2.Anatomy
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Chapter 5. Physiology C h a p t e rP4a. t h o l o g y . . Chapter 5. Pharmacology
. . . . .231 ...265 . . 28.l
Section lV:Reproductive System l. Embryology Chapter
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C h a p t e rH2i.s t o l oM ga y :l e
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Histology: Female ChapterS. Chapter4.Anatomy....
...5,|9
C h a p t e r 5 . P h y s i o. l o g y
...325
ga y :l e C h a p t e rP6a. t h o l oM Pathology: Female ChapterT. Chapter 8. Pharmacology Index
viii iliBhical
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......343 ....555 . .379 ....385
I SECTION
System, Musculoskeletal Tlssue, and Connectlve lntegument
Embryology Musculoskeletal thatarisefrom elements frommesenchymal system arederived Thecomponents of theskeletal and intofibroblasts, chondroblasts, crest. Mesenchymal cellsdifferentiate mesoderm andneural respectively. Boneorgans tissue, cartilage, andbonetissue, whichproduce connective osteoblasts, (intramembranous orfrom ossification) tissue in mesenchymal connective develop directly either (endochondral muscles preformed theskeletal differentiate Ingeneral, ossification). cartilage models gives muscle. andsmooth riseto cardiac Thesplanchnic mesoderm mesoderm. fromparaxial (glands, hairs, nails), andtheunderlying oftheepidermis anditsderivatives Theintegument consists isformed frommesenchyme. thedermis fromectoderm, whereas isderived dermis. Theepidermis crest. fromneural originate whichmayoccurin bothlayers, Melanocytes,
SYSTEM SKELETAL A. Origin l. The skeletalsystem develops from paraxial mesoderm, which forms a column of tissue blocks, called the somites, on either side of the neural tube. Each somite becomesdifferentiated into a ventromedial part, the sclerotome, and a dorsolateral part, the dermomyotome. By the end of the fourth week,the sclerotomecellsform embryonic connectivetissue,known as mesenchyme. Mesenchymecells migrate and differentiate to form fibroblasts,chondroblasts,or osteoblasts. 2. Bone organs are formed by two methods: a. Flat bones are formed by a process known as intramembranous ossification, in which bones develop directly within mesenchyme. b. Longbones are formed by a processknown asendochondral ossification, in which mesenchymal cells give rise to hyaline cartilage models that subsequentlybecome ossified. B. Skull formation. The neurocranium provides a protective casearound the brain, and the viscerocranium forms the skeleton of the face. 1. Neurocranium is divided into two portions: a. The membranous neurocranium consistsof flat bones that surround the brain as a vault. The bones appose one another at sutures and fontanelles, which allow overlap of bones during birth and remain membranous until adulthood. Palpation of the anterior fontanelle, where the two parietal and frontal bones meet, provides information about the progressof ossificationand intracranial pressure.
Musculoskeletal System, Connective Tissue, andIntegument
b. The cartilaginous neurocranium (chondrocranium) of the base of the skull is formed by fusion and ossificationof a number of separatecartilagesalong the median plate. 2. Viscerocranium arisesprimarily from the first two pharyngealarches(TableI-1-1). Thble I-f -f . Origins of viscerocranial bones. Pharyngeal Arch Maxilla Zygomatic bone Part of temporal bone
Dorsal part of first arch
Mandible
Ventral part of first arch
Ear ossicles:malleus, incus, stapes
Tip of ventral part of first arch and second arch
Hyoid bone
Arches 3-6
Laryngeal cartilages
C. Appendicular system. The pectoral and pelvic girdles and the limbs comprise the appendicular system. 1. Except for the clavicle,most bones of the systemare endochondral.The limbs begin as mesenchymalbuds with an apical ectodermal ridge covering, which exerts an inductive influence over the mesenchyme. 2. Bone formation occursby ossificationof hyaline cartilagemodels. a. The processbeginsat the end of the embryonic period in the primary ossificationcenters, which are located in the shaft, or diaphysis, of the long bones.At the epiphyses, or bone extremities,ossificationbegins shortly after birth. b. The cartilagethat remainsbetweenthe diaphysisand the epiphysesof a long bone is known as the epiphysial plate. It is the site of growth of long bones until they attain their final size and the epiphysial plate disappears. D. Vertebral column 1. During the fourth week, sclerotomecells migrate medially to surround the spinal cord and notochord.After proliferation of the caudalportion of the sclerotomes,the vertebrae are formed, eachconsistingof the caudalpart of one sclerotomeand cephalicpart of the next. 2. While the notochord persistsin the areasof the vertebral bodies, it degeneratesbetween them, forming the nucleus pulposus. The latter, together with surrounding circular fibers of the annulus fibrosis, forms the intervertebral disc.
MUSCUTAR SYSTEM A. Skeletal (voluntary) system 1. Origin. The dermomyotome further differentiates into the myotome and the dermatome. a. Cells of the myotome migrate ventrally to surround the intraembryonic coelom and the somatic mesoderm of the ventrolateral body wall. These myoblasts elongate, becomespindle-shaped,and fuse to form multinucleatedmuscle fibers.
4
Embryology: Musculoskeletal
b. Myofibrils appearin the cytoplasm,and, by the third month, cross-striationsappear. : Individual muscle fibers increasein diameter as myofibrils multiply and become arrangedin groupssurroundedby mesenchyme. c. Individual musclesform. aswell astendonsthat connectmuscleto bone,
: 2. Tlunk rnuscrrlature.By the end of the lifth week body-wall musculaturedividesinto a , dorsalepimere,suppliedby the dorsalprimary ramus of the spinal nerve,and a ventral hypomere,suppliedby the ventral primary ramus a- Epimeremusclesforrn the extensormusclesof the vertebralcolumn, and hypomere ' musclesgiverise to lateraland ventral flexor musculature. b. The hypomeresplitsinto tfuee layers. (1) In the thorax,the threelayersform the extemalintercostal,intemalintercostal,and transrrerse thoracicmuscles. (2) In the abdomen,the threelayersform the extemaloblique,intemal oblique,and transverseabdominalmuscles. 3. Headmusculature a. The extrinsic and intrinsic musclesof the tongue are thought to be derived from occipital myotomesthat migrateforward. b. The extrinsic musclesof tle eyemay derivefrom preoptic myotomesthat originally surround t}reprochordalplate. c. The musclesof nastication, facialexpression,t}te pharynx,and the larynx arederived from different pharyngealarchesand maintain their innervation by the nerveof the archoforigin. 4. Limb muscuLfirre originatesin th€ seventhweekftorn somaticmesodermthat migrates into t";J;;;;;.; into the limb bud. with time, the limb rnusculaturesplits ^ extensorgroups. a. The lirnb is innervatedby spinal nerrrcs,which penetratethe lirnb bud mesodermal condensations. Segmentalbranchesof the spinalnervesfirseto form largedorsaland ventral nerv€s, b. The cutaneousinnervation of the limbs is alsoderivedfrom spinalnervesand reflects I the level at which the limbs arise. B. Smoo0rmusde, The smooth musclecomponentsof the gut, trachea,bronchi, and blood vesselsof the associatedmes€nteriesare derivedfrom splanchnicmesodermsurrounding the gastrointestinaltract. Vesselselsewherein the body obtain their smooth muscleftom I local mesenchyme. C. Cardiacmuscle,like smooth muscle,is derivedftom splanchnicmesoderm
Bdd$ to Genenl Prindples Ihe Pharyngealarch areraie €d inthe deriratives Embryology of General section Principles Book2 (volumelD.
Musculoskeletal System, Connective Tissue, andIntegument
CONGEN ITAIABNORMATITI ES A. Cranioschisis (acrania) is an almost complete absenceof the cranial vault. It is often accompanied by a large spinal defea and is incompatible with life when combined with anencephaly. B. Microcephaly is a bony deformation in which the skull fails to expand secondaryto failure of the brain to grow. C. Amelia (absenceof one or two extremities), meromelia (absenceof an arm or leg with presence of the hand or foot), and micromelia (shortened extremities) are usually rare abnormalities. There were increasedincidencesbetween 1957 and 1962as a result of the administration of thalidomide as a sleepingpill and antinauseant. D. Polydactyly refers to supernumerary digits. It is inherited as a dominant trait. E. Syndactyly is fused or webbed digits. It is due to failure of interdigital mesenchymeto break down. It is inherited as an autosomal dominant or recessivegene. F. Clubfoot is an inward flexing of the sole of the foot while the foot is adducted and the plantar is flexed. It is often combined with syndactyly. G. Congenital dislocation of the hip is an underdevelopment of the acetabulum and head of the femur aswell asa laxity of the hip joint. It occurs most often in femalesand resultsin dislocation after birth. It may be associatedwith breechposture during pregnancy. H. Spina bifida occulta is the failure of dorsal portions of one or two vertebrae,usually in the lumbosacral region, to fuse with one another.It is usually not noticeableat the surfaceexcept as a dimple or tuft of hair and is not associatedwith neurological symptoms. I. Meningocele involves several vertebrae such that the meninges or the spinal cord (myelomeningocele) and its nerves bulge out through the opening covered only by a thin membrane. L Achondroplasia results in dwarfism. It is due to abnormal endochondral ossification in the epiphysealplatesof long bones. K. Acromegaly is an enlargement of the face,hands, and feet due to hyperpituitarism. L. Gigantism is a general excessivegrowth that is also due to hyperpituitarism.
INTEGUMENTARY SYSTEM A. Epidermis 1. Origins. The superficial epidermis and deep connective tissue dermis of the skin have different origins. a. The epidermis arisesfrom the surfaceectoderm covering the entire embryo. b. The dermis arisesfrom underlying mesenchyme,which is derived from dermatome, lateral somatic mesoderm,or neural crest,dependingon the location in the embryo. 2. Differentiation of keratinocytes. In the beginning of the second month, the single layer of embryonic epidermis differentiates into an outer periderm and an inner basal layer. a. Continued mitosis in the basal layer leads to the definitive four-layer arrangement of keratinocytesby the end of the fourth month. b. The cells of the periderm are eventually sloughed off into the amniotic fluid.
Embryology: Musculoskeletal
3. Dermatoglyphics are patterns observedon the finger tips, palms of the hands, and soles of the feet that are due to ridges and hollows of the basal germinative layer and underlying dermis. In children with chromosomal abnormalities, these patterns are abnormal. 4. Melanocytes. Invasion of the epidermis by melanin-secretingdendritic cells of neuralcrest origin is responsiblefor pigmentation of the skin. B. Epidermal derivatives. The germinative layer also gives rise to epidermal derivatives by forming epithelial cord or bud-like ingrowths into the dermis,which secondarilyhollow out by death of the central cells. 1. Hair follicles and associatedsebaceousglands. The dermal root sheath and arrector pili muscle of each follicle are derived from surrounding mesenchyme.Fine lanugo hair, shed at the time of birth, first appearsby the end of the third month. Secretionsfrom the sebaconsistingof ceousglands cover the fetus with a protectivesubstance,the vernix caseosa, secretions. degeneratedepidermis,hair, and fatty sebaceous 2. Sweatglands and mammaryglands. In the mammary gland, the lactiferous ducts develop in the persistingmidthoracic portion of the mammary line, which is a band-like epidermal thickening that extends from the base of the forelimb to the region of the hindlimb when it first appears.The epidermal-derivedepithelial lining of the lactiferous ducts and alveoli are supported by mesenchy-ul connective tissue. 3. Nails appear approximately at the beginning of the sixth month. 4. Teeth. Oral cavity ectoderm givesrise to tooth enamel.Associatedmesenchymegivesrise to the associatedtooth structures. C. Dermis consistsof two layers:an upper papillarylayer, which forms the papillae that contain capillaries and sensory nerve endings and project upward into the epidermal ridges; and a deeperreticular layer, which developsinto denseirregular connectivetissue. D. Abnormalities 1. Ichthyosis involves excessivekeratinization (cornification) of the skin, giving it a scalelike appearance. 2. Nevi are skin malformations, such asbirthmarks or hemangiomas.They are due to localized collectionsof differentiatedcells,such as epidermal,pigmented,vascular,or connective tissue,or any combination thereof. They occur frequently and may be superficialor deep. 3. Hypertrichosis is an excessiveamount of hair as a result of increasedformation of follicles.It may be localizedto the midline region or it may be more generalized. 4. Atrichia is an absenceof hair that is usually associatedwith abnormalities of teeth and nails. 5. Polythelia is a developmentof supernumerarynipples along abnormally persistingfragments of the mammary line. 6. Polymastia is a developmentof supernumerarycompletemammary glands. 7. Inverted nipple is a failure of the original epithelial pit, into which the lactiferous ducts open, to evert.It may alsobe causedby the presenceof a fast-growingtumor in the gland, leading to the retraction of the nipple.
Connective Tissue Histology provides Connective tissue thebodywitha continuous system of support, nutrition, defense, and maintenance. lt makes uptheframework oftissue andorgan structures, andpossesses thetensile strengh to allowtissues to withstand forces. shearing Connective tissue iscomposed of cells embedded in anextracellular matrix, consisting offibers andground substance infiltrated withtissue primary (e.g., fluid.Incontrast to theother tissues epithelum, muscle, nerve) thataremainly cellular greater in composition, connective tissue hasa relatively amount of extracellular components.
CETLS OFCONNECTIVE TISSUE A. Fibroblasts are the most numerous connective tissue cells.They are responsiblefor the synthesisof the matrix components:fibers (i.e., collagen,elastin) and ground substance(glyproteoglycans,glycoproteins). cosaminoglycans, 1. Fibroblastscontain abundant euchromatin, nucleoli, and rough endoplasmicreticulum (RER). 2. They are spindle-shapedcells with large, pale, elongatednuclei and a prominent Golgi apparatus.
Note Cells of connective tissue maybedivided intothree categories: . Cells responsible for synthesis andmaintenance of extracellular matrix (fibroblasts, mesenchyme)
3. Resting(inactive)fibroblasts,sometimescalledfibrocFtes, are smallerand contain a more acidophilic cytoplasm due to a reduced endoplasmicreticulum. Restingfibroblaststhat are stimulated to synthesizenew matrix components, as in wound healing, resume the appearanceof activefibroblasts.
. Cells responsible for storage of andmetabolism of fat(adipose)
4. Myofibroblasts are connectivetissuecellsthat resembleboth fibroblasts and smooth muscle cells.They contain large amounts of the contractile proteins actin and myosin, which are important in contraction of wounds during the healing process.
. Cells withdefense and (mast immune function cells, histiocytes)
B. Mesenchymalcells havethe appearanceof undifferentiated fibroblasts.Thesecellsare found in connectivetissue and in associationwith blood vessels(pericytes).They function as a pluripotential reserveof mesenchy-ul stem cells. C. Adipose cells (adipocytes) are derived from mesenchymal cells or fibroblasts. They are specializedfor the synthesis and storage of lipid. D. Mast cells arelargeround or oval-shapedcellsthat contain largecytoplasmicgranulesand a single round nucleus. 1. The granules have a strong afiinity for basic dyes.With dyes such as toluidine blue, they also stain metachromatically. Mast cell metachromasia is a result of their proteoglycan and heparin content.
Tissue, andIntegument Musculoskeletal System, Connective
ClinicalCorrelate in Mastcellsareinvolved immed iatehypersensitivity Antigens flypel) reactions. canbindto lgEonthesurface of mastcells andinduce the -release of histamine A potentially allergic reaction. fataltypeof immediate hypersensitivity reaction is anaphylactic shock.
Bridgeto Heme/tymph in Blood cellsarediscussed inthe detail phoreticu lar Hematologi{Lym Histology in Organ chapter Bookt (Volume lll). Systems
ln a Nutshell
2. Mast cells are induced to degranulate by mechanical trauma, radiant energy,chemicals, and the binding of allergensto IgE molecules (from plasma cells), attachedto specific receptors on mast cell membranes.This attachment accounts for their role in allergic reactions.Substances releasedfrom mast cellsinclude histamine, eosinophil chemotactic factor of anaphylaxis(ECF-A), leukotrienes,and neutral proteases. 3. Mast cellsresemblebasophilsof the blood (also found in connectivetissue)but are derived from different precursorsin the bone marrow and, thus, are considereda separatecell type. Mast cellsdifferentiatein connectivetissuewhereasbasophilsdifferentiate in bone marrow. E. Formed elements of the blood (i.e., neutrophils, eosinophils,basophils,monocftes, lymphocytes),in responseto tissueinjury and immune reactions,migrate into the connective tissue,where they carry out their respectivefunctions. F. Plasma cells are oval-shapedbasophilic cellswith an eccentricallyplaced nucleus containing clumped chromatin with a "spoked-wheel"appearance.Plasmacellsare derivedfrom B 1y-phocytes. 1. The intenseamount of cytoplasmicbasophiliais due to the extensiveRER that is usedfor the synthesisof large quantities of antibodies. 2. Eachplasmacell producesone specificantibody. G. Macrophagesof connectivetissue(histiocytes) are derived from monocftes that migrate from the blood into the connectivetissues. 1. They contain a small irregular nucleus with a prominent nucleolus and extensivecytoplasm that may contain a variety of particlesand vacuoles.
Precursor cells in bonemarrow --+moflocytes (which circulate - miSration in blood) into --+ mature connective tissue intomacrophages.
2. These cells are active in phagocytosis of particulate matter and are members of the mononuclear phagocyte system (MPS) that also includes osteoclasts,microglia, Langerhanscellsof the epidermis,as well as macrophagesof the liver (Kupffer cells),the lung (dust cells),and immune organs.
In a Nutshell
4. The macrophagerecognizesits prey by the interaction of its membranereceptorwith specific regionsof an antibody or complement that coatsthe foreign particle.
TheMajorFunctions of Macrophages . Ingestion of particles and theirdigestion by lysosomes . Resistance to infection by protozoa, bacteria, viruses, fungi, andmetazoa . Cell-mediated resistance to tumors . Destruction of aged erythrocytes . Antigen presentation to lymphocytes
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3. They act asscavengers by recyclingdamagedand dead cellsand asprotectorsby ingesting and killing bacteriaand foreign substances.
5. They respond to a variety of chemotactic stimuli, including lymphokines (signal moleculesreleasedby lymphocytes). 6. When macrophagesencounterlarge foreign bodies,they fuse togetherto form large cells with multiple nuclei, called multinuclear giant cells. 7. The macrophageis an antigen-presenting cell and, thus, is an important participant in the immune response.This function is reviewed in the BasicImmunology chapter of General PrinciplesBook 1 (Volume I).
Histology: Tissue Connective
EXTRACELLUTAR MATRIX A. Fibrous components (Figure l-2-l).
Note MajorTypes of Collagen
Microfibril
Figure l-2-1.Collagen microfibrils, fibrils, fibers, and bundles.
l . Collagen is the most abundant body protein. It contains many positively chargedamino
acidsand, thus, stainswith eosin.Type I collagen,the most abundant type found in connective tissue,is synthesizedby fibroblasts in the following way: a. Ribosomessynthesizetwo types of peptide chains (cr, and or) that are rich in glycine, lysine,and proline. b. In cisterna of RER, three units (two a, and one crr) bind via disulfide bridges and intertwine to form a triple helix. Component lysines and prolines become hydroxylated in the cisterna to form hydroxylysine and hydroxyproline. c. In the Golgi, sugars(i.e., galactose,glucose)bind to the hydroxylysine,and the "finished" glycoprotein procollagen is secretedfrom the fibroblast. d. Peptidasesoutside the fibroblast excisethe ends of the procollagenmolecule,forming a soluble substancecalled tropocollagen. These helicesaggregateto form low-tensile strength microfibrils. e. Another extracellular enzyme,lysyl oxidase, covalently binds lysine and hydrorylysine residuesto form aldehydes,which cross-link adjacenttropocollagenhelicesto form insoluble,high-tensilestrengthcollagen fibrils. f. Thesefibrils intertwine and form noncovalentbonds with matrix glycoproteinto produce collagen fibers. The characteristiccross-bandingof collagenis due to the overlapping of the parallel end-to-end fibers. Large,white, collagenfibers are visible with the naked eyein tendons,ligaments,and other sheetsof denseconnectivetissue.
TypeI . Mostabundant . Found in dermis, bone, tendon, dentin, fascias, fibrous organ capsules, cartilage Typell . Hyaline andelastic cartilages;intervertebral disc;notochord Type lll . Majorcomponent of reticular fibers . Canco-polymerize with othertypesof collagen . Found insmooth muscle, arteries, liver, spleen, kidney, andlung TypelV . Found in basal lamina of basement membranes TypeV . Placenta, liver, lung;now classified asV/Xtfamily Type Vll . Basement membranes; major component of anchoring fibrils
g. More than two dozen types of collagen have been identified. All have the same tropocollagensubstructurebut differ in their amino acid and hexosecontent. Many
tl
Tissue,and Integument Musculoskeletal System, Connective
cell types, including chondroblasts,smooth muscle cells,and epithelial cells,are also able to synthesizecollagen. 2. Reticular fibers are delicate branching fibers composed mainly of type III collagen. a. They form a delicatesupporting reticulum for cells and tissuesand are abundant in the framework of the spleen,lymph nodes,bone marrow liver, kidney, and endocrine glands. b. Reticularfibers are abundant in embryonic connectivetissue,or mesenchyme,but are replacedby collagenfibers during tissuematuration. c. They are able to react with silver salts (argyrophilia) and thus appear black under the light microscope. d. Becausethey are collagenfibrils, they demonstratethe characteristiccross-bandpattern.
Clinical Correlate Diseases Resulting from Defectsin Collagen Synthesis Ehlers-Danlos Defect: Deficient typelll collagen, faultylysinehydroxylation, or J in procollagen peptidase activity. Increased Symptoms: skin andarticular mobility; elasticity, aortic or intestinal rupture. Scurvy (VitC is Defect:Vit C deficiency forproline cofactor hydroxylase) Symptoms: Ulceration of gums, hemonhages (Ol) Osteogenesis impedecta Defect: Single base substitution in geneforcollagen typeI Symptoms: Spontaneous fractures, insuff cardiac iciency
3. Elastic fibers are abundant in tissuesthat must stretch and recoil, such as skin, lung, blood vessels, and vertebralligaments. a. Like collagen,elastic fibers are synthesizedas subunits by fibroblasts. They are easily distinguishedfrom collagenfibers becausethey are thinner, lack longitudinal striations, and appearyellow to the naked eye. b. Under the light microscope,elasticfibers stain weakly with eosin.They are best seen when stainedpurple-black by specialelasticstains. c. Under the electron microscope,elastin may be resolvedinto its two components: a central pale elastinfiber bulk surrounded by glycoproteinmicrofilaments. d. The amino acid composition of elastinis similar to collagen(i.e.,proline, glycine).In addition, it containstwo specificlysine derivatives,desmosineandisodesmosine,that are mainly responsiblefor the elasticproperties of thesefibers. B. Ground substanceis a hydrated,amorphous,extracellularmaterial that occupiesthe spaces betweencellsand fibers. It is viscousand slippery and it acts as a molecular sievethat permits diffusion of metabolitesbetweentissuesand blood; however,it inhibits the movement and spreadof larger particles such as microorganisms.It consistsmainly of proteoglycans and glycoproteins. 1. Proteoglycans are a complex of glycosaminoglycans (GAGs) and core proteins. with abundant acidic (sulfateand a. GAGsarelong-chainedpolyanionic polysaccharides carboxyl) groups. b. Based on their substituted sugar residues, several GAGs have been identified: hyaluronic acid, heparan sulfate, heparin, keratan sulfate, chondroitin 4-sulfate, chondroitin 6-sulfate,and dermatan sulfate.
Note Cround substance isformed bytwoclasses of components: . Proteoglycans consisting of glycosaminoglycans and proteins . Adhesive glycoproteins
t2
c. With the exception of hyaluronic acid, GAGs bind to core proteins, forming bottlebrush-like molecules with an exceptional negativecharge density. d. The most abundant GAG is hyaluronic acid, which is a large charged polyanion that overlaps to form dense charged networks. The abundance of negative chargesin this moleculebinds water and is largely responsiblefor the hydrated gel properties of the ground substance.Hyaluronic acid is not stainedby hematorylin-eosin;but in wellpreserved connective tissue, it is metachromatic with toluidine blue and can be demonstratedwith PASstain. 2. Glycoproteins are moleculesof protein with carbohydrateattached.In contrast to proteoglycans,the protein portion in glycoproteinsis usually the most abundant.
Histology: Connective Tissue
a. Severalglycoproteinshavebeen identified that are important in the binding of cellsto the extracellularmatrix. b. Fibronectin, which is synthesizedbyfibroblasts,is a glycoproteinthat containsbinding domains for cells,collagen,and GAGs.It helps mediate normal cell adhesionand migration. c. Thrombospondin, which is synthesizedbyfibroblasts,containsbinding domains for cells,collagen,heparin, and fibronectin.
CTASSIFICATION OFCONNECTIVE TISSUES A. Embryonic connective tissues 1. Mesenchymalconnectivetissue occursthroughout the developingbody and is composed of stellatemesenchymalcells, abundant ground substance,and later, delicate reticular fibers. 2. Mucous connective tissue,found in the umbilical cord, resemblesmesenchymebut contains more collagen fibers and a more viscous,jelly-like ground substancecomposed mainly of hyaluronic acid. B. Adult connective tissues 1. Connective tissue proper a. Looseconnectivetissue is composedof few fibers,an abundant ground substance,and a variety of resident cells aswell as those derived from the blood. Examplesof this type are found in subcutaneousfascia,in the lamina propria of organs,and in mesenteries. b. Dense connective tissue ( 1) Denseregular connectivetissue is composedof parallel arraysof thick collagen fiberswith scantground substanceand cells.It is ableto withstand stressin a definite direction and is found in ligaments,tendons,and the cornea. (2) Dense irregular connective tissue is composed of collagen and elastic fibers interwoven and oriented in many different directions.Examplesof this type are found in the dermis, capsulesof organs, perichondrium of the cartilage,and periosteum of the bone. 2. Reticular connectivetissue is a speciallooseconnectivetissuecomposedof delicatereticular fibers (type III collagen)and reticular cells (fibroblasts),which provide the framework for bone marrow liver, spleen,and lymph nodes. 3. Elastic connective tissue is composedof coarse,parallel elasticfibers or sheetsinterspersed with fibroblasts and, often, delicate collagen fibers. Elastic tissue is found in yellow ligaments of the vertebral column and in walls of hollow organs,such as the large arteries.
In a Nutshell LooseConnective Tissue . Alsoknown asareolar tissue . Abundant ground substance andcells; fewfibers . Found inserosal linings of peritoneal andpleural cavities, andinglands and mucous memDranes Dense Connective Tissue . Predominance ofcollagen fibers; fewercells andless ground substance . Less flexible andmore resistant to stress than loose connective tissue . Found in dermis, ligaments, perichondriu tendons, m andperiosteum.
4. Adipose tissue is looseconnectivetissuein which the adipocytepredominates.It provides insulation as well as an energyreserve. 5. Blood and hematopoietic tissue. See the Hematologic/Lymphoreticular Histology chapterof Organ SystemsBook 1 (Volume III). 6. Cartilage (seebelow) 7. Bone (seebelow)
t5
Musculoskeletal System, Tissue, andlntegument Connective
CARTITAGE .
Cartilage is a supportive conn€ctive tissue consisting of cells that secretean extracellular matrix composed of fibers embedded in al amorphous ground substance.Cartilage is avascular and is nourished by diffi.rsion of metabolites ftom surrounding blood vessels. A. C€ll6 1. Chondrocytes are round cartilage cells that secrete and maintain the fibers and ground substance that make up the extracellular matrix. a. Chondrocftes occupy microscopic spaces within the extracellular matrix tlat are called lacunae. b. Chondrocytes occur singly or in isogenous groups, resulting from the mitotic diyisions of a single cell. c. Active chondroc)'tes have tle appearanceoftypical protein secretory cells and contain an extensive RER and prominent Golgi apparatus. 2. Chondrogenic cells are undifferentiated mesenchymal cells that are important for the development and growth of cartilage. a. With some exceptions, cartilage is surrounded by a specialized layer of dense connective tissue called the perichondriun. b, The outer portion of the perichondrium is more fibrous, while the inner portion contains mesenchymal cells. These mesenchymal cells can differentiate into chondrogenic cells calleddrondroblasts, whidr are the immediate precursorsto chondro+es. B. Extracellular matrix of cartilage 1..Fibers secretedby chondroc''tes consisting of collagen (mainly type II) and elastin 2. Ground substance,consisting of proteoglycans and glycoproteins a. Proteoglycans of cartilage occur as aggregatesof GAGs and are associatedwith core proteins and hyaluronic acid. (1) These aggregatesassociatewiti cartilage fibers and bind water becauseof their large number of negative charges. (2) These molecular interactions provide cartilage matrix with its unique properties (resistanceto compression) and its firm, yet resili€nt, consistency,
drondronectin' a molecule thatbindschondro!!te Thefirmness ofcartilage depends on: . Electrostatic bondsbetlveen collagen fibersandthe glycosaminoglycn side chainsof matrix proteoSlycans . Thebindingof water(the solvation of u/ater)to the negatively charged proteoSlycn complexes
t4
" #.:,:"::ilx'to'#*'include C.lpes of cartilage l' Hyaline cartilage is the most commont1ryeof cartilage(FigureI-2-2)' a. Most of the bonesof the axial skeletonand all of the bonesof the appendicularskeleton arefirst laid down in hyalinecartilage,Iaterto be replacedbybone. b. In the adult, hyalinecartilageis retainedastlre articular surfacecoveringofthe bones and the support for tlre upper r€spiratorytract. c. Exceptat articular surfaces,hyzline cartilageis surroundedby a fibrous perichondrium. Perichondriumis essentialfor gro*th and maintenanceof cartilage. d. The extracellularmatrix of hyalinecartilageis a firm gel,consistingof a networkof submicroscopict'?e II collagenfibersembeddedin a hydratedmatrix of groundsubstance.
Histology: Connective Tissue
The efiracellular matrix immediately surrounding the chondrocytes, called the capsule or territorial matrix, is highly basophilic and metachromatic becauseof the high content of polyanionic GAGs.
Fibrouslayer of perichondrium Chondrogeniclayer of perichondrium lntercellular matrix
Chondrocytein lacuna Cell nest
Figure l-2-2. Hyaline cartilage.
2. Elastic cartilage is more opaque than hyaline cartilage and is yellow as a result of the many elastic fibers that it contains. a. It is found in areaswhere elasticity is required, including the external ear, epiglottis, and eustachiantube. b. Collagen fibers (tfpe II) and a perichondrium are also present. 3. Fibrocartilage is a combination of dense,regularly or irregularly arranged type I collagen fibers (dense connective tissue) and cartilage cells, which are enclosed in lacunae and surrounded by scant amounts of hyaline matrix. a. Fibrocartilage is found where increasedtensile strength is needed,such as intervertebral disks, pubic symphysis,and tendon insertions that are adjacent to hyaline cartilage or articular surfaces. b. A perichondrium is not present in fibrocartilage, but chondrocytes arise from existing fibroblasts. D. Growth of cartilage is accomplished via two mechanisms: interstitial growth and appositional growth. 1. Interstitial growth is an enlargement of the internal massof the cartilageby mitotic divisions of existing chondrocytes and continued deposition of the extracellular matrix. a. Interstitial growth, leading to the formation of isogenous groups, usually occurs in soft, young cartilage. b. It is important in the epiphysial plates of developing long bones and accountsfor their growth in length. c. It also occurs in the articular cartilages,where the perichondrium is absent.
t5
Tissue, andlntegument Musculoskeletal System, Connective
2. Appositional growth occurswhen the inner layersof perichondrium cellsdivide and differentiateinto chondroblasts. a. Chondroblastssurround themselveswith matrix and gradually turn into chondrocytes.
In a Nutshell of Cartilage TwoMechanisms Growth lnterstitial . Mitotic of predivision existing chondrorytes . Occurs plates in epiphysial cartilages andarticular growth Appositional . Results fromdifferentiation of perichondrial cells . Occurs oncartilage "surfaces"
b. Appositional growth increasesthe cartilagemassby adding to the surface.
BONE Bone is a supportive connective tissue characterizedby mineralization of its extracellular matrix. Its mineral content servesas an important body reservefor calcium and phosphorus. Bone supports body tissues,protectsvital organs,and contains bone marrow. It also acts as a lever systemwherebyforcesgeneratedduring skeletalmusclecontraction are transformed into body movements. A. Cells 1. Osteoblastsare plump basophilic cellsthat activelysecretebone matrix. 2. Osteocftes are mature bone cellsthat occupy lacunaein the solid matrix and have cytoplasmic extensionsthat extend through canaliculi to reach neighboring lacunaecontaining osteocl.tes.Osteocytesare differentiatedosteoblastssurrounded by newly synthesized matrix. a. Communication betweenosteocytesoccursvia gap junctions.
Mnemonic - B forbuild Osteoblasts bone
b. Osteocytesmaintain bone matrix and, therefore,play an important role in calcium homeostasis. 3. Osteoclastsare large, motile multinucleated cells found on bone surfacesat sites of resorption. They are often found in shallow pits of the bone matrix called Howship lacunae. a. They ariseby the fusion of monocytesand may contain up to 50 or more nuclei. b. Osteoclastserode formed bone by releasingacid and proteolytic enzymes,such ascollagenase,which attack the inorganic and organic bone matrices,respectively. c. Theselarge cells have an acidophilic cytoplasm containing vacuolesand lysosomes. Their rytoplasmic bordet which abuts the surfacesof bone tissue,is elaboratelyfolded and appearsas a striated or ruffled border under the light microscope. d. Osteoclastsare stimulated by parathyroid hormone (PTH) to resorb bone tissue, therebyincreasingserum calcium. e. Osteoclastsare members of the mononuclear phagocytesystem. 4. Osteogeniccells are mesenchymal-likecells in adult bone that differentiate into boneforming osteoblastsfor remodeling and repair. a. They are located in the inner layersof the periosteum and endosteum. b. In developingbones,they are the stem cellsfor bone tissueformation. B. Extracellular matrix 1. Organic matrix consistsof fibers and ground substance. a. Fibersconsistof type I collagenin the form of cross-bandedfibers. b. Ground substanceconsistsof proteogly.ur aggregatescomposedof keratan sulfate, chondroitin sulfate,and hyaluronic acid.
t6
Histology: Connective Tissue
2. lnorganic matrix, which accounts for approximately 50o/oof the dry weight of bone matrix, consistsprimarily of a complexof calcium and phosphatein the form of hydroxyapatite. Calcium carbonate,citrate, fluoride, magnesium,and sodium are also present. C. Organization of bone tissue 1. Immature bone (i.e., nonlamellar,bundle, woven) is newly depositedbone tissue with looselyinterlacedcollagenfibers that contains a high density of osteocytes. 2. Mature bone is a highly structured lamellar arrangementof cellsand extracellularmatrix that is organizedinto osteons,interstitial lamellae,and circumferentiallamellae. a. Osteons (Haversian systems) are composedof concentric lamellaearound a central neurovascularcanal (Haversian canal). Theserylindrical units run more or lessparallel to the long axis of compact bone. b. Interstitial lamellae are wedgesof compact bone located between the cylindrical osteons. c. Circumferential lamellae are parallel lamellar arrays of compact bone tissue surrounding the osteonson the outer surface(outer circumferentiallamellae)and on the inner surface(inner circumferentiallamellae)of bone. 3. Periosteum is a double-layeredtissuemembranebound firmly to the outer bone surface. It consistsof an outer, mostly fibrous, layer and an inner, more cellular,layer that possesses osteogenicpotential. 4. Endosteum is a delicatemembrane of osteogeniccellsthat lines the internal surfacesof bones adjacentto the marrow cavities.
ClinicalCorrelate In Paget disease, thereisa disturbance inthebalance of (an bonehomeo$asis increased rateof bone destruction andconsequent rebuilding) thatleads to the creaiion of wovenor immature bone.People suffering fromPaget arepredisposed to fractures.
Note Primary Functions of Periosteum andEndosteum . Nutrition of bonetissue . Provision of continuous supply of newo$eoblasts
D. Typesofbone l. Cancellous (spongy) bone consistsof delicateanastomoticspiculesor larger trabeculae of bone tissuein the form of a porous meshwork fi.lledwith marrow. 2. Compact (dense)bone consistsof numerous osteons,interstitial lamellae,and circumferential lamellae. E. Organization of long bones 1. Epiphysesare extremitiesof long bones composedof cancellousbone coveredby a thin layer of compact bone. 2. Diaphyses are cylindrical shaftsof long bones composedof compact bone. 3. Metaphysesarethe regionsbetweenthe epiphysesand the diaphysesand consistof a shell of compact bone around a massof cancellousbone. F. Bone formation. Bone organsform by two distinct processes. In intramembranous ossification, bone is formed directly within layers (membranes) of mesenchyme,or primitive connectivetissue.In endochondral ossification, a model of the bone is first laid down in hyaline cartilage,and then the cartilageis replacedby bone. In both processesof bone formation, a temporary, immature nonlamellar tissue appearsfirst and is then replacedby lamellar bone. 1. Intramembranous ossification. Bonesformed in this way are the membrane bones and include certain bones of the skull (i.e., frontal, parietal, temporal, part of the occipital bones),facial bones,the clavicles,and part of the mandible. a. This processbegins in the primary ossification center within the connectivetissue layer.
l7
Tissue, andIntegument Musculoskeletal System, Connective
(1) Mesenchyme cells aggregateand differentiate into osteoblasts,which deposit spiculesof bone matrix in the loose connective tissue. (2) Cells of the connective tissue membrane divide to give rise to more osteoblasts, which contribute to the growth of the ossification center. b. The matrix is calcified after it is secretedby the osteoblastsin the woven bone. After calcification, the spiculesof bone become coated with more osteoblasts,which transform the spiculesinto larger trabeculae.The trabeculaeinterconnect around the blood vesselnetwork in the mesenchymeto form cancellousbone. c. The growth of bone is appositional and osteoblastsbecome trapped in expanding bone to become osteocftes. (Unlike cartilage, bone is able to grow appositionally only.) In lacunae,osteocftes rarely divide, and thus, interstitial growth is impossible. d. The intramembranous bone has two fates: ( 1) It may remain cancellous,in which casethe intertrabecular connectivetissuecavities become filled with bone marrow or fat. (2) It maybecome compact,in which caseappositionalgrowth continuesuntil all of the mesenchyme (except blood vessels)is replaced by bone. In this case,the immature woven bone is replaced by lamellar bone through the concomitant processof resorption and apposition. e. The connectivetissue layer that does not undergo ossification givesrise to the periosteum and endosteum of the bone.
lfot,g ossification, Inendochondral thereis notransformation of cartilage intobone;bone replaces thecartilage tissue model.
2. Endochondral ossification. Bonesformed in this way are the cartilagebones and include most of the long and short bones of the skeleton.Later in development and growth, the cartilage is resorbed and replacedby bone tissue (Figure I-2-3). a. Hyaline cartilage models are formed by differentiated mesenchymalcells called chondroblasts. The mesenchymearound the cartilage model condensesto form the perichondrium. Cartilage models increasein length by interstitial growth (i.e., division of chondroblasts) and in width by appositional growth (i.e., new cartilage cells are contributed by the perichondrium). b. Ossification of the cartilage model begins at the primary ossification center,which is located in the diaphysis of long bones. It begins as the chondrocytes in the region of the primary ossification center hypertrophy, resorb some of the organic matrix, and die, leaving large lacunae. c. A solid mineral phaseof calcium and phosphate is deposited in the remaining matrix to form a calcified cartilage.At the sametime, the cells of the inner layer of perichondrium differentiate into osteoblasts.The perichondrium is now called the periosteum.
t8
Histology: Connective Tissue
Epiphysealbone Restingzone
Proliferativezone
Hypertrophic cadilage zone Calcifiedcartilage
-ugile zone Ossification
Figure l-2-3.Endochondral ossif ication.
d. Osteoblastssecretebone matrix on the surfaceof the calcifed cartilage.Capillaries, osteoclasts, and osteoblastspenetratethe periostealbone to form the primary marrow (central) cavity. e. Cartilage cells adjacentto the primary ossificationcenter then begin to hypertrophy and undergo the samesequenceof events:cell death, calcification of organic matrix, capillary and osteoclastinvasion,and deposition of bone spicules.This processgradually progressesin the cartilagemodel, moving in a direction awayfrom the ossification center.Thus, not all chondroblastsundergo the samechangesat the sametime. There are five distinct zonesin the cartilageskeleton,which representa progressionof cellsfrom the diaphysealprimary ossificationcenteroutward. (1) Ossification z,oneconsistsof osteoblastslaying down bone matrix over calcified cartilage. (2) Calcified cartilage zoneconsistsof cartilagematrix becoming calcified. (3) Hypertrophic cartilage zone consistsof chondrocytesthat appearlarge and have abundant glycogenin their cytoplasm.
Note Growthof a LongBone (l) Proliferation of chondrocytes inthe plate epiphyseal (2) Chondrocytes of the diaphyseal side hypertrophy (3) Matrix calcifies (a) Chondrocytes die (5) Osteoblasts laydown layer of primary bone along thebonespicules (Steps l-5, repeat)
(4) Proliferative zone consists of chondrocytes dividing rapidly to form parallel rows of stackedcellsalong the long axis of bone. (5) Restingr-oneconsistsof hyaline cartilagewithout morphologic cell changes. f. At later stagesof development,usually after birth, secondaryossificationcentersarise in the epiphyses.Growth at thesecentersis radial rather than longitudinal. g. All zoneslocatedbetweenthe diaphysisand epiphysis(in the metaphysisof the bone) are caught between ossification centers.The result is a transversedisk of cartilage, called the epiphyseal plate, which separatesepiphysealbone from diaphysealbone.
t9
Tissue, andIntegument Musculoskeletal System, Connective
( l.) It persists postnatally until longitudinal growth of bone is completed. (2) When the cartilage of the epiphyseal plate stops growing (at approximately age 20), it is replaced by bone tissue.
NOte
. Endochondrar = ossification 1 in len$h . Appositional = ossification I rngirth
G. Growth and remodeling of bones. Bone growth is associatedwith concomitant resorption of preformed tissue and deposition of new tissue. Bone remodeling occurs tlroughout life.
t :rffiJffiffiffirT"lfgbonesgrowinlengthbvthecontinuedinterstitialgrowth a. This radial growth of cartilagetendsto thicken the epiphysealplates;however,subsequent endochondralossificationkeepsthe Plateat about the samethickness,while addingto the length of the bone shaft' proceedat th€ samerate in the two epib. The processof elongationdoesnot necessarily phpeal platesof a long bone. z. Growth in girth. The shaftsof long bonesincreasein width by appositionof new bone subperiosteally. a. At the sametime, bone is removedfrom the internal surfacebeneaththe endosteum so that the bone marrow cavity may increasein diameter. b. Growth in outside diameterresultsftom peripheral apposition of bone. Growth in cavity diameterresultsfrom centralresorptionof bone. H. foints are definedasthe articulation betweentwo bones.Th€rearetwo tfpes of connective tissueioints. l. Synarthrosesarejoints that permit very litde or no movementofbones. a. Syndesnosesare articulationswherebonesarejoined by bandsof denseconnective tissue.This type of joint forms the suturesbetw€enthe growingbonesof the skull but is convertedinto a synostosisin adults. b. Synchondrcsesare ioints where bonesare united by hyaline cartilage.Examplesof this tfpe of ioint arethe epiphysealplatesof growinglong bones. c. Synostosesare joints where bones are united by bone tissue.This type of joint is found in the suturesof the adult skull. d. Symphysesarejoints wherebonesare united by combinationsof hyaline and fibrocartilage.The symphysispubis and intervertebraldisksare consideredsymphyses. 2. Diarthroses arejoints that permit ftee movement.They are presentin the union of long bones,suchasat tle elbowand knee. a. In a diarthrosis,a twoJayeredarticular capsulejoins the extremitiesof long bones. The capsuleis composedof an externalfibrous layerand an internal synoviallayer. (1) The denseconnectivetissue frbrous layer is especiallywell developedin ligamentsand someof tlle tendonsinsertedinto the bone nearthe ioint. (2) The internal synovialmembraneis lined by squamousor cuboidalcellsof mesenchymalorigin calledrynovial cclls. b. The capsuleencloses the articularcavity,which is filled with a hyaluronicacid-richsynovial fluid; this fluid facilitatesthe sliding of the articular surfacesof the bonesat the joint.
20
Muscle Histology Muscle isa tissue specialized forirritability andcontractility. lt iscomposed of elongated cellscalled proteins myofibers thatcontain contractile arranged in rytoplasmic filaments. Muscle cellsattach to bones andsofttissues andarearranged in circular sheets around tubular organs to accomplish mechanical bodymovements uponcontraction. There arethreetypes of muscle: skeletal, cardiac, andsmooth. Skeletal andcardiac muscles areclassified asstriated muscles, based onthe appearance of striations thatrunperpendicular to thelongaxisofthemuscle fiber. Thestriations are dueto thehighly ordered repetitive organization ofthecontractile filaments. Smooth muscle lacks striations dueto a lessstructured, looser arrangement of itscontractile filaments. ln muscle terminology, thesarcolemma refers to themuscle cellmembrane, thesarcoplasm refers to the cytoplasm, andthesarcoplasmic reticulum refers to theendoplasmic reticulum.
SKETETAL MUSCTE Skeletalmuscle is derived from mesodermalsomites.Single-nucleatedmyoblastsfuse to form the multinucleated skeletalmuscle cells (fibers). A. Skeletal muscle cells are long rylindrical fibers. Their multiple ovoid nuclei are located peripherally beneath the sarcolemma. This distinguishes skeletal muscle cells from cardiac muscle cells,which usually have one centrally located nucleus. Each skeletalmuscle fiber is surrounded by a basallamina. 1. Light microscopy. Stainedwith hematorylin and eosin,the sarcoplasmappearshomogeneous or stippled in crosssection and striated in longitudinal section. a. The striations, composed of alternating dark and light bands, are contained in 1-2 pm myofibrils that lie in the sarcoplasmparallel to the long axis of the muscle fiber. Myofibrils are composed of a seriesof sarcomeresthat consist of interdigitating polarizedthin filamentsand bipolar thick filaments (Figure I-3-1). The sarcomeresare the basicunits of contraction of striated muscle. b. The dark bands of the sarcomeresare called A bands becausethey are anisotropic (birefringent) in polarized light. In the center of the A band, a paler region, the H band, is seenin relaxed muscle. c. The light bands of the sarcomereare calledI bands (isotropic), and a dark transverse line, the Zline,bisects eachI band. d. A singlesarcomereis bounded by two Z lines and containsone A band separatingtwo semi-I bands.
2l
Muscle Histology Muscle isa tissue specialized forirritability andcontractility. lt iscomposed of elongated cellscalled proteins myofibers thatcontain contractile arranged in rytoplasmic filaments. Muscle cells attach to bones andsofttissues andarearranged in circular sheets around tubular organs to accomplish mechanical bodymovements uponcontraction. There arethreetypes of muscle: skeletal, cardiac, andsmooth. Skeletal andcardiac muscles areclassified asstriated muscles, based onthe appearance of striations thatrunperpendicular to thelongaxisofthemuscle fiber. Thestriations are dueto thehighly ordered repetitive organization ofthecontractile filaments. Smooth muscle lacks striations dueto a lessstructured, looser arrangement of itscontractile filaments. Inmuscle terminolory, thesarcolemma refers to themuscle cellmembrane, thesarcoplasm refers to the and the sarcoplasmic reticulum refers to the reticulum. endoplasmic rytoplasm,
SKELETAT MUSCTE Skeletalmuscle is derived from mesodermalsomites.Single-nucleatedmyoblastsfuse to form the multinucleated skeletalmuscle cells (fibers). A. Skeletal muscle cells are long rylindrical fibers. Their multiple ovoid nuclei are iocated peripherally beneath the sarcolemma. This distinguishes skeletal muscle cells from cardiac muscle cells,which usually have one centrally located nucleus. Each skeletalmuscle fiber is surrounded by a basallamina. t. tight microscopy. Stainedwith hematorylin and eosin,the sarcoplasmappearshomogeneous or stippled in crosssection and striated in longitudinal section. a. The striations, composed of alternating dark and light bands, are contained in 1-2 pm myofibrils that lie in the sarcoplasmparallel to the long axis of the muscle fiber. Myofibrils are composed of a seriesof sarcomeresthat consist of interdigitating polarizedthin filamentsand bipolar thick filaments (Figure I-3-1). The sarcomeresare the basicunits of contraction of striated muscle. b. The dark bands of the sarcomeresare called A bands becausethey are anisotropic (birefringent) in polarized light. In the center of the A band, a paler region, the H band, is seenin relaxed muscle. c. The light bands of the sarcomereare calledI bands (isotropic), and a dark transverse line, the Zline,bisects eachI band. d. A singlesarcomereis bounded by two Z lines and containsone A band separatingtwo semi-I bands.
2l
Connective Tissue, andlntegument System, Musculoskeletal
AIH z l i ne band band band
Myofibril Sarcomere . lZline lri-----t
A band
Z I band,'
M l i ne
ll'.1
o c o
E (g o
Myosinfilament
I
F-actinfilament \ \ \
Myosinmolecule
f------ra
oe
f,o G-actinmolecules
Heavy Light meromyosin meromyosin Figure l-3-1. Sarcomere structure. 2. Electron microscopy. In skeletalmuscle cells examined with the electron microscope,the repeatingpattern of bands and sarcomeresis due to the arrangementof the myofilaments. a. Thin filaments are composedof the proteins actin, tropomyosin, and troponin. ( 1) Actin is a long fibrous structure (F-actin) composedof two strandsof spherical or globular G-actin monomers twisted in a double helix. The filament is polar and containsmyosin-binding sites on the G-actin monomers.
Note are Actinandtropomyosin filaments, whereas long,thin isa complex of troponin threesubunits.
22
(2) Tropomyosin is a polar molecule containing two polypeptide chainsin the form of an o-helix. The tropomyosin moleculeslie head-to-tail to form filaments that lie in the groovesof the actin helix. (3) Troponin is composed of three polypeptides: TnT binds to tropomyosin at intervals along the thin filament, TnC binds calcium ions, and TnI inhibits actin-myosin interaction. b. Thick filaments are composed of myosin. Myosin is a molecule that contains a tail and two heads.
Histology: Muscle
( 1) The tail fiber is formed from portions of two heavychains,which arewound in a coil. (2) The headsare globular regions formed by the associationof part of one heavy chain with two light chains. Myosin heads function as active sites for AIPase activity and as actin binding sites. c. Actin and myosin together represent55o/oof the total protein in striated muscle. d. Thick filaments occupy the central portions of the sarcomere;thin filaments attach at one end to the ZIine and run parallel to, and between,the thick filaments. (1) I bands are composedof thin filaments only. (2) Abands .ue composedmostly of thick filaments and the thin filamentsbetweenthem. (3) H bands are composedof thick filaments only. B. Connective tissue investments of skeletal muscles and fibers (Figure I-3-2).
Skeletalmuscle
Epimysium
Perimysium
Myofibrils
Nucleus Endomysium Sarcolemma
Figure l-3-2. Connective tissue investments of a striated skeletal muscle.
2!
Tissue, andIntegument System, Connective Musculoskeletal
1. Endomysium is a connective tissue framework composed mainly of reticular fibers that surrounds and supports individual muscle cells. 2. Perimysium is a connective tissue septum that surrounds groups (fascicles) of muscle cells.
Note . Connective notonly tissue bindsmuscle cells together, inthe butalsoassists generation offorceand movement during contraction. . Tendons attach muscles to bones. . Ligaments attach bone to bone.
3. Epimysium is a connective tissue sheath that surrounds an entire muscle. 4. Connectivetissuefibers from the endomysium, perimysium, and epimysium come together at the ends of the long rylindrically shapedmuscle to form a tendon. 5. Skeletalmuscle is a highly vascular tissue; capillaries are located in the connective tissue surrounding all muscle cells. C. Muscle contraction 1. Sliding filament model has been generally acceptedas the explanation of how a muscle cell shortenson contraction. a. According to this theory, the filaments maintain constant lengths during muscle shortening, with thin filaments sliding past thick filaments. b. The sliding movement is due to cross-bridges formed between the actin monomer and the myosin head.Thesecross-bridgesbind the thin and thick filaments during muscle contraction. c. Tensiondevelopmentis proportional to the number of myosin headsoverlappedby thin filaments. 2. Sequenceof events.At the onset of muscle contraction, myosin headsmove out from the thick filament backbone to interact with ATP and actin molecules.
ln a Nutshell Filament Model Sliding isnotcaused by Contraction theshortening of individual bythe filaments, butrather increase intheamount of overlap between thick andthinfilaments.
a. The myosin head movement pulls thin and thick filaments in opposite directions. As the filaments slide, the sarcomeresand myofibrils shorten. The myosin heads then detach from the actin molecules and the rycle is repeated. b. As a consequenceof this action, thin filaments slide into the A band, and the sarcomere and overall muscle shorten. (1) The H band narrows and disappears. (2) The I bands shorten. (3) The Z lines are pulled closertogether. 3. ATP providesthe energyfor muscle contraction in the following manner: a. AlP-bound myosin is active and binds actin. b. This complex is altered when AIP is split by AIPase to liberate energy. 4. Tubules formed by finger-like invaginations of the sarcolemma into the muscle cell surround eachmyofibril to form the transverse (T) tubule system (Figure I-3-3). a. Each tubule lies between the two terminal cisternaeof the sarcoplasmicreticulum to form a triad.
24
Histology: Muscle
Sarcomere I band
Terminalcisterna
Transverse tubules
Figure l-3-3.Striated muscle fiber showing sarcoplasmic reticulum and T-tubulesystem. b. There are two triads in each sarcomere,which are present at the junction between the A and I bands. c. Theseunits serveto couple excitation of muscle cellsto their contraction (excitationcontraction coupling). 5. Muscle contraction is summarizrdas follows: a. Skeletalmuscle cells are innervated by motor neurons located in the CNS. b. The axon of the motor neuron branchesin the muscleto contact severalmuscle cells, forming a motor unit. c. The terminus of each branch forms a specialization at the muscle surface called a motor end plate. d. An action potential from the motor neuron arrives at the motor end plate and causes the releaseof the neurotransmitter acetylcholine onto the surfaceof the muscle. This, in turn, causesdepolarizationof the sarcolemma. e. Electrical impulses travel into the cell via the T tubules and stimulate the sarcoplasmic reticulum via gap junction-like bridges to releaseCa2+. f. Released Caz+ binds to the TnC unit of troponin and induces movement of tropomyosin deep into the actin helix groove. g. As a result of this displacement,the actin filaments can bind to the myosin head, move deeperinto the A band, and the I band then shortens. D. Muscle relaxation 1. The sarcoplasmicreticulum possesses an AlP-driven Ca2+pumping mechanism,which accumulatesCa2+within its membrane system and, thus, reduces the cytoplasmic concentration of Ca2+around the myofilaments. 2. At low Ca2+concentrations,the tropomyosin falls out of the groove of the actin helix in a position where it sterically blocks the myosin-binding site on each actin molecule.
Note Summary of Contraction Mechanism --+ . Depolarization of nerve release of neurotransmitter acetylcholine at junction neuromuscular . Acetylcholine causes depolarization of sarcolemma anditsT tubules . Increased release ofCazr fromSR r fsz*binds toTnCsubunit oftroponin, exposing actin's myosin binding site . Thisallows themyosin headto interact withthe actin's myosin binding site . Myosin headbends (ratchet-motion), pulling actinpastmyosin . Myosin headisreleased onlyafteraddition of new ATPmolecule
2t
Tissue, andIntegument System, Connective Musculoskeletal
MUSCTE SMOOTH A, Smooth rnusde cells are derived ftorn a mesenchymalnetwork of cellscalled myoblasts. nonstriated cells. Ihey areelongated,spindle-shaped, eosinophiliccytoplasm. 1. Theycontaina single centrallylocatednucleusin a homogeneous 2. Eachcell is surroundedby a basallarnina and delicatereticular fibers3. Laversof smooth musclecellsarefound in the walls of blood vesels and hollow viscera. Bandsof smooth rnusclecellscanbe found in the erectorpili musclesof the skin. {. Smoothmusclecellsin a tissueareelectrically coupledwith eachother. a. With the electronmicroscope,areasof adjacentsmooth musclecellscanbe seenwith their cell membranescloselyapposedand forming gapjunctions. b. Similar electricaliunctions occur in cardiacmusclebut not in skeletalmuscle. 5. Smooth musclecells contain actin and myosin filaments,but they are not arrangedin orderly arrayslike thosefound in skeletalmuscle. llota
a. Bundlesofmyofilamentscourseobliquelyin the cell,forming a lattice-likearrangemenl
Densebodiesin smooth musclecellsservethefunction of Z linesin striatedmuscle.
b. A stding filament mechanismof contractionis tlought to occur' c. Thin filamentsinsert into densebodies,locatedwithin smoothrnusclecyoplasm and attachedto their membranes. B. Contraction of smooth muscle is slow and sustained.Individual cellsmay contract completelyor a waveof contractionmay propagatefrom one end of the tissueto the other. 1. Musclecell contraction maybe triggeredby variousstimuli. a. In somestructures(e.g.,ductusdeferens),nervesupplyto smoothmuscleis abundant. b. In the smooth muscleof the intestinal wall, contraction is modulatedby intrinsic rhythrnic depolarizationand by neural input. c. Hormonesmay also causesrnoothmusclecontraction;for example,oxytocin stimulatesuterine contraction, 2. Smoothmusclecellsare able to conc€ntrateCa2+in their cftoplasm. This ion playsan important role in the contractionof thesecells. a. Depolarizationof the cell membraneresultsin an influx of Ca2+from outsidethe cell. reticulum. b. Ca2+is sequestered in eitherthe cellmembraneor in the sparsesarcoplasmic
MUSCLE CARDIAC Cardiac muscle is discussedin the CardiovascularHistology chapter of Organ SystemsBook I (Volume III).
26
Histology: Muscle
SUMMARY OFMUSCLE TYPES Thble I-3-f . Tlpes of muscle. Muscle Type
Description
Skeletal
Bundles of long, cylindrical multinucleated cells
Yes
Strong, quick, discontinuous, voluntary contraction
Cardiac
Elongated, branched individual cells that lie parallel to eachother; intercalated disks between ends of cells
Yes
Strong,quick, continuous, involuntary contraction
Smooth
Fusiformcells
No
Weak,slow, involuntary contraction
Cross Striations
Activity
27
Integument Histology Theintegument consists oftheskin(epidermis anddermis) (sweat andassociated appendages glands, glands, sebaceous hairs, andnails). Considered thelargest bodyorgan, theintegument comprises approximately 16o/o oftotalbodyweight. lt isa highly specialized organ thatfunctions to protect thebodyfrominjury, desiccation, andinfection. lt alsoparticipates in sensory reception, excretion, thermoregulation, andmaintenance ofwater balance.
EPIDERMIS Epiderrnisis the outermostlayerof tJleintegument.It is a stratifiedsquamousorthokeratinized epitheliallayerof ectoderrnalorigin. A. Layersof the epiderrnisftom deepto superficialconsistof four strata. l. Stratum basale (stratum germinatirum) is a proliferative basallayer of columnar-like cellsthat containthe fibrous protein keratin. 2. stratum spinosum is a multilaminar layerof cuboidallike cellsthat are bound togetler by meansof numerouscltoplasmic extensionsand desmosomaljunctions. 3. Stratum granulosum consistsof flat polygonalcellsfilled with basophilickeratohyalin granules.Viewed at the electron microscopiclevel, thesecells also contain numerous membrane-coatinggrarules 4. Stratum corneum is the superficialstratum of deadcellsand consistsof severalto many layersofflat, anucleated,and cornified (keratinized)cells.In the epidermisofthe palms and soles,a thin, transitional zone of flat eosinophilicor pale-staining "r,o.leatei ""u, may occur asthe stratun lucidum. This layeris found only in regionswith a thick stratum corneum.
illnemonic BiG
Stratum Basale (Germinativum)
Sta6
Stratum Spinosum
GNe
Stmtum Gnnulosum
Lotsof Stratum lu.idum -, . charlty Stratum corneum
B. Cellsof the epidermis 1. IGratinoc''tes arethe most numerousand areresponsiblefor the production oftle family of keratin proteinsthat provide the barrier function of the epidermis. 2. Melanocytesare derivativesof neural crestectoderm,They are found in the dermis and arealsoscatteredamongthe keratinocftesin the basallayersof the epiderrnis,Thesedendritic cellsproducethe pigment melanin in the form of melanosomesthat are transferredto keratinocftes. 3. Langerhanscellsaredendritic cellsbut aremembersofthe immune systemand function asantigen-presentingcells.Theyhavealsobeenfound in other parts of the body,including the oral cavity and lymph nodes.
29
Tissue,andIntegument Connective System, Musculoskeletal
ClinicalCorrelate Psoriasis . T in number of proliferating cellsin stratum + stratum spinosum. basale thereisan1 Inaddition, This rateof cellturnover. greater epidermal results in andcontinous thickness oftheepidermis. turnover Addison Disease . J A C T H* t p i g m e n t a t i o n of skin Albinism . Melanocytes areunable to (either melanin synthesize oftyrosinase byabsence or inability of cells activity to takeuptyrosine).
4. Merkel cells are found in the basalepidermis and appearto function in concert with nerve fibers that are closelyassociatedwith them. They appearto have a sensoryfunction. At the electron microscopic level,their cytoplasm contains numerous membrane-bound granules that resemblethose of catecholamine-producingcells.
DERMIS Dermis is a connectivetissue layer of mesodermal origin subjacentto the epidermis and its basementmembrane.The dermis-epidermaljunction, especiallyin thick skin, is characterized by numerous papillary interdigitations of the dermal connectivetissueand epidermal epithelium. This increasesthe surface areaof attachment and brings blood vesselsin closerproximity to the epidermal cells. (The epidermis, like epithelia in general,is devoid of blood vessels.) Histologically,dermis consistsof two identifiable regions. A. Papillary layer, associatedprincipally with the dermal papillae, is the most superficial layer. It consistsof a looselypacked,irregular meshwork of collagenfibrils that contain fine blood vesselsand nerve endings. B. Reticular layer is the deeperdermal layer and consistsof coarsecollagenbundles intertwined with elasticfibers in a gel matrix. This layer is a typical denseirregular connectivetissue.
HYPODERMIS
Vitiligo This layer of loosevascularconnectivetissueis infiltrated with adipocytes and correspondsto the superficial fasciaof gross anatomy.However,since it contains the deepestportions of the . Disorder inwhich melanocytes aredestroyed, cutaneousglandsand hairs, it is alsoan important part of the skin. The hypodermis fastensthe skin to underlying musclesand other structures. to thought to besecondary nedysfu nction, autoimmu leading to depigmentation.
APPENDAGES CUTANEOUS
ClinicalCorrelate Bullous Pemphigoid . Abnormality ofthedermaljunction, leading epidermal to a blistering disorder. Pemphigus . Another blistering disorder; bylossof it iscaused junctions intercellular keratinocvtes. between
Cutaneousappendagesare all derivativesof the epidermis. A. Eccrine (merocrine) sweat glands are simple, coiled, tubular glands that are widely distributed over the body. 1. Secretoryportions are tightly coiled and consistof a single layer of columnar-like pyramidal cells. They extend deep within the dermis or hypodermis, where they are surroundedby myoepithelialcells,which aid in the dischargeof secretionby contraction. 2. Duct portions, composed of two cuboidal cell layers,are corkscrew-shapedand open onto the epidermalsurface.The luminal diameterof the duct is lessthan that of the secretory coil. 3. These glands are important in thermal regulation. When hypotonic sweat is released onto the body surface,heat is lost by water evaporation. 4. Control of the eccrineglandsis mainly by the innervation of cholinergic fibers. B. Apocrine sweatglands are alsosimple,coiled,tubular glandsbut are much lessabundant in their distribution than eccrineglands.They can be found in the axillary, areolar, and anal regions. 1. Secretoryportions of theseglands are composedof a singlelayer of cuboidal or columnar cells.They are larger and have a much wider luminal diameter than eccrine sweat glands.Myoepithelial cells surround the secretorycellswithin the basementmembrane and contract to facilitate secretion.
50
Histology: Integument
2. Duct portiom aresirnilarto thoseof eccrinesweatglandsbut generallyopenonto hair folIiclesinsteadof onto the epidermalsurfaces.
'In a NUbhell
3. Functionsof theseglandsin humansis not at all clear.In other mammals,apocrinesweat glandsarewidely distributedoverth€ bodyandserveavarietyoffirnctions relatedto olfaction and behavior.Specializedapocrine glands in the ear canal (ceruminous glands) producea secretionin conjunctionwith adjacentsebaceous glandsto form the protective earwax(cerumen), Apocrine sweatis normally odorlesswhen secretedbut becomes noticeabledue to ttre activity of cutaneousbacteria,
sLe ::Tlt ,.fn lff:,.|n [o@_Esserrja'yArtkry, doo €v€rywnerq ar€o.r, wihsome and anal erceplionsrcson (e8,slans
4. Control of the apocrineglandsis hormonal and via the innervation of adrenergicfibers. Theseglandsdo not begin to function until puberty.
* n lil']r** opcis
glandsaresirnple,branchedholocrineacinarglands.Theyusuallydischargetheir C. Sebaceous secretionsonto the hair shaft within hair follicles. Theseglands are found in the dermis throughout the skin, excepton tle palrnsand soles.
::*.
Hair foricl*
il;iffil lf:t mainty H,0 producing Nacl, urea, NH'uricacid
l. Seqetorl'portions consistofperipherallylocat€d,flattenedstemcellst}lat resemblebasal keratinocftes.Towardthe centerof the acini, enlargeddifferentiatedcellsare engorged with lipid. Death and ftagmentation of cells nearestthe duct portion result in the holocrine mechanismof secretion.
Inner-cholineqicMrcneqic trdion
2. Duct portions of sebaceous glandsare cornposedof stratified squamousepithelium that is continuouswith the hair canaland epidermalsurface.
I{Ote
3. Functionsinvolvethe lubrication of both hairs and cornified layersof the skin, aswell as resistanceto desiccation.
PrimaryContollingFactorof Sebaceous ClandSecretion
4. Control of sebaceous glandsis hormonal.Enlargementof the acini occursat puberty.
MalFte$osterone
D. Ilairs arelong, filamentousproiectionsconsistingof deadkeratinizedepidermalcells.Each hair derivesftom an epidermalinvaginationcalledthe hair follide, which possesses a terminal hair bulb, locatedin the dermis or hypodermis,from which the hair shaft grows. Bundlesof smoothmusclecells,calledarrector pili musd€s,areattachedto the hair follicle at one end and to the papillar),dermis at the other. C,ontractionof tlese musclesraisethe hairsand dimple the epidermis("gooseflesh").The folliclesand associated sebaceous glands areknown aspiloseboceousunits.
Female-combination of ovarian andadrenal anorogens
E. Nails,like hair, area modified stratum corneumofthe epidermis.They containhard keratin that forms in a manner similar to the formation of hair. Cells continuallv proliferate and keratinizeftom the stratum basaleof the nail natrix
5l
Anatomy Musculoskeletal muscles aswellastheirassociated of theskeleton covers themajorbones Thisextensive chapter group. foreachmuscle arereviewed Blood supply andinnervation andtendons.
SKULL Bonesof the skull may be classifiedasbelonging to the neurocranium (chondrocranium) (i.e., the portion of the skull that surrounds and protectsthe brain) or the viscerocranium (i.e.,the skeletonof the face). A. Osteology 1. Bones of the neurocranium a. Frontal b. Parietal c. Temporal (squamousand petrous portions) d. Occipital e. Ethmoid f. Sphenoid 2. Bones of the viscerocranium a. Maxilla b. Nasal c. Zygomatic d. Mandible e. Vomer f. Lacrimal g. Palatine h. Inferior nasalconcha
t5
Musculoskeletal System, Connective Tissue, andIntegument
B. Articulations. Most skull bones meet at immovable joints calledsutures. The soleexceptionis the temporomandibular joint (TMI), a synovialjoint that has a hinge-gliding movement. 1. The coronal suture is between the frontal and the parietal bones.
Clinical Correlate
2. The sagittal suture is between two parietal bones.
Theanterior fontanelle, or "softspot,"serves asa sitefor prenatal withdrawal of blood samples fromthesuperior sagittal sinus, Theanterior fontanelle usually closes by18 months, andtheposterior fontanelle by6 months.
3. The lambdoid suture is between the parietal and the occipital bones.
Clinical Correlate Thepterion isa landmark for themiddle meningeal artery, whichgrooves theboneofthe skullinternal to thissite.A blowto thelateral aspect, or "temple," oftheskullmay cause theartery to rupture, thereby causing anepidural hemorrhage. lf bloodis allowed to accumulate inthe epidural space, shifting ofthe brainmayoccur, whichcan cause thesharp, freeedgeof thetentorium cerebelli (tentorial incisure) to cutinto brainstemtissue ontheside opposite thein1ury. This pressure mustberelieved quickly, or death ensues.
4. The bregma is the point at which the coronal suture intersects the sagittal suture and is the site of the anterior fontanelle in an infant. 5. The lambda is the point at which the sagittal suture intersectsthe lambdoid suture and is the site of the posterior fontanelle in an infant. 6. The pterion is the point on the lateral aspect of the skull where the greater wing of the sphenoid,parietal,frontal, and temporal bones converge. 7. The temporomandibular joint is betweenthe mandibular fossaof the temporal bone and the condylar head of the mandible.
FACE A. The muscles of facial expressionare derived from the second pharyngeal arch and are supplied by motor branchesof CN VII (TableI-5-1).
Thble I-5-f . Muscles of facial expression. Muscles of the scalp Frontalis Occipitalis Muscles of the ear Anterior auricular Superior auricular Posteriorauricular Muscles of the rim of the orbit Orbicularis oculi Corrugator supercilii Muscles of the nose Procerus Nasalis Muscle of the neck Platvsma
t4
Muscles surrounding the lips Levatorlabii superioris alaequenasi Levator labii superioris Zygomaticus minor Zygomaticus major Levator anguli oris (caninus) Risorius Depressoranguli oris (triangularis) Depressorlabii inferioris (quadratuslabii inferioris) Mentalis Buccinator Orbicularis oris
Anatomy: Musculoskeletal
Superficial temporalartery
ClinicalCorrelate
Temporal Facial artery
Marginalmandibular Mandi bul ar nerve (CN V3)
byan Bellpalsy iscaused paralysis idiopathic ofthe present facial nerve. Patients withaninability to close the of eye,sagging ofthecorner to themouth, aninability voluntarily, and smile drooling, aninabilityto movefoodfrom thevestibule to theoralcavity proper. Thecondition usually resolves spontaneously.
Posteriorauricular
Figure l-5-1.Theface and the parotid gland.
B. The parotid glurd is the largestof the salivary glands and has a denseconnectivetissue capsule (FigureI-5-1). Structuresfound within the substanceof this gland include the following: 1. Motor branches of the facial nerve. CN VII entersthe parotid gland after emergingfrom the stylomastoidforamen at the baseof the skull. 2. Superficial temporal artery and vein. The artery is a terminal branch of the external carotid artery. 3. External carotid artery 4. Retromandibularvein, which is formed from the maxillary and superficial temporal veins 5. Great auricular nerye, which is a cutaneousbranch of the cervicalplexus 6. Auriculotemporal nerve, which is a sensorybranch of Vr. It suppliesthe TMJ and conveyspostganglionicparasympatheticfibers from the otic ganglion to the parotid gland. 7. Parotid (Stensen)duct, which entersthe oral cavity at the level of the maxillary secondmolar 8. Transversefacial artery, a branch of the superficial temporal arrery C. The facial artery is a branch of the external carotid artery in the neck. It terminatesas the angular artery near the bridge of the nose.
Note Thefacial veinhasmany thatcommunicate tributaries withthecavernous sinus. Because theveinshaveno infections valves, extracranial area a triangular arising within ofthe bounded bythebridge andtheangles ofthe nose, mouthmaymove the intracranially to reach Thisareais cavernous sinus. to asthe sometimes referred "danger triangle."
D. The facial vein parallelsthe courseof the facial artery.It terminatesby joining the anterior branch of the retromandibular vein to form the common facial vein.
55
Musculoskeletal System, Connective Tissue, andlntegument
NECK A. Osteology
Thalamus
Superiorsagittal
Tentor ium cere belli C ere bellum
Corpusca
P ons Frontalsinus Cribiformplate of ethmoidbone
External occipital protuberance
Torus tubarius
Internal occipital protuberance
Hard palate
Falxcerebelli
Tongue Atlas
Epiglottis Ma n d i b l e Geniohyoid
Dens of axis
Posterior wallof pharynx
Mylohyoid Thyroidcartilage
Retropharyngeal space
Larynx Oricoidcartilage,arch
Trachea
Laminaof cricoidcartilage
Figure l-5-2.Sagittal section of the head and neck.
Note Movement attheatlantojointcauses occipital flexion andextension, or nodding of "yes"). thehead(e.g., saying Movement attheatlantoaxial jointcauses lateral rotation "no"), (e.g., saying
Note Thehyoidistheonlybonein thehuman bodythatdoesnot directly articulate withatleast oneotherbone.lt isstabilized bytheattachment ofvarious muscles andligaments.
56
1. Cervical vertebrae. There are sevencervicalvertebraeof which the first two are atypical. All cervicalvertebraehaveopeningsin their transverseprocesses, the foramina transversaria, which, when aligned,produce a canal that transmits the vertebral artery and vein. a. Atlas. This is the first cervical vertebra (Cl). It has no body and leavesa spaceto accommodatethe dens of the secondcervicalvertebra. b. Axis. This is the secondcervicalvertebra (C2).It has a tooth-shapedprocess,the dens (odontoid process),which articulateswith the atlasas a pivot joint. Movement at this joint allowslateral rotation of the head. 2 . Hyoid bone is a small U-shapedbone, which is suspendedby musclesand ligamentsat the level of vertebraC3.It occupiesthe angle of the throat that separatesthe neck from the floor of the oral cavity.
3 . Laryngeal prominence is formed by the lamina of the thyroid cartilage.It is more prominent in men than in women and children. 4 . Cricoid cartilage. The arch of the cricoid, another laryngealcartilage,is palpablebelow the thyroid cartilageand superior to the first trachealring (vertebrallevel C6).
Anatomy: Musculoskeletal
B. Triangles of the neck. The neck is divided into a posterior and an anterior triangle by the sternocleidomastoid muscle. These triangles are subdivided by smaller muscles into six smallertriangles (Figure I-5-3).
Submandibular triangle
Mastoidprocess Sternocleidomastoid muscle Occipitaltriangle
CN XI Submentaltriangle
Carotidtriangle Subclaviantriangle
Musculartriangle
Figure l-5-3.Trianglesof the neck.
1. Posterior triangle is bound by the sternocleidomastoid, the clavicle, and the trapezius. The floor of the posterior triangle is formed by the splenius capitis, the levator scapulae, and the medial and posterior scalenemuscles. a. Occipital triangle is located abovethe inferior belly of the omohyoid muscle. Its contents include the following: (1) CN XI is the cranial nerve that suppliesmotor innervation to the trapeziusand sternocleidomastoidmuscles.
Cliniol Conelate presence ofa Theoccasional pressure cervical ribmayexert trunk ofthe onthelower plexus brachial oronthe rib artery. Cervical subclavian type isa particular syndrome syndrome. ofthoracic outlet
(2) Cutaneousbranchesof the cervical plexus are the lesseroccipital, great auricular, transversecervical, and supraclavicular nerves. b. Subclavian (omoclavicular, supraclavicular) triangle is located below the inferior belly of the omohyoid. Its contents include the following: (1) Brachialplexus (supraclavicularportion-roots, trunks), the branchesof which enter this region from behind the scalenusanterior muscle.The branchesinclude the dorsal scapular,long thoracic, subclavius,and suprascapularnerves. (2) The third part of the subclavian artery entersthe subclaviantriangle from behind the scalenus anterior muscle anterior to the brachial plexus. Branches may include the transversecervical and/or suprascapulararteries. (3) The subclavianvein passessuperficid to scalenusanterior muscle. It receivesthe externaljogol"t vein, a superficialvein that crossesthe sternocleidomastoidmuscle.
t7
Musculoskeletal System, Connective Tissue, andIntegument
ClinicalCorrelate prominent Anunusually jugular external vein(known asjugular venous distension may be a sign of heart [JVDI) failure whenaccompanied by pressure a riseinvenous in thesuperior venacava andits tributaries. lt mayalsobea signof obstruction ofthe superior venacavabya tumor.
Bridgeto Cardiovascular (thecarotid A chemoreceptor (the body)anda baroreceptor carotid sinus) arelocated in thewallof thecarotidarteryat or nearitspointof bifurcation. Theformerissensitive to oxygen levels intheblood, whereas thelatter responds to increases in bloodpressure. Visceral afferent impulses from eachof thesereceptors are conveyed byCNlX. Baroreceptors and chemoreceptors arediscussed intheCardiovascular and Respiratory Physiology chapters in Organ Systems Bookt (Volume lll).
2. Anterior triangle is bound by the sternocleidomastoid muscle, the midline of the neck, and the inferior border of the body of the mandible. a. Muscular triangle is bound by the sternocleidomastoid muscle, the superior belly of the omohyoid muscle, and the midline of the neck.Its contents include the infrahyoid (strap) muscles,which function to control movementsof the hyoid bone and larynx during speechand deglutition (swallowing). b. Carotid (vascular) triangle is bound by the sternocleidomastoidmuscle, the superior belly of the omohyoid muscle, and the posterior belly of the digastric muscle. The carotid triangle contains the following: (1) Internal jugular vein (2) Common carotid arterf, bifurcates at the upper border of the thyroid cartilage (i.e., vertebral level C3) to form the internal and external carotid arteries. The external carotid artery has six branches (i.e., the superior thyroid, the ascending pharyngeal,the lingual, the facial, the occipital, and the posterior auricular arteries). Thesesupply structuresof the neck and face (Figure I-5-4). (3) Vagusnerve (CN X) (a) Hypoglossalnerve (CN XII) (5) Internal and external laryngeal branches of the superior laryngeal branch of the vagus nerve. The internal larygeal nerve conveyssensory information from the laryngeal mucosa above the level of the vocal folds, and the external laryngeal nerye supplies motor fibers to the cricothyroid, an intrinsic muscle of the larynx. c. Digastric (submandibular) triangle is bound by the anterior and posterior bellies of the digastricmuscle and the inferior border of the body of the mandible. The floor of this triangle is formed by the hyoglossusand mylohyoid muscles.It contains the submandibular salivary gland. d. Submental triangle is bound by the anterior belly of the digastric muscle, the hyoid bone, and the midline of the neck. The floor of this triangle is formed by the mylohyoid muscle.It containsthe submentally-ph nodes. C. Root of neck This area communicates with the superior mediastinum through the thoracic inlet. Structures of the region include the following: 1. Subclavian artery and vein. The subclavian artery passesposterior to the scalenusanterior muscle,and the vein passesanterior to it. Branchesof the artery include: a. Vertebral artery b. Thyrocervical trunk, which gives rise to the inferior thyroid, the transversecervical, and the suprascapulararteries. c. Internal thoracic artery d. Corticocervical trunk
58
Anatomy: Musculoskeletal
Note
temPoralarterY Superficial
Mnemonic for Branches of External CarotidArtery "Salfops Max"
Transverse facialartery
thyroid Superior Maxillary artery
artery
Facialartery
Descending branch
Externalcarotid
Internalcarotid
artery
artery
pharyngeal Ascending Lingual Occipital Posterior auricular temporal Superficial I terminal Maxillary Jbranches
Lingualartery Superior thyroidartery Vertebral
Inferiorthyroidartery
artery
Commoncarotidartery
Costocervical trunk
First
ClinicalCorrelate
Internal thoracicartery Thyrocervicaltrunk
Subclavianartery
Figure I-5-4.Arteries of the neck. 2. Phrenic nerve is a branch of the cervicalplexus,which arisesfrom C3, C4, and C5. It is the sole motor nerve to the diaphragm. It crossesthe anterior scalenemuscle from lateral to medial to enter the thoracic inlet. 3. Recurrent laryngeal nerve is a branch of the vagus nerve. This mixed nerve conveyssensory information from the laryngealmucosabelow the level of the vocal folds and provides motor innervation to all the intrinsic musclesof the larynx except the cricothyroid muscle. 4. Thoracic duct terminatesat the junction of the left subclavianand the left internal j,tgnlar veins.On the right side of the body, the right lymphatic duct terminatesin a similar fashion. D. Fasciasof the neck 1. Superficial investing fascia enclosesthe platysma, a muscle of facial expression,which has migrated to the neck. 2. Superficial layer of deep investing fascia surrounds the trapezius and sternocleidomastoid muscles. 3. Pharyngeal (visceral) fascia surrounds the pharynx.
nerves Therecurrent laryngeal during thyroid arevulnerable nerves lf oneofthese surgery. quality ofthe isdamaged, the resulting voicemaybechanged, in extreme hoarseness. ClinicalCorrelate Infection withinthepotential between thefascial spaces planes poorly to responds because the treatment antibiotic avascular. spaces areessentially usually therefore Treatment of involves thee$ablishment of theaffected external drainage between the area. Thespace fascial alarandprevertebral (danger is layers space') withthe continuous infection can mediastinum; pass intothe therefore potentially media$inum, resulting ina fatalpericarditis.
59
Musculoskeletal System, Connective Tissue, andlntegument
4. Prevertebral fascia investsthe prevertebral muscles of the neck (i.e., longus colli, longus capitis). This layer givesrise to a derivative known as the alar fascia. E. The major muscle groups and their innervations. A simple method of organizing the musclesof the neck is basedon two basicprinciples: (1) The musclesmay be arrangedin groups, according to their functions; and (2) all musclesin a group share a common innervation with one exceptionin eachgroup.
In a Nutshell MuscleGroupInnervation Exception Tongue
CNXII
Palatoglossus (cNx)
Larynx
Recunent laryngeal branch of vaSus
Cricothyroid (external laryngeal branch of vagus)
Pharynx
CNXand CNXI
Stylopharyngeus(CNlX)
Softpalate
CNXand CNXI
Tensor veli palatini (cNv3)
lnfrahyoid
AnsacervicalisThyrohyoid (branch of cervical of Cl) plexus (Cl, O, C3)
1. Group l: Muscles of the tongue. All intrinsic musclesplus all but one of the extrinsic muscles(i.e., those containing the suffix, glossus)of the tongue are supplied by CN XII. The one exceptionis palatoglossus, which is supplied by CN X. 2. Group 2: Muscles of the larynx. All but one of the intrinsic musclesof the larynx are supplied by the recurrent laryngeal branch of the vagus nerve. The sole exception is the cricothyroid muscle, which is supplied by the external laryngeal branch of the vagus. 3. Group 3: Muscles of the pharyruc All but one of the longitudinal and circular musclesof the pharynx are suppliedby CNs X and XI (cranial portion). The soleexceptionis the stylopharyngeusmuscle,which is supplied by CN IX. 4. Group 4: Muscles of the soft palate. AII but one of the musclesof the palate are supplied by CNs X and XI (cranial portion). The soleexceptionis the tensor veli palatini, which is supplied by CN Vr. 5. Group 5: Infrahyoid muscles.All but one of the infrahyoid musclesare suppliedby the ansa cervicalisof the cervicalplexus(Cl,Cz,and C3). The exceptionis the thyrohyoid,which is suppliedby a branch of Cl. (This branch of Cl alsosuppliesthe geniohyoidmuscle).
THORACIC WAtt A. Osteology 1. There are l2thoracic vertebrae.
Note Thesternal angle isa useful landmark formanythoracic structures andevents:
a. The vertebraehavefacetson their bodies to articulatewith the headsof ribs; eachrib head articulateswith the body of the numerically correspondingvertebraand the one below it. b. The thoracic vertebraehave facetson their transverseprocessesto articulate with the tuberclesof the numerically correspondingribs. 2. Sternum a. The manubrium articulates with the clavicle and the first rib. It meets the bodv of the sternum at the sternal angle, an important clinical landmark.
. Thesecond pairof costal cartilages attaches here, and theribsarecounted from thispoint.
b. The body articulates directly with ribs 2-7; it articulates inferiorly with the xiphoid processat the xiphisternal junction.
. Bifurcation ofthetrachea formstheprimary bronchi.
c. The xiphoid processis cartilaginousat birth and usually ossifiesand unites with the body of the sternum around age40.
. Thesuperior venacavais formed fromtherightand leftbrachiocephalic veins. . Thesternal angle marks the beginning andendofthe aortic arch.
40
3. Ribs and costal cartilages. There are 12 pairs of ribs, which are attached posteriorly to thoracic vertebrae.
Anatomy: Musculoskeletal
Firstrib Clavicle Second rib
Scapula
Manubriumof sternum Sternalangle Body of sternum Costochondral junction
ClinicalCorrelate
Figure l-5-5.Thoracic wall.
a. Ribs l-7 aretermed "true ribs," and attach directly to the sternum by costalcartilages. b. Ribs 8-10 are termed "false ribs," and attach to the costalcartilageof the rib above. c. Ribs 11 and 12 have no anterior attachments,and are therefore classifiedas both "floating ribs" and falseribs. d. The costalgrooveis locatedalong the inferior border of eachrib and providesprotection for the intercostalnerve, artery,and vein. Ribs 1, 2, L0,11, and 12 areatypical. B. Muscles 1. External intercostal muscles a. There are 11 pairs of externalintercostalmuscles.Their fibers run anteriorly and inferiorly in the intercostal spacesfrom the rib above to the rib below. b. Thesemusclesfill the intercostalspacesfrom the tuberclesof ribs posteriorly to the costochondraljunctions anteriorly; they are replacedanteriorly by externalintercostal membranes. 2. Internal intercostal muscles
Ribfractures represent the mostcommon chest injuries andusually result fromdirect blows suchassteering wheel impact, falls, andcrushing injuries to thechest. Since the first2 ribsareprotected bythe clavicle andpectoralis major muscle, andthelast2 ribsare "mobile," theyaretheleast commonly injured. Themiddle onesarethemostcommonly fractured. Insomecases, fractured ribsmaycause damage to theheart, lungs, trachea, bronchi, esophagus, spleen, liver, andkidneys. Note Thefibersof theexternal intercostal muscles runinthe "hands-i n-pockets" direction; thoseoftheinternal intercostal layerrunatright angles to theexternals.
a. There are 11pairs of internal intercostalmuscles.Their fibers run posteriorly and inferiorly in the intercostal spacesdeep to the external layer. b. These muscles filI the intercostal spacesanteriorly from the sternum to the angles of the ribs posteriorly; they are replacedposteriorly by internal intercostalmembranes.
4l
Tissue, andIntegument System, Connective Musculoskeletal
3. Innermost intercostrl muscles a. The deeplayersof th€ intemal int€rcostalmusclesarethe innermostintercostalrnuscles' b. Thesemusclesareseparatedftom the internal intercostalmusdesby intercastalnerves andvesels. .
4. Subcostalismuscles (1) Fibersextendfrom the inner surfaceof the angle of one rib to the rib t}rat is inferior to it. (2) Fibersmay crossmore than one intercostalspace. 5. Tranwersusthoracismuscle (1) Fibersattadr postedorlyto the sternum. (2) Fiberscrossmore than one intercostalspace. (3) Intemal thoracic vessels,branchesof the subclavianarteries,run anterior to thesefibers. C. Intercostal structrf€s
'
1 lntercostal nerves a. Thereare 12 pairsof thoracicnerves:11intercostalpairs,and 1 subcostalpair. b. Intercostaln€rvesarethe ventralprimary rami of thoracicspinalnerves.Thesenerves supplythe skin and musculatureof the thoracic and abdominalwalls. 2. Int€rcostal arteries a. There are 12 pairs of posterior and anterior arteries,11 intercostalpairs, and 1 subcostalpair. b. Anterior intercostalarteries (l) Pairs1-{ are derivedftom the internal thoracicarteries. (2) Pairs7-9 arederivedfiorn the muscr:lophrenicarteries. (3) Thereare no anterior intercostalarteriesin the last two sPaces; thesespacesare suppliedby branchesof the posterior intercostalarteries. c. Posteriorintercostalarteries ( I ) The first two pairs ariseftom the superiorintercostalartery a branchof the costocervicd trunk of the subclavianartery. (2) Nine pairsof intercostaland onepair of subcostalarteriesarisefrom the tloracic aorta.
'
3. Intercostrl veins
andmuscuveinsdrainto theinternalthoracic of theintercostd
F"I1!g|-Cf,g-.-*
" ffi'f;:n'jfifts
Achest tubeisplaced iust i above thelower ribofthe intenpace soasnotto disrupt thenerve, artery, andveinthat lieinthecoshlgroove behind margin theinferior Ofeachrib.
drainto theazygos b. Post€riorbranches rystemof veins.
42
4' Lymphaticdrainageof intercostalspaces nod€s. is to theinternalthoracic(parasternal) a.Anteriordrainage is to thepara-aorticnodesof theposteriormediastinurn' b. Posteriordrainage
Anatomy: Musculoskeletal
ANTERIOR ABDOMINAT WAtt
Lumbar vertebrae
Sacrum
Coccyx Pubic crest
Pubic tubercle
Figure l-5€. The abdominopelvic cavity.
A. Osteology.Unlike the thoracic wall, the bony support of the abdomen is minimal, consisting only of the lumbar vertebraeand portions of the pelvis (the ilium and the pubis). 1. There are five lumbar vertebrae, Ll through L5. 2. The ilium is part of the hip bone or os coxae. The osteology of this bone is presentedin detail in the section on the pelvis.Only the landmarks pertinent to the anterior abdominal wall are listed here. a. Anterior superior iliac spine (ASIS) b. Iliac fossa c. Iliac crest d. Iliac tubercle 3. Pubis (part of os coxae) a. Pubic tubercle b. Pubic crest c. Pubic symphysis
45
andlntegument Tissue, System, Connective Musculoskeletal
B. Surface anatomy 1. Linea alba is a shallow groove that runs vertically in the median plane from the xiphoid to the pubis. It separatesthe right and left rectus abdominis muscles. 2. Lineasemilunaris is a curved line defining the lateral border of the rectus abdominis, a bilateral feature. 3. Inguinal groove indicates the site of the inguinal ligament, the rolled-over, free border of the external oblique aponeurosis. It separatesthe abdomen superiorly from the lower extremity inferiorly. The inguinal ligament extends from the ASIS to the pubic tubercle. C. Planesand regions. There are four planesto define nine regions of the abdomen (Figure l-5-7).
Figurel-5-7.Regionsof the abdomen.RH = righthypochondrium; RL - rightlumbar;LL = leftlumbar; LH = lefthypochondrium; = leftinguinal. Rl = rightinguinal;Ll
1. Subcostalplane (horizontal) passesthrough the inferior margins of the 10th costalcartilages. 2. Tianstubercular plane (horizontal) passesthrough the iliac tubercles(body of L5). 3. Midclavicular lines (vertical) are the two planes that passfrom the midpoint of the clavicle to the midpoint of the inguinal ligament.
M
Anatomy: Musculoskeletal
D. Fascial layers 1. Superficial fascia a. Camper fascia is subcutaneousand variable in thicknessdue to the presenceof fat. b. Scarpa fascia is a deeper membranous layer devoid of fat and is continuous with the fascia lata of the thigh below the inguinal ligament, the dartos fascia of the scrotum or the labia majora, and Colles fascia of the perineum. 2. Deep (innominate) fascia is the investing fascia of the abdominal musculature and is continuous with the externaloblique aponeurosis. E. Muscles 1. External oblique a. The fibers run anteriorly and inferiorly (i.e., the hands-in-pocketsdirection like the externalintercostallayer in the thorax).
ClinicalCorrelate A potential space exists between Scarpa fascia andthe deepinnominate fascia where bloodor urineextravasated froma ruptured membranous urethra mayaccumulate in a patient. male Thespread of fluidislimhed along a line approximately oneinchbelow theinguinal ligament, where Scarpa fascia blends withthe fascia lata.
b. As fibers passmedially,they becomeaponeurotic and contribute to the anterior layer of the rectussheath. c. Inferiorly, the free border of the external oblique aponeurosisforms the inguinal ligament. d. The superficial inguinal ring is an opening in the external oblique aponeurosisjust superior and lateral to the pubic tubercle. e. In men, this layer (externaloblique aponeurosis)givesrise to the external spermatic fascia of the spermaticcord. 2. Internal oblique a. The fibers run posteriorly and inferiorly at right anglesto thoseof the externaloblique like those of the internal intercostallayer in the thorax. b. As the fibers passmedially, they become aponeurotic and split to contribute to the anterior and posterior layersof rectus sheath. c. Inferiorly, thesefibers contribute to the formation of the conjoint tendon. d. In men, this layer (internal oblique aponeurosis)givesrise to the middle spermatic fascia and the cremaster muscle of the spermaticcord. 3. Transversus abdominis a. The muscle fibers run horizontally.As the fibers passmedially,they contribute to the posterior layer of the rectus sheath. b. Inferiorly, the fibers join with those of the internal oblique to form the conjoint tendon. 4. Rectus abdominis a. The fibers run vertically betweenthe pubic symphysisand the xiphoid process. b. The right and left recti musclesare separatedmedially by the linea alba. c. The rectussheathis formed by aponeurotic fibers of three lateral musclelayers. (1) The arcuate line is located one-third of the distancebetween the umbilicus and pubis. It is a landmark for the changein disposition of the aponeuroticfibers.Above the arcuateline, posterior and anterior layersof the rectussheathhaveequal thickness;belowit, all aponeurotic fibers run anterior to the rectusabdominis.
45
Tissue, andlntegument Connective Musculoskeletal System,
ClinicalCorrelate lndirect inguinal hernias are andinvolve oftencongenital anoutpouching of peritoneum through thedeep orviscera just inguinal ring,beginning lateral the to thepointwhere vessels inferior epigastric cross ligament. Direct theinguinal areacquired inguinal hernias asa result of abdominal Theybypass the straining. ringandgo deepinguinal ring. directly to thesuperficial to the Theybeginmedial inferior epigastric vessels and burgeon through theinguinal (Hesselbach) triangle, which isboundbytheinferior epigastric vessels, theinguinal ligament, andthelateral borderoftherectus abdominis.
(2) Superior and inferior epigastricvesselstravel in the posterior layer of the rectus sheath. F. Transversalisfascia 1. The transversalisfascialines the abdominal cavity.It forms the posterior layer of the rectus sheathbelow the arcuateline and the internal spermatic fascia of the spermatic cord. 2. The deep inguinal ring begins as an outpouching of transversalisfasciajust lateral to where the inferior epigastricvesselsintersectthe inguinal ligament. 3. The transversalisfascia is separatedfrom the peritoneum by a layer of fatty areolar extraperitonealconnectivetissue. G. Nerves, blood vessels,and lymphatics 1. Innervation of the skin and musculature of the anterior abdominal wall is via branchesof the ventral primary rami of the lower six thoracic spinal nerves(includes subcostalnerve), plus the iliohypogastricand ilioinguinal branchesof the ventral primary ramus of Ll. 2. The major arterial blood supply to the anterior wall is derived from the superior epigastric branch of the internal thoracic artery as well as the inferior epigastricand the deep circumflex iliac branches of the external iliac artery. 3. Venousdrainage from the anterior wall is to the superficialepigastric,the lateral thoracic veins superiorly, and the greatsaphenousvein inferiorly. a. Lymph from tissuesof the anterior wall drains to axillary nodessuperiorly and to superficial inguinal nodes inferiorly.
WAtt POSTERIOR ABDOMINAT The posterior abdominal wall is locatedbehind the posterior layer of the parietal peritoneum. A. Osteology. The bony structure of the posterior wall includes many of the samefeaturesas the anterior wall of the abdomen and bony landmarks from the thorax and the inferior extremity. 1. Five lumbar vertebrae(L1 through L5) 2. Iliac crest 3. Iliac fossa 4. Twelfth pair of ribs 5. Lessertrochanter of femur B. Muscles
Note
1. The quadratus lumborum extends upward from the iliac crest to the inferior border of the 12th rib. It stabilizesthe 12th rib during inspiration. 2. The psoasmajor arisesfrom the transverseprocessesof the lumbar vertebrae.
Theiliopsoas muscle isthe thatinserts onlymuscle trochanter. onthelesser (Filet mignon comes from thepsoas muscle in cows.)
a. Insertion, along with iliacus,is on the lessertrochanter of the femur. b. It is the chief flexor of the hip. 3. The iliacus originatesfrom the iliac fossa. a. It joins with the psoasmajor to insert on the lessertrochanter. b. Togetherwith psoasmajor, it is known as the iliopsoas.
46
Anatomy: Musculoskeletal
PEwTS A. Osteology 1. Pelvicgirdle is formedanterolaterallyby the pairedhip bones(oscoxae)and is completed posteriorlyby the sacrumand cocc''n a. The oscoxaeis composedof the ilium, the pubis,andthe ischium,includingthe ischial spineand the ischialtuberosity b. Greaterand lessersciaticnotches(foramina) c. Sacrospinous and sacrotuberousligaments 2. Pelviccavity a. Pelvismajor (falsepelvis)lies abovethe pelvicbrim betweenthe iliac fossae.
Oinkal GOrrelab
b. Pelvisminor (true pelvis) is th€ spac€betweenthe pelvic inlet (pelvic brim) and the ouuet.
;"rnesplne isan "* of theischium obstetric landmark inthe administration of anesthesia for a pudendal nerveblockto eliminate sensation inthe
B. Pelvicdiaphragn is the muscularfloor ofthe pelviccavity. 1 Levatoreni hasopeningsto transmit the urethra andthe anusin both sexesand the vagi" na in women.
a.pubococcygeus b. Puboreaalis c.Iliococcygeuscnalinthevicinityofthe 2. coccygeusis the posterior portion of the pelvic diaphragm
lhe : r:ff:T:::'.1{elivery puoenoat neryepasses (Alcock) throughthepudendal ischialspine'
Note
UPPER IIMB A. Pectoral region, axilla, and shoulder 1. Osteology (Figure I-5-S)
Theclavicle isthefirstboneto ossify in fetallifeandisthe mo$frequently fractured boneinthebody.
47
Tissue, andIntegument System, Connective Musculoskeletal
Acromion Coracoidprocess Lessertubercle Greatertubercle Intertubercular groove
Surgical neck
Deltoidtuberosity
Lateral
Medialepicondyle
Capitulum Head of radius
Trochlea
Tuberosity of radi
Coronoidprocess
Radius
Styloidprocess of radius Proximal phalanx
Carpalbones Metacarpalbones
Distal
phalanx
Anteriorview
Figure l-5-8.Osteology of the upper limb.
48
Anatomy: Musculoskeletal
major Pectoralis Serratus anterior
Pectoralis minor Intertubercular groove
Latissimus dorsi Teresmajor Subscapularis Rib
Scapula
Figure l-5-9.Transversesection through the axilla.
a. Sternum has three parts: the manubrium, the body, and the xiphoid process. b. Clavicle is an S-shapedbone, which articulateswith the manubrium of the sternum medially and with the acromion processof the scapulalaterally. c. Scapula landmarks include the acromion process, or point of the shoulder, and the coracoid process,which is an anteriorly projecting "crow's beak."The glenoid fossa of the scapulaarticulateswith the head of the humerus. The subscapular fossa forms the major portion of the anterior surfaceof the scapula.The spine of the scapula,or shoulder blade, is located posteriorly and separatesthe supraspinous fossa above from the infraspinous fossa below. d. Humerus is the bone of the arm. In addition to the head of the humerus, landmarks include the bicipital groove (intertubercular sulcus)and the lateral and medial lips of the bicipital groove. The greater and lesser tuberosities are located inferior to the head of the humerus. The deltoid tuberosity is an elongated,roughened area of the shaft of the humerus. 2. The axilla is a space shaped like a truncated pyramid, which serves as a passageway between the neck and the upper limb. Its apex is formed by the cervicoaxillary canal and is bounded by the clavicle,scapula,and first rib. The baseis formed by the fasciaand haircoveredskin of the armpit.
Nole Thesurgical neckofthe humerus isafrequent siteoffractures. The axillary nerveisatrisk.
a. Walls of the axilla (Figure I-5-9) (1) The anteriorwall is formed by the pectoralismajor and pectoralisminor. The pectoralismajor forms the anterior axillary fold. (2) The posterior wall is formed by the subscapularis, teresmajor, and the latissimus dorsi muscles.The latissimusdorsi forms the posterior axillary fold. (3) The medial wall is formed by the serratusanterior muscle and the underlying ribs and intercostalspaces. ( ) The lateral wall is formed by the bicipital groove of the humerus.
49
System, Connective Tissue, andlntegument Musculoskeletal
ClinicalCorrelate
b. Contents of the axilla ( 1) The axillar'' arter'' is a continuation of the subclavian artery asit passesover the outer border of the first rib. It becomesthe brachial artery at the outer border of the teres major. The axillary artery has six branches.Of these,the most clinically significant are the thoracoacromial, the lateral thoracic, the subscapular,and the posterior humeral circumflex arteries.
trunkof Damage totheupper plexus mayresult thebrachial to flex,abduct, in aninability rotate the andlaterally dueto a weakness of shoulder thedehoid androtator cuff (When thisoccurs muscles. frombirth,it isknownasErb plexus palsy.) Lower brachial theulnarnerve injuries involve andresult in reduced ofthemedial arm, sensation forearm, andhand, aswellas weakness intheforearm and (When this occurs from hand. trauma,ifs knownasKlumpke palsy.)
(2) The axillaryvein follows the samepattern asthe artery.It receivesthe basilic and cephalic veins. (3) The axillary ly-ph nodes drain ly-ph from the upper extremiry the lateral breast, and the superficial portions of the thoracic and upper abdominal wall. The axillary nodes are divided into five groups: apical, central, humeral, pectoral, subscapular.Efferent lymphatics from the last four groups drain to the apical nodes,which then drain to the subclavian ly-ph trunk. (a) The bradrialplexus is the somatic nerve plexus of the upper limb. It is formed from the ventral primary rami of cervical nerves 5-8 and the ventral primary ramus of the first thoracic nerve. The roots of the plexus emerge from between the middle and anterior scalenemuscles in the neck. Th.y combine to form trunks, which divide into anterior and posterior divisions. The divisions pass through the cervicoaxillary canal to reach the axilla and reunite to form lateral, medial, and posterior cords in relation to the second part of the axillary artery.Each trunk divides into nryoterminal branches,which comprise the major nerves of the arm, forearm, and hand (Tablel-5-2).
Thble I-5-2. Major Branches of the brachial plexus. INFRACIAVICUTAR
SUPRACI.AVICUI.A,R
Roots
C5: Dorsal scapular nerve; supplies rhomboids C5, C6, C7: Longthoracic nerve; supplies serratus
Trunl$
Cords
Upper trunk Lateral cord 1. Lateral pectoral nerve; supplies Suprascapularnerve; pectoralismajor supplies supraspinatus and infraspinatus Medial cord 1. Medial pectoral nerve; supplies pectoralis major and minor 2. Medial brachial cutaneous nerve; supplies skin of the medial arm
Branches(Terminal)
1.Musculocutaneousnerve 2.Lateral head of median nerve 1. Medial head of anterior median nerve 2. Ulnar nerve
3. Medial antebrachial cutaneous nerve; supplies skin of the medial forearm C8, T1
Posterior cord 1. Upper subscapularnerve; supplies subscapularis 2. Middle subscapularnerve (thoracodorsalnerve); supplies latissimusdorsi 3. Lower subscapularnerve; supplies teres major
50
1. Radial nerve 2. Axillary nerve
Anatomy: Musculoskeletal
Thble I-5-3. Nerve supply of shoulder muscles. Muscles Acting on the Shoulder Flexors Coracobrachialis Deltoid (anterior segment) Pectoralismajor Extensors Teresmajor Latissimusdorsi Deltoid (posterior segment) Abductors Deltoid (middle segment) Supraspinatus(initial abductor) Adductors Teresmajor Latissimusdorsi Pectoralismajor Teresminor Medial rotators Subscapularis
Nerve Supply Musculocutaneousnerve Axillary nerve Medial and lateral pectoral nerves Lower subscapularnerve Thoracodorsalnerve Axillary nerve
Mnemonic Witha rotator cuffinjury, the pitcher SITS onthebench: supraspinatus, lhfraspinatus, feres minor, subscapularis.
Axillary nerve Suprascapularnerve Lower subscapularnerve Thoracodorsalnerve Medial and lateral pectoral nerves Axillary nerve
Teresmajor Latissimusdorsi Pectoralismajor
Subscapularnerves(upper & lower) Lower subscapularnerve Thoracodorsalnerve Medial and lateral pectoral nerves
Lateral rotators Infraspinatus Teresminor
Suprascapularnerve Axillary nerve
3. Shoulder. The shoulderjoint is a shallowball-and-socketjoint. The head of the humerus is held againstthe glenoid fossaby ligamentsand muscles(TableI-5-3). B. Arm. The portion of the upper extremity betweenthe shoulder and elbow joint is the arm. It is enclosedin alayer of deep fascia.Two septaoriginate from this fasciaand divide the arm into an anterior (preaxial) and a posterior (postaxial) compartment. Flexor musclesoccupy the anterior compartment,and extensorsare found in the posterior compartment (Figure I - s - 10) . 1. Osteology.The bone of the arm is the humerus. a. Radial (spiral) groove is located posteriorly; this shallow depressionis occupied by the radial nerve and the deep brachial (profunda brachii) artery. b. Trochlea is a pulley-shaped feature of the distal humerus, which articulates with the trochlear notch of the ulna.
5l
Tissue, andIntegument System, Connective Musculoskeletal
Coracoid
Acromion
SuprasPinatus GlenoidcavitY
Infraspinatus SubscaPularis
Teresminor
Inferiorangle
Figure l-5-10.Muscles of the rotator cuff (lateral view). c. Capitulum is a rounded processlocated lateral to the trochlea and articulating with the head of the radius. d. Medial and lateral epicondyles are subcutaneous projections from the distal humerus, and give rise to the musclesof the forearm. 2 . Anterior (flexor) compartment of the arm
ClinicalCorrelate "Colfer's (medial elbovV" results froman epicondylitis) inflammation oftheflexor tendons onthemedial ofthehumerus epicondyle (imagine golfing thestandard theelbow). swing, flexing "Tennis (lateral elbow" results froman epicondylitis) inflammation oftheextensor tendons onthelateral epicondyle ofthehumerus (imagine thebackhand swing, extending theelbow).
52
a. Muscles (1) The coracobrachialis is a small muscle arising from the coracoidprocess. (2) The biceps brachii is the principal flexor of the forearm at the elbow joint. The bicepsis also a powerfi.rlsupinator of the forearm. (3) Brachialis lies deep to bicepsbrachii. b. Innervation. All musclesof the flexor compartment of the arm are supplied by the musculocutaneous nerve. 3 . Posterior (extensor) compartment of the arm a. Muscles.The long head of the triceps arisesfrom the scapula;lateral and medial heads of the triceps arisefrom the posterior surfaceof the humerus. b. Innervation. The three headsof the triceps are supplied by the radial nerve. 4 . The cubital fossa is a triangular areaanterior to the elbow.The roof of the cubital fossa is formed by deepfasciaand by the bicipital aponeurosis,which is part of the insertion of the bicepsbrachii. Contents of the cubital fossainclude the following:
Anatomy: Musculoskeletal
a. The median cubital vein is a superficialvein, which communicatesbetweenthe basfic and cephalicveins.It lies superficialto the bicipital aponeurosis. b. The biceps tendon inserts on the radial tuberosity. c. The brachial artery lies medial to the biceps tendon and terminates by dividing into radial and ulnar arteries. d. The median nerve supplies no musclesin the arm but is responsiblefor motor innervation of many musclesof the flexor forearm. 5. Elbow joint. This joint is a hinge joint that includes three articulations. The articulation between the humerus and the bones of the forearm allows flexion and extension at the elbow. The articulation between the radius and the ulna is a pivot, which allows rotation of the radius around the ulna (i.e.,supination and pronation). C. Forearm is the portion of the upper limb between the elbow and the wrist joint. The forearm is enclosedin a layer of deep fascia.The two bones of the forearm, the radius and ulna, aswell as an interosseousmembrane and two fibrous septa,divide the forearm into an anterior (preaxial) compartment and a posterior (postaxial) compartment. 1. Osteology a. Radius (l ) The head articulates with the capitulum of the humerus. (2) The radial tuberosity is the site of insertion of the bicepsbrachii. (3) The dorsal (Lister) tubercleis locatedon the posterior surfaceof the distal aspect of the radius. The tendon of the extensorpollicus longus passesmedial to this prominence. (a) The styloid process is the prominent subcutaneousdistal expansion of the radius.
ClinicalCorrelate Subluxation oftheheadofthe radius occurs inyoung children whoare"pulled along" by theupper limb.Theannular ligament, whichsurrounds the headoftheradius, stretches ortears. Thisisknown as "nursemaid's elbow"
b. Ulna (1) The olecranon,coronoid process,and trochlear notch form the articular surface of the ulna with the humerus. (2) The radial notch is the articular surfacefor the radius. (3) The tuberosity is the site of insertion of the brachialismuscle. (a) The sryloid processis the prominent subcutaneousdistal expansionof the ulna. 2. Anterior (flexor) compartment of the forearm a. Muscles. The eight muscles of the flexor forearm are arranged in three layers, from superficial to deep. (1) First layer includes four muscles,which arise from the medial epicondyle of the humerus. From lateral to medial, they are the pronator teres, the flexor carpi radialis,the palmaris longus, and the flexor carpi ulnaris ('PFPF" muscles). (2) Secondlayer has only one muscle,the flexor digitorum superficialis(sublimus). (3) Third layer has three muscles:the flexor digitorum profundus, the flexor pollicis longus, and the pronator quadratus.
Clinical Correlate Damage to theanterior interosseous nerve, also known asthedeepbranch of themedian nerve, results in theinability to forma round "0" withthethumbandindex finger. The"flatpinch" is caused byimpaired function pollicis oftheflexor longus andlateral twotendons of profundus. flexor digitorum
b. Innervation. The median nerve supplies all the musclesof the anterior compartment of the forearm, except for the flexor carpi ulnaris and the medial (ulnar) half of the flexor digitorum profundus, which are supplied by the ulnar nerve.
55
Musculoskeletal System, Connective Tissue, andIntegument
3. Posterior (extensor) compartment of the forearm a. Muscles. There are 11 musclesin the posterior compartment. They can be classified in three groups accordingto function. (1) Extensors of the hand at the wrist include the extensor carpi radialis longus, extensorcarpi radialis brevis, and extensorcarpi ulnaris. (2) Extensors of the digits are the extensor digitorum, extensor indicis, and extensor digiti minimi. (3) Extensors of the thumb are the abductor pollicis longus, extensorpollicis brevis, and extensorpollicis longus. (4) Additional musclesof the extensorcompartment include the brachioradialisand the supinator. b. Innervation. All musclesof the posterior compartment of the forearm are supplied by the radial nerve.
ClinicalCorrelate is Carpal tunnel syndrome bycompression ofthe caused median nerve withinthe bythecarpal tunnel formed retinaculum. bones andflexor Insevere cases, themuscles of eminence atrophy, and thenar isunable to thepatient oppose thethumb tothe is digits. Thedisorder people in whose common worknecessitates repetitive movements ofthewrist, e.g., keyboard operators.
4. Wrist a. Osteology.The eight bones of the wrist, or carpus,are arrangedin two rows of four. (1) The distal row, medial-to-lateral:hamate,capitate,trapezoid,and trapezium. (2) The proximal row, lateral-to-medial scaphoid,lunate, triquetrum, and pisiform. b. Flexor retinaculum (transversecarpal ligament) is a band of deep fascia, which through which the extendsanteriorly acrossthe carpal bones. It forms a passageway tendons of the flexor musclesand the median nerve enter the palm of the hand. D. Hand 1. Osteology(FigureI-5-11) a. Metacarpals. Five metacarpal bones articulate proximally with the carpal bones and distally with the proximal phalanges.They form the support for the palm of the hand. b. Phalanges. The thumb has two phalanges,proximal and distal. The remaining four digits eachhave three phalanges:proximal, middle, and distal. 2. Intrinsic muscles
ClinicalCorrelate bone-most Scaphoid frequently fractured of carpal bones Lunate bone-most frequ entlydislocated.
a. Thenar muscles (1) Abductor pollicis brevis (2) Flexor pollicis brevis (3) Opponenspollicis b. Hypothenar muscles (1) Abductor digiti minimi (2) Flexor digiti minimi (3) Opponens digiti minimi c. Lumbrical muscles. There are four lumbrical muscles. They flex the digits at the joints and extend at the interphalangealjoints. metacarpophalangeal
54
Anatomy: Musculoskeletal
d. Interosseous muscles. There are seven interosseous muscles. The three palmar interosseiadduct the digits, and the four dorsal interosseiare responsiblefor abduction of the digits.
Distal phalanx Middle phalanx Proximal phalanx
Head Fifth metacarpal Trapezoid
Hookof h Pisiform
Trapezium
Tri Lunate
Tubercle of scaphoid
Right palmar view Figure l-5-11.Osteology of the right hand (palmar view).
3. Innervation a. Motor innervation of intrinsic muscles(Figure I-5-12) (1) The median nerye suppliesthe musclesof the thenar eminence,via the recurrent branch, as well as the first and secondlumbrical muscles. (2) The ulnar nerve supplies the remaining intrinsic musclesof the hand.
55
System, Connective Tissue, andIntegument Musculoskeletal
Note andartery Theulnarnerve thepalm through enter canal. theCuyon
Palmardigital nerves Branchesto first and secondlumbricals
Palmardigitalnerves
'Recurrent branch of mediannerve
Clinical Correlate AllenTest Thistestisusedto determine anastomoses between the radial andulnararteries.
Thenarmuscles Mediannerve Ulnarnerve
Figure l-5-12.Innervation of the palm.
Palmarview
Figure l-5-13.Distribution of cutaneous nerves to the palm and dorsum of the hand.
56
Anatomy: Musculoskeletal
b. Sensoryinnervation of the hand. The median, ulnar, and radial nervesprovide specific areasof the palm and dorsum of the hand with sensoryinnervation (Figure I-5- 13). 4. Blood supply a. The superficial palmar arch is derived mainly from the ulnar artery. b. The deep palmar arch is derived mainly from the radial artery.
TOWER IIMB A. The thigh is the region extending from the inguinal ligament to the knee. The thigh is surrounded by a denselayer of deep investing fascia,called the fascialata. Fibrous septa divide the thigh into three compartments:anterior, medial, and posterior.
lliaccrest Anterior superior iliacspine Anteriorinferior
lliac fossa
Superior ramus of pubis Pubictubercle Crestof pubis
iliacspine
Pecten pubis
Head of femur Greater
Bodyof pubis
trochanter
lntefirochanteric line
Pubicsymphysis Obturator foramen lschialtuberosity
Femur
Lesser trochanter
Adductortubercle Lateral epicondyle
Medialepicondyle Patella
Head of f ibula Neck of f ibula
Tibialtuberosity
Figure l-5-14.Osteology of the lower limb: hip, thigh, and knee.
57
Tissue, andIntegument Connective System, Musculoskeletal
I. Osteology(FigureI-5-14) a. The anterior-superioriliac spineis the superolateralattachmentof the inguinal ligament. b. The pubic tubercle is the inferomedial attachment of the inguinal ligament. c. The ischial tuberosity is the site of origin of the hamstring muscles. d. The greater and lessertrochanters of the femur and the intertrochanteric line are sites of muscleand ligamentousattachments. e. The linea asperaof the femur is the site of insertion for the adductor muscles. f. The adductor tubercle of the femur is the site of insertion for the ischiocondylar portion of the adductor magnus. 2. Anterior thigh muscles. The anterior compartment of the thigh contains postaxial muscles,which are supplied by the femoral nerve: a. The quadricepsfemoris is comprised of the vastus lateralis,vastus medialis, vastus intermedius, and the rectus femoris. The rectus femoris crossesboth the hip and the knee joints. It has a weak flexor action at the hip and a strong extensorfunction at the knee. The three other components of the quadricepsarise from the shaft of the femur. b. The sartoriusmuscle actson both the hip and knee joints, primarily as a flexor.
Note inthelower muscles Postaxial in location; limbareanterior postaxial muscles intheupper posterior in location. limbare of Thisisdueto therotation thelowerlimb,whichbegins andis during thefetalperiod duringthefir$ year. completed
Correlate Clinical hernia, whichenters A femoral through thethighbypassing ringandfemoral thefemoral mayappear asa canal, overthefemoral swelling aninguinal triangle. Unlike inferior hernia, it protrudes to thepubic andlateral tubercle.
58
c. The iliopsoas is the chief flexor of the hip. d. The pectineusmaybe innervated by the obturator nerve aswell asby the femoral nerve. 3. Femoral triangle (Figure I-5-15) a. Boundaries. The femoral triangle is bounded by the inguinal ligament superiorly,the medial border of the sartoriuslaterally,and the medial border of the adductor longus medially. b. Contents (1) The femoral nerve, a mixed branch of the lumbar plexus,contains fibers from L2,L3,and L4; a postaxialnerve,it suppliesthe extensormusclesof the thigh and cutaneousareasof the thigh. The femoral nerve has a long sensorybranch, the saphenousnerve,which suppliesthe kneejoint and the skin on the medial aspect of the foot. (2) The femoral artery, also known as the superficial femoral artery,has three main branches: the profunda femoris, the medial femoral circumflex, and the lateral femoral circumflex arteries.The MFCA and the LFGA are more often branches of the profunda femoris. (3) The deep inguinal lyrtph node (of Cloquet) is locatedin the most medial compartment of the femoral sheath. This compartment is known as the femoral canal, and it communicates with the abdomen via a small opening, called the femoral ring. a. Inguinal lymph nodes a. Superficial nodes (1) Horizontal group. Thesenodes lie along the inguinal ligament. They drain the anterior abdominal wall below the umbilicus; the perineum, including the external genitalia;and the lower one-third of the anal canal.
Anatomy: Musculoskeletal
Anteriorsuperior iliacspine Inguinalligament
Pubic tubercle
Femoralartery Sartorius Adductor longus
Adductor tubercle
Figure l-5-15.Anterior thigh and femoraltriangle.
(2) Vertical group. These nodes follow the great saphenousvein and drain most of the superficial lymphatics of the lower limb. b. Deep nodes. Thesenodes receively-ph from the superficial nodes and from the deep compartment of the leg. Efferent vesselsfrom the deep nodes drain to the external iliac nodes. 5. Medial thigh, or medial compartment, contains musclesresponsiblefor adduction of the thigh. Theseare preaxial muscles,which are innervated by the anterior and posterior divisions of the obturator nerve. They arise from the pubic bone and the ischium. a. Muscles (l) Adductor longus (2) Adductor brevis (3) Adductor magnus (4) Gracilis b. Nerves (1) The anterior division of the obturator nerve, which is a preaxial nerve derived from L2,L3, and L4, suppliesthe pectineus,the hip joint, the adductor longus, the gracilis,and part of the adductor brevis.
59
Tissue, andIntegument Sy$em,Connective Musculoskeletal
(2) The posterior division of the obturator nervesuppliesthe obturator externus,the knee joint, the adductor magnus,and part of the adductor brevis. c. Blood supply (1) Profundafemoris (2) Obturator artery 6. Posterior thigh, or posterior compartment, contains musclesthat extend the thigh at the hip and flex the leg at the knee. These preaxial muscles are known as the "hamstrings." They arise from the ischial tuberosity and are supplied by the tibial division of the sciatic nerve (FigureI-5-16). a. Muscles (1) Semitendinosus (2) Semimembranosus
Rectus femoris muscle
Yi'nitirioi
Femur
Adductor magnus muscle
MeSU_aliaj)
Hamstrings Figure l-5-16.Gompartments of the left thigh (transverse section).
(3) Long headof the bicepsfemoris.The short headof the bicepsarisesfrom the shaft of the femur. It is a postaxial muscle and is, therefore, supplied by the common peroneal division of the sciatic nerve. The ischiocondylar portion of adductor magnus arisesfrom the ischial tuberosity. It inserts on the adductor tubercle and not on the linea asperawith the remaining fibers of adductor magnus.Hence,the ischiocondylar portion of adductor magnus acts as a hamstring. It is, therefore, supplied by the tibial portion of sciatic and not by the obturator nerve.
60
Anatomy: Musculoskeletal
b. Nerves. The sciatic nerve is actually two nerves:the tibial nerve, which is preaxial and supplies the hamstrings as well as the musclesof the calf and the sole of the foot, and the common peronealnerve,which is postaxialand suppliesthe short head of biceps femoris and the musclesof the lateral and anterior compartmentsof the leg. c. Blood supply. The musclesof the posterior compartment receivearterial supply from the perforating branchesof the profunda femoris. B.Hip 1. Gluteal region. The musclesof this region extend,abduct, and rotate the thigh. a. Muscles (1) Gluteus maximus is the extensorof the thigh
Clinical Correlate
(2) Gluteusmedius
Anearlyseparation ofthe sciatic nerve intotibialand peroneal common nerves may resuh inthe"piriformis syndrome," inwhichthe peroneal common nerve enters thegluteal region by passing overoremerging from thesubstance ofthepiriformis muscle. Initsmostextreme form,piriformis syndrome can result in "footdrop"("slap foot").
(3) Gluteusminimus (4) Tensorfascialata (5) Piriformis (6) Small gluteal muscles include the obturator internus, superior and inferior gemelli,and quadratusfemoris. b. Nerves ( 1 ) The sciaticnerve is derived from ventral rami L4-S3. ( 2 ) The superior gluteal nerve supplies the gluteus medius, gluteus minimus, and tensor fascialata. (3) The inferior gluteal nerve suppliesthe gluteusmaximus. ( ) The pudendal nerve is a branch of the sacralplexus (S2, 53, S4). It enters the gluteal region through the greatersciaticforamen, archesover the sacrospinous ligament, and leavesthrough the lessersciaticforamen en route to the ischiorectal fossaand perineum. It travelswith the internal pudendal nerve and artery. c. Blood supply ( 1) Superior gluteal vessels (2) Inferior gluteal vessels (3) Internal pudendal vessels 2. Hip joint. This joint is a ball-and-socketjoint. Locatedat the point at which the head of the femur articulateswith the acetabulumof the os coxae,the hip joint is more stable than the shoulder joint. This stabiliry however,is gained at the expenseof range of motion. The upper limb has a 360" range (i.e.,circumduction), whereasmotion at the hip is limited by the range of medial and lateral rotation. a. Ligaments (1) Iliofemoral ligament (Y ligament of Bigelow) (2) Ischiofemoralligament (3) Pubofemoralligament (a) Ligamentum capitis femoris
ClinicalCorrelate Theprognosis forhealing a hipfracture depends on whether thefracture isintraor extracapsular. Withan intracapsular fractu re,chances aregreater thattheheadof thefemurwillundergo necrosis asa result of interruption of itsblood supply. Anextracapsular (i.e., fracture onenearer the greater trochanter) hasa better chance of healing because muchoftheblood supply willbepreserved.
6l
Tissue, andIntegument System, Connective Musculoskeletal
b. Blood supply. The hip is the central axis of an arterial supply, which arrives from four directions and is known as the cruciateanastomosis. (1) Medial femoral circumflex artery (2) Transversebranch of lateral femoral cutaneousartery (3) Inferior gluteal artery (4) First perforating branch of profunda femoris artery C. Knee 1. Poplitealfossa. This is the diamond-shapedspaceat the back of the knee.Contentsof the popliteal fossainclude the following: a. Poptteal artery and vein. As the superficial femoral vesselspassthrough the adductor hiatus, they becomethe popliteal vessels.The femoral artery lies superficialto the femoral vein in the subsartorial(adductor) canal;however,in the popliteal fossathe relationship is reversedand the artery lies deep to the vein. b. Genicular anastomosis is a network of arteries surrounding the knee joint, which may provide alternate pathwaysfor blood flow if there is a blockageof the main artery. c. Tibial nerve entersthe posterior compartment of the leg. d. Common peroneal nerve follows the medial border of the bicepsfemoris to passlaterally around the neck of the fibula. 2. Knee joint is a hinge-Vpe, synovialjoint. a. Osteology (1) Patella is a sesamoidbone located within the quadricepstendon, which inserts on the tibial tuberosity. (2) Tibia is the bone of the shin. It is the weight-bearingbone of the leg. Its medial and lateral condyles articulate with the femur, and its lateral condyle has a depressionfor articulation with the fibula.
Correlate Clinical ofthepresence of a Because large amount offatinthe popliteal fossa andthe ofthe relatively deeplocation pulsemay artery, a popliteal lt is bedifficult to detect. important to e$ablish the existence ofthispulsebecause itsabsence mayindicate proximal obstruction ofthe artery dueto atherosclerosis.
(3) Fibula. The head of the fibula articulateswith the tibia. A groove in the neck of the fibula indicates the path of the common peroneal nerve. b. Ligamentous and cartilaginous structures (1) The medial collateralligament is a wide, flat ligament that attachesthe medial condyle of the femur to the shaft of the tibia. It is also firmly attached to the medial meniscus. (2) The lateral collateralligament is a discretecord-like structure that attachesthe lateral condyle of the femur to the head of the fibula. (3) The oblique popliteal ligament is an extensionof the semimembranosusinsertion. (a) The anterior cruciate ligament runs from the anterior intercondylar surfaceof the tibia to the lateral femoral condyle. It prevents hyperextension of the knee. (5) The posterior cruciateligament runs from the posterior intercondylar surfaceof the tibia to the medial femoral condyle. It prevents hlperflexion of the knee. (6) The medial semilunar cartilage (medial meniscus) is a nearly circular disk of fibrocartilage that lines the articular surface of the medial tibial condyle. It is attachedto the medial collateral ligament.
62
Anatomy: Musculoskeletal
(7) The lateral semilunar cartilage(lateral meniscus)is a C-shapeddisk of fibrocartilage that lines the articular surfaceof the lateral tibial condyle. It is not attached to the lateral collateral ligament. c. Muscles related to the knee joint (1) The popliteus is a small muscle located posterior to the knee joint. Its tendon inserts on the femur deep to the lateral collateral ligament. It initiates flexion of the knee joint by medially rotating the femur on the tibia. (2) The quadricepsfemoris is an extensorof the knee. (3) The sartorius,gracilis, and semitendinosusmusclesinsert on the medial aspect of the knee as the "pes anserinus." D. The leg is the portion of the lower extremity between the knee and the ankle. Like the thigh, the leg is encasedin a denselayer of deep fascia,the crural fascia.The nvo bones of the leg, the interosseousmembrane between them, and two fibrous septa divide the leg into three compartments. 1. Osteology (Figure I-5-17) a. Tibia. The anterior surface of the tibia is devoid of muscular attachments and is palpable throughout its length as the shin. The lower end of the tibia articulates with the talus and forms a subcutaneousprojection, the medial malleolus. b. Fibula is coveredthroughout its length by muscle. It is palpable only at its head and most distal projection, the lateral malleolus, which articulates with the talus. 2. Posterior compartment a. Muscles. The preaxial muscles of the posterior compartment are arranged in two groups, superficial and deep.They plantar flex the foot. (1) Superficial . Gastrocnemius . Soleus . Plantaris
Clinical Correlate A fracture of theneckof the fibulamaycause common peroneal nerve damage, resulting in "footdrop"-aloss offunction inthemuscles of theanterior compartment of thelegthataresupplied by thedeepperoneal branch of peroneal thecommon nerve. Therefore, therewouldbe difficulty in dorsiflexing the foot.Alsoaffected wouldbe themuscles supplied bythe peroneal superficial nerve: peroneus longus andbrevis, whichevertthefoot.
ClinicalCorrelate Theanterior compartment is limited bythepresence of threefeatures: thetwobones of theleg,theinterosseous membrane, andthecrural fascia. Fluidbuildup withinthis compartment mayoccur asa result of direct trauma, other serious injury, or infection. Thisfluid,whichmaybe bloody, willexertpressure on thedeepperoneal nerve and theanterior tibialblood vessels, resulting in"anterior compartment syndrome." This condition warrants immediate fasciotomy.
65
Tissue, andlntegument Musculoskeletal System, Connective
Neckof fibula
Tuberosity
Lateralmalleolus
Medialmalleolus
Calcaneus
Talus
Cuboid
Navicular Cuneiforms Metatarsals Proximalphalanx Distalphalanx
Figure l-5-17.Osteology of the lower limb: leg and foot. (2) Deep . Tibialis posterior . Flexor digitorum longus . Flexor hallucis longus b. Nerves. The flexor musclesare supplied by the tibial nerve, which also supplies musclesof the plantar surfaceof the foot. c. Blood supply. The posterior tibial artery supplies the posterior compartment of the leg and terminates by dividing into the medial and lateral plantar arteries. 3. Anterior compartment a. Muscles. The postaxial musclesof the anterior compartment act to dorsiflex (i.e., extend) the foot.
il
Musculoskeletal Anatomy:
(1) Tibialis anterior (2) Extensorhallucislongus (3) Extensordigitorum longus (4) Peroneustertius b. Nerves.Motor branchesof the deepperonealnervesupplythe musclesof the anterior compartment.The terminal sensorybranch of the nerveconveyssensoryinformation from tlle dorsum of the foot in the areabetweentlle greatand secondtoes (i.e., fust web space). c. Blood supply, The anterior tibial branch of the posterior tibial artery supptes the anterior compartment.The artery terminateson the dorsum of the foot lateralto the tendon of extensorhallucislongusasthe dorsalispedisartery. 4. Lateral compartment
In a NUbhell
a. Muscles.The major function of the peroneuslongus and the peroneusbrevis, the postaxialmusclesof the lateralcompartment,is to eyert the foot.
compart-Nerve Adery r.d
b, Nerves.The peronealmusclesof the lateralcomPartmentare suppliedby the superficial peronealnerve,which alsoconveyssensoryinformation ftom most of the dorsal
Anterior Deep Anterior peronealtibial bnnch
surface ofthefoot. c. Blood supply.The p€ron€alartery a branch ofthe posterior tibial, suppliesthe lateral compartm€ntof the leg. This artery doesnot enter the lateral compartmentitself but givesof branchesthat piercetlle lateralintermuscu.larseptumto supplythe peronealmuscles.
il,trff::i peroneal Lateral Superficial peroneal pone;or Tibial posterior tibial
E. Anlle. The anHejoint is a rynovial hinge-typejoint locatedbetweenthe tibia, the fibula, and the body of the talus. 1. Osteologf a. The talus is the weight-bearingbone of the foot. b. The calcaneusis the bone of the heel. c. The tuberosityofthe navicularbone is palpableanterior to the medialmalleolusand servesaspart of the attachm€ntof the tibialis posterior muscle. d. The cuboid bone is the most lateralof the smallbonesof the foot. bonesthat articulate proximally with e. The cuneiform bonesare three wedge-shaped of the foot. They areprimarily the navicularboneand distallywith the metatarsals responsiblefor the formation of the transversearch of the foot.
2.Lisamenrs a. Medial The deltoid ligament is the strong, medially located,reinforcementof the anHeioint. It attachesthe medialmalleolusto the talus. b. Irteral
(1)Anteriortaronburar (2) Posteriortalofibular (J'' LiucaneonDuar (4) Anterior and posterior tibiofibular
Cliniol Correlate of theankle Evenion sprains
:fiilf:lTn'Ji',#"**' ligam-enq inversion sprains are morecommonbeouse*n to laterallisamenb aresubiect
*:Tiif,il1ff:iltJH., istireinterior rrgamern followedbYthe talofibular, Repeated injury calcaneofibular results in to theseligamenb joint. instability of theankle
65
Musculoskeletal System, Connective Tissue, andIntegument
F. Foot 1. Osteology a. There are five metatarsalbones. b. Phalanges.The great toe, or hallux, has two phalanges,a proximal and a distal phalanx Eachof the remaining toes (i.e.,digits) hasthree phalanges:proximal, middle, and distal. 2. Ligaments. The plantar calcaneonavicular,or "spring" ligament, supports the head of the talus, which forms much of the medial arch of the foot. 3. Muscles. The musclesof the sole of the foot are arranged in four layers.Thesemusclesare similar to those of the palm of the hand. 4. Nerves. The intrinsic muscles of the sole are supplied by the medial and lateral plantar nerves,which are branches of the posterior tibial nerve. 5. Blood supply. The arterial supply of the sole of the foot is derived from the medial and lateral plantar branches of the posterior tibial artery.
66
Physiology Musculoskeletal potential istransmitted along thesarcolemma Anaction forcontraction. Muscle cells arespecialized (muscle There arethreemajor mechanism. thecontractile that,inturn,activates cellmembrane) (striped isunder theliShtmicroscope), under muscle, whichisstriated skeletal types of muscles. islocated in bloodvessel whichisnotstriated, muscle, smooth voluntary control, andisrapidacting; (having andisslow contractile activity), inherent rhythmic isinvoluntary wallsandinternal organs, of both buthassomecharacteristis muscle likeskeletal muscle, whichisstriated acting; andcardiac mechanisms of skeletal and willdiscuss thecontraction muscle. Thischapter andskeletal smooth Physiology chapter of intheCardiovascular isdiscussed separately muscle; cardiac muscle smooth lll), Book1 S/olume Systems Organ
MUSCTE SKEIETAI Skeletalmuscle is typically composedof many parallel muscle fibers (myofibers) that run the length of the muscle and terminate in tendonsthat attach the fiber to the skeletalsystem.Each myofiber is a multinucleated structure surrounded by the sarcolemma. A. Structural changesduring contraction 1. The shortening of a muscle results from an increasein the extent of thin-thick filament overlap, owing to the sliding of the former over the latter toward the center of the sarcomere.This method of contraction is therefore termed the sliding filament mechanism the lengthsof both thick of musclecontraction.Although the sarcomerelength decreases, (Figure I-6-1). and thin filaments essentiallyremain constant
+l
l-sarcomere+ |+1tztband
1/zt oand+l l*
Contraction .'...'.''.''.'.'''''''.''''''''''''''''''''''''''''* Handl bands shorten
F--+l
H band Relaxedstate
it-
H band Contractedstate
Figure l-6-1.Contraction of the sarcomere.
67
Musculoskeletal System, Connective Tissue,andIntegument
2. Molecular aspectsof contraction (Figure I-6-2). a. Upon stimulation of a myofiber, myosin heads can make connectionswith neighboring thin filaments. b. Once an actomyosin complex is formed, the head undergoes a conformational change(state3), displacingthe thin filament toward the center of the sarcomere. c. The actin-myosin bond is subsequentlybroken (state6) and the cyclemay be repeated aslong asthe muscle remainsstimulated. d. The molecular events in the rycle are driven by the hydrolysis of AIP. The myosin headsin state 1 contain ADP and inorganic phosphate(P,) that remain bound during the binding of the head to the thin filament. Dissociationof the phosphateis thought to acceleratethe tilting step (or power stroke) from state2 to state3. Finally,the ADP dissociatesfrom the attachedtilted state (state4). ATP in the cytoplasm replacesthe previouslybound ADR resulting in the dissociationof the head.
ClinicalCorrelate Rigor Mortis Theabsence ofATP results in theinability ofmyosin heads to bereleased. Theactin-myosin complex becomes stable, leading tomuscular rigidity.
e. The final step involvesthe hydrolysis of the bound AIP with the liberated energy repositioning the myosin head for another rycle. The head in the restingposition (state1), therefore,is consideredto contain stored potential energy,which is expendedduring the power stroke.If ATP supplieswere to run out, all the headswould be trapped in state 4, the so called rigor state.The complex equilibrium involving the actomyosin ATPaseshowsall of the coexistingchemical species. f. Although a single contraction resultsonly in an extremelysmall movement and little force generation,the combination of continuous asynchronouscyclingof many heads and the multiplicity of interprotein connectionsin the myofibriis greatly amplifr the molecular events.
thin filament
Pi
4 Jtoo,
Figure l-6-2.The contractile cycle (mechanochemicalcoupling).
g. There have been recent developmentsinvolving the precisemechanism of contraction at the level of the actin-myosin interaction. There is some evidencethat a single cross bridge cycleinvolving the motion of a myosin head may slide the actin and myosin filament more than the distancebetween two adjacentactive siteson the actin filament. B. Excitation-contraction coupling (EC coupling) refersto the mechanism by which an action potential generated by a motor neuron in the muscle initiates the mechanical events describedabove. 1. An action potential generatedin a muscle fiber is transmitted along the surfacemem-
68
Physiology: Musculoskeletal
brane and down the T tubule to the sarcoplasmic reticulum, resulting in a releaseof the sequesteredCaz+ into the cytoplasm. Cytoplasmic Ca2+rises to approximately 10-sM (FigureI-6-3).
T tubule
Figure l-6-3.Thetransverse tubule system. 2. Ca2+releasedfrom the sarcoplasmicreticulum diffusesinto the myofibrils, where it comes into contact with the thick and thin filaments. 3. When Ca2+binds to the TnC subunit of troponin, it initiates a conformational changein TnC that is transmitted to the other thin-filament proteins, ultimately causinga shift in the position of tropomyosin with respect to the actin surface. The movement of tropomyosin exposesa site on actin that is the binding site for cycling myosin heads. 4. In the absenceof further stimuli, the Ca2+-AIPaseof the sarcoplasmicreticulum rapidly depletesthe cytoplasmicCa2* concentration,causinga return to the inactivatedstateof the thin filament. C. Summary of the contraction sequence 1. Releaseof ACh at the neuromuscularjunction occurs when an action potential reaches the end of the axon; ACh difuses acrossthe gap. 2. The nicotinic acetylcholine receptor at the muscle end plates reactswith ACh, which, in turn, depolarizesthe muscle cell membrane at the motor end plate from the -90 mV resting potential. 3. The threshold is reachedwhen the membrane is sufficiently depolarized,initiating an action potential along the muscle cell membrane that propagatesbidirectionally from the end plate and extendsinto the T tubules. 4. T tubule depolarizationinfluencesthe sarcoplasmicreticulum of the triads, and the sarcoplasmicreticulum releasesCa2* into the cytoplasm. 5. Ca2+binds to troponin-tropomyosin. Myosin heads are now able to bind, and myosin ATPaseis activated.Cross-bridgesattach and detach cyclically at the expenseof AIR and the "rowing motion" causesthick and thin filaments to slide past each other. 6. After a time lag, the sarcoplasmicreticulum actively pumps Ca2+back into the lumen, decreasingavailableCa2+and removing Ca2* from the troponin-tropomyosin complex. The regulatory proteins then rebind to the actin outside the groove, and the actin-myosin interaction is inhibited. A single action potential thus results in a muscle twitch, a brief contraction followed by relaxation. The twitch starts approxim ately2 msecafter the depolarization of the membrane begins,i.e., during repolarization (Figure I-6-4).
69
Musculoskeletal System, Connective Tissue, andIntegument
ClinicalCorrelate TheCa2*re-uptake mechanism ofthesarcoplasmic reticulum is called theryanodine receptor. ln somepeople, thisreceptor is blocked bygeneral anesthetis suchassuccinylcholine. When these aregiven drugs to such patients, isnottakenup Ca2* quickly enough andthe "overcontracf' muscles and generate enormous amounts of heat. Thiscondition iscalled malignant hyperthermia and canbefatalif nottreated with dantrolene.
response electrical {Beginnin.g
ffi time
to peak of contraction)
Figure l-6-4.Relativetiming of action potential and muscle contraction.
D. Muscle mechanics 1. Definitions. An isometric contraction occurs when both ends of a muscle are fixed and no changein length occurs during the contraction, but tension increases.An isotonic contraction occurs when a muscle shortens during contraction while tension remains constant (Figure I-6-5). When both the muscle length and force changeduring the contraction, it is referred to as a dynamic contraction. In a dynamic contraction, the muscle may shorten (concentric contraction) or be pulled out by the load (eccentric contraction). Most physicalactivity includesboth isometric and isotonic contractions.
In a Nutshell Typesof Contraction lsometric: Change inforce butnochange in lengh lsotonic: Change in lenghbutno change inforce Dynamic: Change in both lenghandforce
70
Figure l-6-5.lsotonic contraction. 2. tength-tension relationship. The tension developedby an intact muscle in an isometric contraction varies with the initial length of the muscle fiber; there is an optimal length at which the muscle is able to developmaximum tension (Figure I-6-6). Figure I-6-7 plots the isometric tension developed by a single muscle fiber at different sarcomerelengths. Active tension refers to the difference between the total tension measuredon stimulation and the passivetension (resistanceto stretch) of an unstimulated muscle fiber, i.e., the resting tension. Thus, active tension refers to the tension produced by the active contraction alone.
Musculoskeletal Physiology:
c .o o c o F
Lop,
Length(for an intactmuscle) Figure l-6-6.Length-tension relationship.
a. In part A of the curve in Figure l-6-7, active tension is not developedby the fiber
becausethe sarcomeresare stretchedpast their usual maximum length and there is no overlapbetweenthin and thick filaments (Figure I-6-84); no cross-bridgescan form to generateforce.
c
.o
U' c o o o
1 .2 71 .6 52 .0 2 .2 5 Sarcomerelength(p) Figure l-6-7.Active tension generated as a function of sarcomere length. b. In part B, the sarcomeresbegin to overlap,and the increasein tension is proportional to that form (FigureI-6-88). the extentof overlap,i.e.,to the number of cross-bridges c. Part C of the curve is the plateau tension; no further increasein tension is observed with further shortening becausethe thin filaments overlap the thick filaments up to the bare areasin the central region, in which no cross-bridgesare present(FigureI-6-8C). Increasedshortening only overlapsthe thin filaments with more bare area;hence,no further increasein active tension is generated.The sarcomerelength is optimal for generating tension at approximately 2 mm, the length that correspondsto the in situ resting length of the sarcomeresin the fiber. d. Part D of the curve shows a linear decline in active tension becausethe thin filaments have moved past the bare areasof the thick filaments and begin to overlap one another; thin filaments from opposite halvesthen interfere with eachother (Figure I-6-8D). e. Part E of the curve showsfurther decline in tension at a fasterrate until zero tension is reached.The thick filaments havereachedthe Z lines and begin to crumple asthe Z lines compressthem (FigureI-6-8E).
7l
Musculoskeletal System,Connective Tissue,and Integument
A
r-Fl-Fl-FHFFtIHi
I B
I
Fl-BFr-Hr-r-H-H{
I
nnnr+lnnn
c I II
r-tFH{.|HH{lH{ H-fi-t+{H.|{{{{{J r+#.|flf-fi.|fl#{
D
:
I I
r{++++{H+t+fl+{ r{{.|{.t{H{+il+{.|
Figure l-6-8.A, No overlap of thick and thin filaments; B, initial overlap and tension increase; C, plateau tension; D, initial relaxation of tension; and E, rapid relaxation and thick filament crumbling.
3. Sarcomeresacting in seriesdo not generateadditional force,sincethe forcesact in opposite directions on the two sidesof the Z line and therebycanceleachother (Figure I-6-9). The total force generatedby many sarcomeresin seriesis thus the sameasthat of one sarcomere. a. The displacementprovided by the sarcomeresincreaseswith more sarcomeresin series,sinceeachsarcomereshortensby a given amount. b. Becausethe sarcomeresin seriescontract nearly simultaneously,the speedof shortening is increasedby the arrangementof sarcomeresin series,proportionally to the number so arranged.
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Physiology: Musculoskeletal
...--->
F--+
-----t-----
tt-
-----+-----r--------l----T------T---
----r---
Note Sarcomeres ofthesame myofibril donotgenerate additive force. Therefore, to generate moreforce, more muscle fibers mustberecruited.
Figure l-6-9.Opposing forces in sarcomeres in series.
4. Sarcomeresacting in parallel generate additional force proportional to the number in this arrangementbecausethe amount of force that is generatedis proportional to the number of cross-linksacting in parallel simultaneously(Figure I-6-10). Thus, the force that a musclegeneratesis proportional to the cross-sectionalareaof the contractilematerial. The tension provided by a muscle can thereforeincreaseby increasingthe cross-sectional areaof eachfibril (adding more filaments in parallel),by increasingthe number of fibrils per muscle fiber (cell), thereby increasingthe number of cross-links(force-generating attachments)acting in parallel.
Figure l-6-10.Sarcomeres in parallel.
5. Isotonic contraction. If a muscle contracts isotonically, it is found that the velocity at which the muscle contractsvaries inverselywith the load it lifts (Figure I-6-11). At zero load, a muscleexhibits a rapid but finite velocity of shortening,which correspondsto the maximum velocity for unloaded cross-bridgerycling. With increasingload, the velocity asymptomatically approachesa value of zero.At zero velociry the contraction becomes isometric. This point representsthe maximum activeforce of the muscle.
E (d
lsometriccontractionmaximumforce
o
o () L
o
TL
Initialvelocityof contraction Figure l-6-11.Force-velocity relationship in skeletal muscle.
73
Musculoskeletal System,Connective Tissue,and Integument
E. Tlpes of skeletal muscle fibers. TWo types of fibers occur interspersedin most muscles, although one type usuallypredominatesin any given muscle.Their properties are summarized in ThbleI-6-1. Thble I-6-f . Properties of fast-twitch and slow-twitch fibers. Propertyand Type
Fast TWitch
Slow TWitch
Color Sarcoplasmicreticulum and T tubules Myosin AIPase Mitochondria
White Many
Red (myoglobin) Few
High Few,(short, rapid movements)
Low Many (sustained contractions)
1. Fast-twitch fibers are white in appearance(hence the term "white muscle"), large in diameter, and usually arranged with relatively few muscle fibers per motor unit. The light color is due to the absenceof red myoglobin. a. Fast-twitch fibers use glycolysisto generateenergy; thus, they usually function under anaerobicconditions. b. These muscle fibers are adapted for rapid contraction: the sarcoplasmic reticulum system and T tubules are extensive and regularly arranged, and the myosin AIPase activity is high.
In a Nutshell FastTwitchVersus SlowTwitch Think ofa chicken: . Whitemeat(whitemuscle) isinthebreast andisused forintermittent flapping of thewings. . Darkmeat(redmuscle) is inthethighs, whichare usedforsustained maintenance of posture.
c. Thesefibers enable fine, careful movements, for example,contraction of the extraocular musclesof the eye. 2. Slow-twitch fibers (or red muscle) are red becauseof the presenceof myoglobin. a. The fibers are smaller in diameter than white muscle fibers,there is lesssarcoplasmic reticulum and fewer T tubules than in white muscle, and the motor end plates are smallerthan those of white muscle. b. Red muscle,such as back muscle,is slower to contract and is adaptedfor long, sustained contractions;oxidative metabolism is used for energy.Largenumbers of mitochondria permit sustainedcontractions,and there is a greaterblood supply. c. Muscle with little sarcoplasmicreticulum contractsslowly,sincelessCa2*is releasedat a slow rate, and contraction takeslonger becauseof the slower removal of Ca2*. Motor units 1. Motor units consist of all the muscle fibers innervated by a single nerve axon (alpha motor neuron). Excitation of the motor neuron of the unit resultsin contraction of all the fibers in the motor unit. a. Eachof the musclefibers of a given motor unit is of the samemuscletype. The nerve exertsa tropic influence on the muscle fibers. b. If the pattern of neural firing is experimentally changed,the muscle changesin type to that determined by the motor nerve.Thus, the firing of any given axon resultsin either slow or fast contraction. c. If the motor nerve is destroyed,all muscle fibers innervated by that neuron atrophy.
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Physiology: Musculoskeletal
2. Length and tension developedby skeletalmuscle is determined by the rate of firing of the motor neuron. Each muscle fiber has one end plate and is innervated by one motor neuron. a. No activiry occurs in the absenceof motor nerve stimulation (i.e., relaxation).
b. All motor neuron inputs are excitatory,and all reachthreshold; i.e., they all generate the action potential necessaryto initiate contraction. c. Skeletalmusclemotor neuron cell bodies are locatedin the ventral horn of the spinal cord gray matter. (1) A single,rapidly conducting myelinatedaxon directly connectswith the muscle fiber motor end plate. (2) Initiation and coordination of the control occursin the cerebralcortex, cerebellum, specificbrain stem nuclei, and basalganglia,and via reflexes. G. Tr,nitchand tetanus l. Single twitches. Elasticelements(tendons,connectivetissue)within muscleand between the muscle and its attachmentsrepresentslack that must be stretchedbefore the active tension generatedby the muscle can be exerted. a. When contraction is initiated, the active tension first stretchesthe elasticelements. This time delayfor elasticstretchis sufficient for the activetwitch to begin to decline. Thus, the peak tension is never exertedby a singletwitch (Figure I-6-12A).
100
75
E
Unfusedtetanus (colonus)
.9 th
b", lz
(u o
(L
25 Responseto two stimuli
1 Time (sec)
Figure I-6-12.A, twitch amplitudeand relativetiming and amplitudefor force generated (for frog sartorius muscle at 0"C); B, tetanus.
75
Tissue, Musculoskeletal System, Connective andIntegument
ln a Nutshell
b. The force exerted increaseswith the frequenry of twitches, since the slack is exhausted at the beginning and the firll energy of the twitch is then made available.
Tetanus results fromhigh frequency neural stimulation periods over short oftime.
c. The elasticelementsrecoil at the end of one or more twitches,returning the energyinput during initiation; this smooths out the decline of tension at the end of contraction. 2. Tetanus is the summation (fusion) of contractions that occurs when the fiber is stimulated repetitivelywithin a short time, resulting in greater contractions (developmentof more tension) than from a singletwitch. a. Tetanusis causedpartly becausethe elasticelementshavebeen frrlly stretchedfrom the early contractionsso that the maximum tension can be developedby the musclefiber, assumingit is not allowedto relax (FigureI-6-12B). b. Another reasonfor the occurrenceof tetanus involvesthe increasedavailabiliw of Ca2+ over repeatedcontractions. c. Tetanuscan be maintained until fatigue setsin due to an accumulation of lactic acid from anaerobicglycolysis. 3. Graded forces are generatedthrough increasingthe number of motor units (recruitment) and increasingthe firing rate to increasemuscletension (rate coding).
In a Nutshell (intrafusal Muscle spindles fibers) contain a contractile element innervated bygamma motorneurons, anda noncontractile element thatis enveloped bystretch-sensitive afferent neurons.
H. Muscle receptors. TWo tfpes of specializedreceptorsexist in skeletalmuscle: muscle spindles, which are embedded within groups of muscle fibers, and Golgi tendon organs, arrangedin tendons in serieswith the myofibers. 1. Muscle spindles a. Intrafusal fibers are small muscle fibers that are innervated bv small motor neurons called gamma motor neurons. b. Primary, or annulospiral, terminals in muscle spindles are rapidly conducting tfpe Ia fibers that innervate the centersof both the nuclear bag and nuclear chain fibers (the two types of intrafusal muscle fibers, named after the arrangementof nuclei in their equatorialregion). c. The secondary,or flower-spray, terminals are slightly slower conducting tfpe II fibers that innervate only the nuclear chain fibers. d. Motor innervation of intrafusal fibers is through small, slowly conducting gamma fibers (Figure I-6-13). Theseprimarily terminate at the poles of the spindle on the nuclearbag fibers.
Gamma efferents
la afferent ll afferent
Nuclearbag
Nuclearchainfiber
Figure l-6-13.Intrafusal fiber and innervation.
76
Physiology: Musculoskeletal
e. Stretching of a muscle causesstretching and deformation of the muscle spindle, which resultsin a volley of impulsesin the primary endings that synapsedirectly on the alpha motor neurons innervating the extrafusal fibers of the musclein which the spindle is embedded.For example,a contraction of the quadricepsmuscle is elicited when the patellar tendon is tapped and the familiar knee-jerk reflex occurs. f. Primary endings dischargerapidly during the actual lengthening of the muscle and lessrapidly when this increasedlength is maintained (Figure I-6-14). Primary endings thus respondto length aswell asvelocity of stretchof the muscle.
Note Muscle stretch causes an increased rateoffiringfrom spindle afferents. Thisresults in increased firingofalpha m0t0rneurons to cause muscle contraction.
Musclelength la response
ll response
Figure l-6-14.Muscle length changes and responses from la and ll fibers.
g. Secondaryendings dischargerapidly during the entire period of stretch of the muscle; thus secondaryfibers respondprimarily to length.
2. Golgi tendon organs a. The Golgi tendon organ is a receptorin serieswith a discretenumber of skeletalmuscle fibers. When a skeletalmuscle contracts,the tendon in which the muscle inserts lengthensand stretchesthe nerve endings of the afferentfibers, causingthem to fire. b. Golgi tendon organsare arrangedin serieswith extrafusalfibers and are supplied by Ib afferentfibers.Excessive stretchof a musclecausesfiring of Ib fibers,which synapse on inhibitory interneurons,which, in turn, synapseon alpha motor neurons.Excessive stretchthus inhibits muscle contraction, resulting in the inversestretchreflex.This is a protection againstthe possibledamagethat may be causedby excessive stretchingof a muscle. 3 . Golgi tendon organs and the muscle spindleswork in concert during muscle stretching, but function somewhatdifferently from eachother.
ln a Nutshell
a.If a muscleis stretched,both afferentsfire.
. Muscle spindles sense muscle length.
b. If the stretchedmuscle is made to contract actively,the tendon organ further increases its discharge,but the musclespindle decreases or ceasesits rate of discharge;this is becausespindle organs are arranged in parallel and tendon organs are arranged in serieswith the muscle.
. Colgi tendon organs sense muscle tension.
c. Tendon organs are more sensitiveto muscle tension, and muscle spindlesare more sensitiveto musclelength. d. Extrafusalmuscle fibers are controlled by alpha motor neurons,whereasthe control of intrafusal muscle fibers is by smaller gamma motor neurons.Gamma motor neurons regulatethe sensitivity of the spindle afferentsto dynamic and static phasesof stretch.Input through the CNS via gamma motor neurons can thus regulatemuscle tone and contraction.
77
Musculoskeletal System, Tissue, andIntegument Connective
SMOOTH MUSCTE Smooth muscleis involved in regulatingthe internal environment of the body. Smooth muscles are generally smaller than skeletalmusclesand are usually uninucleated. A. Structure of smooth muscle fibers. Smooth muscle fibers have fewer myofibrils per cell and are lessmorphologically organizedthan are skeletalmusclefibers. 1. Densebodies on the cell membraneand in the cytoplasm,analogoustoZ lines,act assites of thin filament insertion. 2. Smooth musclefibers havemuch lessmyosin than skeletalmuscle cellsand no thick filaments. Only small aggregates of myosin bridge the actin filaments. 3. Theyhaveno T-tubule systemand only sparsesarcoplasmicreticulum; most Ca2*appears to enter from the extracellularfluid. 4. Unlike skeletal and cardiac muscle, smooth muscle does not have troponin. Ca2+ is necessaryfor activation of myosin kinases,which in turn mediate excitation-contraction coupling. B. Contraction and relaxation, which occur slowly, probably involve overlap of actin and myosin. Thin filaments inserted into densebodies are pulled closer together by bridging myosin units. Densebodies on the cell surfaceare pulled so that the cell is deformed. 1. Myosin moleculesconsistof two heavychainsand four light chains;the light chainscontain the regulatory subunits. a. After an appropriatesignal,intracellular calcium concentrationsrise,and calcium will bind to calmodulin (FigureI-6-15).
t tcq2*l calmodulin
Ca2{catmodulin I I
myosinlight chainkinase (inactive)
ln a Nutshell Inskeletal muscle, Ca2+ binding to troponin allows actin-myosin interaction. Insmooth muscle, the phosphorylation ofthe myosin lightchain allows actin-myosin interaction.
* ,Ca2*-calmodulinmyosinlightchain kinase(active) ATP I ADP rll
. \* myosin (inactive)
-/
(active)
Figure l-6-15.Contraction and relaxation.
b. Ca2+-calmodulinwill activatemyosin light chain kinase (MLCK). c. MLCK phosphorylatesthe myosin light chain, which allowsthe myosin head to interact with actin. C. Pharmacologicalconsiderations. Knowledgeof the mechanismof smooth musclecontraction easilyexplainswhy autonomic drugs havetheir effects.Arteriolar regulationwill be used for this example. 1. Neutrotransmitters(e.g.,norepinephrine) or drugs (e.g.,phenylephrine)causevasoconstriction by activatingclr-receptors.Thesereceptorsincreaselevelsof inositol triphosphate
78
Physiology: Musculoskeletal
(IP3), which in turn, increasesintracellular Ca2+.This Ca2+ will lead to the cascadeof eventsdescribedculminating in vasoconstriction. 2. Neurotransmitters(e.g.,epinephrine) or drugs (e.g.,isoproterenol)activateBr-receptors that produce vasodilatation by increasing the level of cAMP. cAMP activates cAMPdependent protein kinase, which phophorylates MLCK. This inactivates the enzyme; the myosin light chain cannot be phosphorylated, and vasodilatation occurs. D. Types of smooth muscle 1. Multiunit smooth muscle is characterized by individual muscle fibers having separate innervation for initiation of activity. Muscle fibers are not interconnected by g"p junctions. There is little spontaneousactivity or responseto stretch.This type of muscle allows fine, graded contractions to occur, such as those that occur in the iris of the eye. 2. Unitary (visceral) smooth muscle has many separate fibers that operate as a unit (functional syncytium) becauseof gap junctions (nexus), which are regions of electrical coupling (low electrical resistanceand good current flow). Their fibers are sparselyinnervated by the ANS.
Bridge to Pharmacolry . NEproduces vasoconstriction by -receptors. activating This cr,l increases lP,andtherefore Ca2*levels. Thisleads to theactivation of MLCK. . EPIproduces vasodilatation pr-receptors. byactivating Thisincreases cAMP, which leads to theinactivation of MLCK.
a. Muscle fibers exhibit spontaneousactivity. The resting potential is close to threshold and is unstable. Oscillations of the resting potential, known as slow waves,bring the membrane potential to threshold repeatedlyand rhythmically. Thesechangesare probably due to high Na* permeability. b. Stretch activation occurs,where deformation initiates activity by depolarizingthe cells more rapidly. Muscle fibers are also frequently responsiveto circulating hormones. c. The ANS innervation to some fibers enablesregulation (but not initiation) of contractile activity. d. Contractions in unitary muscle are very slow, sustained, and rhythmic (e.g.,the gastrointestinal tract). They are initiated by action potentials that fire at the end of the slow waves.
79
Muscu loskeletal, nective Con Tissue, Pathology andIntegument Musculoskeletal andskinpathology encompass a broadrange of congenital anomalies, autoimmune diseases, andneoplastic disorders. Thischapter willdiscuss thecharacteristis of eachdisease state, presentations, theirclinical and,whenidentifiable, andtreatments. theircauses
BONE A. Congenitalanomalies 1. Osteogenesis imp€rfecta is a term usedto describeseveralclinical phenotypesof hereditar)' bone ftagilit)'. a. Four types are generallyrecognized.All arerare. (i) Type I shows autosomaldominant inheritance and causesmild-to-rnoderate long bone disease, blue sclerae,deaftress, and litde progressionafter puberty. (2) TypeII is autosonal recessive andoften producesa stillborn infart, or deathafter birth, with generalizedcrumpledbones. (3) Tfpe III is autosomal recessiveand producesprogressiveseveredeformity. Patientshavewhite sclerae. (4) TypeIV is autosomaldominant with variableseverirynormal sclerae,and fracturesof the long bonesand spine. b. Etiology.The caus€in all casesof osteogenesis imperfectaseemsto be a d€f€ctit n" synthesisof type I collagen.Genesfor the peptide chainsof collagenarelocatedon chromosomes17 and 7. Many different typei of lesionshavebee'ndescribed,from chainterminationto aminoacidsubstirution'
!!!!!!91-e!!*!:
;:::$:::;ffi:T* co agensynth*rs. c. Pathology Heritability varis among ( I ) In bones,wovenboneinsteadof trabecularboneand abnormalarrangements61 : thetypes;bluesderae andlaxligamenbare collagenfibers are seen.Jointsshowtigametrtouslaxitl' asa resr.t of abnormal : commonfeatures. collagen. (2) In the eye,somepatientshavean abnormallythin sclerawith a blue hue. (3) In the ears,theremay be fracturedossicles,producingdeaftress. (4) Teethmay be smali and discolored(dentinogenesisimperfecta),there may be mitral valveprolapse,and the dermismaybe abnormallythin
8t
Musculoskeletal System, Connective Tissue, andIntegument
Nole Thedefect inosteopetrosis to be seems aninability of o$eoclasts toresorb bone.
2. Osteopetrosis is a group of hereditary disorders characterizedby increased density and thickening of bone cortex with narrowing of medullary cavities. Bones are brittle and fracture easily.Membranous bones are not affected(e.g.,cranium). It may be associated with anemia,blindness, deafness,hydrocephalus,and cranial nerve palsies.There are two forms of inheritance. a. Autosomal recessivediseaseaffectschildren and produces early death due to anemia as the bones grow and squeezeout the marrow space. b. Autosomal dominant diseaseaffects adults and does not causedeath but may cause increasedfractures and encroach upon cranial nerves as they exit from the skull.
ClinicalCorrelate Achondroplasia isthebe$ known formofdwarfism, characterized byshortlimbs, large body, frontal bossing, and"saddle nose."
3. Achondroplasia is an autosomal dominant diseasecharacterizedby abnormal cartilage synthesis with subsequentdecreasedepiphysealbone formation. It sparesthe cranium and vertebral bones. Clinically, achondroplasia is characterizedby dwarfism with short extremities and a large body and head. 4. Osteochondromatosis is a hereditary disorder characterizedby the formation of multiple exostoses. a. Clinical features (1) Exostosesmay be asymptomatic or produce deformity and compromise the blood supply. (2) Gardner syndrome is a rare genetic disorder in which there is an associationof exostoseswith sebaceouscysts,desmoid tumors, and colonic polyps, which may becomecarcinomas. b. Pathology. Exostosesare bony metaphysealprojections capped with cartilage. They are multiple, often symmetric, and originate from epiphysealcartilage. 5. Enchondromatosis (Ollier disease)is a nonhereditary syndrome characterizedby multiple cartilaginous masseswithin the medullary cavit'' of bone, most commonly in the hands and feet. It often presentswith pain and fractures.These massesmay undergo malignant transformation; half of all chondrosarcomasarisefrom enchondromas.Maffrrccisyndrome is a tamilial associationof enchondromasand hemangiomasof the skin.
Ngte Ino$eoporosis, theboneis formed normally butin decreased amounts.
B. Osteoporosisis a decreasein bone mass,causingfragility of bone. Osteoporosismost commonly occursin postmenopausalwomen. 1. Pathogenesis a. Primarycauses include estrogendeficienry,low density of original bone,lack of exercise,and nutritional factors associatedwith acceleratedbone loss. b. Secondary causesinclude immobilization, endocrinopathies(e.g.,Cushing, thyrotoxicosis),and malnutrition (e.g.,deficienciesof calcium, vitamins C and D, protein). 2. Clinical features
ln a Mbhefl O$eoporosis mayleadto easy fracturing, especially of hips andvertebrae.
a. Patientsmay experiencepain and fractures without obvious trauma. b. X-rays show generalizedradiolucenc)'of bone. c. Laboratory testsrevealnormal serum calcium, phosphorus, and alkaline phosphatase. 3. Pathology. Thinned cortical bone and an enlarged medullary cavity are seen.All bones are affected.Weight-bearing bones (vertebrae,femoral neck) are predisposedto fractures. There is otherwise normal bone histology and a normal ratio of mineraUorganicbony elements(Figure l-7 -I).
82
Pathology
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' "r',&,&.' w"
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Figure l-7-1.Osteoporosis of vertebra (microscopic). C. Osteomalacia and rickets l. Etiology. Both diseasesare causedby vitamin D deficiency from chronic renal insufficienry, intestinal malabsorption,or dietary deficiency. 2. Clinical features a. Rickets occursin children prior to closureof the epiphyses,leading to bone deformities and pain. Patientsshow the "rachitic rosary" (deformity of the chestwall asa result of swellingat osteochondraljunctions of ribs), bowing of legs,and fractures. b. Osteomalaciais an impaired mineralization of the osteoid matrix. It causesfractures and bending of bones and widening of osteoid seams. (1) Laboratory tests show low serum calcium and phosphorous and high alkaline phosphatase,which distinguishesthis syndromefrom osteoporosis. (2) X-rays show diffuse radiolucencyof bone.
Note Rickets andosteomalacia aredisorders of o$eoid mineralization; osteoid is produced in normal amounts properly. butisnotcalcified
D. Pagetdisease(osteitisdeformans) is due to excessivebone resorption with replacementby soft, poorly mineralizedmatrix in a disorganizedarray. 1. Ctinical features a. Pagetdiseasemay presentwith pain, deformity, and fractures.It is usuallypolyostotic (affecting many bones), involving the skull, pelvis, femur, and vertebrae.When the skull is involved, impingment of cranial nerves often causesdeafness.Involvement may causebone hypervascularity with increasedwarmth of the overlying skin. b. X-ray showsenlarged,radiolucent bones. c. Laboratory tests show an extremely elevated alkaline phosphatase. 2. Pathology. The diseaseprogressesfrom an osteolyticto an osteoblasticprocess.Resorbed bone is replacedby a vascularconnectivetissue,which later becomesmineralized.There is a mosaic rather than trabecularpattern from persistentosteoid seamsat the margin of new bone. E. Fibrous dysplasia causesfocal areasof fibrous replacementof bone. Incidenceis higher in teenagers,with men more frequently affectedthan women.
8T
Musculoskeletal System, Connective Tissue, andIntegument
1. Clinical features. Monostotic fibrous dysplasia is often asymptomatic or may lead to pathologic fracture.Albright syndrome is an associationof polyostotic fibrous dysplasia, caf6-au-laitspots,and sexualprecocity in women. 2. Pathology. Fibrous dysplasiais usually monostotic, affectingthe long bones,ribs, skull, and facialbones.Fibrosisstartswithin the medullary cavityand remainsencasedin cortical bone. F. Bone abnormalities in hlperparathyroidism (osteitisfibrosa cystica) 1. Pathogenesis.Excessparathyroid hormone activatesosteoclaststo resorbbone and causes the kidney to waste calcium. 2. Clinical features. Osteitis fibrosa cystica occurs more comrnonly in primary hyperparathyroidism,causingbone pain and fractures. 3. Pathology
Note Brown tumors areclassic signs ism. of hyperparathyroid
a. Microscopically, there is an increasednumber of osteoclastswith excessbone resorption and fibrous replacementof marrow causingcystic spacesin trabecularbone and "brown tumors" (areasof organizedhemorrhage). b. Grossly,brown tumors may produce rystic enlargementsof bones. G. Hypertrophic osteoarthropathy 1. Clinical features a. Clinically,hypertrophic osteoarthropathypresentswith painfirl swellingof wrists, fingers,ankles,knees,or elbows.The pathogenesisis unknown. b. This is a periosteal inflammation, and new bone forms at the ends of long bones, metacarpals,and metatarsals. c. Arthritis of adjacentjoints is commonly seen,often with digital clubbing. 2. Etiology. Causesinclude intrathoracic carcinoma (a paraneoplasticsyndrome), sepsis, endocarditis,ryanotic congenitalheart disease,and inflammatory bowel disease.The syndrome regresses when the underlying diseaseis treated. H. Fibrous cortical defect (nonossifring fibroma) is a common developmentalabnormality seenin bones of the lower extremitiesin children. They are non-neoplasticlesionsof bone cortex that are composedof fibrous connectivetissue. 1. Clinical features. Fibrous cortical defect is usually asymptomatic,non-neoplastic,and usually resolvesspontaneously. 2. Pathology. There are irregular, well-demarcated,radiolucent defectsin the bony cortex, with an intact subperiostealshell of bone. In the metaphysis,there are whorls of connective tissue.Occasionally,multinucleatedgiant cellsare seen.This entity must be differentiated from giant cell tumors of bone, which may cross the epiphysis (fibrous cortical defectdoesnot do this). The stromal cellsof giant cell tumors are alsomore atypical,with larger,darker nuclei and lesscytoplasmthan seenin fibrous cortical defect. I. Osteomyelitis 1. Pyogenic osteomylitis a. Etiology. Causedby direct innoculation of bone or by seedingof bone after bacteremia. Organisms include Staphylococcusflnreus, Streptococcas, gonococci, and Haemophilusinfluenzae.Salmonellamay be seenin patients with sickle cell disease. Pseudomonas is common in intravenousdrug usersand diabetics.
84
Pathology
b. Clinical features include fever,localized pain, erythema, and swelling. The x-ray may be normal for up to 2 weeks,then may initially show periosteal elevation. c. Pathology. Suppuration begins within the metaphysealmedullary cavity and penetrates the cortex. Compression by exudateleadsto vascular insufficiency and ischemic necrosis.Specific findings include: (1) Sequestrum,a necrotic bone fragment (2) Involucrum, new bone that surrounds the area of inflammation (3) Brodie abscess,localizedabscessformation in the bone 2. Tuberculous osteomyelitis occurs in 1oloof casesof TB, causing caseatinggranulomas in the bones. The term "Pott disease" refers to spinal involvement. L Tumors 1. Osteoblastic tumors a. Osteoma is a benign growth that frequently involves the skull. ( 1) "Hlperostosis frontalis interna" describesan osteomathat extendsinto the orbit or sinuses. (2) Pathologyshowsdensenormal bone. b. Osteoid osteoma is a benign growth of the diaphysisof long bones,often the tibia or femur. (1) Clinical features include pain that is worse at night and relieved by aspirin. X-rays show a central radiolucencysurrounded by a scleroticrim. (2) Pathology shows a l-cm brown nodule surrounded by densesclerotic cortical bone. Microscopically, the nodule is formed of vascular, woven bone with partially mineralized osteoid. c. Osteoblastoma is similar to a large osteoid osteoma,but is large, painless,often involves vertebrae,and may be malignant. d. Osteosarcomais a malignant bone tumor that producesosteoid and bone. (1) Incidence. Men are affected more often than women, and the tumor usually occursin the secondand third decadeof life.It is the most common bone tumor in older people and is often associatedwith Paget'sdisease.Over one-third of patientswith retinoblastomaalso developosteosarcoma. (2) Pathogenesisis unclear.There is an increasedincidencewith irradiation, Paget disease,and other previous bone pathology. (3) Clinical features. Patients present with localized pain and swelling, weight loss, and anemia. Classicx-ray findings include Codman triangle (periostealelevation) and bone destruction. (4) Pathology. Grossly, osteosarcoma,particularly in teenagers,often affects the metaphysealends of long bones, usually around the knee, producing large necrotic and hemorrhagic mass. Microscopically, the tumor may be sclerotic (with mineralizedosteoid) or osteolytic (with little osteoid).It alsomay contain collagen or cartilage. The classicfinding is anaplastic cells with osteoid, pink, amorphous material that is variably mineralized (FiguresI-7-2 andl-7-3). (5) Prognosis is poor. Patients are treated with amputation and chemotherapy. Metastasisto the lungs is common. Prognosisis improved with aggressive management,such as resectingsinglepulmonary metastases.
85
Musculoskeletal System, Connective Tissue, andIntegument
Figure l-7-2.Osteogenicsarcoma(microscopic).
Figure l-7-3.Osteogenic sarcoma with vertebral collapse (gross). 2. Chondromatous tumors a. Osteochondroma is an exostosisthat forms benign metaphysealgrowths. They may be solitary.Lesionsare identical to those in multiple form (osteochondromatosis). b. Enchondroma is a solitary cartilaginous growth within the spongiosa of bone. Solitary growths are similar to those in multiple form (Ollier disease). c. Chondromyxoid fibroma is a benign,rare tumor affectingyoung men. It forms a firm masswithin the metaphysealmarrow cavity of the tibia or femur. The tumor contains fibrous and mlxomatous tissue,which must be differentiatedfrom a malignant lesion. d. Chondrosarcoma is a malignant tumor of chondroblasts.The agerangeis from 30-60 years.Men are more often affectedthan women.
86
Pathology
(1) Etiology. The tumor may arise de novo or secondaryto a pre-existingenchondroma or exostosis.
ln a NuBhell
(2) Clinical features. Chondrosarcomas are slower growing than osteosarcomas. They typically present with pain and swelling.
Osteochondroma Exo$osis frommisdirected growthof growthplate
(3) Pathology. Tumors typically involve the spine, pelvic bones, and upper extremities. Microscopically, they are characterizedby atypical chondrocytes and chondroblasts,often with multiple nuclei in a lacuna. 3. Giant cell tumor is a malignant neoplasm containing multinucleated giant cells and aqrq7ical stromal cells.This is an uncommon tumor, affecting patients from age2G-50 years. a. Clinical features
Enchondroma growthof benign Solitary cartilage inside bone Chondrosarcoma g Malignantcartilage-producin tumor
(1) Tumors presentas a bulky masswith pain and tenderness. (2) X-rays show an expandingareaof radiolucencywithout a scleroticrim. b. Pathology (1) Grossly,tumors arisein the epiphysealregion of long bones,forming a club-like deformity at the end of the bone. (2) Microscopically, multiple giant cells, resembling osteoclastswithin a matrix of fibroblast-like cells with large, atypical nuclei, occur. a. Ewing sarcoma is a malignant neoplasmof undifferentiated cellsarising within the marrow cavity.It is rare, usually affecting adolescents.Men are affectedmore often than women. a. Etiology. The tumor arisesfrom mesenchymalcellsthat havebeen shown to havesome expressionof neural antigens. b. Clinical features are pain, tendernessand early widespread dissemination. c. Pathology (1) Grossly, the tumor commonly affectsthe pelvis and metaphysesof long tubular bones.Cellserodethrough the cortex and invadesurrounding tissues.Half of the caseshave"onion skin" or concentriclayering of new bone. (2) Microscopically, undifferentiated small cells resembling lymphocytes occur. Surfaceantigensmake the diagnosis.
forNTs A. Arthritis 1. Suppurative arthritis a. Pathogenesis. The primary mechanism of suppurative arthritis is hematogenous seedingof joints during bacteremia,which is more common than direct invasion. H. inlluenzae,and GramStreptococcns, Organismsinclude gonococci,Staphylococcus, negativebacilli. b. Clinical features include tender, swollen, and erythematous joints that require rapid intervention to prevent permanent joint damage.
Nole System ic Iupuserythematosus jointpain. typically includes Because it isa multisystemic immune it is disorder, discussed intheClinical lmmunology chapter of Principles BookI Ceneral (Volume l).
87
Musculoskeletal System, Connective Tissue, andlntegument
ln a Nutshell Arthritis Suppurative . Manife$ed bya tender, red, joint "a sruollen (e.g., hot knee"). . Usually monoarticular, high neutrophil count injoint fluid,andoftendueto staph, strep, andgonococci.
Note Tuberculosis ofthespineis called Pott's disease. lt maybe confused withbrucellosis of thespine.
c. Pathology. This disease is usually monoarticular, affecting a large joint. Characteristicsof typical suppurative infection are cloudy synovial fluid with a high neutrophil count that clots readily. If the organism is very virulent or if it is left untreated, the synovium may ulcerate and infection may erode articular cartilage. 2. Tirberculous arthritis a. Incidence.This form occursmore commonly in children. b. Clinical features include an insidious onset and joint destruction. c. Pathology. It occurs most often in the spine and hip. The synovial lining is covered with tuberclesand granulation tissue.Pannusdevelopsover the articular cartilage and may erodeit. Destruction of joint spaceensueswith fibrosis and calcification,eventually leading to ankylosis. 3. Osteoarthritis (degenerativejoint disease) a. Incidence. Osteoarthritis increaseswith age, affecting women more than men. It affects80o/oof people over 70 yearsold in at leastone joint. b. Pathogenesis ( 1) Aging or wear and tear (biomechanical)is the most important mechanism.Also, chondrocyte injury and abnormal collagen activity (biochemical) contribute; usually,both act together. (2) Predisposingfactors include obesity,previous joint injury, and synovial disease. Most retired football players have at least some osteoarthritis in the knees and ankles. c. Clinical features. There is an insidious onset with joint stiffness,decreasedrange of motion, effrrsions,crepitus,and bony swelling.Symptoms of nerve compressionmay developsecondaryto compressionby osteophytes. (1) Heberden nodes (nodules at the base of terminal phalanges)occur more frequently in women. (2) X-ray showsnarrowing of the joint spacedue to loss of cartilageand osteosclerosis.
In a Nutshell 0steoarthritis . Dueto aging orwearand joints. tearon . Erosion ofarticular cartilage leads to boneeburnation andchipping. . X-rays showthelossofjoint space. . Heberden nodes arefound attheDIPjoint.
88
(3) foint fluid showsfew cellsand normal mucin. d. Pathology (1) The most commonly affectedjoints include vertebrae,hips, knees, and distal interphalangeal(DIP) joints of fingers. (2) Ioint mice are flakes of cartilage in the joint spacefrom erosion. (3) Osteophytes and bone spurs develop. Denuded, sclerotic, subchondral bone may becomeexposedin areas(eburnation). 4. Rheumatoid arthritis is a systemic chronic inflammatory diseasecharacterizedby progressivearthritis. There are many clinical variants. a. Incidence. Women are affected three times more frequently than men. There is a familial predisposition,and the diseasecommonly presentsfrom ages2G-60years. b. Pathogenesis involves an autoimmune reaction with the formation of circulating antibodies (rheumatoid factor) against the Fc fragment of autologous IgG, leading to immune complexes.
Pathology
c. Clinical features (1) Symptoms include low-grade fever,malaise,fatigue, and morning stiffness. (2) Physicalexamination showsjoint swelling,redness,and warmth. In late stages, ankylosis may develop. (3) Synovialfluid showsincreasedcells (usually neutrophils) and poor mucin. (4) There is an elevatedsedimentation rate and hlpergammaglobulinemia. The level of rheumatoid factor may correlate with the severity of the arthritis. (5) X-rays show erosionsand osteoporosis. (6) Systemicfeaturesinclude subcutaneousnodules (20o/opatients),Sj6grensFndrome (l5o/o),glaucoma,pericarditis,vasculitis,hepatosplenomegaly, and adenopathy. d. Pathology (1) The diseaseusually starts in the small joints of the hands and feet but may involve any joint. There is usually symmetric involvement. Patients develop a diffirse proliferative synovitis in which the synovium becomes replaced by pannus, a vascularized mass packed with lymphocytes, macrophages, and plasmacells.Pannuserodesarticular surfaces,bone,joint capsule,and ligaments. Adhesions and ankylosis may result. (2) Rheumatoid nodules are composed of proliferative connective tissue with areas of central necrosis. They may be seen in skin, heart valves, lung, pleura, pericardium, and spleen.Skin nodules are usually on extensor surfaces. (3) Arteries may show acute necrotizing vasculitis due to circulating antigenantibody complexes. e. Other types of rheumatoid arthritis (1) Juvenile rheumatoid arthritis (Still disease) has a peak incidence from 1-3 years.Girls are affected more frequently than boys. It is often preceded by acute febrile illness. There is periarticular swelling, lymphadenopathy, hepatosplenomegaly,and absenceof rheumatoid factor. The course is variable and may resolve. (2) Ank/osing spondylitis occurs predominately in young men with HLA-B27.It is also associatedwith inflammatory bowel disease and usually involves the sacroiliacjoints and spine. (3) Arthritis associatedwith ulcerative colitis occurs in 25o/oof patients with ulcerative colitis. It is not progressiveand resolvesspontaneouslyor with treatment of the ulcerative colitis. There is no pannus formation. (4) Psoriatic arthritis has pathology similar to rheumatoid arthritis but an absence of rheumatoid factor. It is also associatedwith HLA-B27. (5) Felty syndrome is a polyarticular rheumatoid arthritis associatedwith splenomegaly,leukopenia, and leg ulcers.Neutropeniais relatedto splenomegaly, antineutrophil antibodies, and bone marrow failure.
Note Ankylosing spondylitis occurs mainly in HLA-B27-positive patients. Notethatpsoriatic arthritis andReiter syndrome arealsomorecommon inthe presence of HLA-827.
5. Gout. In gout, there is hlperuricemia associatedwith recurrent bouts of acute arthritis, resulting from deposition of monosodium urate in joint tissues.
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a. Types (1) In primarygout (90oloof cases),there is an inborn error of purine metabolism. The metabolic defectis usually not known. Specificenzfme defectsaccount for only about l0o/oof cases(e.g.,Lesch-Nyhansyndrome). (2) Secondarygout is hyperuricemia resulting from a disorder unrelated to purine cell breakdown as in leukemia and polycythemia). metabolism (e.g.,excessive b. Incidence. Most casesare in men, but it occasionallyaffectspostmenopausalwomen. It is familial (primary gout) in about 20o/oof cases.
ln a Nutshell Gout . Coutisthedeposition of leading to uratecrystals painful attacks of acute, Thebigtoeis arthritis. affected. classically . Coutmayresult from overproduction or of uricacid. underexcretion . Tophi arepathognomonic. . Uratecrystals areneedleandnegatively shaped birefringent, In a Nutshell Pseudogout . Calcium pyrophosphate deposition Reitersyndrome . Arthritis, uveitis, and conjunctivitis . Possibly dueto Chlamydia
c. Pathogenesisis an overproduction of uric acid (under 10o/o)or underexcretionof uric acid (over 90o/o). d. Clinical features. There is an asymptomatic period of hyperuricemia (>7 mgldl) followed by acute episodesof joint pain and swelling. After approximately 10 years of recurrent attacks, chronic disabilities ensue (i.e., decreasedrange of motion; joint deformities).Uric acid kidney stonesdevelopin up to 25o/oof patients. e. Pathology. Precipitation of urate crystals in joint fluid causes an acute inflammatory synovitis with synovial edema and leukocytic infiltrate. It usually affectsthe joints of the lower extremities,particularly of the large toe. Formation of tophi (urate deposits surrounded by inflammatory cells, including foreign body giant cells) is pathognomonic. Tophi may form in the helix of ear,bursae,ligaments,and kidney. Chronic changesinclude urate deposition along articular surfaces,pannus formation, erosionof cartilageand bone, adhesions,and anlcylosis.Uric acid crystalsarebestpreservedin tissuesamplesby fixing in ethanol rather than formalin. 6. Pseudogout (chondrocalcinosis) is arthritis secondary to deposition of calcium pyrophosphate crystals in joint fluid. It is associatedwith many metabolic diseases(e.g., Wilson disease,hypothyroidism, diabetesmellitus). The crystals are recognizably different from urate on light microscopy. 7. Reiter syndrome is an associationof arthritis, urethritis, conjunctivitis and mucocutaneous lesions, possibly secondary to Chlamydia infection. The relative risk of this syndrome is raisedapproximately40 times by the presenceof HLA-827. B. Tirmors 1. Synoviosarcoma a. Incidence. This is a rare tumor with a peak incidence in early adulthood, affecting boys and girls equally. b. Clinical features. These tumors form slow-growing, painless masses.They are very aggressivewith early metastasesto the lung and pleura. c. Pathology.Two-thirds of synoviosarcomaform in the lower extremitiesand one-third form in the upper extremities. They arise from synovial lining cells of bursae and tendon sheaths.The picture is often biphasic with a spindle cell fibrosarcomaelement enclosingan epitheloid (glandular) component. 2. Matignant fibrous histiocytoma a. Incidence. This is a relatively common soft tissue malignancy, affecting adult men more than women. b. Pathology.Ttrmors arisein soft tissueor bones.They are locatedin the lower extremities more often than in the upper extremities and in the abdominal cavity. Microscopically, tumors are pleomorphic, composedof fibroblasts,histiocytes,and tumor giant cells.
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C. Other lesions 1. Ganglions are small cystsof tendon sheath or joint capsule,often in the wrist. 2. Tenosynovitis is an inflammation of tendon sheaths and tendons, often secondary to excessstressor trauma. Rare forms include suppurative or tuberculous tenosynovitis. 3. Bursitis is an inflammation of the bursa, often causedby excessivestressor trauma and occasionallybacterial invasion. 4. Pigmented villonodular synovitis is a villous proliferation of synovium colored brown by hemosiderin deposition. It is probably a reactive responseto recurrent trauma and possiblya neoplasticprocessthat doesnot metastasize.
SKELETAI MUSCLE PATHOTOGY A. Clinical features. Signsand physical findings of muscle diseaseinclude myotonia (continuous tonic contraction), weakness,muscle atrophy (wasting),fasciculations(twitching), and pseudohypertrophy.The symptoms and history of muscle diseaseinclude various combinations of the following: 1. Tripping, clumsiness(distal weaknessespecially) 2. Difficulty climbing stairs or rising from chairs (proximal weakness) 3. Family history, which includes three common patterns of inheritance: sex-linked (Xlinked) inheritance, autosomal recessiveinheritance, and autosomal dominant inheritance. B. Diagnosis. Laboratory findings that may help differentiate muscle diseasesinclude: 1. Creatine kinase is elevatedin myositis and some dystrophies. 2. The erythrocyte sed.imentation rate (ESR) may be elevated in myositis or any other inflammation. 3. Serum potassium may be abnormal in periodic paralysisand raised wheneverthere is cell necrosis. 4. Pyruvate or lactate may be abnormal in metabolic, particularly mitochondrial, muscle diseases. 5. Urinarymyoglobin is elevatedif there is acute muscle destruction (e.9.,rhabdomyolysis). 6. Electromyography (EMG) and peripheral nerve conduction velocities (NCVs) may help differentiate neurogenic from myopathic disorders;in general,proximal weaknessis often myopathic, while distal weaknessis often neurogenic. 7. Muscle biopsy is often the definitive diagnostic procedure in myopathic disorders. Diagnosisis made by the presenceor absenceof certain histologic featuresor by staining with enzymaticstains. C. Neurogenic muscle atrophy covers a large class of disorders secondary to loss of normal nerve supply; muscle is lost secondarily. 1. Features of denervated muscle include fiber shrinkage and angulation with nuclear pyknosis. 2. Initially, the histologic picture is of scatteredatrophic fibers, but, since a nerve typically supplies many fibers, a picture of group fiber atrophy eventually becomesapparent. 3. Types I and II fibers show atrophy.
9l
System, Tissue, andIntegument Musculoskeletal Connective
4. Intact neighboring axonsmay sprout and reinnervatefibers,which resultsin a singlefiber tfpe, regardlessof the initial fiber rype. This is known as "fiber-type grouping." Fibers becomeheterogeneouslygrouped together accordingto the "fiber tFpe" (white or red) of the innervating neuron. 5. Ultimately, denervatedmuscleis replacedby connectiveand adiposetissue. 6. Polyarteritisnodosa (PAN) may show musclevascularinfiltration and infarction of muscle and nerve; PAN is particularly notorious for causing mononeuritis multiplex by infarction of multiple peripheral nerves,leadingto neurogenicatrophy.
ln a Nutshell gravis Myasthenia isan autoimmune disease inwhich antibodies aremadeagain$ receptors. NMJacetylcholine it presents with Clinically, muscle weakness that worsens withuse.ftosisis commonly seen.
D. Myasthenia gravis typically affectsyoung women. 1. Pathogenesis.This is an autoimmune disorder causedby IgG directed against the acetylcholine (ACh) receptor. 2. Clinical features include fluctuating weakness.This weaknessinvolves muscles supplied by cranial and peripheral nerveswith no sensoryabnormalities,and it is especiallyprofound late in the day. 3. Diagnosis is establishedby a decrementalresponseto repetitiveelectricalstimulation on EMG or by clinical improvement when a cholinesteraseinhibitor (e.g.,edrophonium) is administered.Muscle biopsy shows group atrophy and, occasionally,mononuclear cell infiltrates. Patients may have thymic abnormalities, including thymoma (10-20o/o)or thymic hyperplasia(70-80o/o).In thesepatients,thymectomy is often curative.
E. Myositides include both polymyositis and dermatomyositis.Both polymyositis and der-
In a Nutshell Themyositides aredisorders thatprobably havean autoimmune etiology. Theyarecharacterized by muscle fascicle atrophy, edema, andnecrosis.
matomyositisare classifiedas autoimmune or collagenvasculardiseases. 1. Incidence. Polymyositisis more common in females. 2. Pathogenesis.These disordersare associatedwith autoantibodies,with a cell-mediated immune response,C2 deficienry,and HLA-DR3. 3. Clinical features a. Neck and proximal limb muscleweakness,dysphagiaand musclepain, tendernessand swellingare all common in polymyositis and in dermatomyositis. b. Dusky erythema of the skin with plaquesover the joints or purple discolorationof the eyelids (heliotrope rash) is also a feature of dermatomyositis. c. Adults with dermatomyositisare at increasedrisk of having internal malignancies, particularly stomach,colon, lung, and breast. d. Laboratory studies show elevated creatine kinase and ESR. Creatinuria can result from breakdown of muscleproteins. e. Electromyographicabnormalitiesreflect abnormal muscle function. 4. Pathology. There is variation in fiber size, peripheral atrophy in fascicles,necrosis, myofiber vacuolation,edema,and perivascularmononuclear cell infiltration. Muscular dystrophies are a heterogeneousgroup of disorders that have a common feature of muscledegeneration.Dystrophic musclesare shrunken,flabby,and pale.Microscopically, there may be vacuolization,cytoplasmicfragmentation,hyalinization,and necrosis. 1. Duchenne muscular dystrophy is the most severefype of muscular dystrophy. a. Pathogenesis. This disorder shows X-linked recessive inheritance. The dystrophin protein, encoded on the X chromosome and normally present in muscle cell membranes,is usually absent. b. Clinical features
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Pathology
( 1) Elevation of creatinekinase and histologic degenerationprecedesclinical features. (2) The classicpresentation is with pelvic girdle weaknessand ataxia. The course is progressive,and children are unable to walk by the ageof 10. (3) Pseudohypertrophy of the calves is characteristic. (4) Myocardial muscle involvement accompaniesother muscle degenerationand may causedeath. (5) Mental retardation is also an associatedfeature.
ClinicalCorrelate Calfpseudohypertrophy (replacement of muscle tissue withadipose andfibrous tissue) ischaracteristic of Duchenne muscular dystrophy.
c. Diagnosis (1) Muscle biopsy revealsfiber degenerationwith connectivetissueproliferation and myophagocytosis;eventually,muscle is replacedby connectivetissueand fat. (2) DNA testsare availablefor the detection of mutations in the dystrophin gene. (3) Heterozygousfemale carriers may have elevatedcreatinekinase and subclinical degeneration,which is detectedby biopsy. 2 . Becker muscular dystrophy a. Pathogenesis.This diseaseshowsboth X-linked recessiveinheritanceor spontaneous mutations in the samegeneas Duchenne dystrophy. b. Clinical features. Patients may walk until age 20 or 25. Cardiac lesions are mild or absent. c. Diagnosis. Creatinekinase is elevated.Muscle biopsy changesare similar to those in Duchenne'sbut lesssevere.
Note Becker muscular dystrophy is essentially a lesssevere form ofDuchenne. InBecker, present dystrophin isusually butisofabnormal size.
3 . Facioscapulohumeral muscular dystrophy (FMD) a. Pathogenesis.Inheritance is autosomal dominant, but spontaneous mutation is common. b. Clinical features. Presenting symptoms usually involve the face, neck, and shoulder muscles.Pelvicmusclesmay be involved at later stages. c. Diagnosis. Muscle biopsy revealsdegenerativechangeswith fibrosis and inflammatory cell infiltration. 4. Limb-girdle muscular dystrophy (tGD) a. Pathogenesis.Inheritance is autosomalrecessive. b. Clinical features. Weaknessbegins in either the pelvic or shoulder girdle and spreads to involve other muscles.Affected individuals may retain ambulation for 25 years or more. c. Diagnosis. Muscle biopsy revealsstriking myofiber size variation with atrophy and hypertrophy. 5 . Myotonic dystrophy a. Pathogenesis.This disorder ariseswith an autosomal dominant pattern or through spontaneousmutations. The geneticdefect for myotonic dystrophy is a trinucleotide repeatin a protein kinaseencodedon chromosome 19. b. Clinical features.It is clinically unique from other dystrophies.Characteristicsinclude weakness,atrophy, and myotonia (tonic contraction of an affectedmuscle with inability to voluntarily relax it). Head and neck musclesare frequently weak and atrophic,
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Tissue, andIntegument Musculoskeletal System, Connective
while limb involvementis usually distal (handsand feet). Patientsmay havecardiac arrhythmias,cataracts,ftontal baldnes, hlryogonadism,and idiosyncraticreactionsin anesthesia. Muscleenzymesand biopsiesmaybe normal. c. CharacteristicpathologicEndingson light microscopy(ring fibers and sarcoplasmic masses)distinguishthis syndrorneftom other forms of musculardystrophy. Bridge-!o Biochemktry glycogen storage Certain diseases affectthe muscular svstem because the accumulation of glycogen impedes normalcellular processes.
enzfmes that result in G. Glycogenosesare diseasescausedby defectsin glycogen-cleaving glycogenaccumulationin varioustissues,including rnuscle, t ' Tlpe II (Pornpedisease) a. Pathogenesis,This diseaseis due to acid maltasedeficiency (a-1,4-glucosidase). Glycogenaccumulatesin the brain, liver, and muscles(including the heart). b. Clinical features include h€patom€galy,cardiomegaly,macroglossia,weakness,and h ?otonia. Presentationis within 3 months of birth, and deathoccursby 8 months. Serumlipid, glucose,and ketonesare normal. An adult form exists,which is milder and presentsasweaknesswithout organomegaly. c. Diagnosisis madeby enzymaticassayof acid maltasein leukocytesor fibroblasts. 2. TypeIII (Cori disease;limit dentrinosis) a. Pathogenesis. This diseaseis dueto a deficiencyin a debranchingenzyme(amylo-1,5glucosidase) . b. Clinical features.Hepatomegalyand growth failure are early features.Theremay be fastinghypoglycemia,ketosis,and elevatedlipids. c. Tleatment. Responseto glucagonor epinephrineis blunted becauseof inability to cleaveglycogenpastbranchingpoints. 3. Type IV (Andersendisease)
ln a Nutshell andexercise Muscle weakness tmoterance arecommon features of $ycogenstorage mvooathies.
a. Pathogenesis.This diseaseis dueto a deficiencyof the branchingenzymeinvolvedin glycogensynthesis. b. Pathology.A polysaccharidesimilar to amylopectinaccumulatesin th€ h€art, liv€r, muscle,and brain. Hepatomegalyis followedby cirrhosisand liver failure. 4. Tlpe V (McArdle disease) a. Pathogenesis,This diseaseis dueto myophosphorylase deficiency.Glycogenaccumulatesin vesicleswithin muscles. b. Clinical features.Muscle cramping and myoglobinuria are usual.There is no lactic acidosisduring exercise,and the glucagonresponseis normal. 5. TypeVII is due to phosphofructokinasedeficiencyand is clinically similar to McArdle disease. H. Congenital nyopathies typically presentearly in life. Clinical featuresinclude hypotonia and slowly progressiveweakness.They may be distinguishedprimarily by histopathologic features. l. In central core disease,denseryIindrical coresextendttle entire length of the fibers. 2. In nemaline myopathy, nemalinebodiesappearto be derivedfrom Z discsand possess crossstriations. 3. Centronuclearmyopathy (myotubular myopathy)usuallyinvolvesfacial and extraocular muscles.Onset may be in infancy, adolescence,or adulthood. The syndrome is
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Pathology
geneticallyheterogeneous.Nuclei are characteristicallylocated in a central chain, surrounded by vacuoles. I. Werdnig-Hoffrnann disease is not a myopathy but an autosomal recessivedegeneration of the brain stem and spinal cord motor neurons. 1. Clinical features. It may present as neonatal hlpotonia (floppy baby) or decreased intrauterine fetal movement. Intercostal weaknessis frequent. 2. Complications. Respiratorycomplicationsare the usual causeof death. 3. Pathology.There is neuronal loss in anterior horns of the spinal cord as well as the cranial nerve nuclei.
ClinicalCorrelate Werdnig-Hoffman disease is "floppy known as baby syndrome" dueto thelossof neurons innervating both bodily andfacial muscles.
L Myositis ossificanscausesossificationat the site of traumatic hemorrhage.It presentswith pain, swelling,and tenderness.Differentiation from neoplasmscan be made by biopsy. K. Desmoid tumor (aggressivefibromatosis) is an infiltrative, fibrous proliferation, arising from the aponeurosesof skeletalmuscle.They are histologicallybenign and do not metastasizebut can becomelarge,locally invasivemasses.They frequently occur in young women, often in the abdominal wall. There is a possibleassociationwith multiple pregnanciesand previous trauma. Differentiation from sarcomasis made histologicully by the absenceof atypical cells. L. Rhabdomyosarcoma is a malignant neoplasm arising from striated muscle. It is the most common soft tissuesarcomain children. Prognosisdependson the site of origin. Up to 40olo have metastasesat the time of diagnosis. 1. Embryonal rhabdomyosarcoma a. In infanry or childhood, it is most often located in head and neck tissuesand is less aggressive than other forms. b. Sarcoma botryoids is an embryonal rhabdomyosarcoma with a grape-like, soft, polypoid gross appearance.It is usually located in the genitourinary, upper respiratory,or biliary tract. It is extremelyaggressive. M.Skeletal muscle abnormalities in AIDS
Bridgeto Reproductive Sarcoma botryoids is discussed inthe Reproductive Pathology chapter inthisvolume.
1. Incidence. Up to 50oloof HlV-positive individuals have some form of muscular abnormality. 2. The most common fiodirg is similar to polymyositis (i.e., inflammatory infiltrates with macrophagesand muscle fibers showing coagulativeor segmentalnecrosis).The muscle is not directly HlV-positive. Clinically, the picture is also similar to non-HlV-related polymyositis with weakness(primarily proximal in distribution) and EMG and laboratory findings typical of myopathy (increasedserum creatinekinase). 3. Nemaline rod myopathy with atrophy of tfpe I fibers is similar to congenital nemaline myopathy. Weaknessis predominantly proximal in distribution, and the EMG is myopathic. 4. Zidovudine (AZT)-induced myopathy is characterizedby multinucleated cells associated with myositis and by focal infection.
In a Nusthell A myositis-like syndrome may occurinAIDS asa result of infection orAZTtreatment.
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Musculoskeletal System, Connective Tissue, andlntegument
SKIN Note presents Scleroderma withsclerosis oftheskin. in detailin It isdiscussed theClinical lmmunology section of Ceneral Principles l). Bookt 0/olume
A. Epidermal lesions 1. Seborrheickeratoses are benign neoplasms that usually arise in areasexposedto the sun. They are very common in late adulthood. a. Clinical features. Although they are usually left untreated, they may be removed if they become irritated, or for cosmetic purposes.Sudden development of multiple lesionsmay follow an inflammatory dermatitis,hormonal therapy,or may accompany an underlying malignanry. b. Pathology (1) Grossly, lesionsare typically located on the face,back, or trunk. They are typically brown to gray scaly, and greasy. (2) Microscopically, seborrheic keratosis is a squamoproliferative disorder characterized by hyperkeratosis, papillary epidermal hyperplasia, and occasionally, developmentof pseudo horn cysts (epidermal pseudorystsfilled with keratin). Theseare invaginationscreatedbetweenthe papillae of keratin-producing cells.
ln a Nutshell Seborrheic keratoses aregray, greasy scaly, lesions with hyperkeratosis, epidermal papillary hyperplasia, and pseudocyst keratin occasional formation. Theyarebenign.
2. Keratoacanthoma is also a benign squamouslesion, arising in sun-exposedareas.It is most common in middle age. a. Clinical features. Keratoacanthoma is a rapidly growing papule that must be distinguishedfrom squamouscell carcinoma. b. Pathology (1) Grossly, lesions are located on the head and arms. They start as a round pink papule that grows within weeksup to 2 cm with a central depressionfilled with keratin. (2) Microscopically, the squamous cells are well organized and not anaplastic, although mitosesare presentduring the rapid growth phase.A key featureof this neoplasm is a lip of normal, nondysplastic epidermis on both sides of the keratin-filled crater.Keratoacanthomasare said to be composedof large squamous cells with a hyaline, "ground-glass" cytoplasm.
ClinicalCorrelate Skintagsarenormalfindings high onmostpeople; numbers ofthemmay indicate diabetes.
3. Fibroepithelial polyps are benign. Also known as skin tags, theselesions are common in middle agebut may also develop during pregnancy.They are also associatedwith diabetes or intestinal polyposis.They usuallyoccur in intertriginous regionsand on the neck.Skin tagsare composedof benign squamousepithelium covering a fibrovascularcore. 4. Basal cell carcinoma is invasive,but it rarely metastasizes. a. Incidence. It is most common in middle-aged or elderly individuals and those who havefair complexions.They occur on sun-exposedareas. b. Clinical features. Basal cell carcinomas are locally aggressiveand rarely metastasize. Completeexcisionis usuallycurative,but there is approximatelya50o/orecurrencerate from shavebiopsies. c. Pathology (1) Grossly,basalcell carcinomalesionsare locatedon sun-exposedregionsor areas containing pilosebaceousfollicles. Most lesions are on the face.They form pearly grey papuleswith heapedup borders and a central depression(Figure I-7-4).
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Pathology
Figure l-7-4.Basal cell carcinoma (gross).
ln a Nutshell
(2) Microscopically, there are nestsof tumor cellssurrounded by a fibrous stroma. Pallisadingof tumor cellsand retraction from the stroma at the edgesof nestsis a particularly useful microscopiccharacteristic(Figure I-7-5). 5 . Actinic keratosesare premalignant and may developinto squamouscell carcinoma. a. Incidence is highest in fair-skinned people of middle age.It is associatedwith chronic sun exposure.
,."w {:'. *,#;
Basal CellCarcinoma . Dueto sunexposure . Mostcommonly on occur theface . Raremetastases . Nests of tumorcellsin desmoplastic tissue . Pallisading is ofcells characteristic
,i&, b:t V.*
'#
;fi.fu{";i
Figure l-7-5.Basal cell carcinoma (microscopic).
b. Pathology (1) Grossly, there are rough, crusty,red papulesup to 1 cm in diameter.
97
Musculoskeletal System, Connective Tissue,andlntegument
(2) Microscopically, there are focal regions of atypical epidermis cells that do not invadethe basementmembrane and do not occupy the full thicknessof the epidermis. Disruption of the granular layer and formation of parakeratosisare common. 6 . Squamous cell carcinoma is a malignant tumor that is also found most frequently in sun-exposed areas. a. Incidence. The tumor peaksat 60 yearsof agewith a preponderanceamong women. b. Etiology. Chronic sun exposure and fair complexion are the greatestrisk factors. Chronic skin ulcers or sinus tracts, longterm exposureto hydrocarbons,burns, and radiation also contribute to risk. Papilloma virusesare associatedwith squamouscell carcinomasof the anogenitalregion.
In a Nutshell Squamous cellcarcinoma arises in sun-exposed areas, skinulcers, sinus tracts, or theanogenital region. Crossly, squamous cell carcinoma mayappear in manyforms. "squamous Microscopically, pearls" (formed byatypical keratinocytes) helpmake thediagnosis.
c. Clinical features.When squamouscarcinomaoccurson sun-exposedregions,it rarely metastasizes. When it occurson nonexposedskin, up to 50olometastasize, indicating a fundamentally different biology in the two systems. d. Pathology (1) Grossly, the appearanceis variable, depending on location and invasiveness. Squamouscarcinomasmay be firm, erythematous,scalynodules or oozing ulcers with raisedborders. On mucosal surfaces,th.y may be associatedwith leukoplakia (white plaques),madewhite by the keratin produced (FigureI-7-6).
Figure l-7-6.Squamous cell carcinoma (gross).
( 2 ) Microscopic findings include atypical cells restricted to the epidermis (Bowen diseaseor squamouscell carcinoma in situ) and atypical keratinocytesinvading the dermis (invasivecancer).Arypical keratinocytesmay form squamouspearls, i.e.,laminatedsquamouscellswith central keratinization in an "onion skin" configuration (Figure l-7 -7).
98
Pathology
#
,W 'uffi
*.#i!:: ,*' t
,ii"' '4i..*
ffiW,: 3
Mna;:.:
squamous cell carcinoma Figure a-7-7.Well-differentiated with keratin pearls (microscopic).
ln a Nutshell B. Dermal lesions l. Xanthomas a. Incidence. Xanthomas may be idiopathic, or they may be associatedwith hyperlipidemia or malignancies.
arecollections Xanthomas histiorytes of lipid-laden andareoftenassociated withhyperlipidemia.
b. Pathology.They areyellownodules, composedof foamy histiocyteswith eosinophilic cytoplasm.The cellscontain cholesterol,triglycerides,and phospholipids. 2. Capillary hemangiomas (strawberry hemangiomas) a. Clinical features. These lesions usually arise within the first weeks of life and usually resolvespontaneously,starting at 1-3 yearsof age;most are completelygone by age5. b. Pathology.Capillary hemangiomasform a soft, red,lobulated mass,l-6 cm in diameter,composedof thick-walled capillaries. 3. Nevus flammeus (port wine stain) is a common congenitallesion, composedof telangUsuallylocatedon the neck or face,it appearsasa large,flat, irregular pink iectaticvessels. patch that tends to resolvespontaneously. 4. Kaposi sarcomais a malignant mesenchymaltumor (an angiosarcoma),characterizedby an aggressivecoursein patientswith AIDS and by a slower coursein elderly men. C. Pigmentary disorders
ln a Nutshell isan Kaposi sarcoma foundonskin angiosarcoma lt is membranes. andmucous withAIDS and associated herpesvirus caused byhuman typeB (HHVB).
l. Frecklesare areasof increasedmelanin depositionin the basalcell layer of the epidermis. 2. Vitiligo is irregular, completely depigmented patches. a. Incidence is common and may affect any race.Risk is increasedwith a positive family history. b. Etiology is unknown, but it is possiblyautoimmune or relatedto stress. c. Pathology. Microscopically, the skin is devoid of melanocftes in affectedareas.
ln a Nutshell by ischaracterized Vitiligo patchy depigmentation irregular origin dueto ofunknown mela nocyte deficiency.
3. Melasma is irregular patches of hyperpigmentation on the face. It most commonly appearsduring pregnancyand doesnot completelyregress.
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Musculoskeletal System, Connective Tissue, andIntegument
D. Melanocfte tumors l. Nevocellular nevus is a benign tumor of nevus cells and melanocftes. a. Typesof common nevi include junctional, compound, and intradermal.Although the different types may have distinguishing clinical features, histologic examination is neededfor accuratediagnosis. (1) Junctional nevi are recognizedhistologicallyby the presenceof nestsand individual nevus cellsin the lower epidermis, closeto the dermal-epidermal junction. (2) Compound nevi haveboth epidermal and dermal components. (3) Dermal nevi are characterizedby the presenceof mature nevus cellswithin the dermis. In time, the nevus cellsare surrounded by densefibrosis and mav eventually regressaltogether. b. Clinical features (1) The relationship between nevi and melanoma is largely unknown except that both are clearly relatedto sun exposure.Although malignant transformation of nevi is not common, approximately 30o/oof casesof melanoma are associated with nevi. There is also increasedincidence of melanoma associatedwith eiant congenitalpigmented nevi. (2) In most cases,one can distinguish a benign nevus from melanoma on clinical grounds (i.e., colot contour). A nevus is tan to brown and has sharp,well-circumscribedborders.Color is usually uniform, and the lesionsare stablein shape and size. 2. Lentigo maligna (Hutchinson freckle) a. This is a premalignant lesion,occurring on sun-exposedsurfacesin the elderly. b. It is characterizedbyintraepidermalproliferation of atypical melanocytes.Up to 50% progressto invasivemelanoma over the courseof severalyears.
Note Melanomas tendto grow horizontally before spreading vertically. Prognosis relates to depthof invasion.
3. Malignant melanoma a. Incidence. Melanoma peaksby ages40-60. b. Pathology (FiguresI-7-8 and I-7-9) ( 1) tentigo maligna melanoma arisesfrom lentigo maligna with a peak incidenceat age70.It grows horizontally first (radial growth), followed by vertical dermal invasion (nodular growth) and forms a large brown-black patch with an irregular border up to 6 cm in diameter, usually on the face or neck. Small, raised lesions within the patch represent regions of dermal invasion. This form of melanoma has the best prognosis. (2) Superficial spreading melanoma shows extensive horizontal growth with the radiating cells more atypical than those of lentigo maligna. The tumors may form a plaque up to 3 cm with varied coloration and irregular borders.Lesions are most commonly on legs,chest,and back; peak incidenceis by age60.
r00
Pathology
'ffi,!jq'
Figure l-7-8.Melanoma (gross).
Figure l-7-9.Melanoma (microscopic). (3) Nodular melanoma showsextensivedermal invasion and rapid growth. Raised brown-black lesionsmay be found anywhereon the skin or mucosa.Peakincidenceis by age50 and has the worst prognosisof the melanomas. c. Diagnosis. Stagingis by depth of invasion, through the layersof the epidermis and for dermis. Five-yearsurvival ratesrange from 10% for the deepestinvasion to 100o/o the most superficialinvasion.There seemsto be a prognostic cut off at a total thicknessof 0.7 mm. Greaterthan 0.7 mm causesa greaterlikelihood of metastasis.
t0l
Musculoskeletal System, Connective Tissue, andIntegument
d. Treatment is complete excision. Systemic diseaseis treated with chemotherapy or immunotherapy with poor but variable results. Some metastic melanomas resolve spontaneously,and some relapse as internal metastasesmore than a decade after a seeming"cure." E. Primary bullous disease 1. Bullous pemphigoid a. Incidence. This disorder is uncommon; however,it occurs more frequently than other primary bullous diseaseand tends to occur after age60.
ln a Nutshell . Bullous pemphigoid is caused byautoantibodies to ju dermoepidermal nction antigens. . Pemphigus vulgaris isdue to autoantibodies to keratinocyte intercellu lar junction antigens. . Dermatitis herpetiformis isa pruritic vesicular, disease oftenassociated withceliac sprue. lgAisfoundatthe junction. dermoepidermal
b. Clinical features. Bullous pemphigoid causeslarge, tense,pruritic bullae, usually on the lower abdomen, groin, inner thighs, and mouth. Most patients have circulating autoantibodies against the dermoepidermal junction. The diseasefollows a chronic relapsingcourseand is self-limited. c. Pathology. Subepidermalbullae and a linear deposition of IgG and complement at the dermoepidermaljunction on immunofluorescenceis seen. 2. Pemphigus vulgaris a. Incidence is most common from ages40-60. b. Pathogenesis. Autoantibodies against the intercellular junctions between keratinocytes causeacantholysis.The loss of intercellular connections causesan altered cell configuration. c. Clinical features (1) Pemphigus starts with small vesicles,usually on the oral or nasal mucosa, then spreadsto other parts of the body. Bullae are delicateand flaccid. (2) Nikoltky tigt is the development of bullae, causedby rubbing the skin with a finger. Pemphigus may result in erosions;secondaryinfections may lead to 40olo mortdity. Lesions are treated with corticosteroids. d. Pathology.Intraepidermalbullae, acantholysis,intraepidermal IgG, and complement deposition occur. F. Dermatitis herpetiformis 1. Incidence is most common from ages25-30 and is often associatedwith gluten-sensitive enteropathy and specific human HLA haplotypes. 2. Pathogenesis.IgA antibodyis found at the dermoepidermal junction, specifically at the dermal papillaeand in the upper dermis. Somepatientshavecirculating IgA-gluten complexes,which may be trapped in the skin. 3. Clinical features. There is a symmetrical distribution of grouped vesicles,often overlying an urticarial lesion.Vesiclesare intenselypruritic. Patientsexperiencea relapsingcourse. 4. Pathology. Subepidermalbullae and a granular deposition of IgA and complement at the dermoepidermaljunction occur. G. Infectious diseases 1. Impetigo is a superficial skin infection, usually causedby group A p-hemolytic streptococci or staphylococci. It is characterizedby eroded pustules, coveredby honey-colored crusts.Impetigo may lead to poststreptococcalglomerulonephritis.
t02
Pathology
2. Molluscum contagiosumis a poxvirus infection,causingdevelopmentof multiple small, in which viral firm, umbilicated papuleswith a characteristicmicroscopicaPPearance clusterscauseeosinophilicinclusionsin keratinocfes. 3. Verrucre.Wartsarecausedby papillomaviruses,which causeepidermalhlperplasiain a characteristicpapillary configurationwith hlperkeratosisand parakeratosis. 4. Superffcial fungal infections rnay be caused by Trichophyton,Microsporum, and Malassezia-lnfeaionis limited to the cornified layerof the epidermis. a. Tines capitis ("cradlecap") affectsthe scalpin children. b. Tinea corporis infeststhe trunl and extremitiesof children. It usually presentsas expandinground lesionswith erythematouscircinateborders.
Noh Tineacoroorisis alsoknown astingworm',andis actually a tunSalinfeclion.
c. Tineavesicolor causeshlao- or hyperpigmentedgroupsof macules' 'athlete'sfoot." d. Tinea pedis causes 'jock itch." e. Tinea cruris causes f. Tineaunguium (onychomycosis)causesthickeningand discolorationof the nail bed. 5. Scaldedskin syndrome is a pediatric condition causedby an exfoliativetoxin produced by S.aureus.The toxin splitsthe epidermisat the level of the stratum granulosum,causing a global denudationof the skin. H. Hnrersensitivity reactions 1. Urticaria, or hives,are usuallytransient,raised,pruritic, pinl wheals,charact€rizedby dermaledema. 2. Rrzena is a classof very common pruritic skin disorders,characterizedby distinctive clinical and pathologicfeatures. a. Clinical forms ( 1) Atopic dermatitis is of variableand often unknown etiology;usually,there is a family history of atopy (allergy). (2) Contact dermatitis may resultftom allergicor irritant exposure. (3) Lichen simplex chronicus causeschronic, lichenified plaques,probably caused by rubbing. (4) Polymorphouslight eruption is seenafter ultraviolet light exposure. (5) Drug reactions resolvewhent}re offendingdrug is discontinued. (6) Edoliative dermatitis describesscalingand erythemaof the entle skin' b. Pathologictypes ( 1) Acutee€zema(i.e.,contactdermatitis)describesedematous,oozing,red plaques, often witl vesiclesand dermalinflammation. with moist, red (2) Subacuteeczema(i.e.,childhood atopic dermatitis)is associated papulesand plaqueswith epidermalhyperplasiaand derrnalinflammation' (3) Chronic eczema.Dry, scalyplaquesarepresentfor months.Lichenificationcausesaccentuatedskin creasesand thickenedskin. c. Tleatment. Moisturizerscan be usedto control the itching; oral antihistaminesand topical steroidsmay alsobe used.
t05
Musculoskeletal System, Connective Tissue, andIntegument
3. Erythema rnultiforrne a. Pathogenesis.This may be a hnrersensitivityresponseto drugs (e.g.,sulfonamides, penicillins), infections (e.g., herpes, mycoplasma),collagen vascular diseases,or malignancies. In a llubhell Erythema muhiforme isa hypersensitivity reaclion to drugs.StevensJohnson syndrome isthesevere form
b. clinical features.Erythema multiforme is uncommon. There is often symmetrical involvementof the lirnbs' ( l ) In the minor form, tlere arefew lesions,no s),st€micsymptoms;and the disease is selflirnited. (2) In the major form (st€vels-Johnson syndrorne), there is fever, r€spiratory difficulty, widespreadskin involvement(including mucousmembranes),a high risk of sepsis,and a risk of fatality. c. Pathology.A largeerythematouspapulethat dwelops centralvesiculation;erosionis classic.ksions are alsocharacterizedbv edemaand inflammatorv infiltration. I. Psoriasis I . Incidence.One percentof the population of the United Statesis affected.The peakincidenceis 30 yearsof age,and the most commonform is psoriasisvulgaris.
!1 I Nubhell psoriasis . A silveryscalyplaquethat primarily affecbknees , elbows, andthescalp. . Hinologically, it is characterized byepidermal hyperplasia andhyperkeratinization
2. Pathogeresis. The etiology is urrknown, but there is a clear genetic component. Precipitantsincludehormonal changes,infection, andtrauma.Psoriasismayalsobe associatedwith arthritis, enteropathy,and myopathy. 3' clinical featuresof psoriasisvulgaris a. ksions are locatedthroughout the body, especiallyon the nails, knees,elbows,and scalp'They usuallydo not involvemucousmembranesb. lesions arewell-demarcated,coral-coloredplaqueswith white or silver scale. c. The Auspitz sign is seenwhen removalof scaleresultsin pinpoint areasof bleeding. This is characteristicof psoriasis. 4. pathologic featuresofpsoriasis vulgaris a. Hlperkeratinization with parakeratosisappearsin a patc\ distribution. b. Epidermalhyperplasiacausesthickeningand lengtheningofthe reteridges,usuallyto a uniform depth. c. Thinning ofthe surfaceepidermis,particularly overthe dermalpapillae,is characteristic. 5. Treatmentis usuallywith topical steroids and ultraviolet irradiatioL Severe,systemic diseasemaybe treatedwith methotrexate. I. Inflammatorvdisorders l. Acne vulgaris causescomedones,papules,and c)'sts.It may be related to hormones, drugs,diet, irritants, and geneticfactors.An all€rgyto Propionbacteriumacnesis clearly involved. 2' Pitl'riasis rosea a. Incidence.This disorderis common,from ages1G.-40. b. Pathogenesis,Thereis a possibleviral etiology.
t04
Pathology
c. Clinical features. Pityriasis rosea presents first with a "Herald patch," an approximately 4-cm, red, scalingpatch, followed within daysby eruption in "turtle neck-short sleeve"distribution. Lesions are small, pink, oval patchesalong flexural lines (fir tree pattern), appearingin crops.The diseaseis usually self-limited (1-4 months). 3. Rosacea a. Incidence. Rosaceais common from ages30-50. Women are affectedthree times more commonly than men, but the syndrome is more severein men. b. Clinical features. The lesions affect the central face. Erythema and telangiectasias, acneform lesions (i.e., papules, rysts, pustules), and rhinophyma (teleangiectasias and hyperplasiaof nasalsoft tissue) are all seenin various combinations,sometimes causing a severedistortion of the face,particularly the nose.
r05
Musculoskeletal, Tissu€, Connective andlntegument Pharmacology Thenonsteroidal groupof analgesig antipyretic, andanti-inflammatory drugs area heterogeneous organic acids, theprototype being aspirin. Allaspirin-like drugs share certain therapeutic actions and sideeffects, buttherearesomedistinct intheiractivities. differences These drugs aremildanalgesis painof low-to-moderate particularly thatareeffective against intensity, in association with inflammation. Theyareusedclinically asanti-inflammatory inthetreatment agents of rheumatic disorders andgout. fromaninflammatory Coutresults response to thedeposition of sodium uratecrystals inthejoints andperiarticular tissues. Drugs usedinthetreatment of goutactto inhibit synthesis of uricacid, granulocyte increase theurinary excretion of uricacid,inhibit chemotaxis to theinflammatory site,or relieve symptoms of painandinflammation.
SALICYTATES A. Aspirin (acerylsalicylic acid) 1. Pharmacologic properties
Nole Phospholipids I PhosPholiPase Cortico$eroido I
'& Y
a. Pharmacokinetics. Oral preparations are absorbed rapidly in the stomach and small intestine. The half-life of aspirin is approximately 3 hours. b. Metabolism. Aspirin is hydrolyzed to salicylic acid, which binds tightly to plasma proteins. Seventy-fivepercent undergoeshepatic conjugation with glycine. c. Preparations. Aspirin is available in buffered effervescentpreparations, enteric-coated preparations,and rectal suppositories. d. Action. Aspirin relievespain of low intensity (..g., headache,myalgias,arthralgias)by both peripheral and central effects.Unlike opioids, no tolerance or addiction develops. It lowers elevatedbody temperature by inhibition of pyrogen-induced prostaglandin biosynthesisin the CNS. It inhibits the inflammatory responseby blocking the action of cyclooxygenase (COX) and inhibiting prostaglandin synthesis.Aspirin also prolongs bleeding time as a result of altered platelet ryclooxygenasefunction and inhibition of thromboxane production. 2. Indications for use a. Aspirin is used for both rheumatoid arthritis and osteoarthritis. b. Aspirin suppressesthe acute inflammatory processof acute rheumatic fever but has no effect on diseaseprogression.
Arachidonic Acid
NSAtDso i--1
\
/ Cyclooxygenases \ Lipory/ COX-IandC0X-2\ genases
ll
|
/
\\
\lZilenton o
o I le coxibs steroidsr/ ,^glr l
TXA2' / Pro$aglandins Leukotrienes by ReceptorsO -lukasls
Note Therearetwotypesof COX. COX-Iisexpressed in most tissues; C0X-2isexpressed at thesitesof inflammation.
c. Aspirin is used as an analgesicfor headache,arthritis, dysmenorrhea,neuralgia,and myalgia. It is not as effective as narcotic analgesics.
t07
Tissue, Musculoskeletal System, Connective andIntegument
d. Aspirin is indicated for the reduction of fever (antipyresis). e. Aspirin is given to patients after myocardial infarctions and transient ischemic attacks (TIAs) to reducethe risk of reinfarction and stroke. It is also used in some patients for prophylaxis of thrombosis.
Bridge to Biochemistry Acutetoxicityof aspirinresults in uncoupling theelectron fromoxidative transport chain phosphorylation.
3. Side effects and toxicity a. Gastrointestinal effects include gastritis with epigastric distress, nausea,vomiting, abdominal pain, and acute and chronic blood loss secondary to gastric mucosal erosion.Gastrointestinaleffectsare secondaryto a decreasein prostaglandins,which protect the gastrointestinalmucosaand decreasegastric acid production. b. Hypersensitivity syndrome may result in urticaria, rhinitis, or asthma (seenin patients with nasal polyposis). c. Reversiblehepatotoxicity is associatedwith large dosesin juvenile rheumatic diseases and SLE. d. Hemorrhage occurs secondaryto alteredplatelet aggregation.
Note Platelets areirreversibly (other byaspirin inhibited The NSAIDs arereversible). anticoagulant effects ofaspirin arethuslonger lasting. ClinicalCorrelate Aspirin notbe should administered to children and withviral adolescents (because illnesses of therisk of Reye syndrome),
e. Salicylism (i.e., mild chronic intoxication) includes headache,dizziness,tinnitus, hearing loss,drowsiness,nausea,vomiting, and diarrhea. f. Acute salirylate poisoning causeshlperthermia, dehydration, acid-basedisturbances, ketosis,hypokalemia,and acutenoncardiogenicpulmonary edema. g. Aspirin may precipitate renal insufficienry, although this effect is rare. 4. Drug interactions. Aspirin increasesthe bleeding tendency with warfarin and heparin; increasesthe salicylate effect seen with acetazolamideand cimetidine; increaseshypoglycemiawith insulin and sulfonylureas;increasesvalproic acid's effect; and blocks the uricosuric effect of probenecid. B. Diflunisal l. Pharmacologic properties. Diflunisal is a fluorinated derivative of salirylate, although it is not hydrolyzed to salicylate in vivo. Like aspirin, it inhibits cycloorygenaseand has effectssimilar to salirylic acid,but it is much more potent. Its half-life is 8-12 hours. 2. Indications for use.This analgesicis used for mild-to-moderate pain, including musculoskeletalpain and osteoarthritis,especiallywhen antipyrexiais not desired.
Note Diflunisal hasessentially no antipyretic effect sinceit does notentertheCNS.
3. Side effects and toxicity a. Gastrointestinaleffectsinclude nausea,dyspepsia,gastrointestinalbleeding,and diarrhea.Theseeffectsare lessintensethan with aspirin. insomnia,headache,and fatigue. b. Other effectsmay include dizziness,vertigo,neryousness, 4. Drug interactions include an increasedbleeding tendencywith alcohol,warfarin, and heparin. Decreaseddiuretic and antihypertensiveeffectsoccur with thiazides and frrosemide, and an increasedeffect occurswith lithium toxicity. C. Nonacetylated salicylate derivatives, like aspirin, are indicated for the treatment of pain, inflammation, headaches,and fever. 1. Sodium salicylate is probably lesseffective than aspirin. 2. Choline magnesium trisalicylate is a combination of choline salirylate and magnesium salirylate. It may have fewer gastrointestinal side effectsthan other salirylates.It is useful in patients intolerant of aspirin or other nonsteroidal anti-inflammatory agents (NSAIDS).
r08
Pharmacology
3. Salsalateis convertedto salirylic acid, an activemetabolite.Salsalatemay havean advantage over aspirin in that it causeslessgastrointestinalblood loss. D. Selective COX-2 inhibitors: cele- and rofecoxib. The primary difFerencewith NSAIDs are that they causelessgastrointestinalirritation and havelessplateletanti-aggregantproperties. But they increasePT when usedwith warfarin.
ACETIC ACIDDERIVATIVES A. Indomethacin 1. Pharmacologic properties a. Pharmacokinetics.Indomethacinis rapidly absorbedby the gastrointestinaltract following oral administration and reachesa peak plasma concentration in 2-3 hours. It is 90oloplasmaprotein-bound.
ClinicalCorrelate Indomethacin isthe drugof choice for closing a patent ductus arteriosus in a neonate.
b. Metabolism. Indomethacin is converted to inactive metabolites in the liver. c. Action. This drug has potent anti-inflammatory, analgesic,and antipyretic action. It inhibits prostaglandin-formingrycloorygenaseand inhibits the motility of polymorphonuclearleukocytes.It inhibits leukocytephagocytosisof the sodium urate crystals by blocking migration of thesecellsto the site of inflammation. 2. Indications for use a. Indomethacin is used as an analgesicand antipyretic, but the high incidence and severityof side effectslimits its routine use for mild symptoms. b. Its main useis for moderate-to-severe rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, and Bartter syndrome. It is also indicated for tendonitis, bursitis, acute gout, dysmenorrhea,and is the drug of choice for Reiter syndrome. 3. Side effects and toxicity a. Gastrointestinaleffectsare the sameas for aspirin. b. Central nervous system effects include headache,dizziness, vertigo, depression, psychosis,hallucinations,and seizures. c. Hematologic effects include neutropenia, thrombocytopenia, aplastic anemia, and impaired plateletfunction. d. Other effectsinclude hypersensitivity(e.g.,rash,urticaria,asthma),pancreatitis,hepatotoxicity, exacerbationof renal insufficienry, and salt retention. e. Indomethacin is contraindicatedduring pregnancyand in patientswith epilepsy,renal disease,or peptic ulcer disease. 4. Drug interactions. It reducesthe antihypertensiveeffect of furosemide, thiazides, pblockers,captopril, and prazosin.It increaseslithium levelsand prolongs the half-life of digoxin in neonatesand possiblyadults. B. Sulindac 1. Pharmacologic properties a. Pharmacokinetics. Ninery percentis absorbedafter oral administration. It has a long half-life, which allowstwice-daily dosing.
t09
Tissue, andIntegument Musculoskeletal System, Connective
b, Met&bolism. Sulindac undergoesoxidation-reduction reactionsto form an active sulfidemetabolite.Its metabolitesare excretedin urine and feces, c. Action. Sulindacis structurally similar to indomethacinbut lessthan half aspotent. There is no anti-inflammatory activity until it is absorbedand metabolizedto its suifideform. l. Indications for use include rheumatoid arthritis, osteoarthritis,antylosing spondylitis, and acutegouty arthritis. 3. Sid€eff€ctsand toxicitv a. Gastrointestinal effects include abdominal pain, nausea,and constipation.It has fewersideeffectstlan aspirin.There is an increasedrisk of gastrointestinalbleeding when usedwitl warfarin and other anti-inflarnmatorydrugs. b. Central n€rvous system effects include drowsiness,dizziness, headache,and nervousness. c. Odrcr effectsinclude hlpersensitivity reactions(e.g.,skin rash,pruritus) and blood Exacerbationsof renal insuffrciencyand treatedhlpertension arebotl less dyscrasias. Iikely than with other agents.The main advantageof sulindacoverindomethacinis its lack of nephrotoxicity. C. Tolrnetin t. Pharrnacologicproperties a. Pharmacokinetics.Tolmetin is completelyabsorbedafter oral administrationwith a plasmaha.lf-Iifeof I hour andrequiresfrequentdosingto maintain therapeuticlevels. It is 99%bound to plasmaproteins. b. Maebolism. Tolmetin is excretedin conjugatedand unchangedforms in the urine. c. Action. Tolmetin is more potent than aspirin but l€sspotent than indomethacin.
include adult andjuvenile rheumatoid artluitis' l' llJ#frftlse a. Gastrointestinal side effects are most common, alttrough less than with indomethacin. b. OtJrer less common effects include hepatotoxicity, renal toxicity, and hypertension. D. Nabumetone may cause less gastric irritation than indomethacin or naproxen. It exhibits significantly lower gastrointestinal blood loss than aspirin.
PROPIONIC ACIDDERIVATIVES A. Ibuprofen l. Pharrnacologicproperties
l!* lbuprofenhasgreater potency analgesic thanboth aspirinandacetaminophen.
;]tr--,*Tffitriiii"'*il:,Tli:,'$x1L"f;.Tiitlil.T plasmalevels' dosingfour times daily to maintain steady-state
b. Metabolism.It is excretedin urine ashydrorylatedand carboxylatedcompounds. c. Action.Ibuprofen hasanalgesic,antipyretic,and anti-inflammatory actions. l. Indications for useincludedysmenorrhea, musculoskeletal disorders,rheumatoidarthritis, and osteoarthritis.
il0
Pharmacology
3. Sideeff€ctsand toxicity a'Ibuprofenhasfewergastrointestinalsideeffectsthanaspirinorindomethacin b. Other effectsindude thrombocytopenia,skin rashes,dizzines, headache,blurred vision, tinnitus, and exacerbationof renal insufficiency.
:
B. Napro)(€n 1. Pharmacologicproperties
l!9!!
a. Pharmacokinetics.Naproxen is fully absorbedafter oral administration. It has a
plasma halfJife of I2-I5hours andii ee%bound proteins. toplasma
b. Metabolisrn,It is excretedin urine unchangedand asglucuronideconjugates. c. Action. Naproxenhaspotent analgesicactivity in both rhzumatic and nonrheumatic conditions.
itljfrfiffi: f:::ff" theirlonghalf-lives, whic} allowfor les frequentdosing.
2. Indications for use include moderat€-to-severepostoperativepain (e.g. orthopedic surgery dental surgery),postpartum uterine cramps,acute musculoskeletaldisorders, rheumatoidarthritis, osteoarthritis,anJsylosing spondylitis,dpmenorrhea,and acutegoul 3. Sideeffectsand toxicitf a. Gastrointestinaleffectsinclude heartbum, dyspepsia,nausea,vorniting, and gastric bleeding. b. Centralnervouss)'stemsideeffectsincludeheadache, dizziness,ototoxicit)r,dq>ression, andblurredvision. c. Exacerbationof renal insuffciency may alsoorcur.
PYRAZOTONE DERIVATIVES A. Pheny'butazone 1. Pharmacologicproperties a. Pharmacokinetics.Phenylbutazoneis completelyabsorbedfrom the gastrointestinal : tract after oral administration. b. Action. It inhibits prostaglandinbiorynthesis,causingprominent anti-inflammatory effects,although it is not as good an analgesicor antipyretic as the salicylates. Usefulnessas an analgesicand antipyretic agentis limited by the high incidenc.eof toxicity. 2. Indications for use.Phenylbutazonehas a limited role in treatment.It is not a drug of choicebecauseof its toxicity and should not be administeredlong-term. Nonetheless,it is usefirlasa secondaryagentin acutegout and rheumaticdisease. 3. Side€ffectsand toxicit)' a. Gastrointestinaleffectsincludenausea,vomiting, gastritis,diarrhea,andpqrtic ulceratron, b. Other effectsinclude electrolyteand water retention with edemaformation, rashes, aplasticanemi4 agranulocposis,and rarely,thrombocytopenia. c. Contraindications include cardiac,renal,or hepaticdysfunction;peptic r.rlcerdisease; hypertension;and blood dyscrasias. 4. Druginteractions, Phenylbutazone displacesother anti-inflamrnatorydrugs,oral anticoagulants,sulfonamides,and oral hypoglycemicsfrom plasmaproteins.It may inhibit or
ilt
Tissue, andlntegument System, Connective Musculoskeletal
acceleratehepatic metabolism of other drugs. An increasedanticoagulanteffect is seen with warfarin. B. Oxyphenylbutazone is an analog (an active metabolite) of phenylbutazone. Significant accumulationof oxyphenylbutazoneduring chronic administration of phenylbutazonecontributes to the toxic effectsof the parent drug. 1. Pharmacologic properties. There is slow urinary excretionof the glucuronide conjugate. Pharmacologiceffectsare similar to those of phenylbutazone. 2. Indications for use are the sameas for phenylbutazone. 3. Side effectsand toxicity are alsothe sameasphenylbutazone.
NSAIDS OTHER A. Mefenamic acid 1. Pharmacologic properties a. Pharmacokinetics. Mefenamic acid is rapidly absorbed after oral administration. Peakplasma concentrationsoccur in 2 hours with a plasma half-life of 3-4 hours. b. Metabolism. Fifty percentis excretedin the urine as conjugatedmetabolites,and20o/o is excretedin fecesas unconjugatedmetabolites. c. Action.Its anti-inflammatory potencyis half that of phenylbutazone.Analgesiais produced by central and peripheral actions. 2. Indications for use include rheumatic conditions, soft tissue iniuries, musculoskeletal disorders,and dysmenorrhea. 3. Side effects and toxicity a. Gastrointestinal side effects are seenin 25o/oof patients and include dyspepsia,diarrhea, colitis, and gastrointestinalulceration. b. Other effectsinclude autoimmune hemolytic anemiawith long-term use,and exacerbation of renal insufficiency. 4. Drug interactions include an increasedprothrombin time (PT) with warfarin and a decreasedhypoglycemiceffectwith insulin. B. Piroxicam 1. Pharmacologic properties a. Pharmacokinetics. There is rapid oral absorption with peak concentrations in plasma in 3-5 hours. There is enterohepaticcirculation; therefore, the half-life is approximately45 hours, allowing once-a-daydosing. b. Metabolism. Ten percent is excretedunchangedin the urine, while some metabolites are excretedin the urine as well. c. Action. Piroxicam has a similar anti-inflammatory efficacy as aspirin and indomethacin. 2. Indications for use include rheumatoid arthritis, osteoarthritis,and ankylosingspondylitis. 3. Side effectsand toxicity include gastrointestinaleffectssimilar to other NSAIDs.
il2
Pharmacology
NONOPIOID ANATGESICS ANDANTIPYRETICS A. Acetaminoph€n
r- pharmacologicproperties a. Pharmacokinetics.Acetaminophenis rapidly absorbedftom tle gastrointestinaltract following oral administration.Peakplasmavaluesare reachedin I hour with a halflife of l-4 hours. b. Metabolism. It is metabolizedby hepatic microsomalenzymeswith extensivefirstpassdegradation.Most (90-1009o)is recoveredin the urine within 24 hoursafterhepatic conjugationwith glucuronicacid,su.lirric acid,and cysteine. c. Action, Acetaminophenis an effectivealternativeto aspirin as an analgesicand antipyretic,but it has very weak anti-inflammatoryactivity.It is a weakinhibitor of peripheralprostaglandinbiosynthesisand therdore doesnot affectplateletfunction.
!!!1|91!9q!1?.Q Acetaminophen, ratherthan asoirin.istheantiovretic of chotce in children withviral illneses(no riskof Reye syndrome), for patien$on anticoagulanb, andfor Sout pa(en60n uncosunc agens'
2. Indicatioas for use include analgesiaand antipyrexia,especiallywhen aspirin is contraindicated. Note that acetaminophendoesnot havean anti-inflammatory action. 3. Sideeffectsand toxicitf a. Acetaminophencan causea dose-dependent hepaticnecrosis,r€nal tubular necrosis, and hypoglycemiccoma' b. Acute poisoning resultsin nausea,vomiting, anorexia,and abdominal pain. Severe hepatic damage may develop after 2448 hours from a toxic metabolite. Hepatotoicity is decreased if N-acetylqnteine is givenwithin 24 hows ofpoisoning. B. phenacetin
ltl* AcetaminoDhen overdose is treatedwith/V-acetylcysteine, lvtrichhelosto reolenish glutathione depleted stores in theliver.
1. Pharmacologicproperties a. Pharmacokinetics.Most of this drug is rapidly metabolizedto acetaminophenfollowingoral administration. b. Action, Analgesic,antipyretic, and anti-inflammatory activity is similar to acetaminophen. 2. Indications for use,Phenacetinis not in clinical usebecauseof its toxicity. 3. Sideeffectsand toxicit" a. Phenacetin causesrenal tubular necrosis and chronic renal insufficiency. Methemoglobinemiaand hemolytic anemiaare also seenin individuals who havea limited ability to convertphenacetinto acetaminophen. b, Overdosemay caus€cyanosis,respiratorydepression,and cardiacarrest.
ANTIRHEUMATIC OTHER AGENTS A. Diseasenodifying anti-rheumatic drugs (DMARDs) slow diseaseprogressionand maybe usedwith NSAIDSinitially. Hydrorycbloroquineand methotrexateare usedfor mild and severerheumatoidarthritis, respectively. However,new agentstargetingtumor necrosisfactor (TNF) arecurativefor refractorycasesand canbe usedin combination.Theseinclude: 1. Etinerc€pt which binds TNF (recombinantTNF receptor) 2. Infliximab, a monoclonalantibodyto TNF 3. Ieflunomide, a dihydroorotic acid dehydrogenase inhibitor which inhibits lymphocytes' r division and maturation
il5
Tissue, andlntegument Musculoskeletal System, Connective
B. Gold 1. Pharmacologic properties a. Pharmacokinetics. Gold can be administered intramuscularly (e.g., aurothioglucose, gold sodium thiomalate) or orally (e.g.,auranofin). b. Action. Gold inhibits macrophage functioning, including migration and phagocytosis.There is no antipyretic or analgesiceffect. 2. Indications for use. Gold is indicated in rheumatoid arthritis unresponsiveto NSAIDs. It is most effectivetaken early in rapidly progressivediseases. 3. Side effects and toxicity. Most of the following effects,except gastrointestinal effects,are lesslikely to occur with oral auranofin than with intramuscular preparations. a. Gastrointestinaldisturbancesare more common with auranofin, especiallydiarrhea.
Bridgeto GeneglPrinciples
b. Skin effectsinclude erythema, dermatitis, and chrysiasis(grayish-blue skin pigmentation).
isusedinthe Penicillamine disease treatment ofWilson lt biliary cirrhosis. andprimary intheLead isdiscussed Agents Toxicity andChelating Principles chapter of Ceneral ll). Bookz (Volume
c. Mucocutaneous effectsinclude oral ulcers, stomatitis, gastritis, and colitis. d. Renal effectsinclude proteinuria and a reversiblenephrosis. e. Hematologic effectsinclude thrombocytopenia,leukopenia,aplasticanemia,agranulocftosis, and eosinophilia. C. Penicillamine is classedas a chelating agent. Penicillamine decreasesbone destruction in rheumatoid arthritis. Its mechanismof action is unknown but may be relatedto inhibition of collagenformation. Severeside effectslimit its use.
Bridgeto Principles General
D. Chloroquine and hydroxychloroquine are antimalarial agents.Although these drugs have anti-inflammatory actions, seriousside effectslimit their use. The mechanismof action is unknown.
usesof Theantineoplastic arediscussed in methotrexate Agents theAntineopla$ic Principles of Ceneral chapter ll). Bookz (Volume
E. Methotrexate is used primarily as an antineoplastic agent, although it is now approved for treatment of refractory rheumatoid arthritis. Becauseof the much lower doses used in arthritis, side effects are less severethan in cancer therapy. Side effects include hepatic changesand pneumonitis.
TREATMENT OFACUTE GOUT NSAIDs are often preferred in the treatment of acute gout. Although they are as efficacious as colchicine, symptomatic improvement takeslonger. Indomethacin is most commonly used,but naproxen and sulindac may also be employed. Salirylates,such as aspirin, are not used if gout is being treated with probenecid or sulfinpyrazone becausesalicylatesinhibit the uricosuric effect of these drugs. A. Indomethacin (discussedearlier in this chapter) B. Colchicine 1. Pharmacologic properties a. Mechanism of action. Colchicine interferes with microtubules, thus preventing the migration of granulocytesto the inflammatory site. It has no uricosuric effects. b. Routes of administration. Colchicine may be given orally, which causesgreater gastrointestinal toxicity and a slower onset of action, or intravenously, which has a small chanceof anaphylaxis.
il4
Pharmacology
2. Indications for use. Colchicine is used to treat acute attacks of gout, especially when NSAIDs are not tolerated. It is also given prophylactically to prevent recurrent episodesof acutegout. 3. Side effects and toxicity a. Gastrointestinal effects include nausea,vomiting, abdominal pain, and diarrhea, which may necessitatediscontinuation of the drug. b. Effectsof long-term useand high dosesinclude blood dyscrasias(i.e.,aplasticanemia, thrombocytopenia, agranulocytosis),alopecia, neuropathy, myopathy, and hemorrhagic gastroenteritis.
TREATMENT OFHYPERURICEMIA
Bridgeto Biochemistry
A. Allopurinol 1. Pharmacologic properties a. Mechanism of action. Allopurinol is an analog of hypoxanthine that inhibits the conversion of hpoxanthine to uric acid by xanthine oxidase.It lowers both serum and urinary concentrationsof uric acid. b. Pharmacokinetics. Allopurinol is well absorbed orally and metabolized to oxypurinol, a xanthine oxidaseinhibitor with a half-life of 30 hours. 2. Indications for use a. Allopurinol is the drug of choice for most patients with severe hnreruricemia, whether due to gout or other conditions.
"another Allopurinol, meaning purine," isalsoa prodrug that istakenbyHGPRTase and made anallopurinal nucleotide. Thisinturninhibis PRPP amidotransferase, the rat*limiting $epof denovo purine synthesis, resulting in lesspurines made. Therefore, lessisdegraded to uricacid.
b. Acute attacks of gout (1) If a patient is on allopurinol, it should be continued.
Note
(2) If therapy is to be initiated, it should be delayeduntil severaldaysafter the acute episodehas resolvedand the patient is on maintenancedosesof colchicine.
Allopurinol canraise serum levels of someantimetabolites (e.g., azathioprine) by inhibiting theirbreakdown.
3. Side effects and toxicity a. Sideeffectsinclude nausea,diarrhea,and hypersensitivity(e.g.,rash,fever,exfoliative dermatitis). b. Less common side effects include blood dyscrasias,hepatotoxiciry and peripheral neuropathy. 4. Drug interactions. The dose must be reduced in the presence of renal insufficienry. Allopurinol may inhibit the metabolism of oral anticoagulantsand have increasedtoxicity when used with thiazide diuretics. The dosageof mercaptopurine, an antineoplasticthat is metabolizedby xanthine oxidase,must be lowered when administered concomitantly with allopurinol. B. Probenecid l. Pharmacologic properties a. Mechanism of action. Uricosuric agents are organic acids that compete with other acids (including uric acid) at anionic transport sitesin the renal tubule. Low dosesof uricosuric drugs may selectivelyinhibit tubular secretion of uric acid and causesome retention of urate. However, at therapeutic dosestheir predominant effect is to block uric acid reabsorption in the proximal tubule, thereby increasingthe urinary excretion of urate.
Note Allopurinol decreases both serum andurine concentrations of uricacid, whileprobenecid decreases serum levels butincreases urinelevels.
il5
System, Connective Tissue, andIntegument Musculoskeletal
b. Pharmacokinetics. Probenecid is completely reabsorbedin the nephron, metabolized slowly, and excretedin urine. The metabolic byproducts are also uricosuric. 2. Indications for use a. Probenecidis used when allopurinol is not well tolerated. b. During acuteattacks,probenecidshould be continued if the patient is on maintenance therapy but should not be initiated until the acuteattack has subsided. c. It may alsobe used to prevent penicillin elimination and raiseits serum level.
Note of otherweak Thesecretion penicillins, acids, e.g., isreduced by caphalosporins, probenecid, thusincreasing theirhalf-lives.
3. Side effects and toxicity a. Gastrointestinaleffectsinclude nauseaand abdomin"l puitt. b. Hypersensitiviry including rash and fever,may occur. c. Renalcalculi may occur. It should not be used in patients who excretelarge amounts of urate. Patientsshould be instructed to maintain a high fluid intake to help prevent stone formation. d. Nephrotic syndrome and peptic ulceration may occur in rare instances. e. Hemolytic anemia may occur in patients with glucose-6-phosphatedehydrogenase (G6PD) deficiency. f. Severeoverdosescan causeseizuresor fatal respiratory depression.
In a Nutshell DrugsUsedto TreatGout . Colchicine -+ inhibits granuloryte migration by interfering with microtubules . Allopurinol -->inhibits conversion of hypoxanthine to uricacidbyxanthine oxidase . Probenecid -+ blocks uric inthe acidreabsorption proximal tubule (uricosuric) . Sulfinpyrazone + increases of uric urinary excretion acid . NSAIDs + relieve symptoms of painand inflammation
I t6
C. Sulfinpyraznne 1. Pharmacologic properties. Sulfinpyrazone is a derivative of phenylbutazone. Ninety percent is excretedunchangedin the urine. 2. Indications for use. Use for gout is similar to that of probenecid. It may also be used to inhibit platelet aggregationbecauseof its inhibitory action on prostaglandin synthesis. 3. Side effects and toxicity a. Gastrointestinal symptoms are more common with sulfinpyrazone than with probenecid,although gastrointestinalulceration is uncommon. b. Other side effectsinclude rash and renal calculi formation. c. Although the parent compound, phenylbutazone,may, in rare instances,causeblood dyscrasiasand volume overload, these side effects have not been reported with sulfinpyrazone. 4. Drug interactions. Sulfinpyrazone potentiates the effects of insulin, sulfonylureas, sulfonamides,and warfarin.
SECTION II
Gastrol ntestlnaI System
Gastrointestinal Embryology gutisformed Theprimitive asa result of cephalocaudal andlateral foldings oftheembryo. lt is anatomically divided intotheforegufmidgut, andhindgut. Thecranial foregut, fromthe groove, buccopharyngeal membrane to thelaryngotracheal iscovered inthechapter onthe pharyngeal arches andtheirderivatives intheCeneral Principles review book.Theremainder ofthe primitive gutanditsderivatives arereviewed here.Epithelium andglands ofthega$rointe$inal tract andbiliary systems, andtheparenchyma gut oftheliverandpancreas, arederived fromprimitive endoderm. Themuscles, connective tissue, andbloodvessels ofthegutwallarederived from splanchnic mesoderm. Epithelial linings ofthemouthandloweronethird oftheanalcanal arise from theectoderm ofthe$omodeum andproctodeum, respectively.
; i , i I
FOREGUT DERIVATIVES A. Esophagus 1. The esophagusextends from the respiratory diverticulum to the stomach. It becomes elongatedwith the ascentof the pharynx and descentof the heart and lungs. 2. The upper two-thirds of the esophaguscontain striated muscle derived from pharyngeal archesand innervated by the vagus nerve. The lower one-third contains smooth muscle derived from splanchnic mesoderm and innervated by the splanchnic plexus. B. Stomach 1. The stomach appearsin the fourth week as a dilatation of the foregut. During development, the stomach rotates 90" clockn'ise, making its left side anterior and its right side posterior. a. The left side is innervated by the left vagus nerve. b. The right side is innervated by the right vagus nerve. 2. The caudal, or pyloric, part of the stomach moves upward to the right while the cephalic cardiac region moves downward to the left. 3. The greater and lessercurvatures of the stomach ariseby unequal growth of its two sides. a. The posterior part grows fasterthan the anterior part and forms the greatercurvature. b. The anterior part forms the lesser curvature.
il9
System Gasfrointestinal
C. Duodenum 1. The duodenurnis formed by the terminal portion of the foregut and cephalicportion of the midgut. This junction is locatedjust distal to the origin of the liver bud. 2. With the rotation of the stomach,the duodenumbecomesU-shape4is pulledto theright, andcomesto li€ rctroperiton€ally. 3. The duodenumis suppliedby both the celiacand superiormesentericarteries. D. Liver and gallbladder 1. The hepaticdiverticulum (liver bud) appearsasrapidly proliferatingendodermalepithelial cordsat the distal foregutin the middle of the third week. 2, As the liver cordspenetratethe septumtranwersum,the connectionbetweenthe hepatic diverticulum and foregut(duodenum)narrowsto form the bile duct. A ventralgrowth of the bile duct givesrise to the gallbladder and cystic duct. 3. Later in development,liver cordsintermingle with vitelline and umbilical veins to form hepatic stnusoids. 4. Hematopoieticcells,Kupffer cells(macrophages)of the mononuclearphagocytesystem' and connectivetissuestroma (including the fibrous capsuleof the liver) aremesodermal derivatives. 5. Bv the 10th week,nestsof cells,which produce red and white blood cells,are found betweenthe hepaticcellsand the vesseltnat. n formation of blood cellsin the liver declinesduring the last 2 months of intrauterine life, 6. Liver cellsbegin to secretebile during the l2th week E. Pancreasbeginsastwo endodermalduodenalbuds. The dorsal and ventral pancreasand ducts anastomose.The ventral duct remains as the connection to the duodenum. The pancreaticduct. dorsalduct either degenerates or remainsasthe smallaccessory
MIDGUT DERIVATIVES A Primary intestinal loop. Rapid growth of the primary intestinal loop, combined with its herreducedspacewithin the abdominalcavitydueto expansionof the liver,necessitates . niation into the extraembryoniccoelom of the umbilical cord during the sixth week of . dwelopment.Elongationof the small intestinesresultsin the formation of the coiledloops of the jejunum and ileum. The largeintestinefrom the distal part of the ileum to the proximal two-thirds of the transversecolon remainsuncoiled. B. Intestinal rot tion- Within the umbilical cord and during intestinal re-entry into the abdominal cavity in the 10th week,the intestin€srotate a total of 270' counterdockwise around the axisof the superiormesentedcartery. 1. Upon re-entry,tle proximal part of the jejunum comesto lie high on the left side,with the later-retumingloops taking up positionsmore to the right. 2. Last to enter is the cecalswelling,which, becauseof the 270orotation, lies in the right upper region in closecontactwith the right lobe of the liver. a. The cecalswellinggivesris€to the cecumand the appendir b. When the cecumand appendixdescendt}te descendingcolon and hepaticflexureare formed. C. 'Fixation'' of the midgut occursastlle mesenteriesof the intestinesfirsewith the parietal peritoneumof the posterior abdominalwall.
t20
Embryology
HINDGUT DERIVATIVES A. The cloaca is an expandedterminal portion of the hindgut, which is in direct contact with ectoderm at the cloacalmembrane. The ectodermal depressionat the cloacalmembrane is the proctodeum. B. A urorectal septum grows caudally in the angle between the allantois and the hindgut. Its point of fusion with the cloacal membrane is the perineum. The urorectal septum divides the cloaca into an anterior urogenital sinus and a posterior anorectal canal, and thus divides the cloacal membrane into the urogenital membrane and the anal membrane. C. The anal membrane ruptures at about the ninth week, resulting in a direct continuity between the endodermally derived anorectal canal and the ectodermally derived proctodeum (anal pit).Thepectinateline marks the location of this transition.
Amniotic cavity (AM)
Pharyngeal pouches 1
Yolk sac (YS)
Esophagus
Stomach Hepatic diverticulum Yolk stalk
bud
Gall bladder
Foregut
Vitelline duct
f,illdgut
Allantois Cloaca Goelom
Gut tube
Ventral Celiac Dorsal pancreatic artery Inferior Superior pancreatic bud mesenteric mesenteric bud artery artery
Figure Il-1-1.Foregut, midgut, and hindgut with ventral and dorsal mesenteries.
r2l
System Gastrointestinal
Thble II-1-1. Primitive gut derivatives. Borders
Organs Included
Foregut Buccopharyngealmembrane Pharynx, esophagus, stomach,part of duodenum, to anterior intestinal portal liver, gallbladder,pancreas Midgut
Anterior intestinal portal to posterior intestinal portal
Hindgut Posteriorintestinalportal to cloacalmembrane
Blood Supply Celiac artery
Superior Distal duodenum, jejunum, mesenteric ileum, cecum and appendix, artery ascendingcolon, proximal two-thirds of transversecolon Distal one-third of tranverse colon, descendingcolon, sigmoid colon, rectum, upper two-thirds of anal canal
Inferior mesenteric artery
S ITTIT MATFORMATION CONGEN A. Atresias, stenoses,and duplications may occur anywhere along the alimentary tract and often are due to incomplete recanalization following epithelial proliferation and lumen obliteration. 1. In casesof atresia, a thin diaphragm remains acrossthe lumen. 2. Stenosisis marked by a distal narrowing and proximal distention. 3. Duplications may contain mucosathat is very different from that in the segmentof origin. B. Pyloric stenosisis a narrowing of the pyloric lumen, which is due to hlpertrophy of circular smooth muscle in the pyloric region of the stomach.Patientspresent 1-3 weeks after birth with projectile vomiting, constipation,and weight loss.Treatmentsinclude diet management,administration of antispasmodics,and surgicallongitudinal incision through the hypertrophied muscle.It is more common in males. C. Atresia of the gallbladder and bile ducts causespersistent occlusion of the gallbladder or bile ducts. Patientspresent soon after birth with steadilyincreasingjaundice, clay-colored stools,and very dark-colored urine. D. Annular pancreas is an encirclement of the duodenum by pancreatic tissue,which is due to abnormal movement of part of the ventral pancreasto the right of the duodenum rather than to the left. E. Remnants of the vitelline duct 1. Meckel diverticulum is an ileal outpocketing, which may contain gastric and pancreatic tissue.It may becomeinflamed and causesymptoms like those of appendicitis. 2. Umbilical or vitelline fistula is a patent vitelline duct, which allows communication betweenthe umbilicus and the intestinal tract. F. Omphalocele is due to failure of all or part of the intestines to return from the umbilical cord into the abdominal cavity. The viscera outside the abdominal cavity are then covered only by the amnion.
122
Embryology
G. Congenitd umbilical hernia is a herniation of the viscera through a weakenedpart of the abdominal wall where it is not closed completely. Occurring during the fetal period, the sac formed has no muscle or skin and may tear during delivery. H. Malrotation may result in the colon and cecum re-entering the abdominal cavity first and settling on the left. In casesof reversedrotation, the transversecolon passesbehind the duodenum rather than in front of it. I. Congenital megacolon (Hirschsprung disease) is a constriction of a portion of the colon through which the intestinal contents are not moved. It is attributable to the absenceor marked reduction of parasympathetic ganglion cells in that area to which neural crest cells have failed to migrate. As a result, the segment of the gut proximal to the constricted area becomes distended. Symptoms include failure to pass meconium and distention of the abdomen. Tieatment is surgical excision of the distal bowel. It is more common in males. L Imperforate anus may be due to failure of the anal membrane to rupture.
l2t
Gastrointestinal Histology (alimentary) Thegastrointe$inal sy$emconsi$s glands. ofthedige$ive tractanditsassociated Beginning intheoralcavity, thetractcontinues asthepharynx, esophagus, stomach, small intestine, large intestine, rectum, glands, andanalcanal. glands, pancreas, Thelarge consi$ing ofthesalivary liver, andgallbladder, lieoutside thedige$ive tractbutareconnected to it viatheirducts. Theentire tubeislinedbymucosa, or mucous membrane, whichconsists ofa lubricated epithelium withan underlying propria thinlayer of cellular andvascular connective tissue called thelamina thatis generally surrounded bymuscular mucosae.
ORATCAVIIY A.Mucosa oftheoralcavity andofthepharynx aresimilar. l. The qrithelium of the oral cavity is mosdy nonl<eratinizedstratified squamousthat becomeskeratinizedat the lips. It providesa tight and flexiblebarrier. 2. The lamina propria consistsmain.lyof denseconnectivetissuewith manyelasticfibers.It interdigitateswiti tJreepithelium,forming prominent connectivetissuepapillaethat contain bloodvessels andlymphatics.
Note
|}ffil}-^ il:-Hi#g squamous epithelium, except for thema$icatory mucosa palate), which lelneiva;hard ls Keraflnlzed'
3. Scatteredglandular acini releaselubricating mucoussecretionsonto the epithelialsurface via short ducts.Thesesecretionscontain immunoglobulin A (IgA) antibodies. 4. The submucosais rich in adiposecellsandmucousglands.In hard surfaceslike the palate, thereis no submucosa, and the toughlamina propria restsdirecdyon the periost€um. B. T&th are composedof a coreof pulp surroundedby a mineralizeddentin, which is covered by a mineralizedenamelon the crown and a mineralizedcementurnon the root. Eachtooth is anchoredin a socketof alveolarboneby the periodontalmembrane(ligament). 1. Pulp cayitl is the centralcavity of the tooth. a. It is composedof a pulp chamberin the crown and upper root and a root canalin tlte lower root. which containsnervesand blood vessels. b. Tooth pulp is loose connectivetissue that has a mesenchymalappearanceand an abundantground substance.
t25
System Gastrointestinal
ln a Nubhell Enamel . Thehardest component of thehuman bodyandthe richest in calcium . Secreted byameloblasts . Cannot berepaired or replaced without clinical intervention
2. Enamel is the hardest substanceof the body, being approximately 97o/ocalcium salts by dry weight. a. The enamel matrix is secretedby cells of ectodermal origin called ameloblasts; other tooth components are derived from ectomesenchyme. (1) The organic matrix secretedby ameloblastsbecomesminerahzedearly in tooth formation prior to eruption. (2) Ameloblastsdie and arelost after the enamelis fully formed, and the tooth erupts into the oral cavity.For this reason,enamelcannot be repairedor replacedby the body. b. Enamel is organized into prisms (i.e., hexagonalrods) held together by a calcified cementingsubstance. 3. Dentin is approximately 70o/omineralized. a. Dentin is also composedof collagenand proteoglycans. b. The organic matrix is synthesizedby odontoblasts that line the internal surfaceof the dentin and separateit from the pulp cavity. c. Odontoblastprocessesextendto the dentin-enameljunction (DEI) through microscopic canalscalled dentinal tubules, which run approximately perpendicular to the DEI. 4. Cementum is a calcified tissuesimilar to bone that coversthe dentin of the root. Two varieties are present: cellular and acellular. a. In cellular cementum, cementocytes are encasedin a mineralized matrix within lacunae,which intercommunicatevia canaliculi. b. In acellular cementum, cementocytesare lacking. c. Like bone, cementum is labile, and local stressescausereabsorption,which requires subsequentcementum production.
ClinicalCorrelate Inscurvy, vitaminC deficiency in collagen causes defects periodontal synthesis. Because membrane depends ona high rateof collagen renewal, atrophy ofthemembrane ensues. Theteeththen become loose intheir sockets andfallout.
5. Periodontal membrane (ligament) is a specializeddenseconnectivetissuethat binds the tooth to the bony walls of the alveolarsocket.It continues at the socketwith the periosteum of bone. a. On the tooth side,the fibers are anchoredin the cementum. b. On the socketside,the fibers are embeddedin the bone tissue. 6. Alveolar bone, extensionsof the maxilla and mandible, form the socketsof the teeth. This bone has an immature appearance,lackingthe typical lamellar pattern of adult bone. 7. Gingiva (gum) is a mucous membrane firmly bound to the bone by a densefibrous connectivetissue. a. It is coveredby a stratified squamousepithelium that is usually keratinized. b. At the interface with the teeth, this epithelium also attachesto tooth enamel by means of its basementmembrane. C. Tongue 1. The bulk of the tongue consistsof striated skeletalmuscle coveredby the oral mucosa. a. The muscle fibers are arranged in all three planes,resulting in maximum movement. b. The fibers are grouped in bundles separatedby connectivetissue. 2. Thstebuds are found on the tongue, as well as in the epiglottis, pharynx, and palate.
t26
Histology
3. Dorsal surface.The anterior two-thirds of the tongue on its superior surfaceis marked by three different types of mucosal elevations,or papillae. a. Filiform papillae, the most numerous,are elongatedconesthat givethe tongue its rough surface.Th.y do not contain tastebuds and are keratinizedat the superior surface. b. Fungiformpapillae are mushroom-shapedstructuresthat are scatteredamong the filiform papillaeand frequently contain tastebuds. c. Vallate (circumvallate) papillae are large circular and flattened papillae that are surrounded by moat-like invaginations. (1) There are 7-12 cirumvallate papillae arrangedin a V-shaped configuration on the posterior part of the tongue. (2) The lateral surfacescontain numerous tastebuds. Serousglandsempty into the moat-like furrows that surround each papilla to maintain a continuous flow of fluid over the taste buds. 4. Lateral surface. On the posterolateralborders of the tongue, rudimentary foliate papillae also contain tastebuds. 5. Ventral (inferior) surface of the tongue is characterizedby a well vascularized mucosa with a thin, smooth nonkeratinized epithelium. For this reason,sublingual administration of certain drugs is used.
Note
PHARYNX A. Posterior to the oral caviry the pharynx is situated between the oral cavity and the digestive and respiratory systems.It provides the communication between the nasal region and the larynx. The pharynx contains the palatine (oropharynx) and pharyngeal (nasopharynx) tonsils. B. A transition in its mucosacan be observedfrom stratified,squamous,nonkeratinizedto ciliated, pseudostratified,columnar epithelium. Tiansitional zones of stratified columnar epithelium are also seen.
Thepharynx extends fromthe baseoftheskullto theorigin oftheesophagus andis approximately in 6 inches length. lt serves asa transitional areabetween the oralcavity andtherespiratory anddigestive systems.
C. The lamina propria is rich in elasticfibers and tightly binds the mucosato the muscularis.
ESOPHAGUS The esophagusis a nearly straight muscular tube that functions as a rapid conduit from the mouth to the stomach. A. Mucosa of the esophagusconsistsof thick, stratified,squamous,nonkeratinizedepithelium. 1. The lamina propria is made of dense,elastic,connectivetissue.Mucous glandsare occasionally found near the stomach (esophagealcardiacglands). 2. The muscularis mucosae consistsmainly of longitudinal smooth muscle fibers and is thicker closerto the stomach. B. Submucosaof the esophagusforms longitudinal ridgeswhen the tube is contracted.It contains sero-mucousglands (esophagealglandsproper). C. Muscularis externa of the esophagealwall is composed of two thick layers. 1. In the upper third of the esophagus,both layersare striated muscle. 2. Throughout the middle third, striated and smooth musclefibers are mixed.
127
System Gastrointestinal
ln a Nutshell
3. In the lower third, only smooth muscle is present.
Esophagus . Proximal end:striated muscle . Midportions: mixture of muscle smooth andstriated . Distal muscle end:smooth
4. Circular bundles of smooth muscleservea sphincter-likefunction at the lower end of the esophagus(lower esophagealsphincter,LES). 5. Recentstudies show that the esophagealmusculature has a dual innervation with both voluntary and involuntary components.
STOMACH The stomach is a muscular expansionof the digestivetube in which food is stored and mixed with hydrochloric acid (HCl), mucus,water,and proteolytic enzymesto form chyme. A. Mucosa consists of surface epithelium, lamina propria, tubular glands, and muscularis mucosae. 1. Surfaceepithelium is composedof simple, columnar, mucus-secretingcellsthat are periodic acid-Schiff (PAS)-positive. 2. The epithelium is invaginatedinto the lamina propria, forming l-5-mm gastricpits. 3. A large number of tubular glands enter into the bottom of thesepits and exhibit variations accordingto the region.
Note 4. Gastric mucosacellsturn over rapidly, and the whole surfaceis replacedevery 3 days.
(stomach Rugae ridges) are transient foldsofthemucosa andsubmucosa thatare present intheempty stomach butdisappear inthe distended stomach.
5. Muscularis mucosaeconsistsof inner circular and outer longitudinal layers. B. Submucosa participates in producing the ridges called rugae, which are smoothed out when the stomach is distended.No glands are found in this layer.
Junction of gland and base of Pit
lsthmus
€c
G rn
Neck
Gland Lamina. propria
Lamina' propria
L y m p hn o d u l e Submucosa Cardiacportion
BodYand lundic Portion Figure ll-2-1. Regions of the stomach.
t28
PyloricPortion
Histology
C. Muscularis externa consistsof partially overlapping layersof smooth muscle that are oriented circularly, longitudinally, and obliquely. 1. The circular layer thickens to participate in the formation of the cardiac sphincter and the pyloric sphincter. 2. Strong peristaltic wavessend chyme through the pyloric sphincter into the duodenum, and the cardiacsphincter preventsregurgitation into the esophagusabove.
Note glands are Inthestomach, foundonlyinthemucosa.
D. Serosais coveredby mesothelium that is continuous with the gastricmesenteries(omenta). E. Regions of the stomach. Anatomically, there are three regions of the stomach:the cardiac stomach,the body and fundus, and the pyloric stomach (Figure II-2-I).
Note
1. Cardiac stomach is a narrow, circular band at the transition betweenthe esophagusand stomach,consistingof shallow gastricpits and mucous glands.
portion isfound Thecardiac between the atthetransition esophagus andthestomach.
2. Bodyand fundus are packedwith branchedtubular glandsthat open into the basesof the gastricpits. Severaltypes of cellsoccupy the epithelium of theseglands.
Clinical Correlate
a. Parietal (oxFntic) cells are found in the neck and body of the gastricglands. (l) They are large,pyramidal, and acidophilic with a centrai nucleus. (2) The electron microscope revealsintracellular canaliculi lined with abundant microvilli. (3) Parietal cells make and secrete0.16 M HCI so that the environment is highly acidic,with a pH of lessthan 2. (4) Parietalcellsalsoproduce intrinsic factor, a glycoproteinthat binds vitamin B12 in the lumen of the stomachfor absorption in the intestines. (5) Acid secretionby parietal cellsis stimulatedby cholinergicnerveendings,histamine, and gastrin. b. Chief cells are the most abundant cellsat the baseof the gastricglands.They are also found in the neck region and,lessfrequently,in the pyloric glands. (1) These cuboidal-to-low columnar cells have apical membrane-bound secretion granulescontaining pepsinogen in an inactivezymogen form. (2) Thesezymogensare activatedafter secretionby the low pH within the lumen. c. Mucous neck cells are mucus-secretingcellslocatedin the necksof the glands. d. Enteroendocrine (diffuse endocrine) cells are single cellsthat synthesizeamines,lowmolecularweight polypeptides,or proteins with an endocrineor paracrinefunction. ( 1) Thesecellsare scatteredand are usuallylocatedat the baseof the glandsthroughout the cardiac,gastric,and pyloric glands. (2) Some cellshave an affinity for silver (e.g.,argentaffin cells,argyrophils), others for chromium salts (e.g.,enterochromaffin cells), and others are identified by immunohistochemicalprocedures. 3. Pyloric stomach has deepgastricpits into which tubular glandsopen (FigureII-2-1).
HCIand Parietal cells secrete intrinsic factor, whichis of fortheabsorption needed of vitamin 8,,.A deficiency intrinsic factor canleadto and, vitamin B,,deficiency, in to a defect furthermore, known as RBC synthesis pernicious Recall that anemia. a causes B' deficiency with anemia megaloblastic hypersegmented characteristic neutrophils.
Bridgeto Physiology active involves Acidsecretion across cell transport ion Hydrogen membranes. (H*),which into ispumped fromthe thelumen, comes anhydrase of carbonic action and dioxide acting oncarbon carbonic water to produce (Cl-)combines acid. Chloride withH* in thelumento form acid(HCl). hydrochloric
a. Pyloric glandsare similar to the gastricglandsof the cardiacregion. b. The predominant secretionis mucus.
129
Gastrointestinal System
Note
SMAttINTESTINE
Plica circulares areabsent or small in initial duodenum, larger andmorenumerous proximally, andabsent in distal ileum.
The small intestineis a tube approximately4m long that is divided into three anatomic regions: the duodentun, jejunum, and ileum. The final digestion of chyme and the absorption of small moleculesoccursin the small intestine.
Note . Disaccharidases and dipeptidases carryouttheir activity atthestriated (brush) border. . Disaccharidases hydrolyze disaccharides into monosaccharides . Dipeptidases hydrolpe dipeptides intoamino acids. ClinicalCorrelate Lactose intolerance iscaused bythedeficiency ofthe disaccharidase lactase. Lactase hydrolyzes lactose into glucose andgalactose. Without lactase, anyfood product witha significant (dairy amount of lactose products) isnotwelltolerated: lactose remains undigested untilit reaches thelarge intestine, where bacteria can digest andferment it. Symptoms include bloating, gas, anddiarrhea.
r50
A. Mucosa 1. Grossly,the mucosaof the small intestinehasa seriesof permanent folds,plica circulares, which consistof mucosaand submucosa. 2. The hallmark of the small intestine is the presenceof intestinal villi, which are outgrowths of the mucous membrane into the lumen (Figure II-2-Z). 3. Epithelium of the villi contains two major cell types: columnar absorptive cells and goblet cells. a. Columnar absorptive cells have regular closely packed microvilli on their apical surfacesand tight junctional complexesaround their apical borders. (1) Lateralmembranesform complexinterdigitationswith neighboringcolumnar cells. (2) Each columnar cell secretesits own apical surfacecoat of glycoprotein enzymes, which, along with pancreaticenzFmes,completethe chemicalbreakdown of food. (3) Amino acids,monosaccharides,and fatty acids,as well as water, minerals, and electrolytes,enter the cell through the apical membrane. (4) Monoglycerides and fatty acids are esterified to triglycerides in the smooth endoplasmicreticulum (SER)and are coatedwith protein to be releasedas chylomicrons into the intercellularspace. (5) The cells also synthesizea glycoprotein "transport piece,"which attachesto a secretoryIgA from plasma cellsand is releasedinto the lumen. b. Goblet cells become more numerous proceeding distally in the small intestine. They produce acid glycoproteinsthat protect and lubricate the lining of the intestine.
Histology
Striated border Capillary (shownwith red bloodcell)
Lymphatic lacteal
Gobletcells
Myofibroblast Argentaffin cells
&\
Paneth cells Smooth muscle Muscularis mucosae
Figure ll-2-2. Structure of small intestine villus and crypts.
4. Severalshort tubular glands called intestinal glands (crypts of Lieberktihn) open around the baseof eachvillus. a. The simple columnar epithelium of the villus is continuouswith that lining the crlpts. b. The epithelium of the crypts is the site of the production of new epithelial cells.
rumntiate intoco dmavdirrere "' :Tt;lj1T#,iiTL':lT#fr.ffHi:'.fi :" (2) Paneth cells are found only at the base of the crypts and produce acidophilic cytoplasmicgranulesthat contain enzymeswith bacteriocidalactivity. 5. Lamina propria of the small intestine penetratesthe core of the villi and is composedof blood vessels,lymphatics,defensivecells,fibroblasts,and smooth muscle cells. a. The blood vesselsconsistof a densenet of fenestratedcapillaries. b. A central lacteal in the villus absorbs chylomicrons into the lymphatic circulation through its junctional gaps. c. Smooth muscle fibers from the muscularis mucosaecourse up into each villus and
t5l
Gasfrointestinal System
insert on subepithelialconnectivetissue.Villi contract severaltimes per minute as a result of the presenceof smooth muscle in their cores.
In a Nutshell glands Brunner . Duodenum, submucosal . Secrete product alkaline to protect duodenal mucosa andto achieve pHforpancreatic optimal enl/mes. PeyerPatches . Lymphoid tissue in submucosa . lleum
Note Thelarge intestine normally reabsorbs large amounts of water andsmall amounts of (e.9., sugars andvitamins vitamin l0.Thelarge intestine doesnotcontain anyvilli.
B. Submucosaof the small intestine exhibits regional differences. 1. In the duodenum, submucosal (Brunner) glands are found. a. Theseglandsare connectedto the lumen by ducts that open into certain crlpts. b. Their alkalineglycoproteinmucus secretionneutralizesthe acidic chyme entering the duodenum. c. Submucosalglands are lacking in all other portions of the intestines. 2. Submucosallymph nodules are common, especiallyin the ileum, where large aggregatesof nodules form Peyerpatches.
TARGE INTESTINE The large intestine extendsfrom the ileum to the anus and consistsof the cecum, ascending colon, transverse colon, descending colon, rectum, and anal canal. Histologically similar from the ileocecalvalveto the rectum, the large intestine is approximately 1.5 m long and twice the width of the small intestine. A. Mucosa of the large intestine lacksvilli and contains many small holes.Theseholes are the mouths of the straight long tubular intestinal glands (crypts of Lieberktihn). 1. The epithelium is simple columnar enterocytes,with numerous goblet cellsand scattered enteroendocrinecells. 2. The epithelium is continuously renewedby mitosis of the undifferentiated cells in the lower half of the glands. 3. The lamina propria is rich in lymphoid cells and lymph nodules that frequently extend into the submucosa. B. Submucosacontains many lymph nodules,which are especiallyabundant in the appendix. No glandsoccur in this layer of the large intestine.
Note Teniae coli(three thick, longitudinal bands) are uniquely characteristic ofthe largeintestine.
Clinical Correlate Because theappendix isa blindextension, it is frequently a siteof (appendicitis). inflammation
In a Nutshell --+Analopening Analvalves simple.$raffied . $mtified.keraunzed columnai cuboidalsquam0us-squu*ors
lt2
C. Muscularis externa is composedof longitudinal and circular musclelayers. 1. The inner circular layer is similar to the rest of the tract. 2. The outer longitudinal layer is different from that in the small intestinebecauseit is gathered into three thick longitudinal bands calledteniae coli. D. Serosaof the largeintestinecontainssmall pendulousprotuberancesof adiposetissuecalled the appendices epiploicae. E. Vermiform appendix is a blind finger-like extensionof the cecum,which often hasits lumen obliteratedby abundant lymphoid follicles.Its generalstructure is similar to that of the large intestine,but it contains fewer,shorter,intestinal glandsand has no teniaecoli. F. Anal canal is the terminal portion of the large intestine. 1. The proximal half of the anal canal contains a number of vertical folds, which are produced by an infolding of the mucous membrane around the submucosa.They are known as the rectal columns of Morgagni. 2. The columns are separatedfrom eachother by furrow-like rectal sinuses,which end distally in small valve-like folds called the anal valves.
Histology
3. Abovethe analvalvesthe epitheliumchangesftom simplecolumnarto stratifiedcuboidal. l a. At the levelof the valves,it becomesstratifiedsquamous. b. At the anal orifice, the epithelium becomeskeratinized,and apocrine (circumanal) glandsand hairs arepres€nt. 4. The submucosacontainsa large plexusof veins,which form hemorrhoidswhen exctssivelydilated. 5. A circular layer of smooth muscle constitutestle internal enal sPhinct€r, and more superficially,skeletalmuscleforms the external anal sphincter.
TRACT GTANDS DIGESTIVE A. salivaryglands
I !!!!..!!ttbl!.!f
1. Parotid glands are compound,branched,acinarglands. a. Their secretoryportions arecomposedalmostexclusive$of serouscells. b. Their secretorygranulesarehigh in amy'aseactivity. 2. Submandibular glands are compound, branched, tubuloacinar glands composedof mucousand serouscells. 3. Sublingual glands are compound,branched,tubuloacinar glands composedpredominantly of mucouscells. B. Pancreas.The exocrineportion of the pancreasconsistsof parenchymalcellsanangedin the form ofacini, anda systemofbranchingductsthat drain into the lumen ofthe smallintestine. 1. The pancreasis coveredby a thin capsuleof connectivetissuethat sendsseptainto th€ parenchymato divide it into lobules. 2. Acini ar€ composedof pyramidal serous-typecells,eachof which producesmembranebound granulesof mixed enzymesfor secretion.
FunCionol SalivaryGlands ' Moistening andlubricating ' DiSestion 0f crbohydrates (e.9., salivary amylase)
ll.l ltrbhelt Theoancreas is bothan endocrine andan exocrine 8land. . Exocrine + aonarglands . Endocrine _+ lslets ol Lanserhans
a. The acini aresurroundedby a basallarninasupportedby a delicatesheathof reticular fibers. b. The enzymeprecursors(zymogens)are continually synthesizedin the basalrough endoplasmicreticulum (RER),glycosylated,concentratedin Golgi membranes,and releasedby exocytosis. c. Pancreaticen4rmescleaveproteins (e.g.,trypsin, chymotrypsin, carboxyPeptidase, elastase), carbohydrates(e.g.,amylase),fats (e.g.,lipase,lecithinase),and nucleicacids (e.g.,ribonuclease,deoxyribonuclease). 3. The duct systemof the pancreasbeginswith small cuboidalcellsthat extendinto the acinar lumen asc€ntroacinarcells, a- Low cuboidal to columnar intralobular ducts €mpty into large, sirnple,columnar interlobular ducts. b. The main secretoryductscontain gobletcells. c. Enteroendocrinecellsoccur in both largeand small ductsbut not in acini. d. Duct cellssecretewater,electrolytes,and bicarbonate(HCO3J, which dilute enzyme secretionsand neutralizeacidic chvme.
t55
Gasfrointestinal System
Centralvein
Bilecanaliculi Sinusoid ethmoidalcell Sinusoid
Hepatocyte
Inletvenule
Bileduct
Portalvein
Hepaticartery Figure ll-2-3.Organization of a liver lobule.
Nole Portal area= vefiul€, arteriole, bileduct,and, often,lymphatic vessels.
C. The liver is the largest gland of the body. It has multiple and complex functions, including exocrine secretion(via bile ducts into the duodenal lumen), maintenanceof optimal concentrationsof various componentsof blood, and filtering of the blood, which it receivesvia the portal vein from the digestivetract and spleen. l. Parenchyma of the liver is divided into many small lobules shapedlike polygonal cylinders (FigureIl-2-3). a. Each cylinder is composed of plates of cells arranged radially around a central vein. Betweenthe platesare radial blood sinusoids. b. At the periphery of the lobules,branchesof the portal vein, hepatic artery bile ducts, and lymphatics course together. 2. Hepatocytes' or liver cells,are 20-30 pm polyhedral eosinophilic cells. a. Their six or more surfacesmay either contact another cell to form gap junctions and bile canaliculi or form a free surface with microvilli exposed to the perisinusoidal spaceof Disse. b. Abundant glycogen in these cells takes the form of electron-densegranules that are clusterednear the SER. c. There are severalhundred mitochondria per liver cell.
lr4
Histology
d. The liver cell producesproteins for export (e.g.,albumin, prothrombin, fibrinogen), producesand secretesbile, storeslipids and carbohydrates,convertslipids and amino and detoxifies and acids into glucosevia the enzymatic processof gluconeogenesis, inactivatesdrugs by oxidation, methylation, and conjugation.
Bridge to Biochemistry
b. The bile canaliculi form a network that progressesalong the platesof the liver lobule in the direction of the portal canals.
isthede Cluconeogenesis novosynthesis of glucose fromnoncarbohydrate (lactate, glycerol, precursors in aminoacids). lt isreviewed detail intheCarbohydrates intheBiochemistry chapter Principles section of Ceneral BookI (Volume l).
c. At the periphery of the lobule, theseducts empty into Hering canals, which are small ducts composedof cuboidal cells.
ln a Nutshell
3. Bile canaliculi are tubular spaceslimited by the plasma membranesof adjacenthepatocftes (Figure Il-2-3). a. They have a small number of internal microvilli and are delimited by tight junctions formed by adjacenthepatocytes.
d. Theseductulesterminate in the cuboidal or columnar-lined bile ducts,which gradually form the right and left hepatic ducts. e. The hepatic ducts join to form the common hepatic duct. (1) The walls of the common hepaticducts and common bile duct havelayerscomparable to thoseof the intestine.
BileFlow -+ bileductules Bilecanaliculi -+ rightand (Hering's canals) lefthepatic ducts + common hepatic duct
(2) The circular muscle coat forms sphinctersat the terminal part of the duct that regulatebile flow into the duodenum. 4. Sinusoids of the liver are lined with fenestratedendothelial cells and scatteredphagocytic Kupffer cells, which are part of the mononuclear phagocytesystem(Figure ll-2-3). a. Kupffer cellsphagoqtize red blood cellsand particlesand contain cytoplasmicresidual bodies of iron and pigments. b. Fat-storingcellsalso lie in the perisinusoidalspace. 5. Liver regeneration can occur rapidly under some circumstances.As much as90olocan be replacedin about 2 weeks. D. The gallbladder storesand concentratesbile.It is a distensiblepear-shapedsacwith a 50-ml capaciry locatedon the undersideof the right lobe of the liver. The wall of the gallbladderis composedof three layers,with no muscularismucosae. 1. Mucosa a. Surfaceepithelium is composedof simple, tall, columnar cellswith apical surfacesthat bulge into the lumen. They bear irregular microvilli with a glycoprotein surfacecoat. (1) The processof bile concentration dependson active Na+ and Cl- transporting mechanismsin its epithelium. (2) Lateral membranesof thesecellsare extensivelyinterdigitatedbut separateduring the transport of water and ions (especiallyNa*) from the cytoplasmto the intercellular space.From there, the water movesinto blood vessels,and the bile is concentrated. (3) Some mucous cells and enteroendocrinecells are present in the neck of this organ. b. The lamina propria/submucosais a continuous layer of connective tissue because there is no muscularismucosa.
t35
Gastrointestinal System
2. Muscularis externa of the gallbladder consists of a thin layer of irregularly arranged smooth muscle fibers. a. Contraction of the muscle layer of the gallbladder is induced by the hormone cholecystokinin, which is produced in the mucosa of the small intestine. b. When the gallbladderis empry,the contraction of the muscularisthrows the mucosa into folds or rugae. 3. Serosaof the gallbladder coversits surfaceexceptwhere the organ is in contact with the liver. 4. The gallbladder communicates with the common hepatic duct through the cystic duct, which is composedof mucosa(tall columnar epithelium and lamina propria), muscularis, and serosa.
r56
Gastrointestinal Anatomy Theorgans residing withintheabdominal maybeclassified cavity aseither extraperitoneal or (i.e., retroperitoneal lacking a mesentery) orashaving a mesentery. Mesenteries aredouble-layered foldsof peritoneum, theserous membrane thatlinestheabdominal cavity. Theysuspend theviscera fromthebodywallandprovide a conduit whereby nerves andbloodvessels originating retroperitoneally canreach theviscera.
PERITONEUM A. Ligaments and folds. The following is not a completelisting becausethe mesenteriesof specificvisceraarenamedin conjunctionwith the descriptionsof the respectiveorgans. l. Foldsof the inner surfaceofanterior wdl a. Median umbilical fold is producedby a single,midline ligament running ftom the superiorsurfaceof the urinarybladderto the umbilicus,Alsoknownasthe urachus, it was the allantoic duct in fetal life.
b. Medial umbilical folds arebilateralstructuresfolmed by ligamentsrunning ftom the vesicularbranchesof tle internal iliac arteriesto the umbilicus.They werethe obliteratedumbilical arteriesof the fetus. c. Lateral umbilical folds are bilateral structures formed by the inferior epigastric vessels, which function in adult life. 2. L€ss€romertum runs betweenthe liver and the lessercurvatureof the stomach(sastrohepaticligament)and betweentre liver and the first part or trt ar.l."r. ii.piiJrr denal ligament). The hqratoduodenal ligament contains the common bile duct, the properhqraticartery andthe portalvein,i.e.,the portaltriad (FigureII-3-1).
Cliniol Correlate Serous fromthe exudate tinind rrrnrr6.att( rsrJ ^t v' iha u'! nanr^nF,rm P!"!v"Lu"' mayproduce anexcess of ffuidknownasascites that accumulates in theperitoneal cavity.lt isseenwth cancers ol theabdominal organs or it maybetheresultof advanced liverdiseaselt can alsooccurasa resultof riSht neaftlallure'
3. Falciform ligament attachesthe liver to the anterior abdominalwall and dividesthe liver into anatomicright and left lobes.The ligamenturn teres within the fulciform ligament wasthe feta.lumbilical vein.
tt7
System Gastointestinal
Anterior
Lesseromentum
Stomach
Gastrosplenic ligament
Portaltriad Hepatic artery Bile duct Portalvein
Bridge tg Fgbwofggy Aduhsfucture
FetalSbucture
Median umbilical Allantoic duct fold (urachus) MedialumbilicalUmbilical folds arteries Ligamentum teres
Visceral peritoneum (covering spleen)
Omental (epiploic foramen Parietal peritoneum Splenorenal ligament
Umbilicalvein
Left kidney
Right kidney Posterior
lnferiorvena cava
Figure ll-3-l.Transverse section through the abdomen at the level of the omental bursa.
clinical--C.ttqL?tS Thegreater omentum isa mobile$ructure thatmay prevent thespread of infection peritoneal withinthe cavity bysealing offinflamed areas, e.9., aninflamed appendix thatisaboutto rupture.
4. Greater omentum is a four-layered fold of peritoneum that hangs from the greater curvature of the stomach and attachesto the transversecolon. B. Peritoneal compartments. The peritoneal cavity is subdivided into regions by the peritoneal ligaments and mesenteries. 1. Greater sac is the major part of the peritoneal cavity. 2. ksser sac is the area posterior to the stomach and the lesser omentum. It is entered through the epiploic (Winslow) foramen, which is posterior to the hepatoduodenal portion of the lesseromentum. 3. Hepatorenal recessis located posterior to the right lobe of the liver and anterior to the right kidney. 4. Right and left paracolic gutters are located alongside the ascending and descending colons, respectively.
VISCERA ORGANIZATION OFABDOMINAL As discussedin the Embryology section,the organs of the gastrointestinaltract may be classified as derivativesof three embryonic regions: foregut, midgut, and hindgut. Organs belonging to eachof the three regionssharea common blood supply and preganglionic,parasympathetic innervation. Arterial supply is derived from the three unpaired visceral branchesof the abdominal aorta. Venous drainage of the gastrointestinal system and spleen leads to the portal vein, which is formed behind the neck of the pancreasfrom the joining of the splenic, superior mesenteric,and inferior mesentericveins.
t58
Anatomy
A. The foregut includes the esophagusdistal to the respiratory diverticulum, stomach,liver, gallbladder,pancreas,and duodenum to the point of entry of the common bile duct (anterior intestinal portal). The spleen,although not a part of the gastrointestinalsystem,shares the blood supply of the foregut. 1. Arterial supply. The artery of the foregut is the celiac trunk. a. Left gastric artery suppliesthe lessercurvature of the stomach and the lower third of the esophagus. b. The right gastricbranch of the common hepatic artery suppliesthe lessercurvature. The gastroduodenalbranch suppliesthe greatercurvatureof the stomachvia the right gastroepiploic(gastroomental)branch; it suppliesthe pancreasand the duodenum by the superiorpancreaticoduodenal branch.The proper hepaticbranch dividesinto right and left hepaticarteries.The rystic arteryis usuallya branch of the right hepaticartery. c. Splenicartery,the largestbranch of the celiactrunk, passesposterior to the stomach to supply the spleen.It givesoff short gastric arteriesto the fundus of the stomach, pancreaticbranches,and the left gastroepiploic(gastroomental)artery,whichsupplies the left half of the greater curvature and anastomoseswith the right gastroepiploic artery. 2. Venousdrainage. Blood from all parts of the gastrointestinalsystemdrains to the hepatic portal system;thus, products of digestionare first brought to the liver by the portal vein beforebeing returned by the hepaticveinsto the inferior vena cava.Foreguttributaries to the portal systeminclude the splenicvein and the left gastricvein, which hasan important esophageal branch (Figure II-3-2). 3. tymphatic drainage. Most foregut lymphatic channels ultimately drain to the celiac nodes, which surround the celiactrunk. From the celiacnodes,lymph passesto the thoracic duct. 4. Innervation. Preganglionic,parasympatheticfibers to foregut structuresare all derived from the vagi. Preganglionicsympathetic fibers to foregut structures travel in thoracic splanchnicnerves,synapsingmostly in the celiacplexus.
ClinicalCorrelate Portacaval anastamosis occu rs whena blockage ispresent in theliverasa result of cirrhosis orthepresence ofa tumor. Blood withintheportal system mustthenseek analternate routeto return to theheart. A pathway significant alternate involves theesophageal branch oftheleftgastric vein, which ultimately into drains thesuperior venacava. Since theesophageal veins aresmall andarenotmeant forsuch "heavy traffic," theymay become varicose andrupture. patient Thiscauses the to VOmit cODiOuS amOUnts Of blood. Ruptured esophageal varices area common cause patients of death in with advanced liverdisease.
B. The midgut commencesat the point of entry of the common bile duct into the second (descending)part of the duodenum (anteriorintestinalportal). It endsat the junction of the proximal two-thirds and distal one-third of the transversecolon (posterior intestinalportal). The midgut includes half of the duodenum, jejunoileum, cecum, appendix,and ascending colon aswell as two-thirds of the transversecolon. 1. Arterial supply. The artery of the midgut is the superior mesenteric artery. a. Inferior pancreaticoduodenalartery suppliesthe pancreasand the duodenum. b. fejunoileal arteriessupply the jejunum and the ileum. c. The anterior and posteriorbranchesof the ileocolic(ileocecal)arterysupplythe cecum, and the appendicularartery suppliesthe vermiform appendix. d. Right colic artery suppliesthe ascendingcolon and may arisefrom the ileocolic artery. e. Middle colic artery suppliesthe transversecolon. 2. Venousdrainage. The major midgut tributary to the portal systemis the superior mesenteric vein. 3. Lymphatic drainage. Most midgut lymphatics drain to the superior mesentericnodes, which lead to the intestinal trunk of the thoracic duct.
t59
System Gasfrointestinal
Esophagealvein
Azygosvein lnferiorvenacava
Lelt gastricvein
Stomach
vei Paraumbilical
Umbilicus
Epigastric veins
Superiorreclalvein Rectum
Middlerectalveins lnleriorrectafvein
Figure ll-3-2. Portacaval anastomoses.
4. Innervation a. Preganglionic parasympathetic fibers to midgut structures are all derived from the vagi. b. Preganglionic sympathetic fibers to midgut structures travel in thoracic splanchnic nerves,synapsingmostly in the superior mesentericplexus. C. Hindgut begins at the junction of the proximal two-thirds and distal one-third of the transversecolon (posterior intestinal portal). It terminatesat the junction of the upper one-third and middle one-third of the rectum. The hindgut includes the distal one-third of the transverse colon, the descendingcolon, and the sigmoid colon, as well as the upper one-third of the rectum.
t40
Anatomy
1. Arterial supply. The artery of the hindgut is the inferior mesenteric artery. a. Left colic artery suppliesthe descendingcolon. b. Sigmoid arteries(usually three) supply the sigmoid colon. c. Superior rectal artery,the terminal branch of the inferior mesentericartery, supplies the upper one-third of the rectum. 2. Venousdrainage. The major hindgut tributary to the portal systemis the inferior mesenteric vein. 3. Lymphatic drainage. The hindgut lymphatics drain to both the superior and inferior mesentericnodes. 4. Innervation a. Preganglionicparasympatheticfibers to hindgut structures arise from sacral spinal segments2,3, and 4 and run in the pelvic splanchnicnerves.
Note Branches ofthesuperior and inferior mesenteric arteries mayanastomose to forma continuous arterial channel along theperimeter ofthe (marginal largeintestine artery of Drummond). Thepresence ofthisvessel increases the chances thatthearterial supply to thecolonisnot completely interrupted if a smallareaiscutofffromits bloodsupply.
b. Preganglionicsympathetic fibers arise from the lumbar portion of the sympathetic trunk. Postganglionic sympathetic fibers arise from the hypogastric and inferior mesentericplexuses.
STRUCTURES OFTHEFOREGUT A. Esophagus(abdominal portion) 1. The abdominal portion of the esophaguspassesthrough the esophagealhiatus of the diaphragm at the level of the 1Oththoracic vertebra (T10). 2. It entersthe cardiacregion (cardia) of the stomach. B. Stomach 1. The stomachhasa lessercurvature,which is connectedto the porta hepatisof the liver by the lesseromentum, and a greatercurvature from which the greateromentum is suspended. 2. The cardiac region receivesthe esophagus. 3. The dome-shapedupper portion of the stomach,which is normally filled with air, is the fundus. 4. The main centerportion of the stomachis the body. 5. The pyloric portion of the stomach has a thick muscular wall and narrow lumen that leadsto the duodenum. C. Duodenum 1. The duodenum is C-shaped,has four parts, and is locatedretroperitoneallyexceptat the beginning and end.
Clinical€orrelate Pyloric whichoccurs stenosis, mostfrequently infirst-born maleinfants, results inthe narrowing of thepyloric lumen. lt ismanifested by projectile vomiting and requires surgical dilatation of thepylorus.
t4l
System Gasfointestinal
2. It receivesthe common bile duct and pancreatic duct in its second (descending)part. The common opening for thesestructures is the hepatopancreaticampulla (of Vater). Smooth muscle in the wall of the ampulla is known as the sphincter of Oddi. Note that the foregut terminates at the point of entry of the common bile duct or the anterior intestinal portal; the remainder of the duodenum is part of the midgut. 3. The duodenum is suspendedby the ligament of Treitz at the duodenojejunaljunction. D. Liver 1. The liver is investedby peritoneum (i.e.,the coronary ligament and the right and left triangular ligaments) except over the bare area that lies in direct contact with the diaphragm. It lies mostly in the right hypochondrium and is protectedby the rib cage. 2. The liver hastwo surfaces:a superior,diaphragmaticsurfaceand an inferior, visceralsurface(FigureII-3-3).
Common bileduct
Hepatic artery Portal vein Ligamentum teres
Quadrate lobe Gallbladder
Figure ll-3-3.Visceral surface of the liver.
Bridgeto Embryology Theligamentum venosum was theductus venosus infetallife. This$ructure connects the umbilical veinto theinferior venacava; oxygenated blood therefore bypassed theliver andwentstraight to theright atrium.
142
3 . The liver is divided into two lobes of unequal size by the falciform ligament. The right lobe may be further subdividedby fissuresfor the ligamentum teresand the ligamentum venosum,the porta hepatis,and the fossafor the gallbladderinto the right lobe proper, the quadrate lobe, and the caudate lobe. The quadrate and caudatelobes are anatomically part of the right lobe but functionally part of the left. They receivetheir blood supply from the left branchesof the portal vein and hepatic artery and secretebile to the left hepatic duct. 4 . The liver has a central hilus, or porta hepatis, which receivesvenousblood from the gastrointestinal systemvia the portal vein and arterial blood from the hepatic artery. The central hilus also transmits the common bile duct, which collectsbile produced by the liver. Thesestructures,known collectivelyas the portal triad, are located in the hepatoduodenal ligament,which is the right free border of the lesseromentum.
Anatomy
5. The hepaticveins drain the liver by collectingblood ftom the liver sinusoidsand retuming it to the inferior venacava. E. Gallbladder i. The gallbladderlies in a fossaon the visceral surfaceof tle liver to the right of tle qua&ate lobe'
9jUg.'|!g*!* The,trian$eof Calof is 2. It storesand concentratesbile, which entersand leavesthrough the cystic duct. The cysboundbythecysticdu( tic duct joins the common hepatic duct to form ttle common bile duct. hepaticduq andthelower . border of theliver.De{ining
srRucruREsoF THEMIDGUT Thestructures of tle midgutbeginat theanteriorintestinalportalin theduodenum. AJejunoileunthe|oa|izedductsand 1. The jejunum begins at the duodenojejunaljunction and comprisestwo-fifths of the remainingsmall intestine.The beginningof the ileum is not clearlydemarcated;it consistsof the distal three_fifthsof the small bowel.
performing this area when a (emoval cholecystectomy protecS ofthegallbladder) cwtcanery. Cliniol Conelate
2. The jejunoileum is suspendedftorn the posterior body wall by tle mesenteryproper. , Vitamin8,, andbilesaltsare Although the root of the mesenteryis only 9 incheslong, the mobile part of the small absorbed in theterminal intestineis approximately22 feetin length. ileum.pernicious anemiaand can . fat malabsorption B. Cecum 1. The cecumis the first part ofthe colon,or largeintestine,andbeginsat the ileocecaljunctron.
[::tffi::[H]:*'
2. It is a blind pouch,which hasa mesenteryand giv€srise to the vermiform appendix.The appendixhasits own mesenterythe mesoappendil C. Ascendingcolon liesretroperitoneallyandlacl$ a mesentery.It is continuouswith the transversecolon at the right colic (hepatic)flexure. D. Tlansversecolon 1. The transversecolon hasits owrt mesenterycalledthe transversemesocolon, 2. It becomescontinuouswith tle descendingcolon at the left colic (splenic)flexure.Note that the midgut terminatesat the junction of the proximal two-thirds and dista.lone-third of the tranwersecolon (posteriorintestinalportal).
STRUCTURES OFTHEHINDGUT A. The descendingcnlon lacksa mesentery.It ioins the sigmoid colon wherethe largebowel crossesthe pelvic brim. B. The sigrnoid colon is suspendedby the sigmoidmesocolon.It is the terminal portion oftlre largeint€stineand entersthe pelvisto continueasth€ rectum. C. The superior one-third of the rectum is coveredby peritoneumanteriorly andlaterally.It is the fu<ed,terminal, straight portion of tle hindgut.
t45
Gastrointestinal Physiology Thega$rointestinal system iscomposed ofa setof specialized organs involved inthedigestion and absorption of nutrients. Proteins, fats,andcarbohydrates arebroken downintoabsorbable molecules, which, along withwater, enterthebloodandlymphfordistribution throughout thebody. Thiscomplex setof actions ismediated bya variety of hormonal andneural inputs integrated with theinternal feedback controls of thegastrointestinal system.
APPETITE ANDTHIRST A. Appetite is primarily regulated by two regions of the hypothalmus: a feeding center and a satiety center. Normally, the feeding center is active but is transiently inhibited by the satiety center. It is not known whether food intake itsell a body weight set point, or both, are regulated by the hypothalamus. Genetic factors probably account for approximately 70o/oof adult body weight, while the balance is attributable to environmental factors. Appetite accommodatesgrowth in children aswell as maintenance of adult weight. In humans, many poorly understood psychological factors regulate the appetite. 1. Hypothalamus a. Feeding center. The feeding center is situated in the lateral hypothalamus. Stimulation of this areainduceseating,while destruction of this center causesanorexia. b. Satiety center. The satiety center is located in the ventromedial nucleus. Stimulation of this centercausesthe cessationof eating,and lesionsin this arealead to hypothalamic obesity syndrome. 2. Hormones. The introduction of food into the gastrointestinaltract causesthe releaseof hormones that inhibit further eating. a. Cholecystokinin (CCK) is releasedfrom cells in the mucosa of the small intestine. CCK-A receptors in the periphery and vastly more sensitiveCCK-B receptors in the brain reduce appetite when stimulated. b. Calcitonin, releasedmainly from the thyroid gland, has also been reported to decreaseappetiteby an unknown mechanism.
In a Nubhell Hypothalamus ./ :. /\ Feeding center
Satiety center
(lateral (ventromedial hypothalamus)nucleus) (+)+ eating (*) -r cessation of eating -> Destruction anorexia
-> Destruction hypothalamic obesity syndrome
3. Mechanical distention. Distention of the alimentary tract inhibits appetite, whereasthe contractions of an empty stomach stimulate it. Some satiety is derived from mastication and swallowing alone. 4. Glucostatichlpothesis. The ventromedial nucleusis one region of the brain where glucose utilization varies according to levels of blood insulin. Cells in the satiety center, called glucostats, are sensitiveto arteriovenous (AV) dififerencesof glucoseconcentration.
r45
Gasfrointestinal System
a.High AV glucose difference activates the glucostats, which, in turn, activate the center,resulting in inhibition of the feeding center and cessationof eating. b. LowAV glucose difference inactivates glucostats,relieving the satiety center'sinhibition of the feeding center;eating ensues. 5. Lipostatic hypothesis. The size of body fat deposits may regulate appetite by neurohumoral communication with the brain. 6. Ambient temperature. A warm environment inhibits appetite, whereasa cold one stimulates it. B. Thirst. Like appetite, thirst is also regulated primarily by the hypothalamus. It may be regulated in concert with appetite or independently of it.
Bridge to RenaflUrinary Angiotensin ll actsaspartofthe renin-angiotensin-aldosterone qptem.lt isdiscussed in detail Physiology intheRena/Urinary of Organ chapter Sy$ems Bookt (Volume lll).
Nole plasma lncreased osmolarity ADHsecretion alsoincreases pituitary. fromtheposterior water ADHincreases reabsorption inthenephron's collecting duct.
1. Extracellular fluid (ECF) volume. A decline in ECF volume regulates thirst through the renin-angiotensinsystemand through cardiacand vascularbaroreceptors. a. Angiotensin II acts on the subfornical organ in the diencephalon, stimulating neural thirst control areas.It may also act on the organum vasculosum of the lamina terminalis (OVII). Theseregions are located circumventricularly,outside the blood-brain barrier. b. Baroreceptors and sensory volume detectors in the vascular system also regulate thirst. Consequently, blocking the action of angiotensin does not totally ablate the control of thirst. 2. Plasma osmolality. Increasedplasma osmotic pressureleads to stimulation of osmoreceptorsin the anterior hypothalamus.This action promotes drinking. 3. Other factors a. Dryness of the pharyngeal mucosa stimulates thirst. b. Mechanical stimulation of the pharynx and stomach by volume stretching may inhibit drinking.
(MASTTCATTON) GHEWTNG ANDMOTSTENTNG A. Teeth. The incisors and canine teeth cut and tear food into sizes suitable for the buccal cavity. The molars pulverize the chunks into a mash, which is mixed by the tongue with saliva and other secretions from the salivary glands. Mastication is not necessary for digestion, but its absencemakes swallowing very difficult or painful. B. Salivary glands. Approximately 1.5 llday of saliva with a pH of slightly lessthan 7.0 is produced.The pH risesto approximately8.0 during the activesecretionassociatedwith eating or the anticipation of eating. 1. Salivaryglands consistof three main pairs of glandsand some subsidiarybuccaland lingual glands. a. Submandibular glands produce approximately 70o/oof the saliva (moderately viscous secretion). b. Parotid glands produce approximately 20o/oof the saliva (mostly water). c. Sublingual glands produce approximately 5o/oof the saliva (very viscous secretion). d. tingual and other minor buccal cavity gluttdt produce the remaining 5o/oof the saliva.
t46
Physiology
2. Salivary composition. Saliva is generally isotonic with plasma when initially secretedby the glands. a. At low salivary flow rates,as saliva travels down the ducts toward the oral caviry Na+ and Cl- are reabsorbed, and K+ and HCO3- nre secreted.The resultant salivais hypotonic becauseof the low water permeability of the ducts and the fact that more ions are reabsorbedthan secreted. b. At high flow rates(e.g.,with parasympatheticstimulation), salivaosmolality approachesthat of plasma.
3 . Salivary function. Saliva eases swallowing, maintains mouth moisture, dissolves moleculesthat stimulate taste,and initiates starch digestion.Additionally, it helps keep the teeth clean and provides an alkaline rinse for the esophagus,neutralizing any refluxed gastric acid. 4. Salivaryenzymes
ln a Nubhell
a. Salivary a-amylase (ptyalin). Secretory acinar cells of the salivary glands secrete zymogen granules,which releasesalivary u-amylase into the saliva,where it initiates the breakdown of polysaccharides (starch) in the mouth. b. Lingual lipase. Glands on the tongue secretelipase,which initiates the breakdown of fats into monoglyceridesand fatty acids. 5 . Other salivary gland secretions
Digestion begins inthe mouth: . Salivary cr-amylase initiates thebreakdown of polysaccharides (starch).
a. Mucins are glycoproteins that lubricate the food and protect the buccal and esophagealmucosafrom scratching.
. Lingual lipase initiates the breakdown offats.
b. Lysozyme breaks down the cell wall of bacteria, an apparently protective measure againstinfection.
Bridgeto lmmunology
c. Lactoferrin binds iron and is bacteriostatic. d. High-proline proteins protect the tooth enamel and bind toxic tannins. e. Immunoglobulin A (IgA) helps defend againstbacteriaon mucosalsurfaces. f. Kallikrein is a proteolytic enzymethat cleaveskininogens to form bradykinin. 6. Regulation of salivation a. Parasympathetic innervatiorr-+timulation
causes:
( 1) An increasein the synthesisand secretionof watery salivavia acetylcholineacting at muscarinic receptors (2) Secretionof kallikrein, a vasodilatorthat causesan increasein blood flow to the salivaryglands,resulting in an increasein salivasecretion b. Sympathetic innervatiorr--stimulation
lgAdeficiency, themost common immune deficiency, leads to increased susceptibil ityto infections, particularly upperrespiratory infections.
causes:
Bridgeto NeruousSystem Remember thatcholinergic (e.g., blockers atropine) often cause dryness ofthemouth.
(1) Production of viscous saliva rich in amylase,K+, and HCO3-, mainly via norepinephrine'saction on B-adrenergicreceptors. (2) Contraction of myoepithelial cells and constriction of blood vessels,causing a decreasein blood flow to the salivary glands, leading to the production of a thicker, more viscoussecretion. c. Reflex innervation causessalivation as a result of the presenceof food in the mouth; the taste,smell, sight, or thought of food; and the stimulation of vagal afferentsat the distal end of the esophagus.
In a Nubhell Salivation isincreased byboth sympathetic and parasympathetic innervation.
147
System Gastrointestinal
NG(DEcrurriloN) swArrowr ln a Nutshell istriggered Swallowing byCNlXandCNX.
A. Swallowing is a reflex action with its afferent impulses carried primarily by the glossopharyngeal (CN IX) and vagus (CN X) nerves.The nucleus of the solitary tract integratesthe afferent information and coordinates the swallowing mechanism via the nucleus ambiguus and hnroglossal nucleus. Food is moved to the esophagusby the movement of tongue (hypoglossalnerve, CN XII) and the palatal and pharyngeal muscles (CNs IX and X). Swallowing occurs frequently, up to 600 times per day.Approximately one-third of swallowing occurs during eating, one-twelfth during sleep,and the balanceat various times during the waking day. 1. Initiation of swallowing occurs voluntarily when the mouth is closedon a bolus of food and the tongue propels it from the oral cavity into the pharynx. 2. Involuntary contraction of the pharynx advancesthe bolus into the esophagus. 3. Automatic closure of the glottis during swallowing inhibits breathing and prevents aspiration.
Perrslaltic wave
4>
Esopnagus
Stomach
Figure ll-4-1.Peristalsis in the esophagus. 4. Peristaltic contraction of the esophagus(FigureII-4-1) propelsfood along the esophagus junction. Located here is the toward the stomach, starting at the pharyngoesophageal upper esophagealsphincter (UES), a band of esophagusapproximately 3 cm in length with high resting wall tension. The UES automatically relaxesat the initiation of swallowing, closingrapidly behind the bolus of food; it then contracts,preventingreflux. junction. (It is 5 . Lower esophagealsphincter (LES) is the muscle at the gastroesophageal sometimescalled a physiologicsphincterbecauseit is not a true anatomic sphincter.) a. Contraction of the LES occurs tonically, but the LES relaxes on swallowing.
t48
Physiology
b. Regulation of the LES is controlled by the vagus nerve. The most important neurotransmitter is VIP. c. High muscle tone normally keepsgastric contents from entering the esophagus.The tone is supported by: (1) Pressuredifference between intra-abdominal and intrathoracic cavities, which helps keep the LES closed (2) Musculature of the diaphragm (3) Phrenicoesophageal ligament (a) Folds in the esophagealmucosa d. Hormones may modulate the tone of the LES: Gastrin may increasetone, whereas secretin and CCK may decreasetone. B. Achalasia is a pathologic inability of the LES to relax during swallowing. It results in food accumulating in the esophagusand grossly dilating the structure. Characteristicsof achalasia include increased LES tone, incomplete relaxation of the LES on swallowing, weak esophagealperistalsis,and a reduction in VlP-containing neurons in the lower esophagus.It can be treated by pneumatic dilatation of the LES or by esophagealmuscular incision (myotomy). C. Esophageal reflux results from an incompetent LES, allowing gastric acid to enter the esophagus.The condition can be treated with H2-receptor blockers,proton pump inhibitors, prokinetic agents,or fundoplication (a surgical procedure that raisesa fold of gastric fundus up over the baseof the esophagus).
Clinig4l Correlat-e Themostcommon symptomatic complaint of refluxisa burning sensation in thechest(substernal area). Thissensation isoften confused witha myocardial infarction.
t49
Gastrointestinal System
Esophagus Adventitia Longitudinal muscle
Lessercurvature Duodenum
curyature
Gastricrugae
Submucosa Pyloricsphincter
Mucosa
Figure ll-4-2.Major regions and structures of the stomach.
NTESTI NAt MOTIIITY GASTROI A. Stomach.The bolus of swallowedfood is receivedby the stomach,where it is further maceratedand mixed with HCl, mucus, and pepsin.The food is then dischargedat a controlled rate into the duodenum. Only a small amount of chemical digestion actually occurs in the stomach (Figure lI-4-2). The major functions of the stomach are storage,mixing, and controlled emptying. 1. Motiliw
ClinicalCorrelate Withstrong adrenergic stimuli, asin major trauma orsevere pain, gastric mayoccur atony andaspiration of retained contents isa danger.
a. Muscular structure consistsof outer longitudinal and circular muscleswith a unique, third, inner oblique layer. b. The pacemakeris located in the midcorpus of the greatercurvature.Its basalelectric rhythm (BER) is about 3 cpm. Peristalticslow wavessweeptoward the pylorus from this region. (1) The rate of peristalticcontraction is governedby neuronal and other inputs, but cannot exceedthe BER of the pacemaker. (2) The magnitude of contraction is modulated by sympathetic (decreases)and parasympathetic(increases)influencesvia the myenteric and submucosalplexi and by hormonal stimuli. c. The pylorus is continuous with the circular musclelayer and its contraction is modulated by enkephalins. 2. Receptiverelaxation is critical for the storagefunction of the stomach.As the stomachfills, there is a reflex relaxation of muscle tone, principally of the fundus, that allows the retention of gastriccontentswithout increasingstomachwall tension.
t50
Physiology
a. Afferent stimuli originate in stretch receptors. b. Afferent and efferent impulses run through the vagusnerve. The relaxation is mediated byVIP and nitric oxide. 3. Chyme. Contraction of the stomach, principally in the antrum, snd the conical shapeof the stomach permit the mixing of food with the stomach acids and the formation of chyme. This activity is hormonally and neuronally mediated. 4. Gastric emptying. The contractions of the stomach propel chyme through the pylorus at a regulated rate. a. Peristalsis is the coordinated propulsive contraction that advancesfood down the digestivetract. (1) Initiation of the contraction occurs through action potentials in longitudinal and circular muscle. (2) Intensity increasessteadily as the contractions sweeptoward the pylorus. (3) Pyloric sphincter contraction at the time of antral contraction limits the movement of chyme into the duodenum. This encouragesemptying to occur in short spurts, and promotes mixing by forceful regurgitation of antral contents back into the fundus. b. Volume of chyme and liquids entering the duodenum depends on the pressuregradient betweenthe antrum and the duodenum and on the degreeof pyloric relaxation. c. Hormone modulators of emptying include CCK, which inhibits gastric emptying. During fasting, a peptide named motilin is thought to be responsiblefor the migrating myoelectric complex (MMC). This is a cycle of gastrointestinal motor activity, usually initiated in the stomach and propagated through the small intestine, that prevents the stasisof material in the gut. d. Physicochemical modulators of emptying include the liquid-solid nature of food, the particle size,antral distention, caloric densiry osmolariry and the pH of the contents. Favoring emptying are low caloric densiry iso-osmolality, and neutral pH.In contrast, hlperosmolariry low pH, and high lipid content in the duodenum each slow gastric emptying. Receptorsin the small intestine for pH, products of digestion, distention, and osmolality are the major regulators of gastric emptying. This is logical since a major stomach function is to meter out food slowly enough for the small intestine to digest. B. Small intestine. The duodenum is the proximal pyloric end of the small intestine. Distal to the duodenum is the jejunum, and then the ileum. In the small intestine, the chyme from the stomach is mixed with mucosal cell secretions,exocrine pancreatic juice, and bile. 1. Mucus secretion. Mucus is secretedas mucins (complex glycoproteins), which hydrate and gel, forming the mucus covering the intestinal epithelium. a. Mucus production occurs in surface epithelial cells throughout the gastrointestinal tract, Brunner glands in the duodenum, and goblet cells in the mucosa throughout the intestine. b. Mucus functions include lubrication of the gastrointestinal tract, binding bacteria, and trapping immunoglobulins where they have accessto pathogens.
ClinicalConelate A compromise ofthemucus protection canleadto significant damage and irritation of thega$rointe$inal tract,leading to ga$ritis, duodenitis, or evenpeptic ulcerdisease.
c. Rate of mucus secretion is increasedby cholinergic stimulation, chemical irritation, and physical irritation. d. Differently constituted mucins are produced by different varieties of goblet cells.
t5l
System Gasfrointestinal
2. Intestinal motility. Segmentationcontractions and peristalsisrequire an intact myenteric nerve plexus but not extrinsic innervation. a. Small bowel slow waves. The smooth muscle depolarizes caudally in a slow wave in the circular smooth muscle.The rate slowsfrom approximately l2lmin in the jejunum to approximately 9/min in the ileum. b. Segmentation contractions are ring-like contractions that occur at random "nodes" along the intestine. They relax, and then new nodes are formed at the former internodes.This motile action movesthe chyme back and forth, increasingthe mucosal exposure to the chyme. Thesecontractions do not result in any net caudad movement.
Clinical Correlate bythe Peristalsis isactivated parasympathetic For system. thosesuffering from decreased intestinal motility manifesting asconstipation (paralytic ileus, diabetic gastroparesis), dopa minergic andcholinergic agents are oftenused(e.9., cisapride, metoclopramide).
c. Peristalsis is a reflex responseinitiated by stretching of the lumen of the gut, usually by the bolus of food or chyme. The stimulus causesa contraction of the muscle at the oral end of the stimulus and a relaxation of the muscle at the caudal end, thus propelling the contents caudally. (1) The rate of content propulsion variesfrom 20 mm/s to 250 mm/s. Although peristalsisis modulated by autonomic input, it can occur even in isolated loops of small bowel with no extrinsic innervation. (2) The intrinsic control sensesstretch with calcitonin gene-relatedpolypeptide neurons(CGRP). (3) The contractile wave is initiated by acerylcholine (ACh) and substanceP. (a) The relaxation caudal to the stimulus is initiated by nitric oxide (NO) and VIP. 3. Intestinal secretions are generally alkaline, serving to neutralize the acidic nature of the chyme entering from the pylorus. C. Large intestine (colon). The colon is larger in diameter and shorter in length than the small intestine. Three longitudinal bands of muscle, the teniae coli, constitute the outer layer. Sincethe colon is longer than thesebands,pouching occurs,creatinghaustra betweenthe teniae,giving the colon its characteristic"caterpillar" appearance.The mucosahas no villi, and mucus is secretedby short, inward-projecting colonic glands.Abundant ly-ph follicles are found in the cecum and appendix,and more sparselyelsewhere.The major functions of the colon are reabsorption of fluid and electrolytes and temporary storage of feces. 1. Motility. The caudal end of the ileum projects into the larger colon in such a way that increasedcolonic pressuresqueezesit closed (Figure II-4-3). When ileum pressureis greater than colonic pressure,there is free movement of chyme into the colon.
Cecum
Figure ll-4-3.Diagrammaticview of the projection of the ileum into the cecum.
t52
Physiology
a. Peristaltic waves briefly open the normally closed ileocecal valve, passing a little chyme into the cecum. Peristalsisalso advancesthe chyme in the colon. Slow waves, approximately 2lmin, are initiated at the ileocecalvalve and increaseto approximately 6/min at the sigmoid colon. b. Gastroileal reflex. When the bolus passesthrough the pylorus, the cecum relaxes, transiently increasingthe flow of chyme out of the small intestine. (1) Relaxation of the ileocecalvalve may occur through vagal activity. (2) Constriction of the ileocecalvalve occursthrough sympatheticstimulation. c. Segmentation contraction. The contents of the colon are mixed back and forth by segmentalcontractions. d. Mass action contraction is found only in the colon. Constriction of long lengths of colon propel large amounts of chyme from one region to the next. This contraction also moves fecesinto the rectum, distending the rectum and initiating the reflex of defecation. (1) Approximately 4 hours elapsebefore ingestedfood first reachesthe cecum. (2) By 12 hours, almost all ingestedfood has reachedthe colon. (3) As long as 72 hours may be neededfor progressionto the anus. 2. Absorption. The mucosa of the colon has great absorptive capability. Na+ is actively transported with water following, and K+ and HCO3* er€ secretedinto the colon. 3. Fecescontain undigestedplant fibers, bacteria,inorganic matter, and water. Nondietary material (e.g.,sloughed-off mucosa) constitutesa large portion of the feces.Defecation continueseven during prolonged fasting or starvation. 4. Bacteria (flora). In normal feces,30o/oof the solids may be bacteria. a. Bacteriasynthesizevitamin K, B complex vitamins, and folic acid; split urea to NH.; and produce small organic acidsfrom unabsorbedfat and carbohydrate. b. The brown color of fecesis mainly due to the action of bacteriaon bile pigments. c. The odor of fecesis due to sulfidesand indolic compounds. 5. Defecation. Rectal distention with fecesactivatesintrinsic and sacral reflexesthat cause relaxation of the internal anal sphincter (smooth muscle) and producesthe urge to defecate. If the external anal sphincter (skeletalmuscle innervated by the pudendal nerve) is then voluntarily relaxed,defecationoccurs.If the externalsphincteris held contracted,the urge to defecatetemporarily diminishes. 6. Gastrocolic reflex. Distention of the stomach by food produces the urge to defecate,a reflex mediated by parasympathetic innervation as well as by gastrin and CCK. a. In the transverseand descendingcolon, a programmed motor action fitting the pattern of coordinatedperistalsisoccurs. b. This propulsion causes"massmovement" of fecesover considerabledistance. c. Laxatives(castoroil), parasites,and enterotoxinsacting on mucosalreceptorsmay also initiate "power propulsion" or massmovement.
t55
System Gastrointestinal
HORMONES GASTROINIESTINAT PEPTIDE A. Metabolism of hormones 1. Clearanceftom circulation is rapid. 2. Degrad.tion is accomplishedby gut peptidases,hepatic metabolism,and renal metabolism. 3. Function is through receptorswith high affinity and specificiry The hormonal responspathways. esare mediatedby cAMP-dependentand Ca2+-dependent
ln a Nu8hell Gastrin . Produced byG cellsof antrumandduodenum . Secretion is stimulated by vagaldischarge and productof digestion . Mainroleisfre $imulation of byparienlcells HCIsecetion
B. Gastrin 1. Synthesisand storageof gastrinoccurspredorninantlyin the G cellsof the duodenum and in the pyloric antrum. 2. Stirnulus for gastrin secretionincludesincreasedvagaldischarge(mediatedby gastrin releasingpeptide,or GRP),digestiveproducts (i.e., amino acids,polypeptides),calcium salts,and gastricdistention. 3. Inhibition ofgasrin releaseoccursthrough acidfication ofpyloric glandularmucosato pH <1'5' 4. Physiologicroles of gastrininclude: a. Stimulation of HCI secretionby parietal cells
C!!!91 Conglatg Zollinger-Ellison Syndrome Non-pisletcellpancreatic tumorthatproduces Sastrin. ThiSt prOduction of gastrin leadsto t ga$ricacid secretion anddevelooment ol DeDtic ulcerdisease. . Symptoms: pain,dianhea . Diagnosis: t gastrinlevels . Treatment: omeprazore, H, blockers
b. stimulation of histaminereleasefrom enterochromaffin-likecells c. Stimulationof pepsinogensecretionby chief cells (1'lncrease or gastrlcDloootlow e. Prornotion of contractionof circular musde of the stomach f. Trophiceffecton gastricand small-intestinalmucosaand pancreas C. Cholecystokinin (CCK) 1. Synthesisand storageis in I cellsof duodenalandjejunal mucosaand the cNS. 2' stimulus for secretion a' Fat dig€stionproducts (monoglyceridesand fatty acids) b. Amino acids,especiallytr'?tophan, and peptidesin the duodenum 3. Physiologicroles a. Stimulation ofgallbladder contraction and relaxationof the sphincterof Oddi b. Stimulation of pancreaticenzl'rnesecretionpredominantlyvia an atropine-sensitive (cholinergic)pathway. c. Inhibition of gastricemptying d. Trophiceffecton the exocrinepancreasand gallbladdermucosa D. Secretin 1. Synthesisand storagetakesplacein S cellsin the mucosaof the duodenum.
t54
Physiology
2. Stimulus for secretion a. Acidification of duodenalrnucosa(amount releasedis inverselyproportional to pH of dryme enteringduodenum) b. Fatty acids 3. Physiologicroles a. Stirnulation of the secretionofbicarbonate-containing fluid ftom the pancreasand biliary ducts b. Increasesbile production (noncompetitive) c. Inhibits H+ secretionby the pari€talcelt. E. Gastricinhibitorl peptide (GIP) is producedin the duodenalandjejunal mucosaby K cells and is releasedwhenstimulatedby intraluminal glucose,amino acids,and fatty acids.GIP is sometimescalled'glucose-dependentinsulinotropic" peptide (which aids in remembering its tunction)'
In 1m{t9lt MainRoleof CCK ' Stimulates pancreatic enzyme secretion
1. It stimulatespancreaticinsulin releasein the presence ofhyperglycemia(FigureII-4-4).
. stimulates gallbladder contracton
2. It inhibits gastricacid secretion.
. Decreases gastric emptying
F. Vasoactiveintestind polypeptide (VIP) is located in the parasympatheticganglia in sphincters,gallbladder,andsmallintestine,andhasneurotransmitterfunaion (nonidrJnergic and noncholinergic). l. stimulus for releaseis vagalstimulation and intestinaldistention. 2. Inhibition occursby adrenergicinput 3. Physiologicroles a- Stimulation of water and electrolytesecretionby the jejunum, ileum, and colon (via
.AMP) b. Relaxationof intestinalsmoothmuscle,including sphincters.With nitric oxide,mediatesswallow-inducedrelaxationof LESand recqrtiverelaxationof stomach. c. stirnuration of pancr€aticHco3- secretion d. Intestinarvasodilatation G' somatostrtin l. Synthesisand storage occur in D cells of the pancreaticislets, gastric antrum, and throughout the intestine.It is alsopresentin tlle hypothalamus.
MainRoleof Secretin . Stimulates HCO,-secretion fromthepancreas andliver MainRoleof GtP ' Stim-ulates pancrmtic Insullnsecreton
oinial Gonelare ' VlPoma-q tumorof nond" non-Fisletcellsof the thatsecretes vlP Dancreas . Symptoms: watery diarrhea . Treatment resection of tumor
t55
System Gastrointestinal
Increasedpancreatic secretion lncreasedbile secretion
+
Promotion
Figure ll-4-4.Combined actionof gastrin,secretin, peptide(GlP). cholecystokinin (CGK),and gastric-inhibitory
1r';*
6 t,' i
at,
f
'ri
2. Physiologic roles. Somatostatin inhibits the releaseof gastrin, CCK, and most other gastrointestinalhormones.
(' v V 1 1\"
',,1 ,rt
(''
a. Inhibits gallbladdercontraction and pancreaticsecretion b. Inhibits gastricacid and pepsinogensecretion c. Inhibits small intestinal fluid secretion ',{)
!
d. Inhibits ACh releasefrom the myenteric plexus and decreasesmotility i
1
i
I.""''
+
'"t \
e. Inhibits cr-cellreleaseof glucagon,and B-cellreleaseof insulin in pancreaticislet cells
I
'
5ttt'
CCK L
'r'l
[-i
l't i
H. Pancreatic polypeptide
'
'!z
1. Synthesis and storage takes place in F cells of the pancreas and also in the CNS. It is releasedin responseto vagal cholinergic stimulation and protein-containing meals. 2. Physiologic roles include the inhibition of pancreaticsecretionof HCO3- and enzymes and the relaxation of the gallbladder.It plays no role in the regulation of acid secretion.It inhibits vagal activity antrally and acetylcholine releaselocally. I. Motilin l. Production occursin M and enterochromaffin(EC) cellsin the duodenum and jejunum. 2. Secretion occurs during fasting. 3. Physiologic role is to regulatethe migrating myoelectriccomplex (MMC).
t56
Physiology
a. Erythromycin binds to the motilin receptorand seryesasan agonist,promoting gastric emptfing. '': '-''.. L Entemgucagon it.:,t..., 1 Synthesisoccursin the L cellsof the intestine. 2. physiologic roles a. Inhibition of gastricand pancreaticsecretionand smoothmusclecontraction
Clinkal COrrelate Inaddhion to ib useas anantibiotic, erythromycin istherapeutic for patienb withSastroparesis. A common sidetffectof erythromycin
b. Stimulation of insulin s€cretion
1. Synthesisoccursin the enteroduomaffin cellsofthe upper smallintestineand colon and alsoin the CNS.
. -,. : . :' r... 1.,- . .
2. Stirnrdusfor releaseftom tle myentericplexusoccurstlrough vagalefferentpathways.
.'
;......
3 . P h y s i o l o gr oi cl e s
.)
:".,.,,"
K. Substance P
:
',
A
a. Stimulation of salivaryflow and gastroint€stinalmotility b. Tiansmissionof pain impulsesin the nervoussystem
GASTROINTESTINAT SECRETIONS A. Gastric secretions I . Glandular cellsof tlle mucosa a. Cardiac glandular region surroundsthe esophageal opening and containscellsthat s€creteprimarily mucus, b. Oxyntic glandular region is found in the proximal 80% of the stomachand sparsely in the antrum; it contains: ( 1) Parietalcells,which secreteHCI and intrinsic factor (2) Chief cells,which secretepq>sinogen (3) Mucousneck cells,which secretemucus c. Py'oric glandular region contains: ( 1) Mucus-secretingcells (2) G cells,which secretegastrin (3) D cells,which secretesomatostatin d. Other cells: (1) Enterochromaffincells,which secreteserotonin and histamine (2) Paracrinecells,which s€cretesomatostatin,VIB and glucagon (3) Mast cells,which secretehistamine (4) Plasmacells,which secreteIgA 2. Hydrodrloric acid (HCl) a. HCI is secretedby parietal (oxyntic) cells. It denaturesproteins,kills ingestedbacteria, and activatesdigestiveenzymes(e.g.,pepsinogento pepsin).
157
Gastrointestinal System
b. H- is generatedby the combination of CO2 and H2O in the parietal cell. It is secreted into the gastric lumen in exchangefor K*; H* secretion is coupled with secretion of Cl- (FigureII-4-5). c. The HCO3-generatedin the parietal cell is absorbedinto the bloodstreamin exchange for Cl-.
Bridge to Pharmacology (cimetidine, H,blockers ranitidine) decrease acid production bybinding receptors to thehistamine onparietal cells.
d. Major stimuli for acid secretionare substancesthat bind to specificreceptorson the serosalmembrane of parietal cells. (1) Histamine, releasedfrom the mast cellsin gastric mucosa (2) ACh, releasedfrom the vagus nerve, activatesparietal cell muscarinic receptors (3) Gastrin, releasedfrom G cellsinto the bloodstream e. Major inhibitors of acid secretion(many act by stimulating gastric D cellsto release somatostatin).
inhibits Omeprazole acid byblocking theH./K. secretion ATPase oftheparietal cell.
(1) Low pH inhibits HCI secretionby decreasinggastrin production (2) Prostaglandins
Gastric l umen
Interstitial fluid
'Kf
Na+ K+ K+
)) 4
Co2+ H2o | Carbonic anhydrase J HzCOs
6+ ;1+
clHCOt
Figure ll-4-5.Hydrochloric acid secretion by parietal cells in the stomach. 3. Pepsin
In a Nutshell Pepsin isa protease, involved inthedigestion of proteins (peptide bonds). lt isstored as pepsinogen. thenTmogen
r58
a. Pepsin is synthesizedand stored in granules in chief cells as pepsinogen, a zymogen or proenzfme (inactive precursor) of pepsin. The obvious advantageof producing and storing digestiveenzfmes in zymogen form is to protect the cell againstthe effects of its own products. b. Pepsinogenis secretedinto the gastric lumen and is activated to pepsin both by H+ and by pepsin itself (autocatalytic). pH optimum is 1-3; it is irreversibly inactivated at pH >5.
Physiology
c. Pepsin digestsup to 20o/oof.proteins by cleaving them at peptide bonds involving the amino acids tyrosine and phenylalanine. It is especiallyeffective at digesting collagen in connective tissue. d. Secretionis stimulated by ACh (vagalstimulation), gastrin, and HCl. 4. Mucus a. Produced by mucous neck cells, mucus is 80o/ocarbohydrate,20o/oprotein, and highly viscous. b. It forms a gel on the gastric mucosa that protects the mucosa from the proteolytic effects of HCI and pepsin. It also traps HCO3- secretedby the mucosal cells to neutralize acid near the cell surface. 5. Intrinsic factor a. Production occursin the parietal cells. b. Intrinsic factor is necessaryfor vitamin B, absorption by the ileum. Vitamin B, is taken up as a complex with intrinsic factor. B. Phasesof gastric secretion 1. Cephalic phase. The smell, sight, or thought of food can increasegastric secretionvia parasympathetic (vagal) pathwaysacting directly on parietal and chief cells. 2. Gastric phase. Depending on the chemical composition and volume, food in the stomach increasessecretion.The greatesteffectsoccur with proteins and peptides(alcohol and caffeine also exert a strong effect). These changesare mediated by the vagus nerve, by stretch reflexesin the stomach wall, and by gastrin. Gastrin is secretedby endocrine cells in the mucosaof the antrum and travelsvia the bloodstreamto parietal and chief cells. 3. Intestinalphase. Protein digestionproducts in the duodenum stimulateduodenalgastrin secretion.In addition, absorbed amino acids act to stimulate H+ secretionby parietal cells.However,the intestinal phase accountsfor lessthan 10o/oof the gastric secretory responseto a meal. C. Pancreatic secretions. The exocrine secretionsof the pancreasare produced by the acinar cells, which contain numerous enzyme-containing granules in their cytoplasm, and by the ductal cells, which secreteHCO3-. The secretionsreach the duodenum via the pancreatic duct. The major components of the pancreaticsecretionsare H2O, HCO3-, and digestive enzymes.
Bridgeto Pharmacology Inthetreatment of ulcers, agents aresometimes usedto protect themucosa. . Sucralfate + actsasa protective coating onthe stomach . Misoprostil + a synthetic prostaglandin thatalso protects mucosa thegastric These drugs arediscussed intheCa$rointestinal Pharmacology chapter ofthisbook.
ln a Nutshell Pancreatic Secretions ' Hro . HC03-
. Digestive enrymes
1. HCO3a. HCO3- is produced by the action of carbonic anhydraseon CO2 and H2O in the pancreatic ductal cells.HCO3- is secretedinto the lumen of the duct in exchangefor Cl-. b. The function of HCO3- in the duodenum is to neutralize the HCI in chyme entering from the stomach.This also deactivatespepsin. c. The rate of HCO3- secretionis dependenton the degreeof acidity of the chyme and is controlled by the duodenal hormone secretin (nature'santacid). 2. Pancreatic enzymes. Approximately 15 digestiveenzymesare produced by the pancreas. They are responsiblefor the breakdown of proteins, carbohydrates,lipids, and nucleic acids.The primary enzymesare listed in ThbleII-4-1.
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Gastrointestinal System
Thble II-4-f . The primary pancreatic enzymes. En4rme
Reaction Catalvzed
Proteases Tiypsin Chymotrypsin Carboxypeptidase
Proteins + peptides Proteins -+ peptides Peptides-+ amino acids
Polysaccharidases Amylase
Starch and glycogen + maltose, maltotriose,and a-limit dextrins
Lipases Phospholipases A and B Esterases
Phospholipids+ phosphate,fatty acids,and glycerol Cholesterolesters-+ free cholesterol
Triarylglycerol
Triglycerides + fatty acids and
Lipases
monoglycerides
and fatty acids
Nucleases Ribonuclease
RNA + ribonucleotides
Deoxyribonuclease
DNA + deoxyribonucleotides
a. Protection of pancreaticacinar cells againstself-digestionoccurs through two main mechanisms: ( 1) Synthesisas inactive precursors. Someenzymesare secretedas inactiveprecursorsand are activatedby partial proteolysis.For example,the proteolytic enzyme trypsin is secreted in an inactive form, trypsinogen. A duodenal enzyme, enterokinase, splits six amino acids from the N-terminus of trypsinogen to generatethe active enzyme.Tiypsin then catalyzesthe formation of more trypsin and activateschymotrypsinogen,procarboxypeptidase,and prophospholipases A and B. Ribonucleases, amylase,and lipasedo not exist asproenzymes.
(2)Enarme'*:il"x'il:;:,"J:[li]fiffi',".;T;lT:inhibitorsinactivatetrace b. Stimulation of pancreatic enrqe secretion occurs via CCK, which is releasedin responseto amino acids and fatty acidsin the duodenum. Acerylcholinealso stimulates enzymesecretionvia vagovagalreflexes. D. Hepatic secretion 1. Physiologic roles a. Excretion of bfirubin, cholesterol,drugs, and toxins b. Promotion of intestinal lipid absorption c. Delivery of IgA to small intestine 2. Components of bile flow a. Bile salt-dependent canalicular flow
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Physiology
(1) Bile flow is directly proportional to bile salt output. Uptake of bile salt is sodiumdependent and energizedby the Na+ gradient maintained by the sinusoidal Na--K--ATPase. (2) Water flow is a passiveultrafiltrate of plasma with its electrolyte composition modified in the bile ducts.Water flows in responseto the osmotic pressuregenerated by bile salt secretion. (3) Flow is determined by the rate at which bile salts are availableto hepatocytes (enterohepaticcirculation) and the rate of hepatocytebile salt synthesis. b. Bile salt-independent canalicular flow (composition is similar to plasma) c. Ductal flow (1) Added to the canicular flow in the biliary ducts
Note upon Bileflowisdependent and bilesaltconcentration, thusonenterohepatic fromtheileum. circulation
(2) High HCO3- concentration,similar to pancreaticductal secretion 3. Control of bile secretion a. Secretin stimulates the secretion of bile high in HCO3- content from the biliary ductules.Secretindoesnot alter bile salt output. b. Bile flow is also enhancedby the migrating myoelectric complex, which speedsthe enterohepaticcirculation of bile acids. 4. Bilirubin is a product of heme metabolism. It is taken up by hepatocytesand is conjugated with glucuronic acid prior to secretion into the bile. In the large intestine, bilirubin is deconjugatedand metabolizedby bacteriato form urobilinogens (colorless). Some of the urobilinogens are reabsorbed;most of the reabsorbedurobilinogens are secretedinto bile, with the remainderbeing excretedin urine. However,most urobilinogen remains in the gut and is further reduced to pigmented compounds (stercobilinsand urobilins) and excretedin feces. 5. Bile acids are synthesizedfrom cholesterolby hepatocytesasbile acids.
Clinical Correlation (yellowing oftheskin Jaundice isa oftheeyes) andwhites bilirubin. result of elevated canresult bilirubin lncreased etiologies fromnumerous (hepatic failure, hemolysis, etc.). biliary obstruction,
a. The primary bile acids are cholic and chenodeoxycholic acid. Secondarybile acids (deoxycholicand lithocholic) are products of bacterial metabolism of primary bile acidsin the gut. All bile acidsmust be conjugatedwith taurine or glycine beforebeing secretedinto bile. b. The rate of bile acid synthesisis dependentupon the rate at which bile acidsreturn to the liver via enterohepaticcirculation. Somebile acidsare reabsorbedby passivediffusion in the small intestine. Most are reabsorbedby active transport in the distal ileum. c. Bile salts (the ionized form of bile acids) enhancethe efficienry of absorption of fats and fat-solublevitamins. They emulsifyfat droplets into micelles,preparingthem for digestionby pancreaticlipasesand subsequentabsorption. ( 1) Bile saltscarry the products of fat digestion(fatty acids,monoglycerides)and fatsoluble vitamins in micelles and transport them to the brush border of the intestinal epithelium. (2) One therapy for hypercholesterolemiainvolves binding bile salts (e.9., cholestyramine).Thesebound bile saltsareexcretedand not returned to the liver via the enterohepaticcirculation. So, the liver must synthesizemore bile salts from cholesterol. 6. Gallbladder. The function of the gallbladder is bile concentration and storage for release during meals.
t6l
Gastrointestinal System
a. Interdigestive pattern. While the gallbladder is relaxed and the sphincter of Oddi is constrictedat a low resistance,approximately50% of bile is storedand the remainder entersthe duodenum. b. Digestive pattern. Gallbladder contraction begins approximately 30 minutes after a meal, stimulatedby ACh (vagal-cephalicphaseof digestion) and the hormone CCK. c. The gallbladderwall absorbswater (90o/o)and electrolytes.
In a Nutshell Bile= H,O,bileacids, cholesterol, bilirubin, and phospholipids.
ClinicalCorrelate Gallstones Cholesterol stones arethe mostprevalent gallstones in Western society. Remember thefourFs (forrisk factors): . Female ' Fat . Fertile ' FoO
d. The gallbladderconcentratescholesterol,reabsorbsNa+ by an electrogenicpump, and moves Cl- passively. 7. Bile is composedof water,electrolytes,phospholipids,bile acids,cholesterol,and bilirubin. a. When their concentrationis high, lecithin (phospholipids),cholesterol,and bile acids form micelles spontaneouslyin the gallbladder and bfiary tree. The micelles have a hydrophobiccenterand solubilizefattyacids,lipids,monoglycerides,and cholesterol.In the intestine, the phospholipid and some of the cholesterol is replacedby faffy acids, monoglycerides, and fat-soluble vitamins. The lipid-carrying micelles diffirse to the brush border cellsof the mucosa,delivering fatty acids,monoglycerides,and fat-soluble vitamins to the enterocFtes. b. Cholesteroldissolution is proportional to lecithin and bile acid concentrations. (1) When cholesterol concentration exceedsthe capacity of the micelles, bile becomessupersaturated. (2) The presenceof a nucleus (i.e., bile pigment) permits microscopic crystalsto form. (3) Increasing the size of microcrystals eventually results in cholesterolgallstone formation.
E. Small intestinal secretion 1. Water and electrolytesare transferredfrom the serosalto the mucosalsurface. 2. Active secretionoccursin the crypts of Lieberkuhn. a. Cl- and HCO3- are activelysecreted.Na+ and HrO movement is passive,maintaining isotonicity.
ClinicalCorrelate Anytimethereisan1 inthe secretory state(e.9., cholera toxin)a secretory diarrhea will ensue.
b. Secretionis stimulated by local ACh releasefrom plexus. 3. Cholera toxin stimulatesintestinal secretionby increasedcAMP production via the stimulatory G protein action. Cl- and HCO3- secretionis enhanced. Vomiting 1. Vomiting occurs in three phases a. Nauseais a psychicand physicalphenomenon. (1) It is marked by hypersalivation,decreasedgastric tone, and decreasedor absent peristalsis. (2) Increasedduodenal and proximal jejunal tone resultsin reflux of contentsinto stomach. b. Retching ( 1) Spasmodicrespiratorymovement againsta closedglottis decreases intrathoracic pressure.
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Physiology
(2) The pyloric end of the stomachcontracts,and the upper part relaxesin association with contraction of abdominal muscles. (3) Herniation of the abdominal esophagusand proximal stomach into thorax follows contraction of abdominal muscles. (4) Secretionof mucus by the stomachincreases,but acid secretionfalls. c. Vomiting (1) Gastric contentsare forcefully extruded from the mouth with sustainedcontraction of abdominal musclesand pylorus. (2) If the hypopharyngealsphincteris contracted,no expulsion occursand the vomitus refurns to the stomach. 2. Neural pathways a. Chemoreceptortrigger r,olneislocated in the areapostrema in the floor of the fourth ventricle. ( 1) It stimulates the vomiting center. (2) The neurotransmitter is dopamine, which is increased by apomorphine and bromocriptine, and is decreasedby haloperidol, metoclopramide, and marijuana. b. Vomiting center is located in the reticular formation of the medulla adjacent to the salivaryand respiratorycenters.Itcoordinatesactivitiesof the surrounding structures.
Note trigger Thechemoreceptor asits zoneusesdopamine andalso neurotransmitter, irritant senses directly have Antipsychotia molecules. because antiemetic actions theyaredopamine antagonists.
ANDABSORPTION DIGESTION A. Carbohydrate digestion 1. Salivary amylase normally hydrolyzes approximately 10 to 20o/oof ingested starch. It hydrolpes only cr-(f:a)-glycosidic linkages to maltose, maltotriose, and cr-limit dextrins. 2. Pancreatic amylase is found in the highest concentration in the duodenal lumen, where it rapidly hydrolyzes starch to oligosaccharides,maltose, maltotriose, and cr-limit dextrins. 3. Oligosaccharide hydrolases (maltase,lactase,sucrase,and isomaltase) are found in the brush border, with the highest concentrations in the midjejunum and proximal ileum. B. Carbohydrate absorption 1. Glucose absorption occurs in the duodenum and proximal jejunum and affectsplasma insulin levelsvia plasma GIP. a. Glucose is transported acrosscell membranesby a carrier-mediatedactive process. (Galactosecompeteswith glucosefor the carrier.) b. Glucosetransport into the intestinal cell is coupled to Na+ transport by the sodiumdependent glucose transporter. Na+ moves down its concentration gradient to enter the cell. This concentrationgradient is maintained by the activetransport of Na+ out of the cell.
Correlate Clinical lntolerance Lactose deficiency. Dueto lactase lactose lnability to breakdown galactose. glucose and into increased Consequence: riseto load,giving osmotic Very andflatulence. diarrhea and Asians, Blacks, in common andto a lesser Meditenaneans, andtheir in Europeans degree American descendants.
c. Glucoseis transported from the cell into the interstitial layer and through the basolateral membrane bv facilitated diffirsion.
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Gaslrointestinal System
2. Fructose absorption is by carrier-mediateddiffrrsion. 3. Water osmotically follows movement of the carbohydrates. C. Fat digestion 1. Gastric digestion. Emulsification of fat begins in the stomach through the churning and mixing function. However,little fat digestion occurs in the stomach.Gastric and lingual lipase action normally accountsfor approximately l0o/oof fat hydrolysis. 2. Intestinal digestion a. Fats,insolublein water and chyme,are made solublein the duodenum bylecithin, bile salts,and fatty acids.Absorption of most fat has occurred by the time chyme reaches the midjejunum. b. Pancreatic lipase (1) Luminal concentrationis highestwithin the first hour after a meal.
ln a Nutshell
(2) Contact betweenlipaseand triglyceridesis enhancedby emulsifring agents.
Fatdigestion occurs inthe pancreatic smallintestine by lipases andisaidedbythe emulsifying bilesalts.
(3) Colipasebridges the triglyceride-lipaseinterface,allowing lipase hydrolysis to occur. (+) Triglyceridesare hydrolyzedto fatty acidsand 2-monoglycerides. c. Bile salts enter the duodenum on gallbtaddercontraction, usually within 30 minutes of a meal. D. Fat absorption
Clinical Correlate Numerous Etiologies Can GiveRiseto Steatorrhea . Pancreatic insufficiency (chronic pancreatitis, CF, pancreatic cancer) . Bilesaltdeconjugation secondary to bacterial overgrowth . Deficiency of conjugated bilesalts(dueto cholestasis or liverdisease)
1. Monoglycerides,free fatty acids,and other lipids (e.g.,cholesterol,fat-solublevitamins A, D, E, K) collect in micelles, which are mixed by segmentation.Micelles carrytheseproducts of fat digestion acrossthe unstirred (aqueous)layer to the brush border, where they can diffirse into the cell. 2. Enterocytes re-esterifr the fatty acids to form triglycerides,phospholipids, and cholesterol esters. 3. Triglycerides, phospholipids, cholesterol, cholesterol esters, fat-soluble vitamins, and apoproteins are incorporated into chylomicrons in the enterocftes. 4. Chylomicrons are releasedby exocytosisinto the intercellular spaceand enter the lacteals through gapsin their membranes. 5. Glycerol diffrrsesinto portal blood and is either oxidized for energyor is stored as glycogen. 6. Triglycerides with medium- and short-chain fatty acids arehydrolyzed quickly and do not require micelleformation for absorption.They undergo little re-esterificationand are absorbeddirectly into the portal venoussystem. 7. Fat-solublevitamins A, D, E, and K require bile acid micellesin order to be absorbed. E. Protein digestion and absorption 1. Gastric digestion. Maximally, l0-l5o/o of protein is broken down to amino acids in the stomach.Pepsinfunctions best at pH 2 and is irreversiblydeactivatedabovepH 5; therefore, HCI secretionis critical. 2. Intestinal absorption a. Approximately 50o/oof protein is digestedand absorbedby the time it reachesthe end of the duodenum.
T
t64 I
Physiology
(1) Most protein is rapidly hydrolyzed by pancreaticenzymesactivatedby brushborder peptidases. (2) Small polypeptidesare absorbedfasterthan amino acids and are hydrolyzedby enterocytepeptidases.Absorption is activeand carrier-mediated. b. Amino acid absorption is the rate-limiting step in protein digestion. (1) Active transport occursvia a Na+-linked carrier. (2) Amino acidsappearrapidly in portal venousblood. (3) Many different transport systemshave been identified, €.8.,carriersfor neutral, basic,and acidic amino acids.
Clinical Correlate isa disorder Hartnup disease aminoacid of neutral absorption.
F. Water and electrolyte absorption. The absorption of water and electrolytesoccurs mainly in the small intestine. l. Permeability. The jejunum and duodenum are highly permeableto water and electrolytes across"leaky" tight junctions. Tight junctions bind epithelial cells together,forming a barrier to ion and solute movement. The strength of the barrier varies,and some tight distally. junctions are more permeableto solutesthan others.Permeabilitydecreases 2. Na+-K+ exchange. A low intracellular Na+ concentration is maintained by Na+/K+ATPaseon the basolateralmembrane throughout the small intestine. 3. Water flow. As noted, water permeability decreasesdistally. a. Approximately 5-10 liters of fluid must be absorbeddaily (intake and secretion),with 80-90% being absorbedin the small intestine at a maximal rate of 700 ml/h. b. Water flow maintains the osmolarity of chyme in the duodenum. distally.In the proximal intestine, 4. Na+ absorption. Ion and moleculartransport decreases and intercellular flow of Na+ cotransport, Na+-glucose there is Na+-H+ exchange, junctions. through l.uLy tight 5. Cl- absorption occursin associationwith Na+ absorption through tight junctions and in exchangewith HCO3- in the ileum and colon. Cl- movesinward from the lumen of the gut, acrossthe enterocftes and down the electrochemicalgradient maintained by Clextrusion at the basolateralmembrane. 6. K+ absorption occursdown an electrochemicalgradientthrough tight junctions and cells with apical K+ channels. 7. Calcium absorption. Approximately 50olois absorbed through enterocytes by active transport bound to a carrier.Carrier synthesisis mediated byvitamin D. The complex of Ca2+and its carrier is extruded acrossthe basolateralmembrane. 8. Iron absorption. Approximately 10oloof ingested iron is absorbed, depending on its chemicalform, the amount ingested,and need. a. Absorption of iron is a saturable,active transport processthat competeswith other divalent cations and is enhancedby vitamin C. b. Ferrous iron is absorbedbetter than ferric iron. c. Absorption is increasedto two to five times normal in anemia, iron deficiency,or hypoxia.
Bridgeto Endocrine D Theroleofvitamin isdiscussed inCa2* absorption intheEndocrine indetail of thisbook. chapter Physiology
Note MostCa2*,iron,andfolateare intheduodenum. absorbed
d. Iron is transported in the form of transferrin.
t65
Gastroi ntestina I System
Ll !.!JFFI! 8,,absorption requires binding of intrinsic laclor(produced by parietalcellsof stomach). Actual absorption occurs in theileum.
e. VitamiaB12absorption a. Vitamin B12binds to R protein secretedinto saliya,gastricjuice, and bile. b. The R protein-Bl2complexis hydrotped by pancreaticenzyrnesand Bl2 subs€quently binds to intrinsic factor, which is producedby the parietalcellsof the stomach. c. Intrinsic factor-B12complexbinds to a receptoron the terminal ileum, whereabsorptron occurs. G. Absorption in the colon l. The most important absorptivefunction is Na+ absorption(in exchangefor K+). a. H2O and Cl- movementar€passive, b. Thereis paracellularK+ movement, c. Exchangeof Cl- and HCO3- ocrws. d. Thereis litde glucoseor amino acid absorption. 2. The colon canbecomesecretoryif stimulatedby bile saltsor medtanicalor surface-active irritants. Diseaseprocesses canalsohavethis effect.
cti!9al
H' Regulationof absorption and secretion iollelate
uprarcs aso+ moutty of theCl tractpatienbon opiatepainmedications often become con$ipated
l. Glucocorticoids regr:latethe smallintestine,colonicfluid, and electrol)'tetransport. 2. OpiatesstirnulateNa+ absorptionand inhibit secretionin the ileum. 3. SomatostatinstimulatesNa+absorptionand decreases motility. 4. choli!€rgic agonistsincreas€Na+,cl-, and fluid secraion. 5. VIP stimulatesfluid secretionyia cAMp. 6. Bacterialtoxins (e.g.,droleratoxin) stimulatecAMP and therebyactivat€a Cl secr€tory pump in the mucosalcell.
MUSCULAR FUNCTION A. Innervation of the gastrointestinal tract 1. Structure a. Groups of muscle cells are organized into bundles, which contract as a unit after simultaneousdepolarization. b. Bundles are electrically coupled, primarily in the circular layer through gap junctions (areasof low membrane resistance). c. Membrane potential of muscle cellsis maintained by the Na+-K* pr'rrnplocated on the basolateralmembrane and is responsiblefor the resting tension of the muscle cell. 2. Intrinsic innervation of the gastrointestinal tract. The enteric nervous system extends the primary nervous control of the gastrointestinaltract. It is made up of dense,interconnecting networks of nerve cells called plexi. It helps to integrate motor and secretion activity of the gastrointestinal tract. a. Plexus tnres (1) Myenteric plexus (Auerbach plexus) lies between the circular and longitudinal musclelayersfrom the esophagusto the anus.
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Physiology
(2) Submucosal plexus (Meissner plexus) lies in the submucosaof the gut wall.
Bridge to Pathology
(3) Subserosalplexus lies beneaththe serosa.
Disease Hirschsprung to leading defect Congenital of development incomplete ofthe neural innervation (absence of Auerbach colon plexi). to Leads andMeissner obstruction, severe andeven constipation, megacolon.
(4) Deep muscular plexus is located in the circular layer. (5) Mucosal plexus is located in the subglandular, intraglandular, and intravillous areas. b. Neurons of several kinds are found: (l) Cholinergicneurons(myenteric) (2) Serotonergicneurons (3) Peptidergicneurons (containing VIR substanceR and somatostatin). c. Axons are distributed to effectorcells(smooth muscle,secretory,and absorptivecells) and other plexi. d. Efferents stimulate muscular, absorptive, and secretory activity, as well as hormone release. (1) Stretch and the presenceof polypeptides in the stomach stimulate plexus to releaseACh. (2) This inducesHCI secretioninto the lumen via direct effect on parietal cellsand through gastrin secretion. e. Tiansmitters of three ffpes are contained in plexi: (l) Cholinergic(excitatory) (2) Adrenergic (3) Noncholinergic and nonadrenergic(inhibitory) f. Mucosal chemoreceptors sensitiveto H+ and polypeptides and stretch receptors are also found in plexi.
3 . Extrinsic innervation of the gastrointestinal tract. The sympathetic and parasympathetic nervous systemsexert primarily a modulating effect on gut activity. a. Sympathetic nervous system (1) Preganglionicfibers originate in cell bodies in lateral horns of the thoracolumbar region of the spinal cord. (2) Postganglionic fibers synapse indirectly via thoracic splanchnic nerves on smooth muscle cells of blood vessels(constriction) and the lamina muscularis mucosa(excitatory). (3) Postganglionicfibers synapsedirectly on the myenteric plexus (inhibitory), salivary glands (excitatory), smooth muscle cells in the circular layer (inhibitory), and smooth musclecellsof sphincters(excitatory).They also inhibit pancreatic, small intestinal,and colonic function. (4) Effects are accentuatedby epinephrine and norepinephrine from the adrenal medulla, which inhibit smooth muscle (decreasemotility) and stimulate vasoconstriction to decreaseblood supply. b. Parasympathetic nervous system acts in the opposite way,by increasing motility and promoting vasodilatation,thereby increasingblood flow to the gut. (l) Preganglionicfibers (cholinergic, purinergic, and peptidergic) originate in the
167
Gastrointestinal System
craniosacraldivision of the neuraxis and consist of vagus (cranial) and pelvic splanchnic(sacral)outflow to the intrinsic plexi.
In a Nutshell Sympathetic Nervous System . .LMotility . J Blood supply to gut . J Secretion Parasympathetic Nervous System . t Motility . t Blood supply to gut . t Secretion
(2) Vagal parasympathetic fibers originate in the dorsal motor nucleus of the vagus in the floor of the fourth ventricle and project to three areas:esophagealplexus innervatesthe esophagus,heart, and other thoracic structures;the anterior vagal trunk innervates gastric, celiac,hepatic, and pyloric areas;the posterior vagal trunk innervatesthe pylorus, duodenum, pancreas,small intestine,cecum, and ascendingand right transversecolon. (3) Sacral parasympathetic fibers flow out from sacral segments2,3, and 4 and innervatethe anorectalarea,descendingsigmoid, and left colon. (4) Most PNS nerves are postganglionic, cholinergic, and excitatory, providing innervation to longitudinal musclebundles that increasethe motiliry. (5) PNS nerves bring circular bundles closer to their depolarization threshold, increasing motility. The PNS is inhibitory to the LES and stomach. These inhibitory fibers are neither cholinergic nor adrenergic. The predominant transmittersare NO and VIR but dopamine,purine, and small peptidesmay also serveas neurotransmittersin some cases. c. Sensoryreceptors influence secretionand motility. (1) Chemoreceptorsare slow adapting, and respond to changesin pH, osmolariry fat, and carbohydrateconcentrations. (2) Mechanoreceptorsare slow adapting and respond to stretchand distention. (3) Nociceptors transmit painful stimuli over somatic sensory fibers (basis for referredpain). 4. Smooth muscle physiology a. Contraction of the smooth muscle cell follows electrical changesin its membrane potential, which depend on electrolytedistribution, permeability of the membrane, and the Na+-K+ pump. b. Hyperpolarization is associatedwith decreasedwall tension. c. Depolarization is associatedwith increasedwall tension. B. Types of muscle contraction l. Tonic contraction. Constant, low-grade tone is maintained in the gut wall on which strongercontractionsare superimposed.Tonic contractionspreventthe distention of gut. Lossof tone (lossof parasympatheticstimulation) resultsin retention of gut contentsand constipation. 2. Rhythmic contraction. Stretching of any part of the gut (e.g., by filling) directly elicits bursts of action potentials in the enteric nervous systemand causesa reflex contraction. There are two types of rhythmic contraction:
In a Nutshell provides Segmentation for mixing of chyme, while peristaltic propel movements chyme along thegut.
r68
a. Mixing movements, called segmentation, look like beadson a string, with narrow constrictedareasof the gut alternating with bloated areas.The stretch in thesebloated areasinitiates contractions,which causetheseareasto becomenarrow and to bloat the adjoining previously narrow regions.This resultsin mixing of the gut contents. b. Propulsive movements (peristalsis)consistof rhythmic contraction and relaxationof circular and longitudinal muscles,which create a moving ring of constriction that movesfood along the gut.
Gastrointestinal Pathology There aremanydifferent organs included inthegastrointestinal pathology, system. Castrointestinal therefore, includes a widevariety of disorders, frompeptic ulcerdisease to colorectal cancer to gallstones. present Since manyofthese (abdominal disorders initially pain, withsimilar symptoms diarrhea, constipation), it isimportant to beableto recognize thespecific riskfactors andsigns associated witheachdisorder. Thischapter willdiscuss thepathology of eachorgan inthe gastrointestinal presentations. system, along withtheassociated riskfactors andclinical
ORAICAVITY A. Congenital malformations include cleft lip and cleft palate. Both are generally treated surgically within the first six months of life. B. Teeth 1. Enamel hypoplasia is due to a defectin enamelformation, resulting from dysfunction of ameloblasts,which form horizontal bands of discolored,pitted indentations. It may be causedby deficienciesof calcium, phosphorus, vitamins A, C, and D; excessfluoride; infections (e.g., syphilis); hypoparathyroidism;and hypothyroidism. 2. Pigmentation of developing teeth may be causedby excessbile pigments in biliary disease,bilirubin in hemolytic anemias,or tetrarycline. 3. Congenital syphilis leadsto malformation of teeth asa result of inflammatory changesin ameloblastsand odontoblasts.
Bridgeto Pharmacology Thepathologic effect of tetracycline ondeveloping bones andteethhaslongbeen a favorite USMLE sideeffect. Remember: Notetrarycline forpregnant women!
C. Oral mucosa 1. Common periodontal diseases a. Gingivitis is a chronic inflammation of the gingivae. b. Periodontitis, or pyorrhea,is gingivitis that hasspreadinto tooth cementumand alveolar bone. Complicationsinclude suppurativeinfection, abscess, and bone resorption. c. Aphthous ulcers are painfi.rl ulcers commonly known as "canker sores."They are not invasiveand may be presentas a singlelesion or in crops,eachof which is usuallyless than 0.5 cm. They often appear during febrile illness or other physical or emotionally stressfrrlsituations,and are often found in patientswith ulcerativecolitis. 2. Oralmanifestations of systemic disease a. Vitamin deficiencies ( 1) Vitamin B deficienry leads to atrophic glossitis as a result of reduced cell division in the squamousmucosa.
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System Gastrointestinal
(2) Vitamin C deficienry causesbleeding gums as a result of weakenedconnective tissue. b. Pregnancy may causegingivitis and increasedvascularityof the gingivae. c. Hematologic abnormalities (1) Thrombocytopeniamay causepetechiaeand excessbleeding. (2) Leukemiamay causered, boggy gingivaeinfiltrated by leukemic cells. (3) Perniciousanemia causesa smooth, beefr,red tongue due to squamousatrophy. as a d. Diabetes may produce drynessof the mucosa and a tendencyto form abscesses result of impaired microcirculation. e. Addison diseaseleads to generalizedexcessivepigmentation; Peutz-fegherssyndrome leadsto patchypigmentation. f. Systemic infectious diseases (1) Scarletfever,toxic shock syndrome, and Kawasaki'sdiseasecausea strawberry tongue. (2) MeaslesproducesKoplik spots,which are tiny white speckson a red base,found on the buccal mucosain the prodromal stageof illness. 3. Infections a. Necrotizing gingivitis ("trench mouth") producescrater-like depressionsat the gingival margin. It is painful and causesa fetid odor. b. Herpetic gingivostomatitis is due to herpessimplex and is usually seenin children. c. Oral thrush is causedby Candida alhicans,which produceswhite adherent patches. Thrush is associatedwith impaired immunity or debilitation, and is commonly seen in patientswith AIDS or in patients undergoing chemotherapy. d. Herpangina is due to coxsackievirusA and causesvesicularlesions,typically in the pharynx. e. Syphilis may produce a variety of lesions: (1) Primary syphilis produceschancreson the lips. (2) Secondarysyphilis producesmaculopapulareruptions. (3) Tertiary syphilis producesgummae of the palateand atrophic glossitis. 4. Keratotic abnormalities a. Lichen planus appearsaswhite reticulatelesionson the buccal mucosaand tongue. b. Leukoplakia appearsas white plaques on oral mucosa,produced by hyperkeratosis of the epithelium. Ten percent of casesof leukoplakia have epithelial dysplasia,a precancerouslesion.Smoking,smokelesstobacco,alcohol abuse,chronic friction, and irritants are predisposingfactors. c. Erythroplakia (dysplastic leukoplakia) appears flat, smooth, and red. Significant numbers of atypical epithelial cells are seen microscopically.There is a high risk of malignant transformation.
t70
Pathology
d. Hairy leukoplakia is so named becauseof its wrinkled surface.Patchesoccur on the siderather than the middle of the tongue. There arefar fewer arypical cellsthan are seen in erythroplasia.Malignant transformation doesnot occur,despiteits associationwith HIV and associatedinfections,including papilloma and Epstein-Barrviruses. 5. Tumors a. Benign tumors include hemangiomas,hamartomas,fibromas, lipomas, adenomas, papillomas,neurofibromas,and nevi. b. Malignant tumors. By far, the most common malignant tumor is squamous cell (epidermoid) carcinoma.The peak incidencerangesfrom age 40-70. Squamouscarcinoma is associatedwith tobacco and alcohol use, particularly when used together. Pathologicully,it may be papillary or ulcerative.The lower lip is the most common site, but cancerof the floor of the mouth, tongue,and buccal mucosaare frequentlyseen. D. Salivaryglands 1. Inflammation a. Sialolithiasis produces a secondaryinflammatory reaction to obstruction and the resultant enlargementof ducts by stones.It may be complicatedby actual infection with mouth flora. b. Sialadenitisis a primary inflammatory reaction,but it is not alwaysinfectious.It may be part of an autoimmune disease(e.g.,Sjogrensyndrome),or the result of bacterial or viral (e.g.,mumps) infection. 2. Tumors. The parotid gland accountsfor more than three-quartersof thesetumors, most of which are benign. Of the remainder,more occur in the submandibular gland than in the sublingual, and most of these are malignant. Many are surgically cured, but local recurrenceis common. a. Pleomorphic adenoma is generallybenign and accounts for approximately threequarters of all salivary gland tumors. It is composed of multiple epithelial and mesenchymal cell types. Complications may arise due to involvement of cranial nerveVII. b. Warthin tumor (adenolymphoma)is alsobenign, occurring almost exclusivelyin the parotid gland. It is grosslycystic.Microscopic examination revealscell types suggestive of branchial cleft origin embeddedin a lymphoid matrix. c. Mucoepidermoid tumors also occur primarily in the parotid and have a high rate of malignant transformation. The malignant component is usually squamouscell. d. Cylindroma (adenoid rystic carcinoma) is more common in the minor salivary glands found in the oral mucosa,and metastasesare more common than in other tumors of the salivaryglands.Facialnerve complicationsare frequent. (1) Grossly, the tumor forms multiple lobules surrounded by a capsule. (2) Microscopically, small cellsform glandscontaining mucoid material.
l7l
System Gastrointestinal
ClinicalCorrelate ( e"opn"gu"---+ Hil
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Tracheoesophageal fistula
Figure ll-5-1. The most common type of tracheoesophageal fistula
ESOPHAGUS A. Congenital malformations l. A tracheoesophagealfistula (the most prevalent esophagealanomaly) occurs most commonly as an upper esophagealblind pouch with a fistula betweenthe lower segmentof the esophagusand the trachea.It is associatedwith hydramnios,congenitalheart disease,and other gastrointestinalmalformations. 2. Esophagealatresiais associatedwithVATER syndrome(vertebraldefects,anal atresia,tracheoesophagealfistula, and renal dysplasia).It does not usually occur as an isolated anomaly. 3. Stenosis refers to a narrowed esophaguswith a small lumen. It may be congenital or acquired,e.g.,through trauma or inflammation. B. Inflammatory disorders 1. Esophagitis most often involvesthe lower half of the esophagus. a. Clinical features. Patientsexperiencesubsternalburning associatedwith regurgitation, mild anemia,dysphagia,hematemesis,and melena.Esophagitismay predispose to esophagealcancer.
Note whenLES Reflux occurs pressure decreases enough to allowseepage ofstomach contents backintothe esophagus.
b. Etiology (l) Refluxesophagitis is due to an incompetent lower esophagealsphincter that permits reflux of gastricjuice into the lower esophagus. (2) Irritants such as citric acid, hot liquids, alcohol, smoking, corrosivechemicals, and certain drugs, such as tetrarycline,may provoke inflammation. (3) Infectious etiologies include herpes,CMV and C. albicans.The immunocompromised host is particularly susceptibleto infectiousesophagitis. c. Pathology (1) Grossly,there is hyperemia,edema,inflammation, and superficialnecrosis. (2) Microscopically, the inflammatory exudate is usually nonspecific. d. Complications include ulceration,bleeding,stenosis,and squamouscarcinoma. 2. In Barrett esophagus,gastric or intestinal columnar epithelium replacesnormal squamous epithelium in responseto chronic reflux. Ulceration, if present,is usually at the squamocolumnarjunction, increasingthe risk of adenocarcinomaby 30-a0 times when small bowel-type epithelium is present. C. Motor disorders. Normal motor function requireseffectiveperistalsisand relaxation of the lower esophagealsphincter.
In a Nutshell Achalasia isa lackof appropriate LESrelaxation and peristalsis froma esophageal plexus lossof myenteric cells. isthehallmark Dysphagia symptom.
172
1. Achalasia is a lack of relaxation of the lower esophagealsphincter (LES), which may be associatedwith aperistalsisof the esophagusand increasedbasaltone of the LES. a. Clinical features. Achalasiaoccurs most commonly between the agesof 30 and 50. Typical symptomsare dysphagia,regurgitation,aspiration,and chestpain. The lack of motility promotes stagnationand predisposesto carcinoma. b. Pathology. The loss of ganglion cells in Auerbach plexus may be secondary to Chagasdisease(Trypanosomacruzi), or an infiltrating malignancy,or it may have an idiopathic cause.
Pathology
2. Hiatal hernia is the herniation of the abdominal esophagus,the stomach, or both, through the esophagealhiatus in the diaphragm. a. Sliding hernia, making up approximately 90o/oof cases,occurs when the esophagogastricjunction slidesinto the thorax. The condition is often associatedwith reflux. b. Paraesophagealhernia occurswhen an areaof gastric cardia rolls along the esophagus through an incompetent hiatus into the thorax. The esophagogastricjunction remainsin the abdomen.Paraesophageal hernia may causepostprandialbloating and belching.The herniated organ is at risk for strangulationand infarction. 3. Scleroderma is an autoimmune disease,seenprimarily in women, that causessubcutaneous fibrosis and widespreaddegenerativechanges.(A mild variant is known as CREST syndrome, which stands for calcinosis,Raynaud phenomenon, esophagealdysfunction, sclerodactyly,and telangiectasia.)The esophagusis the most frequentlyinvolvedregion of the gastrointestinaltract. a. Clinical featuresare mainly dysphagiaand heartburn due to reflux esophagitiscaused by aperistalsisand incompetent LES. b. Pathology is predominantly atrophy of smooth muscle with fibrous replacement. Chronic reflux results in stenosisand ulceration. Anti-ScL 7O and anticentromere antibodies are typically associatedwith this disease. D. Rings and webs 1. Webs are mucosalfolds in the upper esophagusabovethe aortic arch. 2. Schatzki rings are mucosalrings at the squamocolumnarjunction below the aortic arch. 3. Plummer-Vinson syndrome consistsof a triad of dysphagia, atrophic glossitis, and anemia. Websare found in the upper esophagus.The syndromeis associatedspecificallywith iron deficiencyanemia and sometimeshypochlorhydria.Patientsare at increasedrisk for carcinomaof the pharynx or esophagus. junction secE. Mallory-Weiss tears refers to small mucosal tears at the gastroesophageal ondary to recurrent forcefrrl vomiting, usually seenin alcoholics. The tears occur along the long axis and result in hematemesis(sometimesmassive).The courseis usuallybenign, and the tearsceasewithout intervention if the patient stopsdrinking. F. Esophagealvarices are dilated tortuous vesselsof the esophagealvenous plexus resulting from portal hlryertension. When portal blood pressureincreases,collateral circulation through the coronary veinsto the esophagealveins and then to the arygoussystemdevelops, yielding vesselengorgement.Portal hypertensionis most often causedby hepatic cirrhosis. Another common causeis obstructivethrombosis of the portal or splenicvein. Esophageal varices are prone to bleeding and ulceration, which may be life-threatening,especiallyin cirrhotics. G. Diverticula are sac-likeprotrusions of one or more layersof the pharyngealor esophagealwall. 1. Zenker diverticula occur at the junction of the pharynx and esophagus.They are false diverticula formed by herniation of the mucosaonly. The frequencyis greaterin men than women, and they occur most often in the elderly.Symptomsinclude dysphagiaand regurgitation of undigestedfood soon after ingestion. 2. Tiaction diverticula occur in the midpart of the esophagus.They are true diverticula (all layersof the esophagusoutpouch). Thesediverticula are causedby the adherenceof the esophagusto a scarredmediastinalstructure suchasa calcifiedlymph node.They are usually asymptomatic.
ln a Nutshell Plummer-Vinson Syndrome . Dysphagia . Clossitis . lrondeficiency anemia . Esophageal webs In a Nutshell Esophageal varices areoften dueto portal hypertension. Theymaybleed orulcerate, which canbelifethreatening.
In a Nutshell Mallory-Weiss Tears Versus Esophageal Varices Whilebothareassociated withalcohol abuse andcan present withhematemesis, Mallory-Weiss tears typically occur acutely asa result of retching/vomiti ng.Esophageal varices result fromportal hypertension andwillusually present witha more significant bleeding episode.
l7t
System Gastointestinal
H. Tumors 1. Benign tumors are rare. 2. Carcinoma of the esophagus most commonly occurs after age 50 and has a male:female ratio of 4:1. a. Incidence. Carcinoma of the esophagusis prevalent in northern Iran, Central Asia, and SoutheasternAfrica. In the United States,the incidenceis much higher in African Americansthan in Caucasians. b. Etiology. It is associatedwith smoking, alcohol ingestion,nitrosaminesin food, achalasia,webs,rings, diverticula, Barrett'sesophagus,and deficienciesof vitamins A and C, riboflavin, and some trace minerals. c. Clinical features include dysphagia(first to solids), retrosternal pain, anorexia,weight loss,melena,and symptoms secondaryto metastases. d. Pathology (1) Fifty percentoccur in the middle third of the esophagus,30o/o in the lower third, and2}o/oin the upper third. Most esophagealcancersare now adenocarcinomasin Caucasiansand squamous carcinomas in African Americans. Adenocarcinomas arisemostly out of Barrett'sesophagus. (2) There are three types of carcinomas.Polnroid carcinomasare large fungating massesprotruding into the lumen; ulcerating carcinomas form a central necrotic crater,eroding deeplyinto surrounding structures;and infiltrative carcinomas spreadwithin the esophagealwall. e. Prognosis is poor. Fewerthan l0oloof patients survive 5 years,usually becausediagnosis is made at a late stage.The most common sitesof metastasisare the liver and lung. The combination of cigarettesmoking and alcohol is particularly causativefor esophagealcancer(over 100x risk comparedto nondrinkers/nonsmokers).
STOMACH A. Congenital malformations 1. Pyloric stenosis
ClinicalCorrelgte Pyloric iscongenital stenosis hypertrophy of pyloricmuscle, presenting withprojectile vomiting andrequiring surgical treatment.
a. Incidence. Pyloric stenosisoccurs in roughly 1/600 live births, often in a first*born male child. The syndrome is four times more common in males than in females. b. Clinical features. Projectile vomiting 3-4 weeks after birth associatedwith a palpable "olive" mass in the epigastricregion is observed. c. Pathology shows hlpertrophy of the muscularis of the pylorus and failure to relax. 2. Diaphragmatic hernias are due to weaknessin or absenceof parts of the diaphragm, allowing herniation of the abdominal contentsinto the thorax. B. Inflammation 1. Acute gastritis (erosive) a. Etiology. Alcohol, aspirin and other NSAIDs, smoking, shock, steroids,and uremia may all causedisruption of the mucosalbarrier, leading to inflammation. b. Clinical features. Patientsexperienceheartburn, epigastric pain, nausea,vomiting, hematemesis,and even melena.
174
Pathology
c. Pathology (1) Endoscopicallp patches of congested,edematous,erythematous mucosa are seen;petechiaeand ulceration may alsobe noted. (2) Microscopically, there is superficial acute inflammation and focal necrosisof the mucosa. 2. Chronic gastritis (nonerosive)may lead to atrophic mucosawith lymphocytic infiltration. a. Types (1) Fundal (Type A) gastritis is often autoimmune in origin. It is the type associated with pernicious anemia and, therefore, achlorhydria and intrinsic factor deficienry. It is associatedwith hyperplasiaof G cells,hypergastrinemia,and occasionally with Hashimoto'sthyroiditis and Addison'sdisease. (2) Antral (Type B) gastritis is most commonly causedby Helicobacterpylori and is the most common form of chronic gastritisin the U.S.H. pylori is also responsible for proximal duodenitis in regionsof gastricmetaplasia.H. pylori is a spiralshapedorganism found in the mucosallayer of the stomachbut is not invasive. It damagesthis protectivelayer by producing urease. (3) Lymphocytic gastritis describes a dense lymphocytic infiltration of surface epithelium. It is not associatedwith H. pylori and may representa gastric manifestationof celiacsprue. (4) Hypertrophic gastritis causesextreme enlargement of mucosal folds and thickened mucosa,which may mimic lymphoma on x-ray and may causea proteinlosing enteropathy(Menetrier disease). b. Clinical features. The patient may be asymptomatic or suffer epigastric pain, nausea, vomiting, and bleeding.Gastritismay predisposeto peptic ulcer disease, probably related to H. pylori infection. c. Pathology (1) Grossly, a thin, smooth, mucosawith flattened rugae is seenin atrophic gastritis. (2) Microscopically, there is atrophy of gastric glands with infiltration by lymphocftes and plasma cells; there is also mild atypia in superficial epithelial cells. In H. pylori-associatedgastritis,atrophy is usually not present,but the mucosa is infiltrated by polymorphonuclear leukocFtes.The infecting organism may also be seenin the mucous membrane. 3. Peptic ulcers are usually chronic, isolated ulcers observedin areasbathed by pepsin and HCl; they are the result of mucosalbreakdown (Figure II-5-2). a. Common locations are the proximal duodenum, the stomach, and the esophagus, often in areasof Barrett esophagus. b. Etiology. There are severalimportant etiologic factors. Duodenal ulcers occur predominantly in patientswith excessacid secretion,while gastriculcersusually occur in patientswith lower than averageacid secretion.Other predisposingconditions include smoking, cirrhosis, pancreatitis, hyperparathyroidism, and H. pylori infection. Aspirin, steroids,and NSAIDs are known to be assoicatedwith peptic ulcer disease. Next to H. pylori colonization,aspirin or NSAID ingestionis the most common cause of peptic ulcer.
ClinicalCorrelate Castritis maybeacute (NSAIDs, alcohol, stress, etc.) (autoimmune orchronic or H pylorl.
ClinicalCorrelate H.pylorihas nowbeen shown to beassociated with gastritis, peptic ulcerdisease, gastric adenocarcinoma, and (e.9., somegastric lymphomas MALTomas or mucosal associated lymphoid tumors). SomeMALTomas havebeen shownto regress on treatment withantibiotia that eradicate H.pylori.
Clinical Conelate Recent evidence raises the importance ofH.pyloriinthe pathogenesis of peptic ulcer disease. Modification ofacid secretion alonedoesnot effect a lasting remission, but coupling thiswithantibiotic therapy thateradicates H. pyloriisapparently curative in patients. most
175
System Gashointestinal
c. Clinical features. Patients experienceepisodic epigastric pain. Duodenal and most gastric ulcers are relieved by food or antacids.Approximately one-fifth of gastric ulcer patientsget no relief from eating or experiencepain againwithin 30 minutes. d. Pathology. Benign peptic ulcers are well-circumscribed lesions with a loss of the mucosa,underlying scarring,and sharp walls.
ln a Nutshell maydevelop Castric ulcers into,ordevelop from,a Duodenal malignancy. ulcers malignant. arenever
e. Complications include hemorrhage, perforation, obstruction, and pain. Duodenal ulcers do not become malignant. Gastric ulcers do so only rarely; those found to be malignant likely originated as a cancerthat ulcerated. f. Diagnosis is made by upper gastrointestinalseries,endoscopy,and biopsy to rule out malignancyor to demonstratethe presenceof H. pylori. 4. Stressulcers are superficialmucosalulcers of the stomach or duodenum or both. Stress may be induced by burns, sepsis,shock,trauma, or increasedintracranial pressure.Ulcers occurring in burn victims (Curling ulcers) are particularly susceptibleto bleeding.Those developingin CNS trauma patients(Cushingulcers)posea high risk for perforation.
Figure ll-5-2.Peptic ulcer disease of the stomach (gross).
C. Tirmors 1. Benign a. Leiomyoma, often multiple, is the most common benign neoplasmof the stomach. Clinical featuresinclude bleeding,pain, and iron deficienry anemia. b. Gastric polyps are due to proliferation of the mucosalepithelium. (1) Hyperplasticpolyps accountfor 80o/oof gastricpolyps.Theyare small (<1 cm), oval, and are composedof hyperplasticglands.They do not undergo malignant transformation, but becausethey are associatedwith gastritis, some patients developcarcinomaelsewherein the stomach. (2) Adenomatous polyps are often larger than 2 cm, forming papillary projections on a wide base.They havea high malignant potential (75o/oof lesionslarger than 2 cm demonstratemalignant changes).
176
Pathology
2. Matignant tumors a. Carcinoma (1) Etiology. Primary factors include genetic predisposition and diet; other factors include hypochlorhydria, pernicious anemia, atrophic gastritis, adenomatous polyps, and exposureto nitrosamines.H. pylori are also implicated. (2) Clinical features.Stomach canceris usually asymptomatic until late, then presents with anorexia, weight loss, anemia, epigastric pain, and melena. The Virchow node is a common site of metastasis. (3) Pathology.Approximatelyone-halfof cancersarisein the antrum and pylorus and one-quarterin the gastriccardia.Early asymptomaticgastric carcinomahas not yet microscopicallyinvaded the muscularis propria. Symptomatic late gastric carcinoma may be expanding or infiltrative. In both casesthe prognosis is poor (approximately 10olo5-year survival), and metastasesare frequently present at the time of diagnosis.Adenocarcinomas are most common (Figures II-5-3 and II-5-4). Neuroendocrine(undifferentiated)tumors may presentwith symptoms of hormone excess,which are produced by tumors derived from normally secreting cellsin the stomach.Thesetumors may secreteseveralamine or peptide hormones such as histamine, 5-hydroxytryptamine,and adrenocorticotropichormone (ACTH).
Clinical Correlate TheVirchow nodeisa left supraclavicular lymphnode. presence Its suggests meta$atic stomach carcinoma. Note gastric Aninfiltrating carcinoma witha diffuse fibrous response iscalled a pla$ica (leather-bottle linitis stomach).
Note Signet ringcells are characteristic of ga$ric carcinoma, butarenotthe onlytypeof cellfound.
Figure ll-5-3.Adenocarcinoma of the stomach (gross).
177
Gasfrointestinal System
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Figure ll-5-4.Carcinoma of the stomach (microscopic).
b. Gastrointestinal lymphomas may be primary in the gastrointestinal tract as solitary masses. (1) Grossly, there are three types:polypoid masses,large plaqueswith necrotic ulcers, and infiltrative. (2) Microscopically, the most common are the diffirse histiocytic $rpe, followed by lymphocytic lymphomas. c. Sarcomais a rare,large,ulcerating massthat extendsinto the lumen. d. Metastatic carcinoma. Krukenberg tumor is an ovarian metastasisfrom a gastric carcinoma. e. Kaposi sarcoma. The stomach is the most commonly involved gastrointestinal organ in Kaposisarcoma.It occursprimarily in homosexualmen, appearingas hemorrhagic polypoid, or umbilicated nodular lesions,typically in a submucosallocation. It rarely causessymptoms.
SMAttINTESTINE A. Congenital anomalies 1. Meckel diverticulum (a true diverticulum) is due to persistenceof the omphalomesenteric vitelline duct. It is located within 12 inches of the ileocecal valve. Approximately 50olocauseulceration, inflammation, and gastrointestinalbleeding due to the presenceof ectopic acid-secretinggastric epithelium. 2. Atresia is a congenitalabsenceof a region of bowel, leavinga blind pouch or solid fibrous cord. It leadsto obstruction and vomiting in the neonatalperiod. 3. Stenosisrefersto a narrowing of any region of the gastrointestinal tract, which may cause obstruction. 4. Duodenal diverticula are areasof congenital weaknesspermitting saccularenlargement. The duodenum is the most common region of the small bowel to contain diverticula.
t78
Pathology
5. Diverticula of jejunum and ileum are herniations of mucosa and submucosaat points where the mesentericvesselsand nerves enter. B. Infections 1. Bacterial enterocolitis may be causedby the ingestion of preformed bacterid toxins, producing symptoms ranging from severebut transient nausea,vomiting, and diarrhea (Staphylococcus aureustoxin) to lethal paralysis (Clostridium botulinun toxin). Ingestion of toxigenic bacteria with colonization of the gut (e.g., Vibrio cholera,toxigenic E. coli, jejuni, Shigella,Salmonella,Yersinia, various speciesof Campylobacter and many others) is another potential cause. 2. Nonbacterial gastroenterocolitis a. Viral (1) Rotavirus(children) (2) Norwalk virus (adults) b. Fungal-Candida c. Parasitic (l) Entamoebahistolytica (2) Giardialamblia 3. In HIV patients. Causesof infectious diarrheain HIV patientsinclude Crlrytosporidium, Microsporidia, lsosporabelli, CMV and M. avium-intracellulare.HW infection itself can be associatedwith abnormal small bowel mucosa, including partial villous atrophy and crlpt hyperplasia(also known as"idiopathic AIDS enteropathy"). C. Malabsorption is defined as impaired intestinal absorption of dietary constituents. Clinical features include diarrhea, steatorrhea,weakness,lassitude,and weight loss. Steatorrhea resultsin deficiencyof fat-solublevitamins (A, D, E, and K) and calcium. 1. Celiac sprue a. Etiology. Celiacsprue (nontropical sprue or gluten enteropathy)is causedby an allergic, immunologic, or toxic reaction to the gliadin component of gluten. There is a geneticpredisposition. b. Clinical features reflect malabsorption. There is a reversalof symptoms with a glutenfree diet, and morphologic changesusually revert to normal. The diseasepredisposes to neoplasm,especiallylymphoma. c. Pathology shows atrophy of villi in the jejunum, crypt hyperplasia and lengthening, flattening of the mucosal surface,and a chronic inflammatory reaction in the lamina propria. It affectsonly the proximal small bowel. 2. Tropical sprue a. Etiology. Tiopical sprue is of unknown etiology, but maybe causedby enterotoxigenic E. coli. b. Incidence. There is a high incidence in the tropics, especiallyin Vietnam and Puerto Rico. Occasionally,the diseaseoccurs in epidemics. c. Pathology. Pathologic changesare variable but are similar to the changesin celiacdisease.Unlike celiac sprue, however,tropical sprue affectsthe entire length of the small bowel. It often respondsto long-term treatment with tetrarycline and folic acid.
t79
System Gastrointestinal
3. Whipple disease is a rare systemic disorder characterized by clumps of periodic acid-Schitr (PAs)-positive macrophages in the lamina propria of intestines fi,rll of and surrounded by small bacilli (Tropheryma whippelii). a. Incidence. The ratio of men to women is 10:1. b. Clinical features include diarrhea, steatorrhea,weight loss, fever, arthralgias, lymphadenopathy, and rarely, neurologic abnormalities.Whipple diseasealso respondsto tetracvcline. c. Pathology showsvilli distendedwith macrophagesfull of bacilli in the lamina propria and mesentericlymph nodes.
ClinicalCorrelate leads to Lactase deficiency with milkintolerance, symptoms of bloating, andcramping diarrhea, followingingestion of dairy products.
4. Disaccharidase deficiency is due to a deficiency of brush border enzymes.Lactase deficiency is most common. D. Vascular abnormalities often lead to ischemicbowel disease. l. Transmural infarction is more common in the small intestine,which does not have the rich collateralsof the colon. a. Etiology (1) Thrombosis or embolism of the superior mesenteric artery accounts for approximately 50olo of cases.The thrombosis is most often secondary to atherosclerosis,but emboli may arise from cardiac sourcesor atherosclerotic plaqueshigher in the aorta. The inferior mesentericartery accountsfor approximately 25o/oof cases. (2) Venous thrombosis accountsfor 25o/oof.cases.It typically occurs post CHF, in polycythemia,in hypercoagulablestates,or in inflammations of the abdomen.
ClinicalCorrelate Small bowelinfarcts areoften dueto thromboembolic andpresent asan events, acute abdomen.
(3) Internal hernias can strangulate entrapped loops of bowel. They can occur congenitallyin children and young adults, or as a result of abdominal surgery (peritoneal adhesions)in adults. b. Clinical features. There is a 50-757o mortality rate. Infarction of the bowel usually occurs after age 60 and presentsas an acute abdomen with abdominal pain, nausea, and vomiting. c. Pathology showsa hemorrhagic infarction with fibrinous or fibrinosuppurative exudate on the mucosa,leading to ulceration, secondarybacterial infection, or perforation. 2. Mucosal and mural infarction (acute hemorrhagic gastroenteropathy)is characterized by patchy hemorrhagic necrosisof the mucosaand submucosasparingthe deeperlayers. This pattern is relatedto nonocclusivehypoperfusion in CHF or shock. E. Obstructive lesions 1. Hernias cause l5o/oof small intestinal obstruction. They are due to a protrusion of a serosa-linedsacthrough a weaknessin the wall of the peritoneal cavity.They occur most commonly at the inguinal and femoral canals,at the umbilicus, and with scars.They may lead to entrapment,incarceration,and strangulation of the bowel. 2. Adhesions are fibrous bands connectingloops of bowel to eachother or to other regions of the peritoneal cavity. They usually occur after surgery and are causedby the banding of scar tissue. They may result in internal hernias with subsequentobstruction and infarction.
r80
Pathology
3. Intussusception is due to invagination and telescopingof one segmentof bowel into an adjacentregion. It is more common in infants and children. In children, some may be reduced with a diagnostic barium enema. It is usually causedby an intraluminal mass (e.9.,polyp, tumor, hematoma,Meckel diverticulum, etc.). 4. Volvulus is the twisting of the bowel about its mesentericbase.It may causeobstruction and infarction. Volvulus frequently occurs in the elderly at the sigmoid colon as a result of redundant mesentery at that site. 5. Other causesof mechanical obstruction include obstruction by gallstonesor the extrinsic compressionby a mass (e.g.,a tumor) in adjacentbowel. F. Tirmors of the small bowel account for only 5o/oof gastrointestinaltumors. The benign to malignant ratio is 2:3. 1. Benign tumors in descendingorder of frequencyinclude: leiomyomas,lipomas, adenomas (polyps), angiomas,and fibromas. Adenomatous polyps are most common in the stomachand duodenum and may be singleor multiple, sessileor pedunculated.The larger the polyp, the greaterthe incidenceof malignant transformation. 2. Malignant tumors, in descendingorder of frequency,include: endocrine cell tumors, lymphomas, adenocarcinomas,and leiomyosarcomas. a. Endocrine cell tumors (e.g.,carcinoid, argentaffin carcinoma) are slow growing but may invade,metastasize,or causethe carcinoid syndrome when they metastasizeto the liver. They arise from enterochromaffin cells. This family of tumors is known as APUD (amine precursor uptake and decarboxylation)tumors, which produce, store, and secreteaminesand polypeptides. (1) Clinical features. Carcinoids may present with abdominal pain, weight loss, anorexia,diarrhea,and rectal bleeding.Tumors in the small intestine may cause obstruction and even metastases.Five to ten percent of tumors produce the carcinoid syndrome characterizedbyvasomotor disturbances,such as flushing or cyanosis,intestinal hypermotiliry bronchoconstriction, hypotension, and right-sided cardiac involvement. The carcinoid syndrome occurs if there is widespreadliver metastasesor if the venous blood from the tumor does not drain into the liver. The liver deaminatesthe vasoactiveproducts secretedby the tumor, including serotonin,histamine,various kinins, and prostaglandins.When not metastatic,carcinoid tumors are usually treatedsuccessfullyby surgery. (2) Pathology. Typical tumors are l-2 cm in diameter,yellow, nodular, and cause mucosalelevation.Microscopically, nestsof cellsarrangedin cords and rosettes are seen. There is a uniform cell type with round nuclei and abundant eosinophilic cytoplasm. Electron microscopy examination reveals secretory granules.Carcinoids invade the submucosaand muscularis and may penetrate the bowel wall. b. tymphoma of the small bowel is usually of the non-Hodgkin, large cell, diffr,rsetype. In immunosuppressedpatients, the incidence of primary lymphomas of the small intestine is increasing.Thesehave a poor prognosis.Another form of primary lymphoma of the bowel is called MAtlloma. These are often follicular and follow a more benign course.Some lymphomas that are associatedwith H. pylori infection regress after antibiotic therapy.
ClinicalCorrelate Carcinoid tumors maypresent pain,rectal withabdominal pain,andothersymptoms. Systemic symptoms include flushing, hypotension, and bronchoconstriction. Note Histologically, carcinoid tumors appear asother neuroendocrine tumors, with nests of small. uniform cells.
Bridgeto Heme/tymph Non-Hodgkin lymphoma is discussed in detail inthe phoreticular Hematol ogic/Lym Pathology chapter of Organ Systems Bookt fl/olume lll).
c. Adenocarcinoma is rare. It typically forms an encircling mass.Symptomsoccur late.
t8l
System Gastrointestinal
(COTON) rARGETNTESTTNE A. C,ongenitalanornalies I . Hirschsprungdiseaseproducesa markedly distendedcolon, usuallyproximal to the rectum. a. Incidence.The overallincidenceis approximately1 in 5,000births, with an increased incidencein Down'ssyndrometo about 2qo.
InaNubheil Hrrscnsprung orsease rsa congenital absence of cells ParaslmPathetic Sanslion in thedistalcolonand presents soonafterbirthwith passaSe inadequate of stool.
b'clilicarfeaturcsJ::ii:::.H:HliT:"n$i:Hffi::$xfi:"*H:ffd: tion' vomiting'andabdominaldistention' c. Diagnosisis madeby barium enemaand rectalbiopsy. d. Pathogenesisis an absenceofganglion cellsofMeissner andAuerbachplexus in the distal iolon. Musclein this regionis unableto relaxfrrlly to permit adequateperistalsis.Passage of contentsis blocked,and the proximal colon dilates.The diseasealways involvesthe recturnand may extendasfar backasthe ileum. e. Pathology (1) crossly, there is a distendedbowel with either hypertrophyor thinning of the wall proximal to the segmentthat is aperistaltic. (2) Microscopicalln thereis absenceof ganglioncellsin the submucosaand muscularis with proliferationof nonmyelinaGdnervesin undilatedregionsof the colon.
Note
2. Imperforate anus is due to a failure of perforation of the membranetlat separatesthe endodermalhindgut from the ectodermalanal dimple. B. Benign conditions
Because onlvtwolave6ofthe gutwallareinvolved, the outpouchings aretechnically pseudodiverticula.
1. Diverticular diseaserefersto multiple outpouchingsof the colon. a. Incidence.Diverticular diseaseis presentin 30-50o/oof adult autopsiesin the United States.Thereis a higher incidencewith increasingage. b. Pathogenesis.Hemiation of mucosaand submucosathrough weakareasof the gut wall where arterial vasarecta perforatethe muscularisis a characteristicpathologic finding of the disease.It appearsthat increasedintralurninal pressweand segmental hlperactive peristalsisare not responsiblefor the developmentof diverticula; however,they may exacerbatesymptomsof the disease, c. Clinical featwes (l) Diverticulosis is often asymptomatic,but may presentwith pain and/or rectal bleeding. (2) In contrast,diyerticulitis presentswith pain and fever.It is distinguishedfrom diverticulosisby the presenceof inflammation, which may or may not cause colickyleft lower abdomsymptoms.When symptomatic,the patientexperiences inal pain, changein bowelhabits,and melena,so-called"left-sidedappendicitis." Whenthereareinflammatorychang€s,they maypresentwith fever,leukocytosis, and a left Iower quadrantmassthat raisessuspicionsof cancer. d. Pathology ( 1) Grossly,diverticulaareseenmost frequentlyin the sigrnoidcolon alongmesenteric and antimesentericsurfaces.Oupouchings aretypically 0.5-l cm.
r82
Pathology
(2) Microscopically, attenuation of the musculariswith or without inflammation is seen.In diverticulitis,there may be perforation with inflammation and micro- or macroabscess formation. C. Inflammatory diseases 1. Crohn disease, or regional enteritis, causes a segmental, recurrent, granulomatous inflammatory disease of the bowel. It most commonly involves the terminal ileum and colon but may involve any part of the gastrointestinaltract. There is a familial disposition. a. Etiology. There is probably a similar etiology for both Crohn diseaseand ulcerative colitis, which together are called inflammatorybowel disease.The following possible etiologieshave been considered:infectious; immunologic (both antibody-mediated and cell-mediated);deficienciesof suppressorcells;and nutritional, hormonal, vascular, and traumatic factors. b. Clinical features. Crohn diseaseusually begins in early adulthood and is common in Ashkenazicfews. Patients present with colicky pain, diarrhea, weight loss, malaise, malabsorption,low-gradefever,and melena.Crohn diseaseis a systemicdisorder that may be associatedwith arthritis, erythema nodosum, uveitis,immunologic disorders, and ankylosingspondylitis.There is typically a remitting and relapsingcourse.If the involvedbowel is resected,lesions frequently developin previouslyuninvolvedregions of the bowel. Crohn diseaseleadsto a minimally increasedincidence of small bowel adenocarcinoma,a very rare tumor.
ClinicalCorrelate presents Crohn disease with pain,diarrhea, weight loss, malabsorption, andmalaise.
c. Pathology.Crohn diseasehas a very characteristicpathology. (1) Grossly, there are segmental areas (skip lesions) of involvement, most commonly in the terminal ileum. Edema, inflammation, and fibrosis are seen.The lumen becomesnarrow causinga "string sign" on barium enema.Involved areas lead to adhesions,fistulae, fissures, strictures, possible anal involvement, and serositis. (2) Microscopically, there is classicallya transmural inflammation with lymphoid aggregates and noncaseatinggranulomas in about half the cases(FigureII-5-5).
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e|'i:'qry. i# '', " :'& :'&
%n * a.. !&-
Figurell-5-5.Crohndisease(microscopic).
t8r
System Gastrointestinal
2. Ulcerative colitis is a chronic relapsing diseasecharacterized by ulcerations, predomrnantly of the rectum and left colon, but which may affect the entire colon and occasionally the terminal ileum. a. Incidence is higher in Caucasiansthan in Blacks,and is also more frequent in women than in men. The typical age of onset ranges from 12-35 years of age. There is a definite familial predisposition. b. Etiology. Etiologic theories are similar to those for Crohn disease.Some inflammatory bowel diseasehas microscopic featuresof both ulcerative colitis and Crohn disease.
ln a Nutshell isa chronic Ulcerative colitis disease characterized by and colonic mucosal ulcerations. submucosal Bloody diarrhea isthe presentation. hallmark clinical ln a Nutshell CrohnDisease . Anywhere along gastrointestinal tract (usually terminal ileum andcecum) . Skiplesions (not continuous) . Transmural
c. Clinical course is characterizedby relapsing bloodymucus diarrhea, which may lead to dehydration and electrolyte imbalances,lower abdominal pain, and cramps. The patient may also experience systemic manifestations as with Crohn. The diseaseis treated initially with steroids and antibiotics, but eventually, most patients come to colectomy.There is an increasedincidence of carcinoma of the colon, up to 50o/oafter 25 yearswith the disease. d. Pathology (1) Grossly, the diseasealmost alwaysinvolves the rectum. It may extend proximally to involve part of the colon or its entirety. There are superficial mucosal ulcers, shortening of the bowel, narrowing of the lumen, pseudopolypr, and backwash ileitis. (2) Microscopically, there is vascular congestion,an inflammatory infiltrate characterized by crypt microabscesses,which increase in size and undermine the mucosa,then progressto ulceration.In contrastto Crohn disease,the inflammation is usuallv confined to the mucosa and submucosa. Thble II-5-1. Crohn diseaseversus ulcerative colitis. Pathology
Crohn Disease
Ulcerative Colitis
Grosspathology
Skip lesions,fistulae, strictures,fissures Tiansmural fibrous thickening Rectum often spared Occasionallyinvolves total colon
Continuous involvement, superficial ulcers Pseudopollps Rectum involved Often involves total colon
Micropathology
Tiansmural involvement Granuloma formation
Superficial involvement No granulomas Crypt abscesses characteristic
Endoscopic findings
Cobblestoning, skip lesions,aphthousulcers
Generalizederythema Contiguousinvolvement
. Fissures andfistulas . Cranulomas . Cobblestone mucosa . "String sign"onbarium enema Ulcerative Colitis . Continuous involvement proximally fromrectum . Limited to mucosa and (nottransmural; submucosa nofissures orfi$ulas) . Pseudopolyps . Cryptmicroabscesses . Creater riskof developing colon adenocarcinoma than in Crohn disease
t84
3. Pseudomembranous colitis is an inflammatory processcharacterizedby a pseudomembranous exudatecoating the colonic mucosa. a. Pathogenesis.The syndrome is associatedwith antibiotic use (especiallyclindamycin), allowing proliferation of Aostridium dfficile, which producesan exotoxin. b. Pathology. Gross pathology shows plaques of yellow-green mucinous exudate overlnng an erythematousmucosa.
Pathology
'#+w,fu*. 1*,,
W, Figure ll-5-6.Ulcerative colitis (microscopic).
c. Clinical features include diarrhea that is often bloody, fever,and leukocytosis. d. Diagnosis is made by identification of C. dfficile and toxin in stool. e. Treatment includes stopping the original antibiotic and starting oral vancomycin or metronidaz.ole.This diseaseis often a terminal complication in immunosuppressed patients. D. Vascular lesions 1. Ischemic injury. The large bowel is relatively protected becauseof a dual vascular supply from both enteric vesselsand accessoryvesselsfrom the posterior abdominal wall. When ischemiadoesoccur,pathologic processesare the sameas in the small intestine. 2. Angiodysplasia (vascular ectasia) causes dilated tortuous vesselsof the right colon, which causelower gastrointestinal bleeding in the elderly. The highest incidence is in the cecum. 3. Hemorrhoids are variceal dilatations of the anal and perianal venous plexus. They are causedby elevatedintra-abdominal venous pressure,often from constipation and pregnancy, and are occasionally due to portal hypertension, where they are associatedwith esophagealvarices.Hemorrhoids may undergo thrombosis, inflammation, and recanalization. External hemorrhoids are due to dilatation of the inferior hemorrhoidal plexus, while internal hemorrhoids are due to dilatation of the superior hemorrhoidal plexus. E. Polyps are mucosalprotrusions. 1. Hyperplastic polyps comprise 90o/oof all polyps. They are non-neoplastic and occur mostly in the rectosigmoidcolon. a. Grossly, they form smooth, discrete,round elevations. b. Microscopically, glands and sawtooth crlpts are composed of a proliferation of goblet and columnar epithelial cells.There is no atypia. 2. Adenomatous polyps are true neoplasms.There is a higher incidenceof cancerin larger polyps and in those containing a greaterproportion of villous growth.
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System Gastrointestinal
a. Tubular adenomas (pedunculated polyps) make up 75o/oof adenomatouspolyps. They may be sporadic or familial. For sporadicpolyps, the ratio of men to women is 2:1. The averageageof onset is 60. (1) Grossly,most occur in the left colon; 50o/oaresinglewith a thin stalk supporting a tufted head. (2) Microscopically, there is increasinganaplasiain large polyps. Nuclei lose their basal orientation and pile up. The nuclear-to-cytoplasmicratio decreasesand mitosesincrease.The stalk is coveredby normal colonic epithelium; the head of the polyp is coveredby adenomatousepithelium, forming atypical glands and tubules. Canceroustransformation (i.e., invasion of the lamina propria or the stalk) occurs in approximately 4o/oof patients. About b. Villous adenomasare the largest,leastcommon polyps, and are usually sessile. one-third are cancerous.Most are within view of the colonoscope. (1) Grossly, they form "cauliflower-like" sessilegrowth 1-10 cm in diameter, which are broad-basedand haveno stalks. (2) Microscopically, multiple papillary projections make up at least half the polyps. In different microscopic fields, well-differentiatedareas,carcinoma in situ, and invasivecancermay be seen.
In a Nutshell Tubular, villous, and tubulovillous adenomata are foundinthecolon. lncreased villous nature increases the likelihood of malignancy.
c. Tubulovillous adenomas have combined tubular and villous elements.Any increase in villous elementsincreasesthe likelihood of malignant transformation. 3. Familial polyposis is due to deletion of a genelocatedon chromosome5q. a. Familial multiple polyposis (adenomatouspolyposis coli) showsautosomal domipolyps start in the nant inheritance and the appearanceof polyps during adolescence; rectosigmoidareaand spreadto cover the entire colon. The polyps are indistinguishable from sporadic adenomatouspolyps.Virtually all patients developcancers.When diagnosed,total colectomyis recommended. b. Gardner syndrome refersto colonic polyps associatedwith other neoplasms(e.g.,in skin, subcutaneoustissue,bone) and desmoid tumors. The risk of colon cancer is nearly 100o/o. c. Peutz-feghers syndrome presents with polyps on the entire gastrointestinaltract (especiallythe small intestine) associatedwith melanin pigmentation of the buccal mucosa,lips,palms, and soles.The polyps are hamartomasand are not premalignant. Peutz-|egherssyndrome showsautosomaldominant inheritance. d. Turcot syndrome is characterizedby colonic polyps associatedwith brain tumors (i.e.,gliomas,medulloblastomas). F. Malignant tumors 1. Adenocarcinoma is the histologic type of 98o/oof all colonic cancers.Both environmental and geneticfactorshavebeen identified. a. Incidence is very high in urban, Westernsocieties.It is the third most common tumor in both women and men. The peak incidenceis in the seventhdecadeof life. b. Pathogenesisis associatedwith villous adenomas,ulcerative colitis, Crohn disease, familial pollposis, and Gardner syndrome.Incidenceis possiblyrelatedto high meat intake,low-fiber diet, and deficientvitamin intake.A number of chromosomalabnormalities havebeen associatedwith the developmentof colon cancer.
t86
Pathology
c. Clinical features include rectal bleeding, change in bowel habits, weakness,malaise, and weight loss in high-stage disease.The tumor spreadsby direct extension and metastasisto nodes, liver, lung, and bones. Carcinoembryonic antigen (CEA) is a tumor marker that helps to monitor tumor recurrenceafter surgery or tumor progressionin somepatients.
In a NuBhell
d. Pathology (1) Grossly,T5o/o of tumors occur in the rectum and sigmoid colon (FigureII-5-7). Left-sidedlesions often show annular constriction, infiltration of the wall, and obstruction. Most tumors begin asa small raisedmassforming a flat plaque that encirclesthe colon and begins to infiltrate deeperlayersof the colonic wall. Right colonic lesionsare often bullcy,polypoid, protuberant massesthat penetratethe colonic wall. They rarely obstruct becausethe fecal stream is liquid on the right side.
Adenocarcinoma isthemo$ common typeof coloncancer. It canpresent withrectal bleeding, changed bowel habits, weightloss,andother systemic symptoms.
(2) MicroscopicallS these tumors are typical mucin-producing adenocarcinomas. Differentiation, mucin production, mitotic rate, and stromal fibrous reactionvary. 2. Squamous cell carcinoma forms in the anal region. It is often associatedwith papilloma virusesand its incidenceis rising in homosexualmaleswith AIDS.
Figure ll-5-7.Carcinoma of the colon (gross).
APPENDIX A. Inflammation 1. Appendicitis is almost alwaysacutein onset. a. Pathogenesis.Obstruction leadsto mucus retention and distention, compromise of blood supply,and subsequentbacterialinfection.
ClinicalCorrelate painbegins Appendicitis periumbilically andthen localizes totheactual anatomic siteoftheappendix.
b. Clinical features typically include initial periumbfical pain that then lqsalizesto the right lower quadrant, accompaniedby anorexia,nausea,vomiting, fever,and moderate leukocytosis.
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System Gastrointestinal
c. Pathology. Earh acute appendicitis shows vascular congestion and edema with little cellular infiltrate. Acute suppurative appendicitis shows an extensivetransmural neutrophilic exudate with areasof necrosis.Acute gangrenous appendicitis develops as the blood supply is compromisedby inflammation, edema,and thrombosis. B. Mucocele of the appendix is dilatation of the appendix causedby mucin accumulation. 1. Mucinous cystadenoma is a benign neoplasm,which may perforate. This is the most common type. 2. Mucosal hyperplasia doesnot perforate. 3. Mucinous cystadenocarcinoma is the penetration of the bowel wall by malignant cells, forming peritoneal implants. Pseudomlaromaperitonei is a condition in which the peritoneal caviry is filled with mucin-secretingcellsof rystadenocarcinomas. C. Tumors. Carcinoids are most common; carcinomasare rare. Primary lymphoma is occasionally seen.
PERITONEUM A. Peritonitis is inflammation of the peritoneum. 1. Sterile peritonitis may be causedby bile, pancreatic enzymes,and foreign materials. 2. Bacterial peritonitis. In this condition, the membrane becomesdull with an accumulation of turbid fluid. The exudatebecomesfrankly purulent and may causeabscesses and adhesionsafter healing. B. Mesenteric cysts are cysts within the mesenteriesor attached to the peritoneum. They are usually singleand of variable size.Most are benign. C. Sclerosing retroperitonitis etiology is unknown.
is a dense fibrotic proliferation of the retroperitoneum. The
D. Tirmors of the peritoneum are usually malignant. 1. Primary mesotheliomas are rare. Eighty percent are associatedwith asbestose4posure. 2. Secondary (metastatic) tumors are common; most are ovarian or pancreatic.Implants from metastaticteratomassometimesmature and losetheir capacityto invade or metastasizefurther.
EXOCRINE PANCREAS A. Congenital anomalies
Bridgeto Endocrine System Disorders oftheendocrine pancreas arediscussed inthe Endocrine Pathology chapter ofthisbook.
1. Ectopic pancreatic tissue most commonly occurs in the stomach,duodenum, jejunum, Meckel diverticulum, and ileum. It may be either asymptomatic or causeobstruction, bleeding,or intussusception. 2. Annular pancreas is a ring of pancreatictissue that encirclesthe duodenum and may causeduodenal obstruction. B. Cystic fibrosis is a systemicdisorder of exocrinegland secretion,presentingduring infancy or childhood. 1. Incidence is 1:2,500in Caucasians;it is less common in Blacks,and extremely rare in Asians. 2. Pathogenesis.Cystic fibrosis showsautosomal recessivetransmission;heterozygotesare unaffected.The defect is in the CFTG (the cystic fibrosis transporter gene) located on
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Pathology
chromosomeT. More than 200 mutant alleleshave been demonstrated.It results in a defective chloride channel, which leads to secretion of verythickmucus.
Note
a. Fifteen percent of casespresentwith meconium ileus.
Thegeneonchromosome 7 encodes a 1480 amino acid peptide thatappears to playa rolein chloride andsodium channels in cellmembranes. Themostcommon formof fibrosis cystic seems to result froman inabilityto glycosylate thisprotein andinsert it inthe cellmembrane.
b. Most casespresentduring the first year with steatorrhea (with resultant deficiencies of vitamins A, D, E, and K), abdominal distention, and failure to thrive.
Clinical Correlate
3. Characteristics a. Tissues other than exocrine glands are normal, and glands are structurally normal until damagedby rystic fibrosis. b. The only characteristic biochemical abnormalities are an elevation of sodium and chloride levelsin sweat,and a decreasein water and bicarbonatesecretionfrom pancreaticcells,resulting in a viscoussecretion. a. Clinical features
c. Complications are also related to pulmonary infections and obstructive pulmonary diseaseas a result of viscousbronchial secretions. 5. Pathology a. There is mucus plugging of the pancreatic ducts with cystic dilatation, fibrous proliferation, and atrophy. Similar pathology developsin salivary glands.
CFpresents withsteatorrhea andfrequent respiratory infections inyoungchildren (oftenPseudomonos). An abnormal sweat chloride test willconfirm thediagnosis.
b. Lungs. Mucus impaction leadsto bronchiolar dilatation and secondaryinfection. The emphysema, clinical course is characterizedby bronchitis, bronchiectasis,abscesses, Psezdomonasaeruginosa is the most common etiologic agent. and atelectasis. c. The gastrointestinal tract shows obstruction caused by mucus impaction in the intestineswith areasof biliary cirrhosis,resultingfrom intrahepaticbile duct obstruction. 6. Diagnosis dependson demonstratinga "sweat test" abnormality associatedwith at least one clinical feature.In the sweattest,high levelsof chloride are demonstrated. 7. Prognosis.Mean survival is age20; mortality is most often due to pulmonary infections. C. Degenerative changes 1. Iron pigmentation (e.g.,from hemochromatosis)may be depositedwithin acinar and islet cells and may causeinsulin deficiency. 2. Atrophy
Note Hemochromatosis isalso "bronze called diabetes"; irondeposition causes to pancreatic damage andhepatic arteries.
a. Ischemic atrophy is due to atherosclerosisof pancreatic arteries and is usually asymptomatic. b. Obstruction of pancreatic ducts affects only the exocrine pancreas,which becomes small, fibrous, and nodular. D. Acute hemorrhagic pancreatitis presentsas a diffirse necrosisof the pancreascausedby the releaseof activatedpancreaticenzymes.Associatedfindings include fat necrosisand hemorrhageinto the pancreas. 1. Incidence.This disorderis most often associatedwith alcoholismand biliary tract disease. alcohol It affectsmiddle-agedindividuals and often occursafter a large meal or excessive ingestion;approximately50oloof patientshavegallstones. 2. Pathogenesis.There are four theories.
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Gastrointestinal System
a. Obstruction of the pancreatic duct causesan elevated intraductal pressure,which results in leakageof enzfmes from small ducts. Obstruction may be causedby a gallstone at the ampulla of Vater; chronic alcohol ingestion may causeduct obstruction by edema. b. Hypercalcemia may cause activation of trypsinogen; its mechanism is unclear. Pancreatitisoccurs in 20o/oof patients with hlperparathyroidism. c. Direct damage to acinar cells may occur by trauma, ischemia,viruses, and drugs. d. Hyperlipidemia may occur as a result of exogenous estrogen intake and alcohol ingestion. 3. Mediators a. Proteases,particularly trypsin, may causeactivation of pancreatic proenzymes. b. Lipases such as phospholipase A convert bile lecithin to toxic lysolecithin and also directly damagecell membranes. c. Elastase,after it is activated by trypsin, dissolvesthe elastic fibers of ducts and blood vessels,leadingto enzymeleakageand hemorrhage. 4. Other etiologies include penetratingpeptic ulcers,metabolic abnormalities (e.g.,hlpercalcemia),and familial relapsingpancreatitis. 5. Clinical features are typically the sudden onset of acute,continuous, and intense abdominal pain, often radiating to the back and accompanied by nausea,vomiting, and fever. This syndrome frequently results in shock. Laboratory values reveal elevated amylase (lipase elevatedafter 34 days) and leukocytosis.Hypocalcemia is a poor prognostic sign. 6. Pathology a. Grossly, gray areasof enzymatic destruction, white areasof fat necrosis,and red areas of hemorrhageare seen. b. Microscopic findings (1) Enzymatic necrosis leads to liquefactive necrosis. An inflammatory infiltrate surrounds regionsof necrosis.Necrosisof blood vesselswith hemorrhageis also seen. (2) Fatnecrosis is characterizedby fat cells filled with amorphous, granular pink material. It occurs in the pancreatic parenchyma and stroma and in distant fat depositswithin the abdominal cavity. (3) Bacterial infection may occur late,leading to suppuration and abscessformation. 7. Tieahnent is supportive,including no oral intake, nasogastricsuction, and intravenous fluids. 8. Comptcations. Grey Tirrner sign (bluish discoloration of the flanks) and Cullen sign (periumbilical discoloration) indicate extensivedamage.Abscess,pseudoryst, duodenal obstruction, shock lung, and acute renal failure may all occur in any combination. E. Chronic pancreatitis refers to remitting and relapsing episodesof mild pancreatitis,causing pro gressivep ancreatic damage. 1. Incidence is similar to acute pancreatitis.It is also seenin patients with ductal anomalies. Almost half the casesoccur without known risk factors. 2. Pathogenesisis unclear; possibly,there is excessprotein secretion by the pancreas,causing ductal obstruction.
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Pathology
3. Clinical features include flareups precipitated by alcohol, overeating,and drugs. Attacks are characterizedby upper abdominal pain, tenderness,fever,and jaundice. Laboratory values reveal elevated amylase and alkaline phosphatase. X-rays reveal calcifications in the pancreas.Chronic pancreatitismay result in pseudocystformation, diabetes,and steatorrhea. 4. Pathology
In a Nutshell pancreatitis Chronic presents withsteatorrhea, diabetes, andabdominal (pseudocy$), mass
a. Chronic calcifying pancreatitis is associatedwith alcoholism. (1) Grossly, the organ is indurated, with multiple calcifications.Pancreaticcalculi and pseudorystsare common. (2) Microscopically, there is acinar atrophy,fibrous proliferation, and mononuclear inflammatory reaction in a lobular distribution. Occasionally,there is squamous metaplasiaof the ductal epithelium. b. Chronic obstructive pancreatitis is associatedwith gallstones.The lesions are more prominent in the head of the pancreas.The pattern doesnot havea lobular distribution. F. Carcinoma of the pancreas 1. Incidence a. Carcinoma of the pancreasaccounts for approximalely 5o/oof all cancer deaths. Increasedrisk is associatedwith smoking, high-fat diet, and chemicalexposure.There is a higher incidencein the elderly,Blacks,males,and diabetics. 2. Clinical features a. The diseaseis usually asymptomaticuntil late in its course. b. Manifestationsinclude weight loss,abdominal pain, frequently radiating to the back, weakness,malaise,anorexia,depression,and ascites. c. There is jaundice in half of the patientswho havecarcinomaof the headof the pancreas. d. Courvoisier law holds that painlessjaundice with a palpablegallbladderis suggestive of pancreaticcancer.
In a Nubhell
3. Pathology. Carcinomasarisein ductal epithelium. Most are adenocarcinomas. a. Carcinoma of the head of the pancreas accounts f.or 600/oof all pancreatic cancers.It producessmall, white, fibrous, infiltrating lesionsthat frequently invade the wall of the common bile duct, duodenum, or ampulla of Vater.Theselesionsfrequentlycausebiliary obstruction (50o/oof caseshave a dilated gallbladder). b. Carcinoma of the body (20o/o)and tail (5olo)produce large, indurated massesthat spreadwidely to the liver and lymph nodes.
isoften Pancreatic cancer arisein adenocarcinoma; 600/o head. thepancreatic jaundice, weight 0bstructive painare loss, andabdominal themostcommon symptoms.
c. In 15oloof patients,carcinomainvolvesthe pancreasdiffusely. 4. Complications include Trousseau syndrome, a migratory thrombophlebitis that occurs in 10oloof patients.This may also occur with other mucin-producing adenocarcinomas whosesecretionsactivateclotting. 5. Prognosis is very poor. If resectable,the 5-year survival rate is lessthan 5olo.The usual courseis rapid decline;on average,death occurs6 months after the onset of symptoms. G. Cysts 1. Congenital cysts frequently occur with rystic diseaseof the liver and kidney. They are usually multiple.
l9l
Gastrointestinal System
2. Pseudocystsoccur assequelaeof pancreatitisor trauma. They are causedby loculation of fluid (suppurative,hemorrhagic,or necrotic debris). a. Singlepseudocystsare usually 5-10 cm in diameterwith a fibrous capsule.There is no epithelial lining and no direct communication with pancreaticducts. b. Pseudorystspresentas an abdominal mass,often with pain, and they may causeperitonitis if ruptured. 3. Cystadenomas and cystadenocarcinomas are neoplastic rysts. They are usually single, 5-15 cm in diameter,and multiloculated. Theseare true rysts, lined by epithelium with papillary projections.
TIVER A. Congenital malformations 1. Accessorylobes are most often inferior. They are not associatedwith any specificdisease process. 2. Congenital cystic disease is associatedwith congenital polyrystic diseaseof the kidneys and is asymptomatic. 3. Congenital hepatic fibrosis is a disorder demonstratingautosomalrecessiveinheritance. It is characterizedby periportal fibrosis,resulting in hepatosplenomegalyand esophageal varices. 4. Extrahepatic biliary atresia causes cholestasis,which results in cirrhosis and portal hypertension.It presentswithin the first weeks of life with jaundice, dark urine, light stools,and hepatosplenomegaly. 5. Intrahepatic biliary atresia resultsin a diminished number of bile ducts.It is sometimes associatedwith cr,-antitrypsin deficiency. It presentsin infancy with cholestasis,pruritus, growth retardation,and increasedserum lipids.
In a Nutshell Unconjugated Hyperbilirubinemia . Hemolysis . Decreased uptake dueto diffuse hepatocellular damage . lmpaired conjugation (Crigler-Najjar andCilbert's syndromes) Conjugated Hyperbilirubinemia . DubinJohnson syndrome . Rotor's syndrome . Cholestasis
192
B. |aundice, or icterus, is caused by excessbilirubin accumulation in the skin and sclerae, producing a yellow discoloration of thesetissues.Icterus is visible when the serum bilirubin exceeds2 mgldl. In unconjugated hyperbilirubinemia, bilirubin is not excretedinto the urine becauseof tight protein binding in serum. In conjugatedhyperbilirubinemia, small amounts of bilirubin are excretedin the urine becauseit is lesstightly protein bound. 1. Unconjugated hyperbilirubinemia may be causedby: a. Excessproduction, such as occursin hemolytic disease. b. Reduced hepatic uptake, which may produce kernicterus in neonates. c. Impaired conjugation, such as occurs in Gilbert syndrome and Crigler-Najjar syndrome 2. Conjugated hyperbilirubinemia a. Dubin-Johnson syndrome produces benign conjugated hyperbilirubinemia due to impaired transport of anions.Liver is grosslyblack. b. Rotor syndrome is asymptomatic.It is similar to Dubin-|ohnson, but the liver is not pigmented.
Pathology
c. Cholestasiscausesthe impaired excretionof conjugatedbilirubin. (1) Intrahepatic causes of cholestasis include hepatocellular cholestasis,which may be seenin viral hepatitis,cirrhosis,and drug toxicity. (2) Extrahepatic causesof cholestasisinclude gallstones,carcinoma of bile ducts, ampulla of Vater or head of the pancreas'and cholangitis. (3) Clinical features are typically pale stools,decreasedurinary urobilinogen, fat malabsorption, pruritus, elevatedserum cholesterol,xanthomas,and bilirubin in the urine. C. Hepatic failure 1. Etiology. Chronic hepatic disease(e.g.,chronic activehepatitis or alcoholic cirrhosis) is the most common causeof hepatic failure, although acuteliver diseasemay alsobe responsible. a. Widespreadliver necrosis may be seenwith carbon tetrachlorideand acetaminophen toxicity. Widespread steatosisis seenin Reye syndrome, a causeof acute liver failure most often seenin children with a recenthistory of aspirin ingestion for an unrelated viral illness. b. Massive necrosis may also be seen in acute viral hepatitis, after certain anesthetic agents,and in shock from any cause. 2. Ctinical features. Hepatic failure causesjaundice, musty odor of breath and urine, encephalopathy,renalfailure (either by simultaneoustoxicity to the liver and kidneys or the hepatorenalsyndrome),palmar erythema,spider angiomas,gynecomastia,testicular atrophy (secondaryto impaired estrogen degradation), prolonged prothrombin time (impaired hepatic synthesisof coagulationfactors),weight loss,musclewasting,pruritus, and anemia. malabsorption,hypoalbuminemia,hypercholesterolemia, D. Hemodynamic and vascular abnormalities l. Chronic passivecongestion is associatedwith right heart failure and is a common postmortem finding. a. Pathology shows congestion of central veins and centrilobular hepatic sinusoids known as"nutmeg liver" (FiguresII-5-8 and II-5-9). b. Ctinical features include mild hepatomegalyand, occasionally,a pulsatile liver that is tender to palPation. 2. Central hemorrhagic necrosis may be seenin severeheart failure. a. Pathophysiology is due to hypoxia secondaryto hypoperfusion. b. Pathology. There is a marked "nutmeg-like" appearance,aswell as marked sinusoidal dilatation with parenchymalhemorrhage,atrophy,and necrosisaround central veins.
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Gastrointestinal System
Figure ll-5-8.Ghronic passive congestion of the liver (gross).
Figure ll-5-9.chronic passive congestion of the liver (microscopic).
t94
Pathology
3. Cardiac sclerosis is a sequela of chronic passive congestion and central hemorrhagic necrosis. a. Grossly, the liver is slightly smaller with a "pig skin" grain on the external surface. b. Microscopically, there is delicate fibrosis around central veins fanning out into the liver parenchyma,causing destruction of central hepatocytes. 4. Infarctions are rare becauseof the double blood supply (hepatic artery and portal vein). Occlusion of an intrahepatic branch of the portal vein may causean infarct of. Zahn, a sharply bordered regional purple discoloration. Occlusion does not causean ischemic infarct. 5. Hepatic vein thrombosis (Budd-Chiari syndrome) is arare syndrome that may be acute or insidious. a. Etiology. The Budd-Chiari syndrome may be seen in many unrelated conditions, including neoplasms invading hepatic veins, polycythemia vera, intrahepatic infection, paroxysmal nocturnal hemoglobinuria, myeloproliferative syndromes, and intravascular webs or membranes.All of these syndromes can provoke clotting either through platelet activation, abnormal platelet function, or activation of the extrinsic clotting system.
ln a Nubhell isa syndrome Budd-Chiari veinobstruction hepatic and to clinical leading pathologic of chronic features liver. congested
b. Clinical features include abdominal pain with a large, tender liver and ascites. c. Micropathology is similar to chronic passive congestion and central hemorrhagic necrosiswith fibrosis and rupture at Dissespaces. 6. Portal vein obstruction and thrornbosis a. Etiology (l) Extrahepatic causesinclude abdominal neoplasms(notably renal cell carcinoma), pancreatitis,sepsis,and postsurgicalconditions. (2) Intrah€paticcauses include cirrhosis and primary or secondaryneoplasticinvasion. b. Clinical features include portal hypertension and splenomegaly.
E. Hereditary disorders of bilirubin metabolism l. Gilbert syndrome is a benign autosomal dominant diseasecharacterizedby unconjugated hyperbilirubinemia. It may be causedby a defect in hepatocellular uptake of unconjugated bilirubin or by a deficiency of glucuronyl transferase.Liver histology is normal. The diseasepresentswith chronic jaundice that is worse on fasting. Bilirubin rarely exceeds6 mg/dl. It occurs in approximately 5o/oof the population, sometimes without a family history. 2. Crigler-Najjar syndrome a. Type I shows autosomal recessiveinheritance and complete absenceof glucuronyl transferase, causing marked unconjugated hlperbilirubinemia, severekernicterus, and death. Type 2 shows a mild deficiency of glucuronyl transferase.Kernicterus does not develop. Autosomal dominant inheritance is clear in some families, but in others, the syndrome may represent a homozygous Gilbert syndrome since other members of the family have classic Gilbert disease. Viral hepatitis 1. Hepatitis A (HAV) is a self-limited hepatitis causedby an RNA virus with an incubation period of approximately2-6 weeks.Infection is identified by HAv-specific antibodies (IgM
Bridgeto Microbiology . Hepatitis A isa picornavirus. icosahedral It hasa naked andsinglenucleocapsid RNA. stranded . Hepatitis B isa doubleDNAvirus stranded asa hepadnavirus. classified It hasanenveloped nucleocapsid. icosahedral . Hepatitis asa C isclassified positivelt is a flavivirus. RNAviruswithan strand icosahedral enveloped nucleocapsid. . Hepatitis bythe D iscaused deltaagent-aprotein lowsurrounding capsule RNA. weight molecular . Hepatitis asa Eisclassified lt isa singlecalicivirus. RNAviruswitha stranded icosahedral naked nucleocapsid.
t95
Gasfrointestinal System
if acute,IgG if convalescent).The usual route of infection is fecal-oral transmission by contaminated food, particularly mollusks. There is no carrier state and no chronic disease (FigureII-5-10). 2. Hepatitis B (HBV) may cause acute hepatitis, a carrier state, chronic active disease, chronic persistentdisease,fi.rlminanthepatitis, or hepatocellularcarcinoma.It is caused by a DNA virus; the virions are calledDane particles. The incubation period is from l-6 months. Tiansmissionis through contact with infectedblood or other body fluids. It can be transmitted by sexualintercourseand is frequently transmitted to newborns of infected mothers by exposureto maternal blood during the birth process.
Expoune
z IF
lgG anti- HAV
(r z t!
o z o
O
Fecal HAV
\ 2 to 6 weeks
lgM anti - HAV 1 lo 2 months
1 to 3 months
Figure ll-5-10.Serologic markers in hepatitis A infection.
Ex p o s u re
Onsel of symptoms
f'"o"""+ifJ8i:l":+
z
I
G F
z
\_- -.- \-/ \ )< -/\\ /' \'
HBSAG
UJ
o z o o
Window
6 months
1to3 months
Anti - HBs
A n t i- H B c Anti - HBe
1/2 lo 4 months
Figure ll-5-11.serologic markers in hepatitis B infection.
In a Nutshell . HBsAg indicates current infection. . HBeAg indicates infeaivity.
a. Associated antigens include core antigen (HBcAg) and surface antigen (HBsAg). The latter is usually identified in the blood for diagnosis.HbsAg is the earliest*urker of acute infection. HBeAg is also associatedwith the core. Its presenceindicates active acute infection; when anti-HBeAg appears,the patient is no longer infective (F i g u reII-5 -l 1). b. HBV is associatedwith hepatocellularcarcinoma; HBsAg+ patients have a 200-fold greaterrisk of hepatocellularcarcinomathan subjectswho havenot been exposed.
r96
Pathology
c. Antibodies (t) Antibodies to surface antigen (anti-HBs) are consideredprotective and usually appearafter the disappearanceof the virus. (2) Antibodies to HBcAg are not protective.They are detectedjust after the appearance of HBsAg and are used to confirm infection when both HBsAg and antiHBs are absent(window). (3) Antibodies to HBeAg are associatedwith a low risk of infectivity. 3. Hepatitis C (HCV) is most often mild and anicteric but occasionallyseverewith fulminant hepatic failure. It is causedby an RNA virus, which may be transmitted parenterally (a cause of post-transfusion hepatitis); the route of transmission is undetermined in 40-50o/oof cases. a. Antibody is detectedby enzyme-linkedimmunosorbent assay(ELISA). The incubation period is between 2 and 26 weeks with peak onset of illness 6-8 weeks after infection. b. Most patientsprogressto chronic liver disease,specificallychronic persistenthepatitis or chronic activehepatitis.Cirrhosis is common in patients with chronic activehepatitis and occurs in20-25o/oof infected patients.HCV is also associatedwith hepatocellular carcinoma. 4. Delta hepatitis (HDV) is associatedwith a 35-nm RNA virus composedof a delta antigen-bearing core surrounded by HBV'S Ag coau HDV requires HBV for replication. Delta hepatitiscan causequiescentHBV statesto suddenlyworsen.Its transmissionis the sameas that of HBV. 5. Hepatitis E (HEV) is causedby a single-strandedRNA virus. The diseaseis typically selflimited and does not evolve into chronic hepatitis; it may, however, be cholestatic. Pregnant \romen may develop firlminant disease.Tiansmission is by the fecal-oral route. HEV occurs mainly in India, Nepal, Pakistan,and SoutheastAsia.
ln a Nutshell HEV: fecal-oral HAV, infections HBV,HCV,HDV:parenteral infections
Table l[-s-2.Types of hepatitis. Carrier State?
CausesChronic Disease?
Genome
No
No
ssRNA
Parenteral,sexual 1-6 months
Yes
Yes(5-10% of cases)
DNA
Hepatitis C
Blood transfusion, 2-26 weeks blood products
Yes
Yes(50oloof cases)
RNA
Delta hepatitis
Parenteral,sexual l-several months In association w/hepatitis B
Yes
RNA
Hepatitis E (NANB)
Water-borne, fecal-oral
No
ssRNA
Hepatitis
Mode of Transmission
Incubation
Hepatitis A
Fecal-oral
2-6 weeks
Hepatitis B
6 weeks
Not known
197
Gasfrointestinal System
6. Acute viral hepatitis a. Clinical features. Acute viral hepatitis may be icteric or anicteric. Symptoms include malaise,anorexia,fever,nausea,upper abdominal pain, and hepatomegaly,followed by jaundice,putty-colored stools,and dark urine.In HBV patientsmay haveurticaria, arthralgias, arthritis, vasculitis, and glomerulonephritis (because of circulating immune complexes).Blood tests show elevatedserum bilirubin (if icteric), elevated transaminases,and alkalinephosphatase.The acute illnessusually lasts4-6 weeks. b. Pathology (1) Grossly, there is an enlargedliver with a tensecapsule.
In a Nutshell Pathology of Hepatitis Crossly, enlarged liver; microscopically, coagu lative necrosis withincreased eosinophilia.
(2) Microscopically, there is ballooning degenerationof hepatocytesand liver cell necrosis,forming empty regions or acidophilic bodies causedby the coagulative necrosisof individual cellswith karyolysisof nuclei and increasedeosinophilia of the cytoplasm.Acidophilic bodies are frequently engulfed by Kupffer cells. Associatedfindings are hypertrophy of Kupffer cells and sinusoidallining cells, an acute inflammatory infiltrate of portal tracts, and evidence of hepatocyte regenerationduring recovery(Figure II-5- I 2).
Figure ll-5-12. Viral hepatitis (microscopic).
Note HBVandHCVcanleadto chronic hepatitis, andmay predispose to hepatocellular carcinoma.
r98
7. Chronic hepatitis occurs in 5-10o/oof HBV infections and in well over 50o/o of HCV; it does not occur in HAV. Most chronic diseaseis due to chronic persistenthepatitis.The chronic form is more likely to occur in the very old or very young, in males,in immunocompromisedhosts,in Down syndrome,and in dialysispatients. a. Chronic active hepatitis features chronic inflammation with hepatocyte destruction, resulting in cirrhosis and liver failure. Three gradesof severityof chronic activehepatitis are currently distinguished.Mild: Minimal mononuclear inflammation confined to the portal areaswith no fibrosis or portal enlargement.(Note that the term "chronic persistent hepatitis"is being phasedout in favor of inclusion in the "mild" category.)Moderate: Active portal inflammation with piecemealnecrosisat the borders of often enlargedportal areas.Early fibrosis,but no bridging is noted. Severe:All of the abovewith advanced fibrosis and bridging or frank cirrhosis.
Pathology
(1) Etiology. HBV HCV HDV, drug toxicity, Wilson disease,alcohol,cr,-antitrlpsin deficiency,and autoimmune hepatitis are common etiologies. (2) Clinical features may include fatigue, fever, malaise, anorexia, and elevated transaminases. (3) Diagnosis is made by liver biopsy. Patientsfollow a variable coursewith high mortality if bridging necrosisis present. portal lymphocytic infiltrate that spreadsto adja(4) Pathology showsan excessive cent liver parenchyma.Other featuresare piecemealnecrosis;a condensation, fragmentation,and phagocytosisof hepatocytes;bridging necrosis;a destruction of adjacentregions (lobules) of hepatocytes;and progressivefibrosis leading to cirrhosis. In HBV infections, cells with homogeneouscytoplasm may be seen (ground-glasscytoplasm), representing condensedhypertrophic endoplasmic reticulum. Variablenumbers of acidophilic bodies may be seen. 8. Carrier state for HBV and HCV may be either asymptomaticor with liver disease;in the latter case,the patient has elevatedtransaminases. a. Incidence is most common in immunodeficient, drug-addicted,Down syndrome,and dialysispatients. b. Pathology of asymptomatic carriers shows "ground-glass" hepatocytes with finely granular eosinophilic cytoplasm containing HBsAg particles and "sanded" nuclei, containing HBcAg, which signi$' active viral replication. Otherwise, the liver has a normal architecture.
Correlate Clinical withHBVinfected lnfants postnatally birth or during hepatitis active rarely develop buttheyoftenbecome Theyalso carriers. chronic ratefor haveanincreased and carcinoma hepatocellular cirrhosis. hepatic
9. Fulminant hepatitis leadsto submassiveand massivehepatic necrosis. a. Etiology. HAV HBV HCV delta virus (HDV) superinfection,HEV chloroform, carbon tetrachloride, isoniazid, halothane, certain mushrooms, and other drugs (acetaminophenoverdose)all may causefulminant hepatitis. b. Ctinical features include progressivehepatic dysfunction with a mortality of 25-90o/o. c. Pathology (l) Grossly, one sees progressiveshrinkage of the liver as the parenchyma is destroyed. (2) Microscopically, there arevariable amounts of necrosiswithin contiguousregions. Cells undergo coagulation followed by liquefaction necrosis,leaving only a reticulin framework. If the patient survivesthe initial insult, there is later development of disorganized regeneratinghepatocytesand macronodular cirrhosis. G. Cholangitis is inflammation of the bile ducts. l. It is usually associatedwith biliary duct obstruction by gallstonesor carcinoma,which leadsto infection with enteric organisms.This resultsin purulent exudation within the bile ducts and bile stasis.
ClinicalCorrelate = Charcot triad= Cholangitis jaundice, andright fever, pain. quadrant upper
2. Clinically, cholangitis presentswith jaundice, fever,chills, leukocytosis,and right upper quadrant pain. H. pericholangitis is inflammation around the bile ducts without intraductal involvement. There is usually a mononuclear infiltrate, which is associatedwith sepsis,inflammatory bowel disease,or pancreatitis.The inflammation may causefever,mild jaundice,and moderateelevationof alkalinephosphatase.
r99
Gastrointestinal System
I. \ogenic liver abscessesmay be causedby E. coli, Kebsiella, Streptococctts, Staphylococcus, Bacteroides,Pseudomonts,and fungi. Ascending cholangitis is the most common cause. Seedingof the liver due to bacteremiais another potential cause. l. Parasitic infections
Note Schistoso mo, Echinococcus, andEntomoebc arethree parasitic infections of theliver.
1. Schistosomiasis is causedby different organisms in different parts of the world. a. Clinical features include splenomegaly,portal hypertension, and ascites.Lesions are causedby the immune responseto ova. b. Pathology. Giant cell granulomas form in liver parenchyma surrounding ova. The inflammatory processleadsto diffr.rsefibrosis and nodular regeneration.The pattern of fibrosis is sometimescalled"pipe stem" fibrosis. 2. Amebiasis is causedby Entamoebahistolytica. a. Clinical features include bloody diarrhea,pain, fever,jaundice, and hepatomegaly. b. Pathology shows abscesses of the liver parenchyma,which may contain organisms in the necrotic region. Amebiasis is usually associatedwith amebic dysentery and colonic ulceration.
In a Nutshell Cinhosis isthediffuse fibrosis andregeneration oftheliver dueto hepatocellular injury by toxins, drup,viruselor deposition ofmetabolites or (e.g., minerals glycogen storage diseases; Wilson disease) ClinicalCorrelate Cirrhosis andportal hypertension cancause physical numerous exam findings: . Ascites (J albumin synthesis) . Varices, hemorrhoids, and (dueto caput medusae portosystemic shunts) . Splenomegaly . Cynecomastia, spider angioma, andpalmar (dueto impaired erythema estrogen metabolism) . Dupuytren contractures andclubbing . Bleeding diathesis
200
K. Drug-induced liver damage may be causedby agentsthat are direct hepatotoxins, such as carbon tetrachloride,acetaminophen,methotrexate,anabolic steroids,and oral contraceptive pills. Alternately, it may be caused by damage resulting from hypersensitivity or a metabolic responseto drugs such as phenothiazines,methyldopa,halothane,and isoniazid. L. Cirrhosis is the diffuse involvement of the whole liver by fibrosis due to hepatocellularinjury fibrosisin the form of densescarsor delicatebands,and nodulescausedby fibrous bandsand regeneratinghepatocftes. These so-calledregenerative nodules, which lack the usual architectural landmarkssuch as orderedsinusoidsand a centralvein, are hallmarksof cirrhosis. 1. Epidemiology. Cirrhosis is the third leading causeof death in the 25-65-year-oldage group. Leadingtypes include alcoholic cirrhosis,postnecroticcirrhosis,biliary cirrhosis, and hemochromatosis-related cirrhosis. 2. Clinical features a. Portal hnrertension is most commonly causedby cirrhosis of the liver. (1) Other causesinclude posthepatic (e.g., right-sided heart failure, Budd-Chiari syndrome),prehepatic(e.g.,portal vein obstruction), or intrahepatic (e.g.,schistosomiasis,sarcoid). (2) Signsand symptoms include ascites(an accumulationof fluid in the peritoneal cavity); portosystemic shunts that form hemorrhoids, esophageal varices (which may causemassivehematemesis),periumbilical (caput medusae), and retroperitoneal dilatations, and portosystemic encephalopathy; and splenomegaly with hypersplenism. b. Impaired estrogen metabolism and male hlpogonadism may cause female hair distribution and gynecomastia in males, gonadal atrophy, amenorrhea in females, spider angiomata, and palmar erythema. c. Other associateddisorders include Dupuytren contractures, hypoalbuminemia, peripheral edema,low levelsof vitamin K-dependent clotting factors (causingbleeding diathesis), rare hepatorenal syndromes,and hepatic encephalopathy. 3. Etiologies. Already mentioned are the chronic hepatidites (HBV, HCV but never HAV HEV) and chronic drug reactions.
Pathology
a. Postnecrotic cirrhosis produces a macronodular pattern. (1) Etiology. Most casesare secondaryto chronic activehepatitis.Postnecroticcirrhosis may also arise after exposureto hepatotoxins(o-methyldopa, methotrexate) or after autoimmune disease(lupoid). Postnecroticcirrhosis may alsobe crlptogenic or,less commonly, due to massivehepatic necrosis. (2) Clinical features include a small, knobby liver with evidenceof portal hypertension occurring terminally. There is usually a rapid downhill course once the patient is symptomatic,with death due to hepatic coma or hepatic failure within 3 years.Treatment is unsatisfactory.
ClinicalCorrelate Theprothrombin time (PI),notthePTT, isusedto assess coagulopathy dueto liverdisease, although in severe liverdisease, both areprolonged.
(3) Pathology. Grossly, 3-mm to l-cm liver nodulescomposedof regeneratinghepatocytesseparatedby fibrous scarsare found. Microscopically, broad scarswith a mononuclear,inflammatory infiltrate surrounding the nodules of hepatocytes are seen. b. Biliary cirrhosis (1) Primary biliary cirrhosis has an autoimmune etiology and causessclerosing cholangitis and cholangiolitis. It is associatedwith other autoimmune diseases and primarily affectsmiddle-aged women. (a) Clinical features. It often presentswith fatigue and pruritus. Elevatedalkaline phosphatasediscoveredon a routine blood test often leadsto diagnosis. In more advancedstages,profound hypercholesterolemia is found, signified by the appearanceof xanthomas. Steatorrhea, causedby fat malabsorption, is another significant sign. Antimitochondrial antibody is present in over 90o/oof patients.Definitive diagnosisis by biopsy.Courseis slowly progressiveover 5-25 years.
In a Nutshell Primary Biliary Cirrhosis Autoimmune with antimitochondrial antibodies, predominance, female and phosphatase. elevated alkaline
(b) Pathology varies with stage of the disease.Early on, there is intense mononuclear inflammation around the small portal bile ducts, sometimes with granuloma formation and bile lakes.Later, scarring and portal-portal bridging fibrosis occursand small bile ducts disappear. (2) Second*y biliary cirrhosis is causedby long-standinglarge bile duct obstruction, producing stasisof bile,leading to inflammation, secondaryinfection, and scarring. It usually presentswith jaundice. Histologically,there is a dilation of largerbile ducts with or without polymorphonuclearcell infiltration (depending on if there is cholangitis).With time, portal-portal bridging fibrosis and portal cirrhosis occurs.Early,bile lakesare evident. (3) Sclerosingcholangitis is a chronic fibrosing inflammatory diseaseof the extrahepatic and larger intrahepaticbile ducts.A "beading" pattern is seenon barium radiographsof the biliary tree.It is associatedwith inflammatorybowel disease, Hashimoto thyroiditis, and retroperitoneal fibrosis syndromes. Progressive stenosisof larger bile ducts may lead to secondarybiliary cirrhosis. There is a predispositionfor cholangiocarcinoma. inheritance.Deposits of iron Hemochromatosis is a diseasewith autosomalrecessive occur in the liver, pancreas,heart, adrenal,thyroid, parathyroid, and anterior pituitary with resultant organ dysfunction. It should be distinguished from hemosiderosis, which is a term used to describeiron overload from any cause.An accumulation of pigment occurs in reticuloendothelial cells, resulting from recurrent hemolysis or transfusion. (1) Etiology. Idiopathic hemochromatosisis an autosomalrecessive geneticdisorder
201
Gastrointestinal System
with severediseasein homozygotes and detectableabnormalities in heterozygotes.Organ damagemay also be causedby increasedintestinal absorption and iron overload due to transfusions,high iron intake, hemolytic anemia,and thalassemia. (2) Clinical features of idiopathic hemochromatosisinclude skin pigmentation,cardiac arrhythmias,diabetes("bronze"), hepatomegaly,gonadaiinsufficienry, and arthropathy.There is elevatedserum iron, decreasedtotal iron-binding capacity, and increasedferritin. The diseaseaffectsmen nine times more frequently than women.
ClinicalConelate
(3) Pathology showsmicronodular cirrhosis and pigmentation of the liver; pigmentation and fibrosis of the pancreas;hemosiderin deposition in the heart, pituitary, adrenal,thyroid, parathyroid glands,joints, and skin; and deposition of both iron and calcium pyrophosphatein joints,leading to pseudogout.There is a high incidenceof hepatocellularcarcinoma.
Hemosiderin deposits are seenintheliverandpancreas patients. of hemochromatosis
(4) Tieatment is by phlebotomy to prevent these complications. Deferoxamine is also used. d. Wilson disease (hepatolenticular degeneration) is an autosomal recessivedisease characterizedbyinadequate hepatic excretion of copper. Wilson diseasecauseshepatitis or macronodular cirrhosis, degenerativechangesin the lenticular nuclei of the brain, and pathognomonic Kayser-Fleischerrings, a deposition of copper in the corneallimbus. (1) Clinical features.Wilson diseaserarely manifestsbefore age6. Patientspresent with weakness,jaundice, fever, angiomas, Kayser-Fleischerrings, low serum ceruloplasmin, increased urinary copper excretion, and, eventually, portal hypertension. Central nervous system (CNS) manifestations include tremor, rigidiry and disordersof affect and thought. A rare presentationis as acutehepatitis with severehemolysisthat, without transplant,is likely to be fatal.
Clinical Correlate
(2) Pathology. Early in the disease,fatty changesand inflammation of the liver are seen.In the activestages,patientsprogressto activehepatitis.Late manifestations are micro- or macronodular cirrhosis. In the brain, cavitation of the lenticular nucleusis seen,and in the eye,there is copperdepositionin Descemetmembrane ring. at limbus, forming the Keyser-Fleischer
Bothhemochromatosis and Wilson disease areassociated withanincreased riskof hepatocellular carcinoma.
(3) Treatment is with penicillamine. e. Alpha,-antitrypsin deficiency is an autosomal recessivediseasecharacterizedby deficiency of a proteaseinhibitor, resulting in pulmonary emphysema and hepatic damage.It may alsocauseneonatalhepatitis,childhood cirrhosis (micronodular), or adult cirrhosis (usually macronodular).The pathognomonic finding is periodic acid-Schiff (PAS)-positive cytoplasmic globules within hepatocytes.This representsmutant cx,rantitrypsin, which is retainedwithin the endoplasmicreticulum of the hepatocyte.
ln a Nutshell Alcoholic LiverDisease . Fattyliver . Alcoholic hepatitis . Alcoholic cirrhosis
f.
Syphilitic cirrhosis causesscarringdue to gummas. g. Other causesinclude cardiac cirrhosis due to cardiac sclerosis;cirrhosis secondaryto inborn errors of metabolism,secondaryto infections such asliver fluke or inflammatory bowel disease;and cryptogeniccirrhosis (unknown etiology).
M. Alcoholic liver diseasecausesfaty livea alcoholic hepatitis,and alcoholic cirrhosis,which are separatethough possiblyinterrelatedentities. 1. Epidemiology. Alcoholic liver diseaseaccountsfor 60-700/oof cirrhosis in the Western Hemisphere.The male:femaleratio is 2:1. There is a possiblegeneticpredisposition.
202
Pathology
2. Clinical features. Fatty change is generally asymptomatic. Alcoholic hepatitis presents with fever;hepatomegaly;jaundice;elevatedaspartatetransaminase(AST), alkalinephosphatase,and alanineaminotransferase(Alf); and possibleportal hlryertension.Cirrhosis often presentswith portal hypertension.Patientsdie due to liver failure, infection, upper gastrointestinal bleeds, hepatocellular carcinoma, encephalopathy,and renal failure (secondaryto hepatorenalsyndrome).
Note 3. Pathology a. Fatty liver (steatosis) is reversible. (1) Grossly, fatty changesappear as a yellow, greasy,enlarged liver. (2) Microscopically, coalescenceof fatty cytoplasmicvacuoles,causing peripheral displacementof the nucleus that resemblesa lipocyte, is seen.Coalescedcells may form fatty rysts (Figure II-5-13). Ultrastructure showsswollen mitochondria and proliferation of endoplasmicreticulum among the lipid-laden vacuoles. b. Alcoholic hepatitis is usually associatedwith fatty change and is occasionally seen with cirrhosis.It resultsfrom prolonged alcoholic abuse.Pathologicfindings include swelling of hepatocytes,followed by necrosisand polymorphonuclear inflammation, formation of alcoholic hyaline (Mallory bodies) in swollen hepatocytes,cholestasis, and beginning fibrosis. The appearanceof fibrosis may be linked to the onset of cirrhosis(FigureII-5- 14).
Steatosis isusually asymptomatic andreversible. Fatty vacuoles displace hepatocellular nuclei peripherally.
Note Mallory bodies may alsobe seeninWilson disease, hepatocellular carcinoma, and primary biliary cirrhosis. Besides history, theother helpfulfeaturein distinguishing alcoholic hepatitis fromthese otherentities istheextreme fattychange.
Figure ll-5-13.Fatty liver (microscopic).
205
System Gashointestinal
lry'
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w
'"w i"&,Yt#^ 'M:#
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w
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w
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Figure ll-5-14.Alcoholic hepatitis(microscopic). c. Alcoholic cirrhosis. Early stagesof diseaseshow a large liver with micronodular formation (Figure II-5-15). Later stagesshow a small, macronodular liver with a "hobnail" appearanceon the surface.Microscopically,Mallory bodies may be present. The end stageresemblespostnecrotic cirrhosis. The amount of fat decreasesas the amount of fibrous tissueincreases.
Figure ll-5-15. Micronodularcirrhosis (gross). N. Benign tumors 1. Liver cell adenoma incidence is increasedwith anabolic steroid and oral contraceptive use. It forms a mass,which may be mistaken for carcinoma or may rupture (especially during pregnancy). a. Grossly, adenomasare often subcapsular,well-circumscribedround massesthat may be bile stained. b. Microscopically, they are composedof sheetsand cords of hepatocyteswith slit-like sinusoidalspaces.
204
Pathology
2. Nodular hnrerplasia a. Focal nodular hlperplasia refers to a solitary nodule that often has a fibrous capsule and bile ductules.A stellatefibrous core is usually present. b. Nodular regenerative hyperplasia describesmultiple nodules composed of normal hepatocyteswith a loss of normal radial architecture (normal architecture is a central vein surroundedby six portal triads).They are not encapsulatedand may be associated with FelQ/s syndrome, which is comprised of rheumatoid arthritis, splenomegaly,and neutropenia. 3. Cavernoushemangiomas are large,vascular,endothelial-linedspacesfilled with red cells. Radiologically,they must be consideredin the differential diagnosisof metastasesto the liver. 4. Bile duct adenomasform small nodulesthat are not bile stained. 5. Cysts may be single (with serous fluid) or multiple (with brown, bile-stained fluid). Multiple cystsmay be associatedwith adult polycystickidney disease.
o. Malignant
tumors
1. Hepatocellular carcinoma (hepatoma) a. Epidemiology. Hepatocellularcarcinomacomprises90oloof primaryliver neoplasms.Itis strongly associatedwith cirrhosis and HBV infection, aswell aswith oral contraceptives, androgens,and aflatoxin B. b. Clinical features include tender hepatomegaly,ascites,weight loss, fever, polycfthemia, and hypoglycemia.A friction rub may also be heard. Alpha-fetoprotein (AFP) is presentin 50-90o/oof patients'serum.(AFP is alsofound with other forms of liver disease,pregnanry, fetal neural tube defects,and germ cell carcinomasof the ovariesand testes.)Death is due to gastrointestinalbleed and liver failure. Generally, first occur in the lungs. metastases c. Pathology (1) Grossly, the tumor may be unifocal, multifocal, or infiltrative, causing a large liver. It is often bile stained and invadesvessels.Pre-existingcirrhosis is usually obvious. (2) Microscopically, well-differentiated tumors are composed of hepatocyte-like cells in a trabecular or pseudoglandularpattern. Rarely,a clear cell variant is seen.If it is associatedwith HBV infection, ground-glasscells may be present. Occasionally,Mallory bodies are alsopresent.Anaplastictumors may form pleomorphic giant cellsor spindle cells. 2. Cholangiocarcinomas comprise l0o/oof primary liver neoplasms.In developing countries, this tumor is associatedwith infection with Clonorchis sinensis(liver fluke) and with primary slcerosingcholangitis. a. Clinical features.Patientsexperienceweight loss,jaundice,and pruritus. Fifty percent of tumors metastasizeto lungs,bones,adrenals,and brain, exhibiting both hematogenous and lymphatic spread.
ln a Nutshell Hepatocellular is carcinoma predisposed bycirrhosis, HBV, and oralcontraceptives, toxin). aflatoxin B (fungal
ClinicalCorrelate Inwell-differentiated tumors, themostimportant clues are lackof normal trruo-cell thick The cords andsinusoids. normal veinto portal central triadarchitecture isalso absent. In a Nutshell iscancer Cholangiocarcinoma bileducts, oftheintrahepatic andisusually an lt canbe adenocarcinoma. bythe withinfection associated srnensrs. liverflukeClonorchis
b. Pathology is that of a sclerosingadenocarcinoma,forming both glandular and tubular structures.Mucus is present;bile is absent.Vascularinvasion is not usually seen, although hematogenousmetastasisis rather common.
205
Gashointestinal System
ClinicalCorrelate Inaddrtion to liverdisease, alcoholia froma variety suffer of otherdisorders. lf a que$ion presents patient, in analcoholic keepin mindincreased incidence ofthefollowing disorders: Esophagus . Cancer . Mallory-Weiss tears(after vomiting) . Varices (withportal hypeftension) Stomach . Castritis, reflux . Peptic ulcerdisease Pancreas . Pancreatitis (#1cause of pancreatitis) chronic
3. Hepatoblastoma is a rare, malignant neoplasmof children. a. Clinical features. Patientshave hepatomegaly,vomiting, diarrhea, weight loss,elevated serum levels of AFR and, often, other congenital anomalies (especiallyrenal defects). b. Pathology. The epithelial type is composedof embryonal cells in sheetsor rosettes. The mixed type is hemorrhagic or bile-stainedwith mixed epithelial and mesenchymal tissueshowing calcification. 4. Angiosarcoma is associatedwith exposureto vinyl chloride and arsenic. a. Grossly,the tumor producesspongy,hemorrhagic nodules. b. Microscopically, it is composedof variably shapedblood channelslined by pleomorphic endothelialcells. 5. Metastic tumors are much more common than primary neoplasms,most commonly coming from the breast, lung, and colon. Multiple, well-circumscribed nodules in a markedly enlargedliver are seen(Figure II-5-16). Bile staining of the hepaticparenchyma is common if the metastasescausebiliarv obstruction.
. Cancer Cardiac . Cardiomyopathy (dilated) Respiratory . Aspiration pneumonia . Kebsiello pneumonia . Tuberculosis Heme . Megaloblastic (folate anemia deficiency) . Coagulation (liver defects dysfunction) . Thrombocytopenia dueto congestive splenomegaly . Acquired sideroblastic anemia Neuromuscular . Wernicke encephalopathy . Korsakoff amnestic svndrome . Vestibulopathy . Peripheral neuropathies . Acutecerebellar degeneration . Myopathy (inchronic alcoholism) . Alcohol withdrawal syndrome; delirium tremens Acid/Base . Ketoacidosis (increased anion 8ap)
206
Figure ll-5-16.Pancreaticcarcinoma metastatic to liver (gross). P. Reyesyndrome is characterizedby fatty change in the liver and edematousencephalopathy. It usually affectschildren between 6 months and 15 yearsof age. 1. Etiology is unclear.It is frequently precededby a mild upper respiratory infection, varicella, or influenzaA or B infection. It is also associatedwith aspirin administration at levelsthat are not ordinarily toxic. 2. Clinical features include fever,severevomiting, changein mental status,convulsions,and coma. Laboratory data reveal elevatedserum ammonia, AST, prolonged prothrombin time, and hypoglycemia.There is a 30o/omortality in patients with neurologic involvement, and there are frequent neurologic sequelae.
Pathology
3. Pathology.The liver showsgeneralizedmicovesicuhr fatty chang€but no hepatocfte necrosis.Mitochondrial abnormalitiesmay be seenon electron microscopy.The brain showscerebraledema,which mayleadto herniation.
In a |{Ubhell :
ReyeSyndrome . Fattyliverchanges
BluARy DISEASE
. vomitins
A. Cholelithiasis (gallstones)
' Encephalopalry . Preceded byuRlor chickenpox.with aspirin admlnstraton
f. Incidence.Cholelithiasisoccursin 2096ofwomen and 896ofmen in the United States.It is rarebeforeage20,but is seenin 2596of personsgreaterthan 60 yearsold. 2. Etiologr a. Cholesterolstones ( 1) Puredrcl€st€rol stonesareradioluc€nt,solitary,l-5 cm in diameter,yellow,and smooth,with a glisteningradial pattem on cut section. (2) Cholesterol stones are more common in Northern Europeansand Native Americansand areles common in Asiansand Blacls. (3) The typical patient is fat, fem.le, fcrtile (multiparous),and over forty yearsof age(the"4 Ft"). (4) Exogenousestrogens,clofibrate, high-calorie diet, obesity, +aPetesTe[itus, pregnancy,celiacdisease,and increasingageall predisposeto cholest€rol stones.
Cfini..l .--:;;-;;--"Gonelate
b. Pignent stonesaresmall,black,multiple, andradiolucent.Pigmentstonesareclumps of pigment derivedfrom unconjugatedbilirubin. Thereis a high incidencein Asians. It is associated witlr hemolytic disease,specificallyhereditaryspherocytosisand other chronic hemolyticstates;it is not associated with acutehemolysis. c. Mixed stonescompose80% of all stonesand are associatedwith chronic cholecystitis. They are composedof cholesteroland calcium bilirubinate. Composition deter- : mines color (yellowto black). Thosewith sufficientcalcium content are radiopaque. Mixed stonesareusuallymultiple, facetedand laminated.
Whencholelithiasis occursin a youngperson, thinkof hereditary spherocgosil sicklecelldisease, or other proces' chronichemolytic
3. Pathogenesis.Supersaturationof bile pigment or cholesteroland,/ora decreased amount , of phospholipidor bile saltspredisposesto stoneformation. 4. Clinical features a. Most stonesremainin the gallbladderandareaqrmptomatic. b. Obstruction of the gallbladderor cystic duct may causebiliary colic, acute cholecystitis,or hydrops(mucoceleof the gallbladder). c. Obstruction of tle commonbile duct mayleadto obstructivejaundiceand ascending cholangitis.Pancreatitisand gallstoneileus may also result ftom blockageof the ampullaofVater or distal smallbowel,respectively. B. Acute cholecystitis.Most casesare causedby obstruction of the neck of the gallbladderor cysticduct by gallstones. l. Incidence and risk factorsar€ the sameasthose for cholelithiasis. 2. Pathogenesis. Calculusobstructionis followedby secondarybacterialinfectionrnTlVo of cases,and by chemicaltritation.
!!e (rightupper cholecyslttis quadrant pain, . fevet mayresuhfrom I leukocytosis) : superinfection of cholelhhiasis.
207
System Gastrointestinal
3. Clinical features a. Acute cholecystitis presents with acute onset of right upper quadrant pain, fevet tenderness,and leukocytosis. b. Most casesresolvewith medical management.The remainder progressto empyema, gangrenousnecrosis,or rupture. Patientsexhibit symptoms of acute abdomen and require cholecystectomy. 4. Pathology a. Grossly, patients have an enlarged,erythematous, tensegallbladder.The wall is thickened and edematouswith a fibrinous exudateon the surfaceand stonesin the lumen. b. Microscopically, there is an acute inflammatory infiltrate with mucosal ulceration, erosion, and foci of necrosis with hemorrhage;lymphocytes outnumber neutrophils. Rokitansky-Aschoffsinusesare penetrations of the mucosa through the muscularis associatedwith chronic inflammation. c. Empyema of gallbladder describesa lumen filled with pus. d. Porcelain gallbladder is due to calcium depositionwithin the wall and correlateswith a high incidenceof future malignanry.
In a Nutshell Acalculous cholecystitis mayoccurwithcongenital anomalies, diabetes, infections. or
e. In gangrenous cholecystitis, the mucosa is green-blackand necrotic with frequent perforation at the fundus. 5. Acalculous acute cholecystitis refers to cholecystitis without gallstones. It is associated with congenital anomalies,diabetesmellitus, polyarteritis nodosa, bacterial infections, helminthic infections (Ascarislumbricoides),trauma, burns, and surgery. C. Chronic cholecystitis is usually not precededby acute cholerystitis but is alwaysaccompanied by cholelithiasis. 1. Pathogenesisis unclear.Inflammation is probably due to chemicalinjury from supersaturated bile, not to irritation by stones. 2. Pathology a. Grossly,the wall is thickenedby fibrosis,and stonesarepresentin lumen (FigureII-5-17). b. Microscopically, there is fibrosis with a mononuclear inflammatory infiltrate and outpouchingsof the mucosainto the connectivetissueand smooth muscleof the wall. D. Cholesterolosis refers to lipid foci deposited in the gallbladder wall ("strawberry" gallbladder). It is asymptomaticand unrelatedto cholelithiasis.
E. Benign tumors 1. Papillomas are small, pedunculated,branching lesions. 2. Adenomas form small, flat, elevatedplaques. 3. Adenomyomas are a proliferation of smooth muscle and glands.
208
Pathology
Figure ll-5-17.Chronic cholecystitis and cholelithiasis (gross).
Malignant tumors 1. Carcinoma of gallbladder a. Incidence. The diseaseoccurspredominantly in the elderly. b. Risk factors include cholelithiasisand cholerystitis(in up to 90o/oof patients),porcelain gallbladder,industrial workers (cars,rnetals,fabrics);cholic acid may act asa carcinogen.
In a Nutshell israre, Callbladder cancer oftenasymptomatic, andis usually adenocarcinoma.
c. Clinical features. The diseaseis asymptomatic until late. It may present with dull abdominal pain, mass,weight loss,and anorexia. d. Pathology (1) Grossly, the tumor typically involvesthe fundus and neck. (2) Microscopically, 90o/oare differentiatedor undifferentiatedadenocarcinomas. e. Prognosis is poor, with a 3o/o5-yearsurvival rate. 2. Carcinoma of bile ducts (cholangiocarcinoma) a. Incidence. Men are affectedmore frequently than women, and patients are usually elderly. b. Risk factors include chronic inflammation, infections, (e.g.,liver flukes), and ulcerative colitis. Thesecarcinomasare not associatedwith gallstones. c. Clinical features. The diseasepresents with obstructive jaundice and its associated symptomatology (right upper quadrant abdominal pain, hepatomegaly,and distended gallbladderwith the possibledevelopmentof ascendingcholangitis). d. Pathology (1) Grossly,tumors are usuallysmall,with papillary,fungating,nodular, or infiltrating lesions.Sites of predilection are the distal part of the common bile duct, including the ampulla of Vater,the duodenal papilla, and the confluenceof the common hepatic and rystic ducts. (2) Microscopically, adenocarcinomawith abundant proliferation of fibrous stroma is found.
Clinical Correlate (cancer Cholangiocarcinoma of thebileducts) often presents withobstructive jaundice, rightupperquadrant pain,andsometimes symptoms of pancreatitis dueto obstruction of thepancreatic duct.
209
Gasbointestinal System
€. Prognosis is usually poor because of ductal, lymphatic, and, to a lesser sdent, hematogenous spread.
NI'TRITIONAT DISORDERS A. Marasmus I . Defnition. Marasmusis a condition of severemalnutrition or emaciationresultineftom inadequatccalorie intake. I
2. Clidcal featuresinclude'failure to thrive,"lossof subcutaneous fat, musclewasting,and a lower percentilein weight than in height. Bacterialor viral infection may precipitate superimposedKwashiorkorasa result of increasedrequirementsfor protein synthesisof the immune response. 3. Pathology,Thereis generalizedhypoplasiaand atrophyof tissues,andtheremaybe mild anerma,
In a Nubhell Marasmus . Glorie deficiency . Noedema Kwashiorkor . PrOtein defiCienCy . Edema
B. Kwashiorkor .
1. Definition Kwashiorkorrefersspecificallyto inadequat€protein intake. It may dwelop despiteadequatecaloricintake. 2. Clinical featuresinclude edema,anemia,dermatoses(e.g.,pigmentarychanges,desquamation, dusky erythema),hepatomegaly,hair changes,growth retardation,irritability, apatiy, and low energy. 3. Iaboratorl'values. Serumchemistryshowsdecreased serumtotal protein and alburnin. 4. Pathology.Characteristicpathologicchangesinclude: a. Atrophy of the villi of smallbowel mucosawith associateddisaccharidedeficiency b. Fattyliver c. Mixed anemiaexhibiting changesassociatedwith both folate and iron deficiencies d. Atrophy of the tlrymus and other lymphoid organs C. Iron deficiency 1. Etiology.Although iron deficiencyis causedby dietary insufficiency,rnalabsorptionnay alsoplay a causativerole. In the United States,the most commoncauseof iron deficiency in adultsis blood lossftom the gastrointestinaltract. In childrenit is dietaryinsufficiency. 2. Clinical festuresof iron deficiency,all of whic.haredueto the variedmetabolicfunctions of iron, include: a, Hnnchromic rnicrocytic anenia b. Functionalfolate deficiency c. Depressedcell-mediatedirnrnunity d. Gastricerosions D. Zhc deficiency l. Etiology is usuallydietary insufficiency. 2. Clinical feeturesinclude delayedwound healing,short stature,and dirninishedaxillary, facial,and pubic hair. Zinc deficiencymay predisposeto alcoholiccirrhosis.
2t0
Pharmacology Gastrointestinal inthetreatment Manyagents usedin otherareas of pharmacology maybeuseful of gastrointestinal disorders. Thischapter, however, focuses onthosedrugs thatareusedprimarily inthetreatment of ga$rointestinal problems: antacids, theantisecretory drugs, suchastheH,receptor thegastric pumpinhibitors; protective themucosal antagonists, theanticholinergic agents, andtheproton in Also included laxatives, agents, suchassucralfate; andantibiotis used ulcer therapy. areemetics, (e.g., andantidiarrheal miscellaneous drugs cisapride, metoclopramide). agents, aswellasseveral
DISEASE DRUGS UTCER USEDIN THETREATMENT OFPEPTIC Drugs that acceleratehealing and prevent relapseor recurrenceof peptic ulcers act either by decreasinggastricacidiry or by enhancingmucosal defensemechanisms.Risk factorsthat may break down mucosal defensesinclude the use of aspirin or other NSAIDs and the presenceof Helicobacterpylori bacteria in the gastric antrum. Various pharmacologic approachesare employed. A. Gastric antacids. Antacids are weak basesthat increasegastric pH and, thus, indirectly inhibit pepsin activity.They work by partially neutralizing gastricacid. They are most often used for the treatment of peptic ulcer disease(PUD) and reflux esophagitis.Nonsystemic antacidshave a cationic group, which forms insoluble compounds that are relativelypoorly absorbed.Other antacids(e.g.,sodium bicarbonate)do not form insoluble complexesin the intestine and are absorbed;theseare systemicantacidsthat may produce metabolic alkalosis. In general,antacidsinhibit the absorption of other drugs by forming complexeswith them or ionizing them.
Note NSAIDS andH.pylori predispose to peptic ulcer disease; discontinuation of NSAIDs anderadication of bacteria withantibiotics are essential to treatment.
Note Allantacids neutralize acid. Theirsideeffects vary according to whatcation they contain.
1. Calcium carbonate a. Pharmacologic properties. Calcium carbonate is a nonsystemic antacid with a relatively rapid onset and prolonged duration of action. There is variable absorption of the base,which may produce slight metabolic alkalosis. b. Indications for use. In addition to the treatment of PUD and reflux esophagitis,calcium carbonateis used in the treatment and prevention of osteoporosisand as an acid-basebuffer in chronic renal failure.
Note
c. Side effectsand toxicity include an unpleasantchalky taste,nausea,belching, constipation, hypercalcemia(especiallywith prolonged useof large dosesand with concomitant intake of large amounts of dairy products-the "milk-alkali" syndrome), and renal stones.Calcium ion increasesthe secretionof gastric acid; that is, it increasessecretion of gastrin and HCl. It is not a preferred drug in the treatment of PUD.
Theprimary with concern acid Ca2*isthatit $imulates producing secretion, an "acidrebound."
2tl
System Gastrointestinal
2. Aluminum hydroxide
ClinicalCorrelate Theconstipating effect of by aluminum canbeoffset mixing it withmagnesium, whichisa laxative.
a. Pharmacologic properties. Aluminum hydroxide is a nonsystemicantacid and thus is not absorbed. b. Side effects and toxicity include constipation; hypophosphatemia,osteomalacia,and proximal myopathy with chronic therapy and low phosphate intake; and encephalopathy in patients on dialysis,presumablyfrom aluminum intoxication. 3. Magnesium salts are nonsystemicantacids. a. Specificagents.Preparationsinclude magnesiumhydroxide (milk of magnesia),magnesium carbonate,magnesiumoxide, and magnesiumtrisilicate,which may adhereto an uicer and form a protectivecovering. b. Side effects and toxicity include diarrhea and hypermagnesemia (in patients with renal insufficiency).A number of antacidsare combinationsof magnesiumhydroxide and aluminum hydroxide, which results in a balancebetween the opposing effects theseantacidshaveon bowel motility. 4. Sodium bicarbonate a. Pharmacologic properties. Sodium bicarbonate is a systemic antacid with a relatively rapid onset and short duration of action. b. Sideeffectsand toxicityinclude belching and gastricdistention;milk-alkali syndrome (with chronic use and concomitant intake of large amounts of dairy products); and metabolicalkalosis,especiallyin patientswith renal insufficiency.Sodium bicarbonate may also exacerbatecongestiveheart failure and edema from sodium intake. It is contraindicatedin hypertension.
Note H,antagonists inhibit histamine-induced acid secretion andalso decrease gastric andvagally elicited acid secretion: (ACh) Histamine Vagal Gastrin
lll L_](JV ttl
@ *----_r-_-v H+
ClinicalCorrelate Cimetidine hasthedrawback of inhibiting theP-450system, prolonging thehalf-life of many agen6.
212
B. Gastric antisecretory drugs include histamine (H2)-receptor antagonists,anticholinergic agents,and proton pump inhibitors. 1. H2-receptor antagonists are drugs that block parietal cell H2 receptors.They act as reversible,competitive inhibitors of histamine. These drugs inhibit histamine-induced gastric acid secretion,and also inhibit the acid secretioninduced by gastrin and acerylcholine. a. Cimetidine ( 1) Pharmacologicproperties. Cimetidine containsthe imidazole ring of histamine plus a bulkier sidechain.Gastric acid secretionis effectivelyinhibited for 4 hours following oral administration. (2) Indications for use include the treatment and prophylaxisof peptic ulcer disease (duodenal and gastric); the ZolTinger-Ellisonsyndrome (gastrin-secretingislet cell tumor); conditions associatedwith excessive gastricacid secretion,including hyperhistaminemia,short bowel syndrome, and systemicmastocytosis;and as prophylaxisagainstupper gastrointestinalbleeding in acutelyill patients. (3) Sideeffectsand toxicity include mild gastrointestinaleffectssuchasnausea;central nervous system (CNS) toxicity, including confirsion, dysarthria,hallucinations, and coma (coma is especiallylikely in the very young or old and in those with renal insufficiency);and antiandrogeniceffect with prolonged use of high doses,resulting in glmecomastiaor impotence. (4) Drug interactions. Inhibition of hepatic microsomal enzymes may increase serum levels of many drugs, including ethanol, warfarin, digitoxin, triryclic antidepressants, phenytoin, carbamazepine,p-blockers,quinidine, theophylline,
Pharmacology
methadone, and benzodiazepines.Cimetidine is the only H2-receptor blocker that significantly inhibits the hepatic cytochrome P-450 system.Reduction of hepaticblood flow may increaseserum levelsof morphine, B-blockers,and lidocaine.Antacids decreasecimetidine absorption.Raresideeffectsinclude interstitial nephritis, drug fever, eosinophilia, thrombocytopenia, and elevated liver function tests. b. Ranitidine (1) Pharmacologic properties. Ranitidine is much more potent than cimetidine. It effectivelyinhibits gastricacid secretionand doesnot inhibit hepaticcytochrome P-450enzymesto the sameextent as cimetidine.Ranitidine lacksantiandrogenic effectand penetratesthe CNS lessthan cimetidine.It is given once or twice a day for the treatment of ulcer disease. (2) Indications for use are similar to cimetidine, but ranitidine is preferred in patients prone to CNS toxiciry with cimetidine and in patients taking drugs known to interact with cimetidine. (3) Side effectsinclude confusion and disorientation.
ln a Nutshell Ranitidine andfamotidine aremorepotent blockers thaniscimetidine andhave fewersideeffects.
c. Famotidine has a similar pharmacologicprofile to ranitidine but famotidine is more potent and has a longer duration of action. Dosagemust be decreasedin patientswith renal insufficienry.The usual dosageis once a dayat bedtime. d. Nrzatidine hasa similar pharmacologicprofile to ranitidine.
2. Proton pump inhibitors (omeprazole) a. Pharmacologl. properties. Omeprazole is a prodrug that diffuses from plasma across the gastric parietal cell cytoplasminto the acid spaceof the secretorycanaliculus.There, it is protonated and converted into an active compound that binds to parietal cell H+-K+-AIPase,inhibiting the final stepin the secretionof H+ into the gastriclumen. b. Indications for use.This proton pump inhibitor is used for the treatment of reflux diseaseand peptic ulcer disease,especiallycasesrefractory to treatment with H2-receptor blockers.It is particularly usefi.rlfor the treatment of Zollinger-Ellison syndrome.
Note irreversibly Omeprazole inhibits theparietal cellproton pump.lt isanextremely effective acidinhibitor.
c. Side effectsand toxicity include the overgrowth of bacteria;in rats, dose-relatedgastric carcinoid tumors have been seen.The major concern is the uncertain long-term effect of intenseacid suppression. 3 . Anticholinergic agents (muscarinic receptor antagonists)modifr gastrointestinalsecretory and motor function by inhibiting the effectsof vagalnerve stimulation. Theseagents were usedto decreasegastricacid secretionbefore the introduction of the H, antagonists. H, antagonistsare currently used becausethey have much greaterefficacyand far fewer side effects. a. Belladonna alkaloids (e.g.,atropine) are anticholinergicagents. b. Synthetic anticholinergic compounds (e.g., propantheline) have the same mechanism of action as atropine, but the CNS effect is much lessbecauseof the structural modification (quaternaryammonium group). Generalcontraindicationsto the use of anticholinergicsinclude glaucoma,cardiac disease,and prostatic hypertrophy (when urinary retention is alreadya problem).
Note Anticholinergia, suchas atropine, alsoinhibit acid secretion. However, theirside prohibit effects wideusage.
c. Pirenzepine is a tertiary amine producing the selectiveantagonismof acetylcholineat the M1 (muscarinic) receptor.Becauseof the drug's selectivity,the incidence of systemic anticholinergic side effectsis minimal at therapeutic doses.This drug is currently usedin Europe and is in clinical trials in the United States.
215
Gastrointestinal System
C. Mucosal protective agents 1. Sucralfate
Note Sucralfate isthought to coat damaged tissue andhelp ulcers heal.lt hasfewside effects. lt cannot begivenwith antacids, H,blockers, or omeprazole.
a. Pharmacologic properties. Sucralfate is a complex of a sucrosepolysaccharide and aluminum hydroxide, which polymerizes upon exposureto low pH of gastric acid. Negatively charged sulfate groups bind electrostaticallyto positively charged proteins in ulceratedtissue. (1) By adhering to damagedulcer tissue,sucralfateprotects the tissue againstacid, pepsin,and bile, possiblyretarding acidic and proteolytic damage. (2) It is administered orally, resulting in very little systemic absorption. b. Indications for use. Sucralfateis used to treat duodenal and gastric ulcers. c. Side effects and toxicity. There is very low incidence of side effects,which include constipation and,lessoften, diarrhea,nausea,dry mouth, and rash.
Clinical Correlate Misoprostol canbeusedto prevent gastritis in susceptible patients whomusttake NSAlDs. Note Theantibiotia tetracycl ine, metronidazole, and clarithromycin areusedto treatH.pyloriinfection.
d. Drug interactions. Sucralfate requires an acidic environment for activation and should not be given with antacids,Hz-receptor antagonists,or omeprazole.Sucralfate decreases the absorption of the antibiotics ciprofloxacin and norfloxacin. 2. Colloidal bismuth compounds bind selectivelyto an ulcer, coating the ulcer to protect it from acid and pepsin.There is possiblysome antimicrobial activity againstH. pylori. 3. ProstaglandinsEz (PGEz)and 12(PGI2) inhibit gastricsecretionand stimulate secretion of mucus. Misoprostol, a synthetic methyl analog of PGE' has been approved for the prevention of gastriculcerscausedby NSAIDs. The most common sideeffectis diarrhea. D. Antibiotics. The role of antibiotics in the therapy of gastrointestinalulceration is relatively new. FL pylori may be a causalagent of peptic ulcers.The recurrencerate is much lessin patients receivingantibiotics (tetrarycline, metronidazole) plus an H2-receptor antagonist than in those receivingonly the H2-receptorantagonist.The role playedby H. pylori is still not clearbecausemost people with the bacterium do not developpeptic ulcers.
EMETICS ANDANTIEMETICS A. Overview. Emetics are drugs that induce vomiting. They are most often used following oral ingestion of poisons or overdoses.These drugs should not be used in patients with a depressedlevel of consciousnessbecauseaspiration may occur, or in patients who have ingestedacids/alkalisbecauseesophagealor gastric damagemay occur. They should alsobe avoidedin patientswho have ingestedCNS stimulants,due to the possibility of seizures,or after the ingestionof hydrocarbons,becausechemicalpneumonitis following aspirationmay occur.Antiemetics are drugs usedto treat nauseaand vomiting.
214
Pharmacology
Dopamine antagonists
ot
5HT3
lo V Vomiting centers
A
\o
Serotonin antagonists
Figure ll-6-1 B. Agents 1. Ipecac a. Pharmacologic properties. Ipecacproducesan emetic reaction by local irritation of the gastrointestinaltract and stimulation of the chemoreceptortrigger zone of the medulla. It has greater effrcaq than gastric lavage in emptying the contents of the stomach.It is orally administered,with an onset of action in 15-30 minutes.If emesis doesnot occur,gastriclavageshould be used to removethe ipecac.
Note lpecac initates the gastrointestinal tract andstimulates the chemoreceptor trigger zone-) emesrs.
b. Side effects and toxicity are uncommon with usual doses.Cardiotoxicity is noted with chronic use (e.g.,bulimia). Ipecacshould not be given with activatedcharcoal,as the latter will absorbit and diminish its action. 2. Apomorphine a. Pharmacologic properties. Apomorphine is a morphine derivativewith little analgesic activity. It is a dopaminergic agonist that directly stimulates the chemoreceptortrigger zone,leadingto emesis.It is administeredparenterally(usually subcutaneously),and the onset of action occurswithin 5 minutes. b. Side effectsinclude respiratory and CNS depression.It is more toxic than ipecac. 3. Dopamine receptor antagonists (prochlorperazine,chlorpromazirre,metoclopramide) a. Pharmacologic properties. These drugs are antiemetics that act on D, receptors in the CNS at the chemoreceptortrigger zone. b. Side effects. These drugs can cause sedation and dystonia in addition to their antiemetic effects. 4. Ondansetron a. Pharmacologic properties. Ondansetron is a 5-HT. antagonist used to prevent chemotherapy-induced emesis. b. Side effectsare minimal, but may include headaches,constipation,and dizziness.
ln a Nubhell . Apomorphine directly stimulates dopamine receptors inthechemoreceptor trigger zone-) emesis. . Dopamine such antagonists asphenothiazines actas antiemetia.
215
Gastrointestinal System
TAXATIVES Laxativesact to promote bowel motility. An orderly classificationis hampered becauselaxativeinduced fluid accumulation may be causedby inhibition of ion and water absorption, by stimulation of fluid secretion,or by both. Inhibition of cellular energy production or utilization, mucosal injury and activation of adenylateryclase may be involved in the mucosal action of these agents.Long-term laxative abusemay result in spasticcolitis, dehydration, and depletion of electrolnes. A. Bulk-forming laxatives 1. Pharmacologic properties a. Osmotic effect causesfluid and electrolyteretention in intestinal lumen. b. Increasedfecal massand softnessaccelerateintestinal transit, producing action within 1-3 daysfollowing oral administration.
ln a Nutshell Bulk-Forming Laxatives . lncrease stoolmass and watercontent . "Centle laxatives"
2. Indications for use. Bulk-forming laxatives are used for symptomatic relief in patients with diverticular diseaseand irritable bowel disorders. Bulk-forming laxatives may be prepared from dietary fiber (e.g.,nondigestible plant food, grains, bran, fruits, vegetables) or from semisyntheticpolysaccharidesand cellulose(e.g.,methylcellulose,carboxymethylcellulose,psyllium). 3. Side effects and toxicity include flatulence,electrolyte imbalances,and, rarely, esophageal or intestinal obstruction; theselaxativesshould be taken with fluids. B. Stimulant laxatives are agentsthat act on the intestinal mucosa and have effectsboth on the net absorption of electrolytesand water and on motility. Stimulant laxativesare commonly involved in cathartic abuse. 1. Castor oil a. Pharmacologic properties. Castor oil is hydrolyzed in the small intestine to ricinoleic acid (active ingredient) and glycerol; ricinoleic acid reducesabsorption of electrolytes and fluids and stimulatesperistalsis.Onset of action is 1-3 hours following oral administration. b. Indications for use. Castor oil is not recommendedfor chronic use becauseit may impair absorption of essentialnutrients and exacerbatedehydration and electrolyte disturbances. 2. Bisacodyl a. Pharmacologicproperties. Bisacodylis administered orally or rectally.Onset of action is 6-12 hours after oral administration and lessthan I hour after rectal administration. b. Side effects and toxicity include fluid and electrolyte deficiencies, rash, and rectal burning following rectal administration. 3. Anthraquinones a. Pharmacologic properties
In a Nutshell Castor oil,senna, and cascara irritate thebowels andthusincrease gastro intesti naI motility.
2t6
(1) The effect of anthraquinonesis limited mainly to the large intestine.They contain anthraquinone derivatives, the basis for their laxative action. In the large intestine,bacterialaction (E. coli) causeshydrolysisof the glycosidesand oxidation of freed aglyconesto anthraquinones. (2) Anthraquinones include cascara and senna. The onset of action is usually 6-8 hours after administration.
Pharmacology
b. Side effects and toxicity. Anthraquinones are generally well tolerated when used in recommendeddoses. 4. Docusates a. Pharmacologic properties. Docusatesare anionic surfactants,which soften stool by emulsifring water, fat, and feces,having mild laxative effects. The onset of action is 1-3 daysafter administration. b. Side effects include nauseaand abdominal cramps. They should not be used with mineral oil becausethey promote absorption of the oil. C. Osmotic laxatives 1. Salt-containing agents a. Pharmacologic properties. Salt-containing agents are composed of magnesium, phosphate, and sulfate salts.They causean osmotic effect, resulting in fluid retention in the gastrointestinallumen. This indirectly increasesmotility. Salt-containing agents have a rapid onset of action (2 hours), with semifluid or water evacuation. b. Indications for use. They are used for bowel evacuation prior to surgery and other procedures. c. Specific agents include the magnesium saltsfor oral administration only, magnesium sulfate,magnesium hydroxide (which also has an antacid effect), and magnesium citrate; sodium phosphate(which can be administeredrectally as well as orally); potassium sodium tartrate; and sodium sulfate. d. Side effects and toxicity. Patients with renal insufficiency may develop hypermagnesemia with magnesium salts. Sodium salts may exacerbatecongestiveheart failure. Dehydration may also occur. 2. Nonsalt osmotic laxatives a. Lactulose is a semisynthetic disaccharide that produces laxative action via osmotic effect. It increasesfecal excretion of ammonia from laxative effect and decreases ammonia production by gut flora. Its onset of action is 1-3 days. (1)
Indications for use. It is used as a laxativeand in casesof hepatic encephalopathy with portal-systemicshunting.
(2) Side effects and toxicity include nausea,vomiting, flatulence, abdominal discomfort, diarrhea, dehydration, and hypokalemia. b. Other agents include glycerin and sorbitol. D. Mineral oil 1. Pharmacologic properties. Mineral oil is a petroleum derivative composed of hydrocarbons. It softensstool and may increaseits fluid content. 2. Side effects and toxicity limit its use; they include pneumonitis following aspiration, impaired absorption of fat-solublenutrients (e.g.,vitamin K), and pruritus ani.
ClinicalCorrelate Docusates actto soften stools andtherefore areusedafter abdominal surgery andpost myocardial infarction to prevent patient the from straining andpossibly rupturing thesutures. Note Poorly absorbed salts draw waterintothegastrointestinal producing lumen, a strong laxative action.
ln a Nutshell Lactulose . Osmotic laxative . Acidifies stool, trapping ammonia asNH4+ . Enhances of excretion nitrogenous wastes that buildupin hepatic insufficiency ln a Nutshell . Bran Lactulose Mineral oil J l-3 days (softfeces) . Phenolphthalein Senna Cascara
J 6-8 hours(softorsemifluid stool) . Magnesium sulfate phosphate Sodium Castor oil
J (watery l-3 hours
evacuatron)
217
Gashointestinal System
ClinicalCorrelate
ANTIDIARRHEAT AGENTS
decrease Opiates gastrointestinal motility. Loperamide anddiphenoxylate aretwo opiates thatpoorly cross the barrier and blood-brain therefore havefew sideeffects.
Diarrhea is a symptom; accordingly, treatment should be directed to causative factors. Nonetheless,symptomatic treatment can add to physiologic well-being. Many pharmacologic approachesare available. A. Synthetic, opioid-like agents. Agents include diphenoxylate and loperamide. Addiction potential is negligiblewhen administeredin recommendeddosagerange.The onlyrecognized useis in the treatment of diarrhea.Atropine is often used in combination with diphenoxylate to discourage abuse, although it probably contributes to the decreasein gastrointestinal motility and secretions. B. Adsorbents. Such agents as activated charcoal,hydrated aluminum silicate (kaolin), and pectin adsorb the irritants and mechanicallyprotect the mucosal surface.Belladonnaalkaloids may be added to kaolin and pectin mixtures. C. Protectives,such as bismuth subcarbonate,provide a protective coating over the irritated surfacebecauseof their consistency.
MISCETTANEOUS DRUGS GASTROINTESTINAT A. Metoclopramide hydrochloride is a dopamine receptor antagonist used as a stimulant of upper gastrointestinal motility. 1. Pharmacologic properties a. Metoclopramide hydrochloride increasesresting tone and contractility of gastrointestinal smooth muscle,increaseslower esophagealsphincter tone, and may increase colonic motility. b. In the CNS, metoclopramidehydrochloride has a direct effecton medullary antiemetic chemoreceptorsas well as neuroleptic effects. 2. Indications for use include diabeticgastricstasisand postsurgicalgastricstasis;treatment of emesisin cancerchemotherapy;diagnosticand therapeuticprocedures,such as aiding in radiographic examination of the upper gastrointestinaltract and endoscopyexamination of the small intestine;and gastroesophageal reflux. 3. Side effects a. CNS effectsinclude restlessness, drowsiness,fatigue,depressionand dyskinesias. b. Gastrointestinaleffectsinclude nauseaor constipation. c. There may also be prolactin secretion and a decreasein the absorption time in the stomachof such drugs asdigoxin and food, causinghypoglycemiain insulin-dependent diabetics. 4. Drug interactions. Metoclopramidehydrochloride should not be used in patientstaking neuroleptics.
218
III SECTION
Endocrlne System
Histology Endocrine Theendocrines tissues andorgans thatcoordinate theactivities ofother area group ofdiverse Thehormones tissues andorgans byproducing storing andsecreting hormones. arekansported in where theyexercise a particular effect orresponse. Ihis theblood totarget tissues andorgans, chapter willreview themicroscoDic structural |eatures ofeach ofthedifferent endocrine tissues and organs.
PlrulrARYGLAND
Notc There isnoseparate Endocrine Embryology chapter Thedevelopmert ofthegeographiolly diverse glands endocrine iscovered in theother organ systems and intheCeneral Princioles
books
A. Overview 1. The pituitary gland or hnrophysis is a bilobed organ that lies at the baseof the brain belowthe hypothalarnusin a bony cavity calledthe sellaturcica. a. The functions of the pituitary gland are controlledby the hypothalamus. b. The pituitary gland exertscontrol over otler endocrine glandsby the secretionof tropic hormon€s. 2. The pituitary is divided into the adenohypophysisand neurohypophysisbasedon its embryologic origins(seeFigureIII-1-1). a. The adenohnrophysisarisesfrom an outpocketingof the ectodermin the roof of the consistsof the pars disprimitive mouth calledRathkepoudr. The adenohypophysis talis, the pars tuberalis, and the pars intermedia. The parsdistalisis often referredto asthe anterior lobe. b. The neurohnrophysisis derivedfrom nervetissueat the baseof the brain and grows The neurohydownwardto take a position that is posterior to the adenohypophysis. pophysisconsistsof tlre pars nervosa (neural lobe) and the infrrndibulum (neural stalk). The pars nervosais often referredto as the post€rior lobe. Glial cells,called pituicytes,surround the nerveterminalsin the neurallobe.
221
Endocrine System
Parstuberalis
Medianeminence
Figure lll-1-1.Anatomic divisions of the hypophysis.
Bridgeto Physiology
B. The anterior pituitary functions in the production, storage,and releaseof various polypeptide hormones. Under the light microscope,this area appearsas clusters or cords of cells in a rich network of fenestrated sinusoidal capillaries. Generally, anterior pituitary cells are classified as either chromophils, based on their affinity for acid or basic dyes,or chromophobes, basedon their lack of affinity for these dyes.Chromophils that have an affinity for acid dyesare called acidophils; those with an affinity for basic dyes are called basophils.
pituitary Theanterior is controlled byreleasing hormones fromthe hypothalamus, which reach thepituitary viathe portal hypophysial system.
1. Acidophils contain large granulesin their cytoplasm; the granules stain with eosin and other acid dyes.Immunologic techniques .ue used to subdivide the acidophils with accuraq. a. Somatotropes secretegrowth hormone (GH) or somatotropin. b. Mammotropes secreteprolactin. Th.y increasein number and size during pregnancy and lactation. 2. Basophils havebeen identified by a number of staining techniques,including the periodic acid-Schiff (PAS) reaction for those that contain glycoprotein hormones. Immunohistochemistry is usedto identifr subtypesaccurately.
ln a NuBhell Anterior pituitary crllls I
I
vv Chromophils (stainwith basic or acidic dyes)
Chromophobes do not stain
I
l->Acidophils I l--Somatotrooes-+GH (somatotropin) | | 4Mammotropes--+Prolactit | t'->Basophils ->FSH l-+Gonadotrooes-4 L-+LH I
a. Gonadotropes are large round cellsthat secretefollicle-stimulatinghormone luteinizing hormone (tH).
(FSH) and
b. Thyrotropes produce thyroid-stimulating hormone (TSH). c. Corticotropes produce adrenocorticotropic hormone (ACTH). 3. Chromophobes are cells whose cytoplasm generally remains unstained. They may be either reservestem cells or acidophils and basophils that have degranulatedduring secretion.
I
ISH l+ThyrotropeF-+ L+ Co rt i cotrope s---->ACT H
4. Folliculostellate cells form a network of support-like cells;their function is unknown. C. The pars tuberalis surrounds the infundibulum of the neurohlpophysis. It is composed of highly vascularized cords of epithelial cells forming a thin sheath around the stalk of the infundibulum. The function of this region is unknown.
222
Histology
D. The pars intermedia is presentin humans during fetal life but is greatly reducedor disappearsin adults. 1. This portion is referredto as the intermediatelobe. 2. In other mammals, it is composed of cords of weakly basophilic cells that synthesize melanocyte-stimulatinghormone (MSH). E. Hypothalamohypophysial tract. The median eminence and stalk of the infundibulum and the pars nervosacontain a tract of unmyelinated axons belonging to secretorynerve cells that have their cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus. Thesefibers are collectively known as the hypothalamohypophysial tract. 1. The secretorynerve cells produce the polypeptide hormones oxytocin and antidiuretic hormone (ADH), or vasopressin,which are packagedinto secretorygranules and are moved by axoplasmictransport to the pars nervosa.There they accumulatein nerve terminals near capillaries in clumps called Herring bodies. 2. Thesehormones are secretedby exocytosisupon stimulation of their neurons in the brain. F. Vascular anatomy of the hypophysis is variable, but typically there are two superior hypophysial arteries on each side of the organ: the anterior and posterior superior hypophysialarteries. 1. Thesevesselssupply the median eminenceand the stalk of the infundibulum and form primary looped sinusoidal capillariesthat drain into venous trunks of the hypophysial portal system,which suppliesthe adenohypophysis. 2. The portal systemterminates in the sinusoidal capillariesin the anterior lobe and conducts neurohormonesfrom the median eminenceto the adenohypophysis.
Bridgeto Physiology . Oxytocin induces uterine contractions andstimulates milklet-down. . ADHincreases water resorption inthekidney. Themechanism of action in forADHisdiscussed intheRenal detail Physiology of chapter Book Organ Systems t (Volume lll).
3. The anterior and posterior inferior hypophysialarteriessupply the neurohypophysisand form an arterial circle at the junction to the anterior and posterior lobes. is perfusedvia sinusoidalcapillarieslined 4. The neurohypophysis,likethe adenohypophysis, with fenestratedendothelium.
22t
Endocrine System
Supraopticnucleus Hypothalamic cells that produce releasinghormones
Medianeminence
Hypothalamus
Portalsystem
Anterior pituitarygland Posterior pituitarygland Figu re Ill-1-2.The hypothalamic-pituitary system.
Note
THYROID GTAND
Thethyroid diverticulum arises fromthefloorofthepharynx andenters theneckviathe thyroglossal duct.Thisduct usually disappears, butthyroid tissue andcysts mayremain (e.g., asaccessory thyroids the pyramidal lobe).
A. Overview
In a Nutshell Thyroid Gland . Twolobes connected byanisthmus . Synthesizes T3,T4, andcalcitonin . Tissue composed of follicles whose lumen contains colloid made of thyroglobulin.
224
1. The thyroid is a lobulated gland that consistsof two pear-shapedlateral lobes connected by an isthmus.It is found in the cervicalregion anterior and inferior to the larynx. A pyramidal lobe is frequently presentand points upward from the isthmus near the left lobe. 2. The thyroid synthesizesand secretesthe thyroid hormones triiodothyronine (T3) and tetraiodothyronine (Tl, thyroxine), which regulate cell metabolism, development, growth, and differentiation. T3 and Ta synthesis and releaseis stimulated by thyroidstimulating hormone (TSH) from the adenohypophysis.The gland also releasescalcitonin, which participatesin calcium homeostasis. 3. The stroma of the gland is coveredby a thin fibroelastic capsulefrom which connective tissueseptapenetrate,incompletelydividing the gland into lobules. 4. The parenchyma of the thyroid consistsof follicles, which are lined by a simple cuboidal epithelium surrounding a central lumen. The folliclesare filled with colloid composedof alarge secretoryprotein material calledthyroglobulin. a. During development,the epithelial parenchymalcellsbecomeclumped and form the follicles,the cellsof which secretetheir products into a central lumen calledthe follicular cavity. b. Betweenfollicles,a reticular stroma contains an extensivecapillary bed.
Histology
c. Two cell types occur: follicular cellsand parafollicular cells. (1) Follicular cells are the principal thyroid cells.They are simple cuboidal epithelial cellsthat line the follicular cavity and secretethyroid hormones. Their apical surfacesface the follicular cavity into which thyroglobulin is released,and their basalpoles rest on a basallamina. In periods of increasedactivity,the cells are columnar; their height declinestoward squamousas their activity decreases. The nuclei of follicular cells are rounded, and the cytoplasm is basophilic and PAS-positive,indicating the presenceof glycoprotein. (2) Parafollicular cells, or C cells, are separatedfrom the colloid by follicular cells. Theseare larger cells,which possesslight-staining cytoplasm.The parafollicular cellsare responsiblefor the secretionof calcitonin, a hormone that lowersblood calcium levelsand is secretedinto the capillary bed.
ln a Nutshell -> C cells-+ calcitonin (Ca'.; J blood
B. Synthesis of thyroid hormones 1. Thyroglobulin is synthesizedon membrane-boundribosomesof the rough endoplasmic reticulum (RER), where the nascentpolypeptide is dischargedinto the cisternaeof the endoplasmicreticulum. 2. From the endoplasmic reticulum, the polypeptide is transported to the Golgi, where peripheral sugarresiduesare added. 3. The finished glycoproteinis secretedinto the lumen of the thyroid follicle. 4. The thyroid gland activelyextractsand accumulatesiodide ions from the blood, which are used to iodinate the ryrosine residuesin thyroglobulin. Iodination of tyrosine residues in thyroglobulin occursat the follicular cell surfaceand is catalyzedby thyroid peroxidase enzymeslocalizedin the microvillous border. 5. Under stimulation of TSH, endocytosisof the colloid by follicular cellsoccurs. 6. Endocytotic vesiclesfuse with cytoplasmiclysosomes,resulting in hydrolysisof thyroglobulin and liberation of T3 and Ta. 7. Thyroid hormones are releasedfrom the basal surfacesof foliicular cells into adjacent capillaries. C. Vascular supply. The thyroid is richly supplied by fenestrated capillaries that are closely apposedto the follicular epithelium. 1. The thyroid is supplied by paired superior thyroid arteries (branches of the external carotids) and paired inferior thyroid arteries(branchesof the thyrocervicaltrunks). '(-'l ,aa [ 'r 4 , 2. The thyroid hasmany lymphatic capillaries.
GTANDS PARATHYROID
ln a Nutshell Synthesis of Hormone Stages (l) sv1t!7isofthyroglobulin (2) Uptake of iodide circulatory (3) Activation of iodide peroxidase bythyroid (4) lodination oftyrosine inthyroglobulin residues
Correlate Clinical are abnormalities Thyroid gs. findln common relatively in mayresult Thyroid disease withhigh hyperthyroidism, T3andTa,ot' circulating withlow hypothyroidism, ofT3andTo. amounts
ClinicalCorrelate
A. Overview 1. The parathyroids usually consist of four flat and ovoid glands located behind the thyroid or, occasionally,embeddedwithin it. 2. The stroma of each gland is coveredby a delicateconnectivetissue capsulefrom which septa penetrate and divide the gland into incomplete lobules. Richly vascularized,it contains many reticular fibers.
ofthe Dueto theproximity glands parathyroid to the may removal thyroid, thyroid in hypoparathyroidism, result bylow whichischaracterized caz*andtetanv. serum
225
Endocrine System
Flashback to Embryology
3. The epithelialparenchymal cells,arrangedin irregular cords or clusters,are composedof two cell tnres, which may representdifferent functional statesof a single cell type.
Parathyroid glands arederived fromthepharyngeal pouchesglands thesuperior arederived fromthefoufthpouch, andthe glands inferior arederived fromthethirdpouch. ClinicalCorrelate Hyperparathyroidism . BloodCa"elevated ' BloodPOo'1o*.t.0 . Bonebecomes decalcified, subject to fracture
a. Chief cells are small polyhedral cells with round nuclei. They are generally arranged in cordsbut occasionallyoccur in clumps. They secreteparathyroid hormone (PTH), which is releasedinto the capillary bed. b. Oxyphil cells are larger and much lessnumerous than the chief cells.They appear as eosinophilic cells arranged in three forms: solitary cells,small clumps, or small distinct nodulessurroundedby chief cells.The prominent eosinophilicgranule-likestructures in their cytoplasm are mitochondria. The function of oxyphil cells is unknown. B. Parathyroid hormone (PTH) is synthesizedand secretedby the parathyroid gland. PTH increasesthe serum calcium concentrationby increasingbone resorption, decreasingrenal excretion,and increasinggastrointestinaluptake of calcium (via l,25-hydroxy vitamin D). 1. PTH actsinitially on osteocftesof bone tissue(osteocytic osteolysis) and, subsequently, on osteoblasts, which recruit osteoclasts(osteoclasticresorption) to resorb calcium from bone matrix and make it availableto the circulation. 2. PTH also increasesrenal excretionof phosphate. 3. Secretionof PTH is controlled byblood calcium and magnesiumlevels.For example,low blood calcium levelssignalthe secretionof PTH from the parathyroid glands.This mechanism appearsto be independentof endocrine or neural inputs.
Hypoparathyroidism . Blood Ca,.lowered ' BloodPQ,relevated . Bonebecomes denser, moremineralized
C. Blood supply of the parathyroids is from the superior and inferior thyroid arteries.
GTANDS . Tetany (spastic contractions ADRENAT of muscles andgeneralized A. Overview convulsions) 1. The adrenals are paired glands,eachabout 4-6 cm in length. They are locatedretroperi\i )- I i i ( r i , r toneally,superior to the cranial poles of the kidneys.
i.
li,i
2. The stroma of the adrenal gland consistsof a thick connectivetissuecapsulethat sends trabeculaeof collagenousand reticular fibers into the glandular tissue.
11"
3. The glandular parenchyma is divided into a cortex that secretessteroid hormones and a medulla that secretescatecholamines. B. Adrenal cortex contains cells that synthesizeand secreteglucocorticoids, mineralocorticoids, and certain sex steroid hormones. It is formed by three concentric layersof epithelioid cellsand abundant fenestratedcapillaries.
In a Nutshell -+ inside) (outside Adrenalcortex Zona -) Zona -t Tona glomerulosa fasciculata reticularis JJ J Mineralo- Clucocorticoids Androgens corticoids (cortisol) (DHEA) (aldo$erone) "SALT'
226
"SUCAR"
"SEX"
l. Zonaglomerulosa is the outermost narrow zone in which acidophilic columnar-like cells are arrangedin groups surrounded by capillary networks. a. Thesecellssecretealdosterone,a steroid mineralocorticoidhormone, whosesynthesis and releaseis controlled principally by angiotensinII and plasmapotassiumion (K+) concentration. To a lesserextent,ACTH and atrial natriuretic peptide (ANP), which is secretedfrom the heart, alsostimulatesecretionof aldosterone. b. Aldosterone acts mainly on the distal tubules of the kidney and on the salivary and sweatglandsto promote sodium reabsorption.It also actson the principal cellsof the kidney's collectingduct to secreteK+.
Histology
2. Zonafasciculata is a wide zone with its cells organized in cords, coursing radially inward from the zona glomerulosa and pointed toward the medulla. A longitudinal mesh of sinusoidal capillaries extends the length of the cords. a. The cells are polyhedral or cuboidal and are often binucleated. They contain a high lipid concentration. b. Zonafasciculatacellssecreteglucocorticoids, including the principal hormone cortisol, which havemajor effectson carbohydrate,protein, and lipid metabolism.This zone also secretessome androgensand a minimal amount of estrogens. c. The cellsof this zone are stimulated by the secretionof ACTH from the anterior pituitary. 3. Zonareticularis is a small region at the corticomedullary junction in which the cells of the cords are arranged in irregular networks. This zone secretesdehydroepiandrosterone (DHEA), other l7-ketosteroids,and probably some glucocorticoidsaswell. It is stimulated by ACTH. The zona fasciculata and zona reticularis function together as a unit in some ways (e.g.,some sexsteroidsare made in both fasciculataand reticularis). C. Adrenal medulla consistsof cellsthat are arranged in anastomosingcords intermingled with capillaries and venules. 1. Thesecolumnar cells are oriented with one end facing a capillary and the opposite pole in contact with a venule. Preganglionicsympathetic fibers contact eachcell at the capillary pole. 2. The cells are known aschromaffin cells becausethey are colored by oxidizing agentssuch as potassium dichromate, which turns them brown due to oxidation of the catecholaminesin the cells. 3. The cells produce and secretethe catecholamine hormones epinephrine and norepinephrine, which are stored in their secretorygranules.Glucocorticoidsproduced in the cortex passthrough the medulla and are required by medullary cells for synthesisof catecholamines,especiallyduring stress. 4. The medulla is under sympatheticcontrol, and its hormones function in concertwith the sympathetic flow in the "fight-or-flight" response.In many respects,the medullary cells function as postganglionicsympatheticneurons. D. Blood supplyto the adrenals comesfrom the superior,middle, and inferior suprarenalarteries. E. Innervation of the adrenal glands is mainly sympatheticand is carried via the splanchnicnerves.
to Flashback Embryology Thecellsoftheadrenal from medulla arederived Thecellsof neural crest cells. arederived cortex theadrenal frommesoderm.
In a Nutshell Catecholamines (Epinephrine, Norepinephrine): . t Heartrate . Vasoconstriction (t cardiac t blood output, pressure)
1. These autonomic fibers are the principal means of regulating the release of catecholamines from the medulla.
. t Bloodglucose
2. Although the cortex receivessome fibers, they do not appear to play an important role in regulatingthe releaseof hormones.
ClinicalCorrelate
PANCREAS ENDOCRINE A. Overview. The islets of Langerhans are rounded clustersof endocrine cells dispersedin the pancreaticexocrinetissue. l. There are over one million isletsin the human pancreas,constituting approximatelyl.5o/o of the volume of the pancreas. 2. Theisletsare enclosedin delicatereticular capsules,a few fibers of which penetratethe islets. B. Cells of the islets are polygonal and are arranged in clustersthat are intermingled with sinusoidal capillary networks.
isa Pheochromorytoma thatsecretes neoplasm and epinephrine Thiscauses norepinephrine. hypertension, secondary urinary increased acid(VMA) vanillylmandelic levels levels, andhighplasma lt is treated of catecholamines. such blockers withcr-receptor asphenoxybenzamine.
227
EndocrineSystem
ln a Nutshell
1. When viewed under the electron microscope,thesecells have the structure of cells synthesizingpolypeptides:abundant RER, a prominent Golgi complex, and secretorygranules.
lslebof Langerhans
o cells
p cells
2. Using special staining methods, particularly immunohistochemical procedures,three major cell types havebeen identified in the islets.
6 cells
II
Clucagon Insulin Somatostatin
I
I f ClucoseJ GlucoseJ Glucagon , J Insulin i^ (G.it.. 1,.
''t.c
I
a. cr (A) cells constitute approximately 20o/oof the cellsfound in the endocrine pancreas. They synthesize and secrete the polypeptide hormone glucagon, which acts to increaseblood glucoselevels.cr cellsare found mainly in the periphery of the islets. b. B (B) cells are the major cell type and constitute approximately 60-800/oof the islet cells.They secretethe hormone insulin, which acts to decreaseblood glucoselevels. B cells are found mainly in the center of the islets. c. 6 (D) cells are the least numerous and constitute less than 5o/oof islet cells. They secretethe hormone somatostatin, which actslocally to inhibit the secretionof both insulin and glucagon.6 cellsare found scatteredthroughout the islets.
Clinical Correlate gland Thepineal in humans hasbeenassociated withthe circadian rhythm. Seasonal (SAD) affective disorder and jetlagmayresult from disturbances inthisrhythm.
PINEAT GTAND A. Overview 1. The pineal gland or epiphysis is a pedunculated,cone-shapedbody that is attachedto the roof of the third ventricle by a stalk. a. It is approximately5-8 mm in length and is encapsulatedby pia mater, exceptat its point of attachment. b. Connectivetissuesepta,containing blood vesselsand unmyelinatednerve fibers,originate in the pia mater and penetratethe pineal gland to form irregular lobules around cellular cords and follicles. 2. Maior cell types of the pineal gland consistof pinealocftesand interstitial cells. a. Pinealocftes are epithelial-derived cells with large, irregularly shapednuclei and relatively large nucleoli.
Note A microscopic feature seenin pineal anaging gland is"pineal sand." Thisconsists of calcium phosphate andmagnesium withinanorganic matrix.
228
b. Interstitial cells are characterizedby elongated dark-staining nuclei and are located betweenthe cords of pinealocytesand perivascularareas.Interstitial cellsare comparable to glial cells of the brain. B. Innervation of the pineal gland is by postganglionicsympatheticfibers,which arise in the superior cervicalganglion and terminate on pinealocytes. C. Melatonin, an indoleamine compound, is the principal hormone synthesizedby the pineal gland. The precisefunction of this hormone in humans is unknown. In other mammals,it plays a role in seasonalreproductive rycles; in amphibians, it induces the aggregationof pigment granulesin the melanophores.
Anatomy Endocrine glands, andpancreas. adrenal ofthethyroid, anatomy thegross willhighlight Thischapter Bookt sectionof OrganSystems in theNeuroanatomy of thepituitaryis discussed Theanatomy (Volume lll).
I}IYROIDGTAND The thyroid gland is locat€danterior to the upper trached rings.
!!,$9
A. Arterial supply. The superiorthyroid artery is a branch of the externalcarotid artery and artery. the inferior tlyroid artery is a branch of the thyrocervicaltrunk ftom the sub-clavian 'thyroidea ima" artery may ariseftom the arch of the aortaor one of its branches. A single
glandsare Theparathyroid usuaily fourin numberThE in theDosterior areembedded surface of thelobesof the thyroidgland.
B. Venousdrainage.The superiorand middle thyroid veinsdrain to the int€rnal iugular veins bilaterally.The inferior thyroid veinsusuallyform a commontnurk whidr drainsto the left brachiocephalicvein. C. Lynphatic draimge. The thyroid gland drains primarily to the deepcervicalnodes.
GTANDS ADRENAT A- Adrenal glands are pairedendocrineglandsthat lie on the apicalpolesof the kidnqrc, and arethereforereferredto assuprarenalglands' B. Arterial supply,Like all endocine glands,the adrenalsarevery vascular.All oftheir arteries maybe multiple. 1. The superiorsuprarenalartery is a brandr of the inferior phrenic art€ry. 2. The rniddle suprarenalartery is a branch of the abdominalaorta. 3. The inferior suprarenalartery is a branch of the renalartery' C. Venousdrainage 1. The right suprarenalvein ihains to the inferior venacava. 2. The left suprarenalvein drainsto the left renalvein. D. Lyrnphatic drainagegoesto the superiorlumbar (lateralaortic) nodes. E. Imervation 1. Thepreganglionicsympatheticfiberstravelin the splanchnicnervesandthe celiacplorus. 2. Postganglionicsympatheticcell bodiesform the substanceof the adrenalmedulla.
229
Endocrine System
PANCREAS A. The Pancreas lies retroperitoneally behind the stomach in the transpyloric plane (FigureIII-2-1).
Rightsuprarenal gland
Tail Body Neck Head
Right kidney
Pancreas
Duodenum
Figure lll-2-1.Relations of the pancreas.
ClinicalCorrelate Pancreatic cancer isinsidious andmayor maynotcause jaundice, depending on whether ornotthetumor blocks thebileductsystem. Cancers oftheheadofthe pancreas aremorelikely to produce thanthose of faundice thebody;the latter, therefore, maynotbediagnosed until thetumorislarge enough to cause backpain.
zto
B. The Pancreasis cane-shaped,with a head,body, and tail. The uncinate process,which hooks around the superior mesentericvessels,is continuous with the head of the pancreas. C. Both main and accessoryducts lead from the pancreas.The main duct (of Wirsung) and the common bile duct open into the secondpart of the duodenum at the ampulla of Vater.The accessoryduct (of Santorini) usually opens independently at a secondarypapilla.
Physiology Endocrine primary rolesare whose glands andsecretions ofvarious iscomposed system Theendocrine This andreproduction. promotion, communication, growth maintenance, regulation, metabolic processes aswellastheirinteractions these controlling willfocusonthemajorhormones chapter system, withthenervous associated isclosely system theendocrine Since systems. withotherorgan will be norepinephrine and epinephrine, serotonin, dopamine, including neurotransmitters, specific secretion. rolesin hormone to theirregulatory in relation discussed
SYSTEM OFTHEENDOCRINE ANDORGANIZATION REGUTATION A. Organization of the endocrine system 1. The pituitary glurd (hypophysis) is an unpaired organ that lies just beneaththe brain and is connectedto it by the infundibulum. It is composedof the anterior pituitary and the posterior pituitary. a. The anterior pituitary (adenohlpophysis) is derived embryologically from somatic ectoderm and is devoid of innervation. b. The posterior pituitary (neurohypophysis) is derived from neural ectoderm. The pars nervosa of the posterior pituitary is supplied with nerve tracts directly from the hypothalamus. 2. The hypothalamic-hypophysial portal blood system is the capillary system that connectsthe brain and the anterior pituitary. It originatesin the median eminenceregion of the hypothalamus.The anatomic relationshipsare shown in Figure III-3-1. a. Releasingfactors (RFs) and releasinghormones (RHs) are releasedcloseto the capillary loops of the hypothalamic-hypophysialportal blood system and travel to the anterior pituitary via the portal blood system.Upon reachingthe anterior pituitary, the RHs stimulate the releaseof hormones. Thesehormones, in turn, travel to specific endocrine glandsand causethe synthesisor releaseof specifichormones.
2tl
Endocrine System
Dorsalmedial nucleus
Dorsalhypolhalamicarea Paravenlricular nucleus Laleral hypolhalamic area
Anteriorhypothalamus Venlromedialnucleus Preoptic area Mamrllarybody Supraoplicnucleus
Suprachiasmaticnucleus Optic chiasm Arcualenucleus Median eminence
Superiorhypophysialartery Supraopticand paraventracular nucleinerva lract
Posleriorpituitary {Neurohypophysis)
Long portal vessels
Secondaryportalplexus Anteriorpituitary (Adenohypophysis)
Inferiorhypophysialartery
Figure lll-3-1.Anatomic relationships among the hypotharamus, hypothalamic-hypophysialportal blood system, anterior pituitary, and posterior pituitary.
ln a Nutshell Hypothalamic-Releasin g Hormones . TRH . CRH . CnRH . CHRH . PRH Hypothalamic Inhibitory Hormones . SOmatOStUlin /r:t'1a',! . Prolactin inhibitory factor (dopamine)
252
b. Corticotropin-releasinghormone (CRH), gonadotropin-releasinghormone (GnRH), thyrotropin-releasing hormone (TRH), and growth hormone-releasinghormone (GHRH) are hypothalamic hormones that stimulate pituitary function. CRH controls the releaseof ACTH; GnRH stimulatesthe releaseof LH and FSH; and TRH stimulates the releaseof TSH and prolactin. GHRH stimulatesgrowth hormone secretion. c. Somatostatin inhibits both TSH and growth hormone, whereasdopamine inhibits prolactin secretion. 3 . Neurosecretory cells of the hypothalamus have axons that passthrough the infundibular stalk and terminate either in the pars nervosa or close to the capillary network in the median eminence. Oxytocin and antidiuretic hormone (ADH) are produced by the hypothalamus.They travel via nerve tracts to the pars nervosa,are stored there, and are releasedunder appropriatephysiologicstimulation. 4 . Neurotransmittersinvolved in hypothalamic neurohormone secretionare epinephrine, norepinephrine, dopamine, serotonin (5-hydroxytrlrytamine, 5-HT), acetylcholine (ACh), and y-aminobutyric acid (GABA). Severalpeptidergic neurotransmitters (i.e., neurotensin,substanceR enkephalins,endorphins) also affect neuroendocrinefunction by their effectson hypothalamic hormones and on monoaminergic neurotransmitters.
Physiology
B. Regulation of the endocrine system. There are five distinct mechanisms by which the endocrine system functions. Note that most of the hormones discussedin the following examplesare describedin greater detail later in this chapter. 1. Feedback not involving the hypothalamic-hypophysial axis. The simplest type of endocrinecontrol occurswhen a hormone actson specificcellsand promotes a changein the extracellularfluid, which, in turn, regulatesthe output of the original hormone. For example, parathyroid hormone (PTH) is a peptide produced by the parathyroid glands that regulatesthe concentration of calcium (Cuz*) in the blood, as shown in Figure ril-3-2.
Parathyroid hormone
Figure lll-3-2.Feedback regulation of serum calcium (Ca2*) and parathyroid hormone (PTH).(+) = stimulation;(-) = inhibition. a. The concentration of serum Ca2+in the bloodstream drops (step I in the abovefigure) which stimulatesthe secretionof PTH from the parathyroid (step 2). b. PTH travelsto its target organs(i.e.,kidney,bone, and indirectly to the gut) to stimulate Ca2+absorption and raisethe serum Ca2+level (step 3). c. As the concentrationof serum Ca2+risesin the bloodstream,PTH secretionfrom the parathyroid is inhibited (step4). 2. Endocrine control involving a hormone precursor. A hormone precursor is released into the bloodstreamand is then convertedto an activesubstance.This systemis usedto stimulate the secretionof aldosteronefrom the adrenalcortex. a. Angiotensinogen, an inactivehormone precursor,is secretedinto the bloodstreamby the liver. b. In the blood, the renal enryme renin convertsangiotensinogento another hormone, angiotensin I. c. In the capillariesof the lung, angiotensinI is convertedto angiotensin II by the action of angiotensin-converting enzyme (ACE).
ln a Nutshell (liver) Angiotensinogen J e renin(JCapparatus) Angiotensin I J e ACE(lungs) Angiotensin ll J (adrenal cortex) Aldosterone
d. Angiotensin II stimulatesthe production of aldosterone by the adrenalcortex. e. Aldosteroneactson the kidney and alterselectrolytesecretion,which, in turn,leads to a decreasein renin production by the kidney. 3. Endocrine control involving a dietary precursor. This type of endocrine control occurs when a hormone precursor is derived from the diet or is synthesizedwithin the organism.
2!'
Endocrine System
This precursor goes through successivetransformations in severaladditional sites before becoming biologically active.For example,vitamin D can be either synthesizedin the skin from 7-dehydrocholesterolor ingestedin the diet. It then undergoessuccessive hydroxylations in the liver and kidney to form l,25-dihdroxycholecalciferol (1,25[OH]rDr), the active form of the hormone. 4. Endocrine control involving the hypothalamic-hypophysial axis. This type of control is illustratedin FigureIII-3-3. a. Gonadotropin-releasing hormone (GnRH) is produced in hypothalamic neurons. These neurons terminate in proximity of the capillary network in the median eminenceregion of the hypothalamus. b. After being picked up by this capillary system,GnRH is transported via the hypothalamic-hypophysialportal blood systemto the anterior pituitary where it promotes the synthesisand releaseof luteiniztnghormone (tH) and follicle-stimulatinghormone (FSH). c. LH travelsvia the bloodstream to the testis,where it stimulatesthe production and releaseof testicular steroids (androgens).The androgens,in turn, travel via the blood to the hypothalamusto inhibit the secretionof GnRH, thus functioning in a negativefeedback loop.
Hypothalamus
LH
Anteriorpituitary
LH (_) Long-loop feedbackto hypothalamus androgens)
Shoft-loop feedbackto hypothalamus
LH
(+
Long-loop feedbackto pituitary (androgens)
Testis Figure lll-3-3.Negativefeedback system involving the hypothalamic-hypophysial-testicularaxis. Both long-loopand short-loopfeedbacksystems are shown;(+) = stimulatoryeffects;(-) = inhibitoryeffects; LH = luteinizing hormone;GnRH= gonadotropin-releasing hormone.
214
Physiology
d. Alternately,androgens act directly on the pituitary to decreasethe releaseof LH or FSH by altering the sensitivity of the pituitary cell to GnRH. This is known as direct feedback (pituitary) as compared to indirect feedback (hypothalamic). e. LH could travel via retrogradeblood flow from the pituitary to the hypothalamusto inhibit the synthesisor releaseof GnRH. (1) The effect of LH on the target gland and of the target gland secretionson the hypothalamic-pituitary unit is referred to as long-loop feedback. (2) The effect of LH on the hypothalamusis referredto as short-loop feedback. 5. The interaction between the nervous and endocrine systems is seenwith the releaseof oxFtocin in a lactating woman. a. If the breastis preparedhormonally for lactation,the suckling of an infant sendsneural impulses from the breastto the spinal cord, up into the brain, and eventually,to discretenuclei of the hypothalamus. b. These impulses stimulate the paraventricular nucleus of the hypothalamus to synthesizeand transport oxytocin to the pars nervosaand alsoto causethe releaseof oxytocin from the pars nervosa. c. Oxytocin then travelsvia the bloodstreamto the breast,where it causescontraction of the breast myoepithelial cells,resulting in milk let-down. d. The afferentpart of the arc is nervous,which stimulatesthe synthesis,transport, and releaseof oxytocin. The efferentpart of the arc is endocrine,which is the effectof oxytocin on the breastto induce milk let-down (Figure III-3-4). nucleus Paraventricular
ln a Nutshell
Paraventriculohypophysial nerve tract
OverallOrytocinEffects . Contraction of in myoepithelial cells glands andmilk mammary let-down Anteriorpituitary
pituitary Posterior
. Stimulant of uterine isoftenused contractions; to induce labor
Afferent Oxytoci
Efferent stimulus
(neural)
T,isuckrins
/t \ b* Milklet-down
Figure lll-3-4.Neuroendocrine reflex arc in oxytocin release.
2t5
EndocrineSystem
ANTERIOR PITUITARY HORMONES The hormones synthesizedand secretedby the anterior pituitary are assignedto three basic groups according to their chemical structure.
Note
A. Straight-chain peptides containing disulfide bridges (somatomammotropic group)
groMhrequires Normal normal levels of: . Nutrition
1. Growth hormone (somatotropin, GH) a. Structure. Growth hormone is a protein containing two internal disulfide bridges. It shares similar structural and biologic function with prolactin (PRt) and human placental lactogen (hPt).
.CH
b. Function. Growth hormone stimulates growth in childhood. It acts as an anabolic and anticatabolic agent.It promotes growth in most body tissuesand regulatescell size and number. Growth hormone stimulates the production of somatomedins (insulinlike growth factor, IGF) in the target tissues,which mediate many of growth hormone's key growth actions. Like the insulin receptor, the IGF receptor has tyrosine kinase activity.
. lcF-t . Thyroid hormone . Cortisol . lnsulin
c. Metabolic effects
Clinical Correlate Themajordiseases associated withCHarepituitarydwarfism (insufficient CHsecretion), gigantism (excessive CH growthplates secretion before arefused), andacromegaly (excessive CHsecretion after growthplates arefused). They arediscussed in detail inthe Endocrine Pathology chapter of thisbook.
(1) Increasesprotein synthesiswith a decreasein blood urea and urinary nitrogen. It also increasesprotein synthesisin chondrocftes (increaseslinear growth) with increasedconversion of proline to hydroryproline. Iean bodymass is increased. (2) Decreasessensitivity to insulin; diabetogenic effect. (3) Increased lipolysis results in increased free fatty acids in the bloodstream. Metabolically,this sparesglucoseand protein from being burned as fuel (anticataboliceffect). d. Pattern of secretion. GH is releasedin pulses throughout the day. The most consistent period of secretionoccursapproximatelyone hour after the onset of sleep.GH is releasedfollowing stress,hypoglycemia,vasopressinor r-dopa injection, during exercise,and during sleep. e. Control of secretion (1) GHRH stimulates the production and secretionof growth hormone. (2) Somatostatin blocks the secretion of growth hormone from the anterior pituitary. Recall that besidesthe hypothalamus, somatostatin is also produced in the pancreasand in other tissues.
ln a Nutshell Control of GHSecretion
(3) Somatomedins exert negative feedback by inhibiting GH secretion from the anterior pituitary and promoting somatostatinreleasefrom the hypothalamus.
Hypothalamus
/\
Somatostatin
ol
(+)
Y
GHRH
Y.)
Anterior (+) rPituin" l
-T
u'I
Somatomedins<-Irbbues -+ Somatomedins
216
(a) Both GHRH and GH inhibit their own releaseby feeding back on the hypothalamus and anterior pituitary respectively. 2. Prolactin (PRt) is secretedfrom the acidophilic mammotrophs of the adenohypophysis. a. Prolactin is required for milk synthesis in the mammary gland. b. Prolactin is controlled primarily by an inhibitory hypothalamic system. Dopamine inhibits prolactin releaseby a direct action on the mammotroph and possibly also by releasinga prolactin-inhibiting factor (PIF). The pituitary secretescopiousamounts of prolactin when removed from its hypothalamic inhibitory system.Prolactin inhibits its own releaseby increasing the releaseof dopamine from the hypothalamus.
Physiology
c. TRH stimulatesprolactin release.Although inhibition by dopamine is the major regulator of prolactin, chronically elevated TRH levels can contribute to hyperprolactinemia. d. Chronically elevatedprolactin inhibits GnRH production and secretion. e. Causesof hyperprolactinemiainclude: (1) Pituitary tumors (2) Dopamine antagonists,such as most antipsychotics (3) Primary hypothyroidism (increasedTRH) B. Glycoproteins composed of cr and B subunits include LH, FSH, and thyroid-stimulating hormone (TSH). LH and FSH act on the ovariesand the testes.TSH maintains and stimulatesthyroid folliclesto produce thyroxine (Ta) and triiodothyronine (Tr). 1. All are composedof two polypeptide chainscalled o and B subunits. a. The o subunit is similar in structure in FSH, LH, and TSH.
In a Nutshell Pituitary Clycoprotein Hormones . TSH, LH,FSH
b. The B subunit conveysthe biologic specificiryof the hormone, but both the u and B subunits are neededfor biologic activity.
. crsubunit iscommon to TSH, LH,andFSH
c. Human chorionic gonadotropin (hCG), secretedby the placenta,hasa B subunit that is almost identical to that of LH.
. B subunit conveys the specificity ofthehormone
2. The biochemical arrangement of these glycoproteins'subunits permits dissociation of intact TSH, LH, FSH, and hCG into their respectivecr and B subunits.Thesesubunits can be recombinedunder appropriateconditions to form hybrid moleculeswith an cr subunit from one molecule and a B subunit from another molecule. C. Straight-chain peptides and polypeptides (corticotrophs) l. Overview a. B-lipotropin (B-LPH) and melanocyte-stimulating hormone (MSH) are secreted from the pars intermedia of the adenohypophysis;adrenocorticotropin (ACTH) is secretedfrom the pars distalis. b. Pro-opiomelanocortin (POMC) is a hormone precursor synthesizedin the hypothalamus. It is hydrolyzedin the anterior pituitary to ACTH, p-lipotropin (B-LPH), and B-endorphin. 2. ACTH a. ACTH maintains the sizeof certain adrenalcortical cellsand stimulatesthem to produce glucocorticoid hormones. b. ACTH alsohas the ability to stimulatepigment cells(becauseof its structural similarity to MSH). Therefore,hyperpigmentationis seenin patientssufferingfrom excessive ACTH production, either in Addison's disease,a form of adrenal insufficienry in which ACTH production is elevated,or following adrenalectomyin which ACTH production is elevatedas a result of lack of negativefeedback. c. ACTH secretioncan be inhibited by adrenalcorticosteroids. d. ACTH is discussedin greaterdetail in the sectionon the adrenalcortex. 3. MSH stimulatesmelanocytes(pigment cells). a. MSH is produced by the corticotropin (chromophobe) cells found in the pars intermedia. Increasesin pigmentation are seenin patientswith MSH-secretingtumors.
Note TSHisdiscussed ingreater detailin reference to thethyroid gland FSH, laterinthischapter. in LH,andhCCarediscussed Physiology theReproductive chapter ofthisbook.
ClinicalCorrelate isdueto diseose Cushing hypersecretion of ACTHfrom oftheanterior anadenoma pituitary. syndrome canbe Cushing such dueto multiple causes, AS:
. Adrenal cortical adenoma/carcinoma . Ectopic production ACTH bynonpituitary tumors, cell small mostcommonly carcinoma ofthelung . Corticosteroid medication
257
Endocrine System
b. Control of MSH secretionin humans is not understood, but it can be inhibited by adrenalcorticosteroids.
ln a Nutshell Endorphins andenkephalins areendogenous opioid agonists. Theyactas neurotransmitters andbindto opioidreceptors. Morphine andotheropioid analogs bind to thesereceptors andactas analgesics. In a Nutshell AnteriorPituitary Hormones . Crowth (CH) hormone
a. p-lipotropin (B-LPH) is derived from the carboxy terminal fragment of POMC. Other than being a possibleprecursor for other hormones, the only known effect of p-LPH is weak lipolytic action. 5. A classof opiate-like peptides known as enkephalins and endorphins are derived from POMC, and are fragmentsof B-LPH. a. Endorphins help regulate the limbic system by binding to specific opiate receptors, resulting in effectson pain mechanisms,behavior disorders,and narcotic addiction. b. Enkephalins are endogenouspentapeptidesthat bind to opiate receptorsin the brain. Enkephalins produce transient analgesiaand inhibit electrically evoked contraction in certain tissue preparations.They bind opiate receptorsand are found in nerve endings, thereby modifring the nervous systemresponseto sensoryinformation such as pain and emotional behavior.
. Prolactin . Luteinizing (LH) hormone . Follicle-stimulating (FSH) hormone . Thyroid-stimulating hormone 0SH) . Adrenocorticotropic (ACTH) hormone ' Melanoqrte-stimulating (MSH) hormone . B-lipotropin (B-LPH) P1-.,. ,,,. ,-r', ,l'-f .
f-.r
A. Overview. The pars nervosa receivesdirect nerve supply from hypothalamic neurons and storeshormones produced from thoseneurons.Varicosities(Herring bodies) on the neurons extendinginto the posterior pituitary from the hypothalamuscontain stainableneurosecretory granulessimilar to those found in the supraoptic and paraventricularnuclei. B. Biosynthesis of ADH (vasopressin) and oxytocin. The supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus supply unmyelinated axons that traversethe basalhypothalamusto terminate in both the median eminenceand posterior lobe of the pituitary. 1. ADH and oxytocin are produced in separatecells;both types of cellsare distributed within the SON and PVN. 2. Granulesidentified in the cell body, axon, and terminals contain either ADH or oxytocin, a correspondingcarrier protein (neurophysin),and, probably,a larger precursor molecule or molecules. 3. The neurosecretory cells that make up the SON and PVIrI generateaction potentials that regulatethe releaseof the hormone products from the nerve terminals.
t; r ri
hcvx,',,i
POSTERIOR PITUITARY HORMONES
1-rr
4. Converging inhibitory and excitatory afferents from other brain regions regulate neurosecretion to achieveneuroendocrine control. Neuronal depolarization results in the releaseof the entire granule contentsinto the perivascularspaces,where diffrrsion into the blood rapidly occurs. 5. The posterior lobe storesand releasesoxytocin, ADH, and their associatedneurophysins. a. Nicotine is a potent stimulus for releaseof ADH and its neurophysin,unlessADH is inhibited with large amounts of ethanol. b. Estrogenstimulatesthe releaseof oxytocin and its neurophysin.
2t8
Physiology
Table III-3-1. Regulation of ADH secretion. ProducelncreasedADH Secretion
ProduceDecreasedADH Secretion
t Set,t- osmolarity Volume contraction Pain Nausea Hypoglycemia Nicotine, opiates, antineoplasticdrugs
J Serum osmolariw Ethanol cx-agonists Atrial natriuretic factor (ANF)
C. Physiologic secretionof ADH (TableIII-3-1) dependsprimarily on the changesdetectedby osmoreceptors and baroreceptors. Osmoreceptorsrespond to small changesin the extracellular fluid osmolarity; baroreceptorsrespondto changesin blood pressure(and volume). 1. Osmoreceptors. Osmotic changesare sensedby neural cells in the hypothalamus.A decreasein serum osmolarity leadsto inhibition of ADH release,whereasan increasein serum osmolarity stimulatesADH secretion.The primary site of action of ADH is the kidney. ADH acts to increasepermeability of the distal tubules and principal cells of the kidney's collectingducts, thus causingwater reabsorption. 2. Baroreceptors are found in three anatomic locations: the left atrium, the carotid sinus, and the aortic arch. a. Left atrium. Theseare low-pressurereceptors,which respond to small reductions in central blood volume that are not associatedwith systemichypotension.The impulses are transmitted via the vagus nerve. b. Carotid sinus and aortic arch. These are high-pressurereceptors.The carotid sinus impulses are transmitted via the glossopharyngeal nerve, while the aortic arch impulsesare transmitted via the vagus nerve. Both of thesereceptorstonically inhibit ADH. With diminished stretch (decreasedpressure)there is a reduction in the firing rate, resulting in ADH secretion. c. A small change(as little as 1olo)in plasma osmolarity resultsin ADH release;in contrast, it takesa decreasein blood pressureof )10oloto causean increasein ADH secretion. However,the responseof ADH secretionis much greaterto a volume (and therefore pressure)changethan to an osmotic change.Volume receptorsoverride osmotic receptorsin situations such as hyponatremia and blood loss.
Bridgeto Cardiovasculal Themechanism ofaction of baroreceptors isdiscussed in greater detailinthe Cardiovascular Physiology chapter of OrganSystems Bookt (Volume lll).
d. Volume contraction also stimulatesthirst by the releaseof angiotensinII. 3. Other causes of increased ADH secretion include nausea, severe hypoxemia, hlpoglycemia,and pain. Drugs that stimulate ADH secretioninclude nicotine, opiates,and certain antineoplastics. D. ADH effects on the kidney 1. When ADH is absent, the water permeability of the collecting ducts is low and there is essentiallyno reabsorption of water from tubular fluid in the ducts. This results in excretion of hypotonic urine. 2. During antidiuresis, ADH increasesthe water permeability of the renal collecting ducts and distal tubules, allowing osmotic equilibration of tubular fluid with the hypertonic medullary interstitium. The result is decreasedurine volume and conservationof body water.The urine is hypertonic.
2t9
Endocrine System
3. Diabetesinsipidus. Absenceof ADH secretionor lack of a renal responseto ADH results in either central (neurogenic)or nephrogenicdiabetesinsipidus, respectively.Either type of diabetesinsipidus causesa decreasein renal reabsorptionof water,an increasein serum osmolariry and generationof a dilute (hypotonic) urine.
Bridgeto Pharmacology Certain drugs, suchaslithium anddemeclocycline, inhibit to ADH, renalresponse resulting in anacquired nephrogenic diabetes insipidus. Demeclocycline is usedinthetreatment of chronic SIADH.
a. In central diabetesinsipidus, ADH plasma levelsare reduced;the converseis true in nephrogenicdiabetesinsipidus. b. ExogenousADH is beneficialin central diabetesinsipidus but hasno effectin nephrogenic diabetesinsipidus. 4. ExcessADH secretion,typically by a tumor, resultsin SIADH, or the syndrome of inappropriate ADH secretion.SIADH causesincreasedwater retention, hypo-osmolariry and hyponatremia,concurrent with hypertonic urine excretion. E. Oxftocin 1. Secretionis stimulatedby infant suckling. Dilation of the cervix during labor and orgasm are also stimuli for oxftocin secretion. 2. Physiologic effects
Bridgeto Reproductive isdiscussed Oxytocin in greater detail inthe Reproductive Physiology chapter ofthisbook. In a Nutshell Controlof Glucocorticoid Secretion Hypothalamus
J CRH
J(*) Anteriorpituitary
(-)
J ACTH l(+) Adrenal cortex l(+) Cortisol
a. Milk let-down occurs due to the contraction of the myoepithelial cells in the mammary gland. b. Causesuterine contraction; can be used to induce labor late in pregnancy.
ADRENAT GTANDS A. Zones of the adrenal cortex 1. The outer zolnaglomerulosa is chiefly concernedwith biosynthesisof the mineralocorticoid aldosterone. Its sizeincreaseswith salt restriction and is also affectedby potassium Ievels,angiotensin,and to a lesserextent,ACTH. 2. The two innermost zonesof the cortex-the zonafasciculata (producesglucocorticoids) and the zolnareticularis (producesandrogens)-are controlled by pituitary ACTH. B. Products. The major steroidssecretedby the adrenalcortex include: corticosteroids,mineralocorticoids (primarily aldosterone), and androgen precursors (primarily dehydroepiandrosterone, DHEA). C. Adrenal cortical secretion except for mineralocorticoids is controlled by ACTH. The secretionof hypothalamic CRH and subsequentlyACTH can be suppressedif the concentration of cortisol in the plasmais high, or it can be enhancedif cortisol concentrationis low. D. ACTH l. Origin. As noted earlier,all of the corticotropin-relatedpeptidesare derived by selective proteolytic cleavagefrom pro-opiomelanocortin (POMC). a. Primarycleavage.The corticotropic cellscleavePOMC into ACTH, B-LPH, and an Nterminal fragment. b. Secondarycleavageof ACTH yields a-MSH and the corticotropin-like intermediate lobe peptide (CLIP). Secondarycleavageof B-LPH resultsin B-endorphin and ylipotropin. 2. Synthesisand storage.The human pituitary containsapproximately250 pg of ACTH, which is synthesizedand stored in corticotropic cells.The storagegranulesarebasophilic and periodic acid-Schiff (PAS)positivebecauseof the glycoproteincontent of the POMC precursor.
240
Physiology
3. Action. ACTH stimulates the conversion of cholesterol to pregnenolone. ACTH affects the cortex in a manner typical for polypeptide hormones: It interactswith a cell-surface receptor,and this interaction increasesthe intracellular concentrationof cyclic adenosine monophosphate(cAMP). E. Steroidogenesis l. Cholesterol is the precursor of the steroid hormones. It is availablefrom animal fats in the diet and by biosynthesisin many organs,including the adrenalcortex.
In a Nutshell
2. Immediate sources of cholesterol for steroid synthesis are:
Mechanism of Steroid Hormone Action
a. The free and esterifiedcholesterolassociatedwith the lipoproteins of plasma b. The free and esterifiedcholesterolstored in adrenallipid droplets
Steroid hormone
c. The cholesterolsynthesizedby the adrenalitself
-..,},..^
d. In humans,the cholesterolof plasmalow-densitylipoprotein (tDt) appearsto be the preferredsubstrate.Cellsof the adrenalcortex haveLDL receptors,and uptake of LDL is stimulatedby ACTH.
Hormone binds in to receptor nucleus or cytoplasm and exposes theDNAbinding site onthereceptor
3. The adrenalhandlesnormal steroid production by using free cholesterolfrom plasma or the labile tissuepool but draws on steroid cholesterolestersas a reservewhen rapid synthesisis required. a. Simultaneouslywith the increasedcontribution from stored cholesterolesters,entry of cholesterolfrom the plasmais acceleratedunder stimulation from ACTH so that in the long term, plasmacholesterolremains the major substratefor steroid synthesis.
I
V
DNAtransaiption innucleus
I
V
mRNA translation in cytoplasm
I
b. ACTH is also involved in the side-chaincleavageof cholesterol. 4. Synthetic pathways are summarizedin Figure III-3-5.
cell membrane
V
Newproteins synthesized
5. 2f -B-hydrolasedeficiency is the most common enzymedeficiencyof the adrenalcortex. It is discussedin the Endocrine Pathologychapter.
Cholesterol ACTHstimulates------> | cnobsteroldesmolase thisreaction V 17,20-tyase 17 u-hvdroxvtase ' ' - 17-hydroxY----€ Pregnenolone Dehydroepiandrosterone nregnenolone 3 p-hydroxysteroid I (DHEA) dehydrogenase Y Progesterone 1 3 p-hydroxyI steroiddehy21 p-hydrorylat" \ / drogenase Y -tyase 17,20 \ 11-Deoxycorticosterone 17-Hydroxyprogesterone Androstenedione # I | 21 p-hydroxylase : | 11p-hydrorylase | (most common 'aeficiency) YV Y Y Testosterone 11-Deoxycortisol Corticosterone I tt --------+latdosterone Angiotensin p-hydrorylase I | 11 sVnthase stimulates YV { Y thisreaction Estradiol Gortisol Aldosterone Zona Glomerulosa
Zona Reticularis
Iesfes and Ovaries
Zona Fasciculata Figure lll-3-5.Pathways in steroidogenic cells.
241
Endocrine System
F. Biologic actions of adrenal cortical hormones (corticosteroids) 1. Glucocorticoid effects are involved in intermediary metabolism, inflammation, immunity, wound healing, and muscle and myocardial integrity. These actions are predominantly mediatedby cortisol or other glucocorticoids. 2. Mineralocorticoids are involved in salt, water, and mineral metabolism; these effectsare predominantly mediatedby aldosterone. G. Glucocorticoids 1. Glucocorticoid activities. Glucocorticoidspromote the conversionof protein to carbohydrate (gluconeogenesis).They also reduce the sensitivity of cellsto insulin and increase glucagonreleasefrom the pancreas. a. Glucocorticoids increase protein breakdown and lipolysis. b. Anti-inflammatory effects. The inflammatory reaction is inhibited by glucocorticoids. The arterioles fail to dilate frrlly, the capillary permeability is not increasedfrrlly, and deposition of fibrin around the inflamed areais diminished. Glucocorticoids: ( 1) Inhibit releaseof arachidonatefrom membranes by blocking phospholipase Ar. This inhibits the synthesisof prostaglandins and leukotrienes that are involved in the normal inflammatory response. (2) Inhibit releaseof histamine from mast cells. (3) Inhibit production of IL-2 and proliferation of T lymphocytes.
ClinicalCorrelate Therapeutic usesof synthetic glucocorticoids include. . A$hma/allergicrhinitis treatment . Relief ofinflammation . Therapy forcongenital adrenal hyperplasia . Dexamethasone suppression testtodiagnose Cushing's syndrome . Therapyfor lo,2",or3o adrenocortical insufficiencv . Transplant rejection
c. Normal levelsof glucocorticoidsare permissivefor growth and maintenanceof adequate blood pressure. 2. Clinical use of glucocorticoids a. For replacement therapy in individuals with adrenocorticol hypofunction (e.9., Addison disease). b. To suppressundesirableinflammatory reactions. c. To minimize the immune responseto a variety of antigens,including transplanted organs. d. All glucocorticoidswith anti-inflammatory activity can alsosuppressACTH secretion. Although this effect is usually undesirable, it is the basis of treatment of patients who have congenital adrenal hyperplasia. 3. Steroid withdrawal a. The administration of glucocorticoids inhibits the releaseof CRH and, thus, suppressesboth the synthesisand releaseof ACTH. b. This, in turn, causesatrophy of the adrenals and the ACTH-releasing cells of the anterior pituitary. As long as exogenoussteroid is given, the patient remains healthy. c. When steroidsare stoppedor the patient becomesill, the demand for additional steroid cannot be satisfiedby the atrophied adrenals. d. After chronic therapy with high-dose glucocorticoid,6 months are required for normal ACTH secretionto occur,while 6 to 9 months are required to regain normal cortisol secretion.If the steroid treatment has been minimal in amount, or if large doses have been given for less than I month, the pituitary-adrenal axis remains intact and no specialprecautionsneed be taken. Suppressionof ACTH and endogeneouscortisol secretioncan also be somewhat reducedby administering the glucocorticoid on
242
Physiology
alternate days and by administering the majority of the dose in the morning. Use of ACTH rather than glucocorticoids is one way around the problem of steroid withdrawal (e.g., in patients with rheumatoid arthritis). ACTH has advantagesover steroids,but the need for daily intramuscular injections is a drawback and long-term ACTH preparations can causeallergic reactions. H. Mineralocorticoids 1. Aldosterone activity. Aldosterone promotes renal Na+ retention, which in turn promotes water retention if ADH is present. It also promotes K+ and H+ ion excretion by the kidney. It is synthesizedin the zona glomerulosa. 2. Targettissues a. It increasesactiveNa+ reabsorption,K+ secretion,and H+ secretionin the renal distal tubule and collecting duct. In the presenceof ADH, water is reabsorbedpassively, following the sodium. b. There is decreasedNa+ secretion in the sweat glands. c. Na+ (and water) absorption is increasedin the colon. 3. Regulation of mineralocorticoids a. Renin-angiotensin system (1) Renin is releasedfrom the kidney juxtaglomerular apparatus cellsin responseto decreases in arterial blood pressure,extracellularfluid (ECF), plasmavolume, or ECF sodium; it is alsoreleasedin responseto increasedsympatheticnervoussystem tone. (2) Under the influence of renin, circulating angiotensinogen is converted to angiotensin I. Angiotensin-converting enzfme (ACE) converts angiotensin I to angiotensin II, a potent hypertensive(vasoconstrictive)agent.This occurs mainly in the lung.
Bridge to Cardiovascular Theroleofangiotensin(ACE) converting enzyme inhibitors inthetreatment of hypertension andcongestive heart failure isdiscussed inthe Cardiovascular Pharmacology chapter of Organ Systems Bookt (Volume lll).
(3) Angiotensin II acts directly on the zona glomerulosa to increasealdosterone production from corticosterone(seeFigure III-3-5). b. K+ control is alsoimportant. IncreasedplasmaK+ directly stimulatesaldosteronesynthesis by zona glomerulosa cells.
In A Nutshell
c. The anterior pituitary also plays a minor role in mineralocortoid regulation.
Addison Disease . Alsocalled l' adrenocortical
(1) ACTH stimulates aldosterone synthesis transiently with no negative feedback control. It stimulates synthesis, but the release is primarily controlled by osmoregulators. (2) GH maintains normal responsiveness until there is diminished responsiveness of glomerulosa cellsto GH after a long-term absenceof anterior pituitary stimulation. I. Disorders of the adrenal cortex 1. Adrenal insufEciency (Addison disease) is characterizedby weakness,fatigue, anorexia, gastrointestinalproblems,hypotension,and hypoglycemia.In addition, Na+ wasting and K+ retention occur, leading to hyponatremia, hyperkalemia, dehydration, and acidosis. Primary insufficiency results when cortisol synthesisis inhibited directly, as in a deficiency of biosynthetic enzymes.In primary insufficienry, ACTH levels are elevated and severepigmentation is seen.In secondary insufficiency, ACTH is inhibited and, thus, cortisol production is not stimulated. Secondaryadrenocortical insufficiency is most commonly due to chronic exogenousglucocorticoid therapy.
insufficiency . Mostcommonly dueto autoimmune adrenal atrophy . Characterized by hypotension, increased skin pigmentation, decreased serumNa.,Cl-,glucose, HC0,-, andincreased SCTUM K-
. Discussed in greater detail intheEndocrine Pathology chapter
24t
Endocrine System
2. Adrenocortical excess(Cushing syndrome)
ClinicalCorrelate
pituitary ACTH secretion. a. Cushing diseaseis causedby excessive
glucocorticoid Excessive secretion iscalled Cushing syndrome. Clinical manifestations include:
b. Ectopic ACTH production c. Adrenal adenoma and carcinoma, which are ACTH independent d. Clinical evaluation requires recognition of ACTH-dependent and independent causes. One of the common causesof adrenocorticalexcessis iatrogenic,resulting from chronic glucocorticoid therapy.
. Truncal obesity . "Moon" facies . Hypertension
e. The physiologic consequencesof excessivecortisol exposure include obesity, facial plethora,hirsutism, menstrual disorders,and hypertension.
. Osteoporosis
3. Hypoaldosteronism results in hyperkalemia (K+ retention), metabolic acidosis (H+ retention), hlponatremia (Na+ depletion), and hypotension (plasmavolume loss).
. Protein depletion . Clucose intolerance
4. Hlperaldosteronism results in hypokalemia (K+ depletion), hypernatremia (Na+ retention), metabolic alkalosis(H+ depletion),and hypertension.Note that increasedlevelsof ANP (atrial natriuretic peptide), stimulated by the increasedplasmavolume, increasesodium and water excretion,providing an "escape"from continued increasesin plasmavolume and blood pressure.
. Muscle wasting and weakness . Purple abdominal striae
a. Primary hyperaldosteronism (Conn syndrome). The majority of patients (approximately 90o/o)have adrenocorticaladenomas.It is characterizedby decreasedserum renin. b. Secondary hnreraldosteronism. Elevation of aldosterone results from the stimulation by angiotensinII due to excessrenin production; the condition is characterized by increased renin levels.
Flashback to Embryology crest derivatives Otherneural include sensory and ganglia autonomic and melanocytes.
t.
Notethatin contrast to the medulla, theadrenal cortex isderived frommesoderm.
1 . Catecholamine release involves movement of storage granules to the cell periphery by microfilaments, where the contents are exocytosed.Epinephrine and norepinephrine are stored in different cell types.
244
The adrenal medulla is a specializedneural crest derivative responsiveto cholinergic nerve stimulation. Epinephrine and a little (<10olo)norepinephrine are synthesizedand stored in the adrenalmedulla and releasedinto the blood.
Physiology
cHc_cH-NHe | cooH
TA\tUJ \-/
PhenYlalanine
I
I Y
Phenylalaninehydrorylase
rA>c
- NH2 Hc-cH -
'o-\/
Tyrosine
loorr Tyrosinehydrorylase I
Ho-{A-F ' t t( |
Ho-\z
''t, HO1A). l( )l HO-V
CHc-cH-NHr |
Dopa
cooH
DOPAdecarboxYlase CHz- CH2- NH2 -
Dopamine
''t, DoPamineP-hYdrorylase no-AFcHoH-cH2-NH2 . l( )l
Norepinephrine
,o_*v; I *
Phenylethanolamine-Nmethyltransferase
HO-
CH.--N-H
HO+/
- c H, s -Erp-i'n- 'e-p h-r i n e
Figure lll-3-6. Structures and synthetic pathway in catecholamine production from phenylalanine.
2. C-atecholamine degradation is catalped by catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO), limiting the duration and magnitude of their action. Termination of the local action of catecholaminesis also accomplishedby neuronal reuptake. 3. Catecholamine synthesis (Figure III-3-6) a. Epinephrine is synthesizedfrom phenylalanine,tyrosine or both, with each step in the process catalyzedby a specific enzyme. b. The main site of synthesis is in the adrenal medulla, but catecholamines are also formed in postganglionicsympatheticneurons (norepinephrine) and selectCNS neurons (e.g.,dopamine in substantianigra).
245
Endocrine System
4. Catecholamine activity a. Catecholaminesstimulate both cr- and B-adrenergic receptors. o-receptors typically mediate smooth muscle contraction (e.g.,skin, iris, arterioles),while B-receptorsmediate smooth muscle relaxation (e.g.,bronchi, arterioles in skeletalmuscles)and cardiac stimulation (heart rate, contractility). b. Biologic effects include increasedheart rate, cardiac output, blood pressure,pupil diameter; selectiveeffects on blood flow in different organs; increased oxygen use, blood sugar,and respiration rate. 5. Catecholamine overproduction and underproduction a. Overproduction is mainly associatedwith tumors (e.g.,neuroblastoma,ganglioneuroma, pheochromocytoma). The most common features include hypertension, hlpermetabolism, and hyperglycemia.Diagnosis is made by measuring urinary levels of catecholamine metabolites such as homovanillic acid (HVA) and vanillytmandelic acid (vMA). b. Underproduction is usually a result of adrenaldestruction or surgicalremoval.
THYROID GTAND
ClinicalCorrelate gland Thethyroid is dependent oniodine. Coiter canoccur in geographic certain areas where iodine isdeficient inthediet.
A. Biosynthesis of thyroid hormones. The thyroid gland synthesizes and releases two principle hormones: triiodothyronine (Tl) and tetraiodothyronine (Tl, thyroxine). The process of thyroid hormone biosynthesis and secretion is shown schematically in Figure lll-3-7 . All steps described are stimulated by TSH. l. Thyroglobulin (TG) is a glycoprotein synthesizedby the thyroid follicular cell and secreted into the colloid space(follicular lumen). 2. TG is releasedinto the lumen via exocrtosis.Iodination occurs at the follicular cell surface. a. Before iodination can occur, iodide must be taken up by the thyroid cell and oxidized to iodine. Iodide uptake, or trapping, takes place at the base of the cell via active transport, using energyfrom an iodide pump. b. Oxidation of iodide to iodine occurs at the apex of the follicular cell and involves a peroxidase enzvme system (thyroid peroxidase). The oxidized speciesof iodine is then extruded from the cell by exocytosisand is added to the TG presentin the colloid. The products of iodination, the iodotyrosines 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT), are contained within the iodinated TG molecule.
246
Physiology
FollicularCell
ExtracellularSpace
FollicularLumen
Endop|asmic--}Go|gi....-+Thyrog|obulin--.--+Exocytosis->TG reticulum apparatus lodidepump +lodide (activetransport)
+Oxidized
',?S^)
via peroxidase
) llHiisl;
(l
.h".J
T3 Secretion T4
l-TG = thyroglobulin-containing iodotyrosines(MlT and DIT) and iodothyronine (Ts,T+);MIT = 3-monoiodotyrosine; and DIT = 3,5-diiodotyrosine.
Figurelll-3-7.Biosynthesisand secretionof thyroidhormonesby the thyroidfollicularcell. 3. Formation of Ta involves oxidative coupling of two DIT molecules,whereassynthesisof T3 requiresoxidativecoupling of one MIT and one DIT molecule.Thesereactionsare also catalyzedby thyroid peroxidase. 4. Re-uptake of iodinated TG from the follicular lumen into the cell occurs via endocftosis. Under appropriatephysiologicstimuli, iodinated TG is digestedby lysosomalenzymesto releaseMIT, DIT, T:, and Ta. 5. The Ta and T3 can then be secretedinto the extracellularspace.MIT and DIT normally do not escapeinto the circulation but are deiodinatedin the thyroid cell. 6. The tyrosine residuesand iodide are then recycledor "salvaged"for synthesisand iodination of additional TG. 7. Note that iodinated TG classifiesasa prohormone since,prior to proteolysis,it consistsof physiologicallyinactive iodothyronines.TG is found in the peripheral plasma of euthyroid subjects,but most of it remains sequesteredin the colloid. a. Conditions associatedwith damageto the thyroid gland (thyroiditis and thyrotoxicosis) elevatecirculating TG levels. b. Although the regulation of TG is not yet completely understood, it appearsthat exogenouslyadministeredT3 and T4 decreaseserum TG levels,and stimulatorsof thyroid gland function increasethem. B. Metabolism of thyroid hormones 1. Ta leavesthe peripheral circulation with a half-life of 6-7 days,whereasT3 has a half-life of approximately I day. 2. Inthe peripheralplasma,T4 and T3 arebound to plasmaproteins.Approximately99o/oof the circulatingthyroid hormones areprotein bound, and only lo/oarefree and biologicallyactive.
In a Nutshell ThyroidHormone Synthesis . Synthesis ofthyroglobulin 0C) . lodide (base trapping ofcell, active transport) . Oxidation ofiodide to iodine (apex ofcell); iodine exocytosed fromfollicular cellintocolloid . lodination ofTCtyrosine residues incolloid toform3(MlI) and monoiodotyrosine (DlT) 3,5-diiodotyrosine . Coupling ofMITandDITto formT,andtrruo DIT molecules toformTo . Re-uptake ofTGintothecell; proteolysis MlT, to release DlT,T,,andT, . Secretion ofT,andTointo extracellular space
a.T+ and T3 are bound to thyroxine-binding globulin (TBG). Ta binds much more avidly to TBG than doesT3, which accountsfor the longer half-life.
247
Endocrine System
b. Thyroxine-binding prealbumin (transthyretin) and albumin also bind T, and T' but with considerablylessaffinity than TBG. 3. Both T, and T, are metabolized by peripheral tissuesalong similar metabolic pathways. 4. Peripheral monodeiodination of T, (i.e., the removal of one iodine molecule) and the subsequentformation of T, occurs in many tissues,with the pituitary, liver, and kidneys exhibiting the highest reaction rates.It can proceed along two alternate pathwaysyielding metabolically active T, or relatively inert reverse T, (rTr). 5. Circulating T3 originatesprimarily from peripheral conversionof Tr. a. Thirty-five percent of Tn secretedby the thyroid is convertedby peripheral tissuesto Tr.
Note Peripheral 5Ldeiodinase by: isinhibited . Prolonged fasting orsevere illness . Propranolol . Clucocorticoids . Propylthiouracil
b. The sourcesof rT3 in the circulation are similar. Both T, and rT, are monodeiodinated to 3,3'-diiodothyronine (Tr), and the tyrosine and iodide can be recycledto the thyroid gland. c. Two separatedeiodinating enzymesare involved (S-deiodinaseand 5'-deiodinase)and deiodination is a controlled rather than a random process.Thus, the production of active thyroid hormone can be regulated not only at the thyroidal but also at the peripheral level. ( 1) Inhibition of the 5'-deiodination pathwaywith relativeoverproduction of rT, at the expenseof T, has been observedin starvation and in euthyroid patients with a variety of nonthyroidal diseases.This may representan adaptiveattempt by the organism to conserveenergyduring times of stress.Thesepatients have normal levelsof Tn and TSH. (2) High rT, and low T, levelsare also observedduring fetal life. (3) Pharmacologicinhibition of 5'-deiodination of serum Tn can be achievedwith the p-blocker propranolol, glucocorticoids,propylthiouracil (seebelow), and certain radiocontrast agents,causingthe serum T, to fall and the serum rT, to rise. C. Mode of action of thyroid hormones 1. No one mechanism accounts for all aspectsof thyroid hormone activity; there are different modes of action in various tissuesand even during different stagesof development. 2. The model now widely accepteddescribesthe direct action of thyroid hormones on the nuclear chromatin. a. Thyroid hormone receptors,located on the histone (non-DNA) fraction of the chromatin have been isolated. Thesereceptors are structurally similar to steroid hormone receptors,but are present in the nucleus whether or not thyroid hormones are present. b. Thyroid hormones, specificallyT, more than Tn, enter the cell nucleus and bind to nuclear receptors.This complex then promotes the transcription of required genes. c. The end result of thyroid hormone binding to the nuclear chromatin receptoris protein synthesis. d. Thyroid hormones alsohaveextranuclearbinding sites,locatedon membrane and mitochondrial areas.This extranuclearbinding is implicated in thyroid-hormone-mediated amino acid transport under conditions when protein synthesishasbeenblocked.
248
Physiology
D. Extrathyroidal regulation of thyroid hormone secretion. The thyroid axis consistsof the hypothalamus, the hypophysis, and the thyroid gland, associatedin a classicnegative feedback system. 1. Thyrotropin-releasing hormone (TRH). The hypothalamus synthesizesand releases TRH, which acts directly on the pituitary and stimulates the secretion of TSH. 2. Thyroid-stimulating hormone (TSH). In responseto TRH, the anterior pituitary releasesthe thyrotropin, TSH. TSH is a glycoprotein that stimulates the thyroid gland to secrete both Tn and T' which then inhibit further TSH releaseby negativefeedback.TSH exerts a trophic action on the thyroid gland, maintains its structure, and promotes blood flow. All aspectsof thyroid gland function, such asincreasediodine transport, increasedorganic binding and coupling, increasedproteolysisof TG, increasedsecretionof Tn and T' and acceleratedmetabolism,are controlled by TSH. TSH binds to a receptor on the plasma membrane of the thyroid cell and elevatesthe intracellular cAMP concentrations. 3. The relationship between the thyroid and the pituitary is reciprocal. a. Hypophysectomy causesthyroid atrophy, reduces thyroid blood flow, and decreases thyroid secretion of T, in serum. If TSH is administered to hypophysectomizedsubjects, the effectsare reversed. b. If the thyroid is removed or fails to function, there is an increasein the sizeand weight of the pituitary gland, causing a goiter. Following thyroidectomy, so-called "thyroidectomy cells "appear in the pituitary, and in long-term hypothyroidism, destructive pituitary enlargement can occur. The administration of T, prevents these pituitary changes. 4. Final feedback of the hypothalamic-pituitary-thyroid
axis (Figure III-3-8)
a. The major product of the thyroid gl*d, Tn, is carried in the peripheral plasma bound primarily to TBG. Monodeiodination of T, to T, occurs in the peripheral plasma,and especiallyin the liver, kidney, and pituitary gl*d. Both hormones act peripherally on their target organs and also exert their negative feedback effect on the pituitary gl*d. b. Thyroid hormones reduce the pituitary responsivenessto TRH, inhibiting further secretionof TSH. This inhibition of TRH-induced TSH releaseby thyroid hormone is seenduring TRH testing. c. Thyroid hormones also exert a negativefeedbackon TRH synthesis.
Note T, binds to thethyroid receptor withl0 timesthe affinity of To.Therefore, intracellular T, isresponsible forthyroid hormone effeG andnegative feedback. However, circulating Tois considered themajorsource of negative feedback, since it diffuses intopituitary and hypothalamic cells andis immediately deiodinated to Ti.
249
Endocrine System
Hypothalamus
Pituitarygland
(-) gland
T+
Ts
Figure lll-3-8.Diagram of the final feedback of the hypothalamic-pituitary-thyroidaxis. TRH = thyrotropin-releasing hormone;TSH = thyroid-stimulating hormone.
E. Intrathyroidal regulation. In addition to extrathyroidal regulation, regulatory systems within the follicular cellsmonitor the sizeof the intraglandular organic iodine pool. 1. Autoregulatory mechanisms
Note = llodide = lz lodine peroxidase thyroid
a. Changesin intrathyroidal organic iodine are associatedwith reciprocalchangesin the trapping and organic binding (iodination) reactions,aswell asin the sensitivityof the follicular cell to a given level of TSH. b. Theseintrathyroidal autoregulatorymechanismsmaintain a constantlevel of thyroid hormone production during periods of iodine deficiencyand excess.Iodide deficiency is rare in the United Statesbecauseiodide is traditionally addedas a supplementto table salt.
2l-+lz Thisreaction occurs inthe thyroid follicular cellmembrane andisinhibited bypropylthiouracil.
2. Effects of iodide on thyroid function. The thyroid gland uses approximately 100 pg of dietary and internally rerycled iodide each day. a. When the amount of acutelyingestediodide exceedsa critical level,there is a sudden inhibition of organic binding (Wolff-Chaikoffeffect). This inhibition is usually transient becausean adaptive decreasein iodide pump activity limits further entry of iodide into the cell. b. Iodide has important effectson the sensitivity of the follicular cell to TSH. Iodide loading dampens and iodide depletion increasesthe intracellular accumulation of
250
Physiology
cAMP in responseto TSH. The modulating effects of iodide on sensitivity to TSH, iodide transport, and organic binding protect the constancy of the intrathyroidal organic iodine pool. c. Large dosesof iodide inhibit thyroid hormone releaseand decreasethe vascularity of the gland, and are used as adjunct therapy for hyperthyroidism. F. Assessmentof the thyroid function. Direct measurementof thyroid hormones in the blood by radioimmunoassay (RIA) under basal conditions as well as after pharmacologic stimulation and suppressionmakes it possible to detect and treat thyroid dysfunction at an early stage. 1. Tests a. Total serum T4 (TT4) and totd serum Tt (TTl) can be measured by RtA methods. The antibodies used are highly specific and sensitive. b. Free T3 and Ta. Techniquesto measurefree T3 and Ta are now availableaswell. c. Serum TSH (1) Elevatedserum TSH concentration measuredby RIA is used to discriminate between primary hypothyroidism (thyroid origin and, therefore, increasedplasma TSH concentration) and secondary hypothyroidism due to pituitary or hypothalamic disease(decreasedTSH). (2) Patients with early thyroid failure (subclinical hypothyroidism) have elevations of serum TSH before serum Ta levels fall below the normal range. (3) In patients with hyperthyroidism, TSH is suppressed as a result of Ta feedback to the pituitary. (4) Conventional TSH-RIA methods (TRH stimulation) have detection limits: euthyroid subjects cannot be distinguished from hyperthyroid patients or patients taking suppressivedosesof Ta. Through administration of TRH, TSH levels are stimulated to increaseabove the detection limit in euthyroid patients, whereashyperthyroid patientshave no response(flat) or a blunted response. (5) SensitiveTSH assaysare now widely availablethat are able to distinguish between euthyroid and hlperthyroid patients. d.Tr resin uptake (RT3U) test. The results of this test are compared with the results obtained for standard control serafrom euthyroid individuals with normal quantities of thyroid hormone-binding proteins. The results of the unknown serum are divided by those obtained for the control serum in the same assay.
Patient's RT3 value Mean euthyroid RT3 value
z.
Clinical assessmentof thyroid function should include the measurementof the total Ta concentration by RIA and the determination of some parameter of the Ta-binding capacity of the serum proteins (THBR). From thesetwo measurements,free Ta can be reliably estimated (FT4I). This suffices to diagnose hyper- or hypothyroidism in most patients.
Note RIA(radioimmunoassay) is a methodto measure hormone concentration. . A serum sample with unknown hormone concentration ismixed with quantity a known of antibody to thehormone anda known amount of radiolabeled hormone. . Theradiolabeled hormone andtheunknown amount of unlabeled hormone compete forantibody binding sites. Whenthereis moreunlabeled hormone inthesample, thereisless radiolabeled hormone that canbindto theantibody (morefreeradioactive hormone). . A curve canbeprepared:
aoundfiree ll labeled l\ hormone \|
Unlabeled hormone Theratioof boundfree hormone willbehighest whenthereisnounlabeled present hormone to compete forantibody. Theratioof boundfiree hormone willbelowe$ whenthequantity of isthe unlabeled hormone highest.
251
Endocrine System
G. Thyroid hormone activities 1. Thyroid hormone regulatesoverall metabolic rate and maturation, including: a. Basalmetabolic rate and core temperature b. Appetite c. Normal maturation rate, including onset of puberty 2. Thyroid hormone is permissivefor the effectsof other hormones on many body systems. It is required for normal development and functioning of those systems,including: a. Growth b. Immune systemand wound healing c. GI motiliry d. CNS e. Cardiovascular,e.g.,heart rate and cardiacoutput f. Skin, connective tissue H. Thyroid disorders 1. A goiter is a hlpertrophied thyroid gland and results from chronic stimulation of the gland; goiters can occur with hyperthyroidism or hypothyroidism. a.Any condition causing chronically elevated TSH can cause a goiter, such as Ideficiencyin the diet, or inhibition of gland function by a goitrogen. b. The antibodies responsiblefor Grave'sdiseasestimulate the TSH receptors of the gland, causing hlpertrophy and hyperthyroidism. c. Goitrogens. Any chemical or agent that causesa goiter is referred to as a goitrogen. There are two major types: those that inhibit iodine transport and those that inhibit binding and coupling processes. (1) Inhibitors of iodine transport include the monovalent anions thiocyanate and perchlorate. Theseagentspromote rapid dischargeof inorganic iodide, thereby providing a means of readily distinguishing between "free" and "bound" iodine storeswithin the gland. Their clinical utility is limited by their toxiciry. (2) Inhibitors of binding and coupling. The most widely used agents that affect organic binding and coupling processesand inhibit thyroid hormone formation include the thioamides, propylthiouracil (PTU), and methimaz.ole.Interference with iodination and coupling reducesthe synthesisof thyroid hormones. In a euthyroid individual, this stimulates TSH secretion and leads to hyperplasia of the thyroid gland (goiter). PTU alsoblocks the peripheral conversionof Tn to T' but has no effect on the peripheral action of Tr. 2. Hyperthyroidism production of thyroid hormone in the a. Hyperthyroidism is most often due to excessive production absenceof TSH stimulation (tT' tT., JTSH); it is rarely due to excessive of TSH (secondaryhyperthyroidism: tT4, TT3, tfsff) or excessive TRH production (tertiary hyperthyroidism) . b. Classic symptoms include irritability and nervousness,weight loss with increased appetite, tremor, sweating,and tachycardia. c. The most common causeof hyperthyroidism is Gravesdisease,an autoimmune diseasethat also causesa diffi.rsegoiter and exophthalmos. Graves diseaseis discussed along with other causesof hyperthyroidism in the Endocrine Pathology chapter.
252
Physiology
3. Hypothyroidism a. Hypothyroidism can be classifiedaseither primary (defectin thyroid gland: JTn, JT' ttsFl), secondary(defect in pituitary TSH secretion:JT' JT' JtsFI), or tertiary (very rare defect in hypothalamic TRH secretion).Rare casesare due to peripheral thyroid resistance(partial T, receptordefect:tTn, tT' normal TSH). b. Classicsymptoms include decreasedheart rate, weight gain (often accompaniedby decreasedappetite),lethargy,constipation,dry and coarseskin and hair, and cold sensitivity. c. Autoimmune thyroiditis and destruction of the thyroid gland is the most common noniatrogenic causein adults (discussedalong with other causesin the Endocrine Pathologychapter).
MINERAL HOMEOSTASIS ANDBONEREMODELING There are two hormones of major importance in mineral homeostasisand bone remodeling: parathyroid hormone (PTH) and the activeform of vitamin D, 1,25(OH)2D3,which is secreted by the proximal convoluted and straight tubules of the nephron. A third hormone, calcitonin, is secretedby the thyroid parafollicular cells and inhibits bone resorption and thereby decreases serum Ca2*and phosphate. A. Parathyroid hormone (PTH) l. Structure and biosynthesis a. PTH is secreted from the chief cells of the parathyroid gland and ectopically by certain tumors. and translob. Precursorforms are produced and then modified by a seriesof cleavages cation steps.This occurs in specializedsubcellularorganellesof the chief cells and eventually leadsto the formation of PTH. c. In the endoplasmicreticulum, the initial amino acidsof a preproparathyroidhormone are cleavedto form proparathyroid hormone (proPTH).ProPTH then moveswithin membrane channelsof the endoplasmicreticulum to the Golgi apparatus,where the amine (NHz) terminal hexapeptideis removed. d. The final product, PTH, is incorporated into secretory granules, transported to the periphery of the cell, and releasedinto the extracellularspaceupon physiologicstimuli. 2. Regulation of secretion a. The major regulator of PTH secretionis plasmaCa2*levels. (1) J PlasmaCa2++1 PTH (2) t PlasmaCa2++J PTH b. Increasedlevelsof 1,25 (OH)rD? will decreasePTH. 3. Functions of PTH a. PTH maintains plasma Ca2+and phosphate levelsto ensure the optimal functioning of a variety of cells. b. PTH functions as a trophic hormone by stimulating the synthesis of 1,25(OH)zDr from 25(OH)D3 in the kidney. c. In the major sitesof PTH action (the kidney, bone, and, indirectly, the intestine),the net result of PTH action is an increase in plasma Ca2+ and a decreasein plasma phosphate.
25t
Endocrine System
4. Effects on bone a. It induces osteoblaststo pump Ca2+ into the ECF. The long-term effect of PTH promotes osteoclastic activity (bone resorption) and triggers formation of more osteoclastswhile inhibiting the formation of osteoblasts. b. PTH allows C*+ efflux from small availablepools to the ECF. c. PTH also increasesthe rate of skeletal remodeling by promoting bone resorption via activation of osteocytic osteolysis. 5. Effects on the kidney. PTH acts directly to promote Ca2+tubular reabsorption and phosphate excretion. a. Approximately 50-650/oof Caz+ is reabsorbed in the proximal tubule and approximately 20-30o/ois absorbed in the medullary loop of Henle. This reabsorption is not under hormonal control. In the cortical distal nephron, under the influence of PTH, the remaining 15-20o/oof the Caz+ is reabsorbed.The results of these actions are maintenance of high Ca2+and reduced phosphate concentrations. b. The mechanism operatesbetween the bone and kidney. (1) PTH stimulatesreleaseof both Ca2+and phosphatefrom bone. (2) Uncorrected,this mechanism would causeprecipitation of calcium phosphate crystals.However, PTH also promotes phosphaturia, reducing the precipitation of theseions.
In a Nubhell PTHActions . lncreases boneresorption, releasing bothCa2* and phosphate frombone . lncreases calcium reabsorption inthedistal nephron, decreasing calcium excretion . Inhibits phosphate reabsorption inthe proximaltubule and phosphate increases (phosphatu excretion ria) . Increases Ca2* absorption fromtheinte$ine indirectly by$imulating renal production of 1,25dihydrorycholecalciferol (1,2s[0H]2D3) . Overall effectlncreases plasma calcium, decreases plasma phosphate
254
c. PTH increases the urinary excretion of hydroryproline-containing peptides. Hydro4;'proline is a nonessential amino acid found almost exclusively in collagen and, therefore,can indicate the amount of bone remodeling occurring. 6. Effects on the intestine a. As noted, PTH promotes the conversionof 25(OH)D3 to 1,25(OH)2D3(1,25-dihydroxycholecalciferol) in the kidney. b. This sterol then acts on the intestinal mucosa to increase Ca2+ and phosphate absorption. 7. Mode of PTH action a. PTH binds to the membrane-bound PTH receptor,and the guanyl nucleotide regulatory protein is stimulated to bind guanosinetriphosphate (GTP). b. GTP binding to the guanyl nucleotide regulatory protein converts the membranebound receptor to a low-affi"ity state,inducing dissociation of PTH and the formation of a Gsa-adenylate ryclase complex, leading to activation of this enzfme and the increased production of intracellular cAMP. c. This intracellular cAMP messageis the meansby which PTH exertsit action on target tissues. 8. Parathyroid disorders a. Primaryhnrerparathyroidism is causedby hypersecretionof PTH from the parathyroid (usually secondaryto an adenoma). As would be expected,the result is hypercalcemia and hypophosphatemia. b. Secondaryhyperparathyroidism is causedby hypersecretionof PTH due to hypocalcemia (usually secondaryto chronic renal failure).
Physiology
c. Hypoparathymidism is caused by insufficient secretion of PTH. The result is hypocalcemia and hyperphosphatemia. d. Pseudohypoparathyroidism is a rare diseasecaused by PTH tfiget-tissue resistanc€. This disorder is characterized by hypocalcemia in the setting of elevated PTH. B. cholecalciferols (vitamin D)
in the skinthroughultrar. vitamin D canbeeitheringested in thedietor manufactured violet light activatiotr of 7-dehydrocholesterol ( Figure III-3-9 ).
Note
ylTT,l.D-]t-:::
jil;
:l^t} wm soluDle vmmlns'along
vitamins A,E,andK.
a. Liver enzymesconv€rtvitamin D to 25(oH)Dr. This conversionat the liver is regulatedby a feedbacksysteminvolving th€ liver levelof25(OH)D, itself. b. Under the stimulus of PIII and low serurnphosphate'the 25(OH)D3 m€tabolit€is convert€din the proximal tubule of the kidney to 1,25(OH)rD., which is the active form of vitamin D. 2. Regulationof enzyrneactivity a. The kidney enzyme(25[OH]D-fo-hydroxlase) introducesan OH at the cr position of carbon l of the A ring. b. The hydroxylation occurs in the proximal convolutedand straight tubules of the kidney nephron. c. Regulationof 1,25(OH)2D3is under very tight control. The renal output of 1,25(OH)2Djre{lectsindividualCa'' requirements. 3. Regulatorsof 1,25(OH)'D, levelsinclude: serumcalcium increases1,25(OH)'D, indirectly by increasingserumPTH a. Decreased b. PTH stimulatesla-hydrorylasein the hdney cells;1,25(OH)rD,inhibits PTH secretion c. 1,25(OH)2D,itselfinhibitsthe 1(renzfm€ phosphateintake and hypophosphatemiaincrease1,25(OH)rD, d. Decreased will decrease1,25(OH)2D3 e. An increasein phosphateintake or hyperphosphatemia
255
Endocrine System
7- Dehydrocholesterol
St
v
<_-
Diet
Cholecalciferol (vitaminD3)
I
25(OH )D 3 (Conversiontakes place in liver)
CHz
1,25(OH)2D3 (Conversiontakes place in proximal tubuleof kidneyunderstimulation by parathyroidhormone)
OH Figure lll-3-9.Formationof 1,25(OH)zDg.
4. Effects on intestine. The major actionsof 1,25(OH)zD: facilitate Ca2+absorption from the intestine. Phosphatetransport can accompanythat of Ca2*,but vitamin D stimulates a distinct phosphatetransport systemin the intestine. a. 1,25(OH)2D3interacts with an intestinal receptor for regulation of a Ca2+-binding protein (calbindin-D). b. The amount of calbindin-D in the intestinal mucosais positively correlatedwith the rate of transport or absorption. Increasedtransport of both minerals at the intestine is directedby physiologiclevelsof 1,25(OH)zD:. c. The movement of both Ca2+and phosphateis activeagainstan electrochemicalgradient.
256
Physiology
d. 1,25(OH)2D3actsat the intestinalbrush-border membrane,altering propertiesof the microvillar surface,allowing entry of theseions into the cell. e. The result is increased serum Ca2+and phosphate concentrations, permitting normal skeletalmineralization and other physiologicfunctions affectedby theseions. 5. Effects on bone a. The two most striking changes in bone in advanced vitamin D deficiency (rickets/osteomalacia) are: (1) Failure of the normal mineralization of bone matrix, leading to the accumulation of unmineralized osteoid (2) Decreasein osteoclastcount and bone resorption surfacein relation to the concentration of circulating PTH b. Normal calcificationrequiresvitamin D acting directly on bone.
ClinicalCorrelate in factors thatresult Some (children) and rickets (aduls): osteomalacia . Malnutrition . Intestinal malabsorption . lnadequate exposure to sunlight
( 1) One action of vitamin D is an increasein the osteoclastcount on the endosteal bone surfaces.This change,requiring the presenceof PTH, precedesthe increase in Ca2+and phosphatein the ECF, indicating that vitamin D has a direct action upon bone.
. Liver withimpaired diseases, D. to ofvitamin conversion 2s(0H)D3
(2) In bone as in the intestine, the important metabolite of vitamin D is 1'25(OH)zDE.
. Renal withimpaired disease, form oftheactive synthesis D.) D (1,25[0H], ofvitamin
c. The action of vitamin D to causea dissolution of bone seemsparadoxic,considering that the sterol promotes normal bone mineralization. However,the bone resorption provides Caz+ andphosphatefor new bone formation. The osteoclasticresorption of formation of new bone. bone is normally in equilibrium with osteoblast-mediated (l) 1,25(OH)zD:-inducedstimulation of bone growth and mineralization is not mediatedthrough a direct effect on osteoblasts. (2) 1,2;(OH)zD: stimulatesbone mineralization indirectly by providing minerals for incorporation into bone matrix through increasedintestinal absorption of Ca2+. 6. Effects on the kidney a. Ninety-nine percent of the reabsorptionof Ca2+by the kidney occurs if vitamin D is deficient. b. The 1,25(OH)zD3stimulation of the renal reabsorptionof calcium is of questionable importance. 7. Mode of vitamin D action a. 1,25(OH)2D3actsat the molecularlevelsin a manner similar to steroids. b. 1,25(OH)2D3 interacts noncovalently but stereospecificallywith an intracellular receptorprotein. c. The steroid receptor associateswith the genome and new RNA encoding protein to enhancea spectrum of biologic responsesor mediate a selectiverepressionof gene transcription. C. Calcitonin is secretedby C cells found primarily in the thyroid and secondarily in the parathyroidsand thymus tissue. 1. Increasedserum Ca2+is a stimulus for secretionof calcitonin.Calcitonin decreasesbone resorption and decreasesserum Ca2+.
Note D regulate PTHandvitamin (and plasma calcium phosphate) andaffect levels Calcitonin bonemetabolism. bonemetabolism, alsoaffects plasma butdoesnotregulate ona dailybasis. levels calcium
257
EndocrineSystem
2. Ten percent of thyroid cancersare medullary and are accompaniedby elevatedcirculating levels of calcitonin; its measurementis diagnostic and indicative of effectivetherapeutic action. 3. Calcitonin can be used in the treatment of osteoporosis. a. Sincepostmenopausalosteoporosisis characterizedby bone resorption in excessof formation, calcitonin is administeredto inhibit further bone resorption. b. Although calcitonin deficiencyis not seenin postmenopausalosteoporosis,the therapy is still considereda pharmacologicantiresorptivetreatment. D. Control of Ca2+and phosphate homeostasis and skeletal remodeling 1. The major controlling factor of PTH secretionis the serum Ca2+level, which is held relatively stable and is inversely related to the serum pTH level. 2. The changing serum Ca2+ level is monitored by a sensitive feedback system. (FigureIII-3-10).
Parathyroidchiefcells
lOsteocytic osteolysis 25(OH)D3
CaZ+/POq3released or remodeling occurs
1,25(OH )2D 3
tOa2*reabsorption leOos- excretion
Figure lll-3-10. The feedback mechanism controlling Ca2+ concentration. ([+]= stimulation[-] = inhibition; [t] = increase;[J] = decrease)
In a Nutshell PTH
t Serum Ca2* J Serum phosphate
VitD
t Serum Ca2* ,,t\^ | )erum phosphate
Calcitonin + J Serum Ca2* J Serum phosphate
258
a. A decreasein the serum Ca2+(<10 mg/dl) is monitored by the calciostatin the chief cellsof the parathyroid gland to stimulate the secretionof prH. b. PTH travelsto the bone, wherethe processof osteolytic osteolysiscausesbone breakdown and remodeling with an increasein serum ca2+ and phosphate. c. PTH actson kidney tubules to promote Ca2+reabsorptionand phosphateexcretion. The kidney stimulatesconversionof 25(oH)D, to 1,25(OH)2D3. d. 1'25(OH)rD, then travelsto the intestine,where promotion of absorption of both Ca2*and phosphateoccurs.1,25(OH)rD, alsotravelsto the bone where,togetherwith PTH, it causesremodeling. e. 1,25(OH)rD, directly inhibits secretionof PTH from chief cells operating in a negative feedbackloop.
Physiology
HORMONES PANCREATIC A. Overview 1. Islets of Langerhansarethe functional units of the endocrinepancreagthereareapproximately I million islets. 2. Thereare four cell typesin the pancreaticislets-+ four hormones' a. c cell -+ glucagon b. P cell -+ insulin c. 5 cell -l somatostatin d. PP(F)cell -+ pancr€aticpolypePtide 3. Islet cells contain gap iunctions that link them together,possibly allowing cell-cell communication. 4. Isletsare innervatedby both the sympatheticand paraqrmPatleticsystems. B' Insulin 1. Insulin is secretedby p cellsin responseto incr€asedblood sugar.
2.synthesis asprqrroinsulin; cleavageof the IO0-amino-acidN-terminal signalpepa. Synthesized proinsulin. leaves tide b. Wthin proinsulin, residues1-30 will form the B chain, and residues66-86will form the A chain of insulin. Residues31-65 form the "connecting peptide" (C-peptide). The two regionsforming the A and B chainsform two disulfidebridgesin the proinsulin molecule.
F{S.!__l,if!_a,Aig-y effectsof Themetabolic are insulinandglucagon
fl:iff*:l';'^lt1ffJ';' intheBiochemistry chapter Principles oftheGeneral seclion (Volume I l) Book
c. In the conversionof proinsulin to insulin, two pairs of basicamino acidsare cleaved from either end of the connectingpeptide,leavingone moleculeeac.hof insulin and C-peptide-these are secretedin equimolar amounts. d. Measwementof circulation C-peptide indicatesp-cell secretoryactiYit)'.Note that orogenouslyadministeredinsulin will not contribute circulatingC-peptide' 3. Secretion a. Stimulatory a8€nts (1) Hyperglycemia(tlreshold >l mg/ml) (2) Amino acids(especiallyArg) (3) Fattyacids,esPecially longchain(16-18C) (4) Gastmintestinalhormones,GIP,gastrin,sefietin (oral doseof glucose-) greater production of insulin tlnn via IV becauseof thesehormones) (5) GH, cortisol (6) Acetylcholine(parasympatheticstirnulation) (7) Sulfonylureas(usedto treat noninsulin-dependentdiabetesmellitus)
259
Endocrine System
b. Inhibitory agents (1) Hypoglycemia (2) Somatostatin (3) Norepinephrine (4) Epinephrine c. When stimulated by glucose, secretion is biphasic. (1) Initial burst for 5-15 minutes from secretionof alreadyformed granules (2) More gradual and sustainedreleaseof newly synthesizedinsulin (3) Secretedin fed-state-hormone of nutrient abundance d. Primary target cells for insulin are liver, skeletalmuscle, and adipose tissue. 4. Insulin receptor a. Heterotetramerwith two u-p subunits held togetherby disulfide bonds ( I ) cx-Subunitsare extracellularproteins and contain insulin binding sites. (2) p-Subunits are transmembraneproteins and havetyroxine kinase activity. b. Insulin binding to the receptor causesautophosphorylation of intracellular portions of the B-subunits-this activatesthe tyrosine kinase portion of the B-subunits to phosphorylateintracellular proteins and initiate a cascadeof protein-protein interactions that resultsin activation of a variety of cellular Ser-Thr kinases. 5. Metabolic effects of insulin a. Glucose transport (1) Insulin promotes uptake of glucose from blood into cells. (2) A specific family of carriers are involved to facilitate glucosediffrrsion acrosscell membranes= GLUT 1 to GLUT 6 (GLUT = glucos€transporter). (3) Different carriersare expressedin different tissuesand at different stagesof fetal development. (4) GLUT 4 is the insulin-stimulated transporter in skeletalmuscleand adiposetissue. (5) Insulin promotes translocation of GLUT 4 transportersfrom inactive intracellular pools (smooth ER) to plasmamembrane-therefore, increasedglucoseuptake. b. Glycogen synthesis (l) Activates glycogen synthaseby promoting its dephosphorylation (2) Inactivates glycogenphosphorylase by promoting its dephosphorylation (3) Net result is to increase conversion of glucose to glycogen in liver and muscle c. Glycolysis (1) Promotes glycolysis by increasingglucoseuptake (2) Also activatesthe enrymes glucokinase,phosphofructokinase,pyruvate kinase, and pyruvate dehydrogenaseof the glycolytic pathway
260
Physiology
d. Gluconeogenesis (1) Increasesfructose 2,6-bisphosphate,leading to increasedphosphofructokinase activity (2) Decreasesgluconeogenesis e. Lipogenic and antilipolytic effects (1) In adiposetissueand liver, insulin promotes lipogenesis by increasingproduction of cr-glycerolphosphate and fatty acids (stimulates fatty acid synthase)necessaryfor triglyceride formation. (2) In adipose tissue, insulin inhibits breakdown of triglycerides by inhibiting a hormone-sensitive lipase that is activated by other hormones such as epinephrine and glucocorticoids. (3) Increasesactivity of lipoprotein lipase, which enhancesfatty acid uptake from blood into adipocytesor other tissues. f. Protein synthesis and degradation (1) Stimulates amino acid uptake by liver, muscle, and adipose tissue by stimulating amino acid transport system (2) Increases activity of protein synthesis initiation factors that promote translation; increasesribosome synthesis. (3) Inhibits protein degradation by decreasinglysosomal activity. g. Hypokalemia. Insulin increasescellular uptake of K+. This effect can be used therapeutically-patients with hyperkalemia can be treated by giving insulin in combination with glucose. C. Glucagon 1. Secretedby o cellsin responseto decreasedblood sugar. 2. Synthesis a. Synthesizedaspreproglucagonin c cellsof the isletsand alsoby cellsof the gastrointestinal tract and some brain cells. b. Primary regulator of secretionis a decreasein blood sugarbelow -1 mg/ml. c. Like insulin, glucagon secretion is stimulated by amino acids (especiallyArg) and inhibited bv somatostatin. 3. Secretion a. Stimulatory agents (1) Hypoglycemia (2) Amino acids (3) Acetylcholine (4) Norepinephrine (5) Epinephrine
(6) ccK
25r
Endocrine System
b. Inhibitory agents (1) Hyperglycemia (2) Fatty acids,ketones (3) Somatostatin (4) Insulin 4. Metabolic effects of glucagon are exertedprimarily in the liver. Glucagon binds to one or more tfpes of cell surfacereceptor coupled to G-proteins and promotes increased cAMP via adenylateryclase or increasedcytosolic Caz+. a. Glycogenolysis (1) Promotes glycogen breakdown by phosphorylating phosphorylase B, which is then convertedto phosphorylasec[ (2) Inactivates glycogen synthase b. Gluconeogenesis is increased by increased transcription of mRNA coding for the enzpe phosphoenolpyruvatecarboxykinase(PEPCK),a key enzyme in gluconeogenesis. c. Glycolysis is decreasedby inhibition of pyruvate kinase. d. Ureagenesis (1) Glucagon enhances the conversion of amino acids to glucose, leading to increasedammonia. (2) Glucagon increasesactivig of urea rycle enzfmes to aid in the disposalof the ammonia. e. Lipolysis and ketogenesis (1) Promotes lipolysis in the liver (small effect sincefew lipids are stored in liver). (2) Allows fatty acids to enter mitochondria for oxidation to ketones. Ketones are a fuel sourcethat sparesblood glucosefor other tissues,such asbrain, that require glucose. D. Insulin/glucagon ratio (I/G) 1. Net metabolic status is determined by the relative levels of insulin and glucagon. 2. llc ratio: a. In fed-state= 30 b. Overnight fast = 2 c. Prolongedfast = 0.5 E. Somatostatin 1. Secretedby the islet delta cells Z. Inhibits both insulin and glucagon secretion when given exogenously;probably plays a paracrine role in regulating insulin and glucagon 3. Somatostatinsecretionis increasedbv: a. Hyperglycemia b. Glucagon c. Amino acids
262
Physiology
F. Diabetes mellitus 1. Symptoms include ftequent urination (polyuria), increasedthirst (polydypsia)' increased food consumption (po\phagia), and weight loss. 2. Criterion for diagnosis is elev-atedblood glucose after ovemight fast (tfPically >140 mg/t ). 3. Insulin-dependent diabetes mellitus (IDDM, ryPe f ) a. Characterized by an inability of p-cells to produce ad€quste amounts of insulin b. Most commonly caus€dby an autoimmune disorder in which p cells are destroyed c. kss common is a mutation of the gene for preproinsulin d. Genetic and environmental factors may also determine susceptibility to dwelopment of type I diabetes. e. Tieatment is insulin rqtlacement and matching of insulin, diet' and exercise(exercise, like insulin, increasesglucose uptake into cells). 4. Noninsulin-dependent diabetes mellitus (NIDDM, tyPe 2) a. Characterized by an impairment of target cells to respond to insulin; may also have some decreasedsecretory responsein tlte pancreasitself. b. ln most type 2 diabetes,s€rum insulin i6 normal or elwated; the fundamental defect is often in th€ receptor or a PostrecePtordefect (not well understood). c. There is a strong genetic component to the development of tfpe 2 diabetes;autoimmunity does not play a significant role. d. Many type 2 diabetics are overweight; weight loss can decrease the severity of the disease.
to Prom*. classaPPear e. Tre.tmenl Drugsof thesulfonylurea
T:*11:3.':.]'"::-5i:t msullnsecretron. to normalize pancreaticp-cellresponse tissuesandcorrectthe sluSSish
5. Complicationof diabetesrnellitus a. Acute ( 1) With poor control, tfPe I diab€tics€'.hibit hyperglycernnr'glucosuria'dehydration, andketoacidosis.
pharmacology -Bridge --:?: !o - ' Thesulfonylureas are discussed in greater detailintheEndocrine chapter. PharmacoloSy
frrnction-may leadto (2) The drop in fluid volumemaycomprornisecardiovascular circulatoryfailure. (3) Excessive ketoneformation leadsto metabolicacidosisand electrolyteimbalanccs (renal elimination of ketonesmay depleteNa+ or K+ from blood sincethey are excretedasthe ketonesalts). b. Chronic ( I ) Largevesselsshowchangessirnilar to atherosclerosis. (2) Microcirculation exhibits a thickening of basementmembranes,leading to decreasingdeliveryof nutrients to and removalof wasteftom tissues'which, in turn, leadsto tissuedamage. (3) Deteriorationofblood flow to the retina canleadto retinopathy andblindness. (4) D€terioration of blood flow to the extremitiescanleadto possibleamputation. (5) Deteriorationof renalblood flow leadsto kidney failure. (6) Peripheralandautonomicneuropathy
26'.
Endocrine Pathology pathology Endocrine isprimarily concerned withthehypothalamic-pituitary-end organ axis. Knowledge ofthecomplex homeostatic feedback mechanisms affecting thehypothalamus and pituitary iscritical to making anaccurate diagnosis of hyperorhypofunctioning oftheendocrine glands ororgans. Ingeneral, hyperplasia implies of glands anexcess of stimulating hormone, while mayarise independently regulatory adenomas andcarcinomas completely of normal hormone secretion. Hyperplasias arealmost always functional. Incontrast, adenomas varyintheamount of product functional hormone theysecrete; moreover, theirresponses to regulatory varyconsiderably. Carcinomas areusually theleast functional andareusually independent of regulatory hormonal influence. Flashbackto Physiology
HYPOTHATAMUS ANDPITUITARY GTAND A. Lesions of the hnrothalamus 1. Destructive lesions include tumors such as craniopharyngiomas,gliomas,hamartomas, and inflammatory conditions (e.g.,sarcoidosis). 2. Craniopharyngiomas arisefrom ectodermal remnants of Rathkepouch, forming the most common pituitary tumor in children. Pathology shows stratified squamousepithelium with areasof keratinization and rysts. Lamellar bone depositsand calcium may be seen. Malignant transformation is rare.The tumor may be detectedon x-ray by its opaquecalcifications.
produces Thehypothalamus groMhhormone-releasing (CHRH), hormone somatostatin, dopamine, gonadotropi ng n-releasi (CnRH), hormone g n-releasin corticotropi (CRH), hormone antidiuretic (ADH), hormone thyrotropin(IRH), releasing hormone and oxytocin.
B. Anterior pituitary hyperfunction 1. Etiology. Most casesof anterior pituitary hyperfunction are causedby adenomas,which usually secreteprolactin, growth hormone, or adrenocorticotropichormone (ACTH). 2. Clinical syndromes correspondto the hormone secreted. a. Hnrerprolactinemia (amenorrhea-galactorrheasyndrome) results from elevated serum prolactin associatedwith pituitary adenomas(prolactinoma). It is the most common pituitary tumor. In women, it results in amenorrhea and galactorrhea; in men, this tumor may result in galactorrheaand infertility. Other causesof elevated prolactin, such as reserpine,phenothiazines,estrogens,or a hlpothalamic lesion, should be ruled out. b. Excessgrowth hormone
ClinicalCorrelate A pituitarytumormayimpinge ontheopticchiasm, producing a bitemporal (loss hemianopsia of peripheral fields). Make visual a visual field sureto perform you thistumor testif suspect (oranybrainneoplasm).
( 1) Gigantism occurs if there is excessiveGH secretionbefore the growth plates are fused (i.e., before the end of puberty). Excessiveskeletalgrowth may result in heights closeto 9 feet tall.
265
Endocrine System
(2) Acromegaly occurs if there is excessivesecretion after closure of the epiphyseal plates.There is a gradual coarseningof facial features(i.e.,thick lips, protruding jaw, large tongue) and enlargementof the hands and feet. It may be associated with diabetesmellitus, hypertension,osteoporosis,and other symptoms associated with space-occupyinglesions in the pituitary region, such as visual field defects.
Note Hyperplasia or tumorsof the pituitary areassociated with MENtypel.TheMEN syndromes arediscussed at theendofthischapter.
c. Cushing diseaseis causedby ACTH-secretingtumors. Lesionsare usually small and rarely causemasseffect.Cushing diseaseis discussedlater in this section. 3. Pathology of pituitary adenomas a. Gross findings range from microadenomas(5-10 mm) to large masses(10 cm) that may invade surrounding structures. b. Microscopic findings revealuniform cellsin nests,sheets,or cords in a fibrous stroma. (1) Eosinophilic adenomasusually produce growth hormone and are often large. (2) Chromophobe adenomas have few stainablegranulesand often produce prolactin. (3) Basophilic adenomas have periodic acid-Schiff (PAS)-positive granules and often produce ACTH. C. Anterior pituitary hypofunction is usually manifested as panhypopituitarism, resulting from the destruction of at least75o/oof the adenohypophysis. 1. Clinical features include symptoms of hypothyroidism, hypoadrenalism,and hypogonadism. Growth hormone deficiencyin children resultsin primary dwarfism with normal limb and skull proportions. 2. Etiology a. Sheehansyndrome is due to hemorrhagic or ischemic infarction of the pituitary following postpartum hemorrhage with excessive bleeding or shock.It may present with failure to lactatein the postpartum period. b. Empty sella syndrome is due to atrophy of the pituitary. The sellais enlargedon skull x-ray and may mimic a pituitary neoplasm.Surprisingly,it is usually asymptomatic. c. Nonsecreting-chromophobeadenomasmay present with hypopituitarism or symptoms of a space-occupying lesion. d. Tirberculosis(TB), sarcoid,irradiation, and metastases from other neoplasmsmay also causepanhypopituitarism.
In a Nutshell (Dl) Diabetes Insipidus . Polydipsia . Polyuria . Large volumes of dilute (hypotonic) urine . Highserum osmolality . Hypernatremia Central Dl responds to exogenous ADHtherapy; nephrogenic Dl doesnot because renalreceptors do notrespond to ADH.
266
D. Posterior pituitaryhypo-
and hyperfunction
1. Diabetes insipidus (DI) is due to insufficient or absentantidiuretic hormone (ADH). a. Etiology. Disordersinvolving the hypothalamusor neurohypophysis(e.g.,malignanry, meningitis, TB, sarcoid,postsurgicaltrauma to baseof skull) may all causecentral diabetes insipidus. Nephrogenic diabetes insipidus is caused by a lack of renal responseto ADH. b. Clinical features include polydipsia and polyuria with excretion of large volumes of dilute urine, even during statesof dehydration. c. Laboratory results show high serum osmolality and sodium with hemoconcentration due to loss of free water.Patientswith central DI will respondto administration of exogenousADH, while patientswith nephrogenicDI will not.
Pathology
2. The syndrome of inappropriate ADH secretion (SIADH) is due to inappropriate,excessiveADH secretion unrelated to serum osmolaliw. a. Etiology. SIADH may result from: (1) Malignancies associatedwith ectopic ADH production (usually oat cell lung cancer) (2) Central nervous system (CNS) disturbances(e.g.,skull fracture, subarachnoid hemorrhage,stroke) (3) Drug use (e.g.,chlorpropamide, carbamazepine, thiazide diuretics) (4) Certain pulmonary diseases (e.g.,TB or lung abcess). b. Clinical features include fluid retention, weight gain, and lethargy.There is a rangeof CNS disturbances,including seizuresand coma. c. Laboratoryrestrlts show lowserum osmolaliry hnronatremia, and hypertonic urine.
ln a Nutshell SIADH . Fluid retention . Weight gain
ADRENAT GTANDS
. Lethargy
A. Adrenal cortical hyperfunction
. Lowserum osmolality
1. Cushing syndrome is causedby cortisol excess. a. Etiology. Cushing syndrome may take one of four distinct forms, depending on its cause.They are summarizedin Figure III-4-1.
. Hypertonic urine . Hyponatremia
( 1) Pituitary Cushing syndrome (approximately two-thirds of the casesof Cushing). Pituitary or hypothalamicdysfunction is the most common noniatrogeniccause. It is caused by basophilic adenomas,referred to as Cushing disease, or more commonly, by multiple corticotroph microadenomas. Pituitary Cushing syndrome is characterized by bilateral adrenal hyperplasia and elevated serum ACTH. The diagnosis is establishedwhen the administration of high-dose dexamethasone suppressesACTH secretion, causing decreasedserum cortisol and decreasedurinary l7-hydrorycorticosteroid(l7-OHCS) excretion;in normal ACTH secretion. individuals, low-dose dexamethasonesuppresses (2) Adrenal Cushing syndrome is usually caused by an adrenal adenoma. It is characterizedbylowserumACTH and failure of dexamethasonesuppressionof cortical secretion. (3) Ectopic Cushing syndrome is causedby ectopic secretionof ACTH, most commonly by bronchogenic cancer, but also by pancreaticneoplasmsand thymomas. It is characterizedby bilateral adrenal hlperplasia and failure of dexamethasonesuppression. (4) Iatrogenic Cushing syndrome is rather common and is causedby exogenous administration of glucocorticoidsor ACTH. b. Clinical features usually result from excesscortisol but may also be due to excess aldosterone,corticosterone,or adrenalandrogens.The syndrome is most common in women in the 2040-year-old age group. Patients exhibit hnrertension, abnormal glucose tolerance (frank diabetes 20o/o),truncal obesity, muscle wasting in the extremities,moon facies, buffalo hump, cutaneousstriae, osteoporosis, hirsutism and amenorrhea in women, weight gain, edema,weakness,fatigue, susceptibilityto infection and personality disturbances.Children show growth retardation, delayed skeletalmaturation, and precociouspuberty if associatedwith adrenalandrogens.
267
Endocrine System
Cushing Syndrorne t Cortisol Hypertension Truncal obesity I
v
I
+
I
v
V Pituitary Cushing
Adrenal Cushing
+
I V Pituitary adenoma (Cushing disease)
Adrenal adenoma
I
II
I
t
v
t ecrn
J ecrn
from pituitary
Ectopic ACTH
I V Bronchogeniccancer (or other neoplasm)
Iatrogenic
I * Exogenous administration of ACTH or cortisol
II
v
T ecrH I
I
I V
V
Adrenal hyperplasia
Adrenal hyperplasia
I V Suppression of ACTH with highdosedexamethasone
Z Suppression with dexamethasone
I
Z Suppression with dexamethasone
Figure lll-4-1.Summary of Gushing syndrome and its effects. c. Pathology (1) In the pituitary, Crooke hyaline degenerationof basophils results from prolonged feedbackinhibition by cortisol. (2) In the adrenals,there is bilateral cortical hlperplasia, adrenalcortical adenoma, or, rarely, carcinoma in Cushing syndrome due to primary causes.Nodular hyperplasia or atrophy of the adrenal cortex is seen with exogenousACTH or glucocorticoids,respectively. 2. Primary hyperaldosteronism (Conn syndrome) is due to increasedaldosterone secretion, producing sodium retention, increased total plasma volume, increasedrenal artery pressure,and inhibition of renin secretion. a. Etiology. An adrenal adenoma secretingaldosteroneis the most common cause.Other causesinclude idiopathic hyperaldosteronism,in which bilateral cortical nodular hyperplasia of the zona glomerulosa is seen,or, rarely, adrenal carcinoma, glucocorticoidsuppressiblehyperaldosteronism,or congenitalbilateral zona glomerulosahyperplasia. b. Ctinical features include sodium retention, extracellular fluid expansion,and potassium depletion with diastolichypertension,weakness,fatigue,polprria, polydipsia,and headache.
268
Pathology
c. Laboratoryvalues revealhypokalemia, low renin levels, metabolic alkalosis, hlpernatremia, and (fcrradenomas)failure to suppressaldosteronewith salt loading. d. Pathology usually shows a single benign adenoma,which is a well-circumscribed, encapsulated,small lesion composedof lipid-laden clear cells. 3. Secondary hyperaldosteronism a. Etiology. The causesare decreasedrenal blood flow or perfusion pressure,edematous stateswith sodium retention, renin-producing neoplasms,and Bartter syndrome, which is characterizedbyjuxtaglomerular cell hyperplasia,hyper-reninemia,hyperaldosteronism,and failure to thrive; it is often associatedwith low blood pressure. b. Laboratory values include high renin levels, hypernatremia, and hypokalemia. Secretionof aldosteroneis triggeredby elevatedrenin-angiotensinlevels. 4. Congenital adrenal hyperplasia (CAH) a. Etiology. CAH is usuallydue to a congenitalenzymedeficienry of adrenalsteroidsynthesisresulting in cortisol deficiency and marked enlargementof the adrenals. b. Types. The three most common forms all causevirilism and are called adrenogenital syndromes. (1) 2l-hydroxylase deficiency causessimple virilizing CAH (SOotol. There is normal aldosteronefunction and impaired cortisol production. (2) The salt-losing syndrome is due to 2l-hydrorylase deficiency associatedwith aldosteronedeficiency.Infantspresentwith vomiting, dehydration,hyponatremia, and hyperkalemia. (3) ll-Hydroxylase deficiency causesexcessiveandrogen production and buildup of 11-deoxycorticosterone(strong mineralocorticoid), causing virilization, hypertension,and hypokalemia. c. Clinical features of adrenogenital syndromesare virilization in women, sexualprecociry and prematureepiphysealclosure.
ln a Nutshell Hyperaldosteronism
t ruaJK. Metabolic alkalosis
l ' (C onn syndrome) I
2"
Y
Y
v
V
T Aldosterone T Aldosterone secretion by dueto I gland; perfusion or adrenal othercause usually of t renin adenoma secretion
I
Willsee J renin Willsee1 renin
d. Pathology of all types showsdiffirse or nodular bilateral adrenalcortical hyperplasia. B. Adrenal cortical hypofunction l. Acute adrenocortical insufficiency can be causedby: a. Rapid withdrawal of exogenoussteroids in patients with chronic adrenal suppression b. Stress(e.g.,trauma, surgery,infection), Addison disease,or chronic adrenalsuppression causedby administration of exogenouscorticosteroids c. Adrenal apoplexy, such as in the Waterhouse-Friderichsen syndrome: a massive, sudden adrenalhemorrhageusually associatedwith meningococcalsepticemia 2. Chronic or primary adrenocortical insufficiency (Addison disease) a. Etiology. Tuberculosiswas once the most common cause.The most common etiology today is idiopathic (probably autoimmune). Other possibilitiesinclude infections (e.g., fungal, Waterhouse-Friderichsensyndrome), iatrogenic causes,metastases, adrenalhemorrhage,and pituitary insufficienry. b. Pathogenesis.To produce clinical insufficienc,f,90o/oof the adrenal gland must be nonfunctional.
269
Endocrine System
Note Pigmentation oftheskinin Addison isdueto ACTH also having a weakstimulatory ACTH effect on melanorytes. andmelanoryte-stimulating (MSH) hormone share amino acidsequences.
c. Clinical features are due to insufficient cortisol and aldosteronesecretion,leading to weakness,weight loss, anorexia, nausea,vomiting, hypotension, skin pigmentation, hypoglycemia with prolonged fasting, inability to tolerate stress,and abdominal pain. d. Laboratoryvalues show decreasedserum sodium and chloride with metabolic acidosis and increasedserum potassium.Low serum cortisol and urinary 17-OH CS and low l7-ketosteroids,before and after ACTH administration, should alsobe measured. ACTH levels are high. e. Pathology shows bilateral atrophied adrenal glands. In the idiopathic lrpe, there are lymphocytic infiltrates and zonesof fibrosis surrounding islets of remaining epithelial cells. 3. Secondary adrenocortical insufficiency a. Etiology. Causesinclude metastases,irradiation, infection, and infarction, affecting the hypophysial-pituitary axis and resulting in decreasedACTH. b. Clinical features. Secondary insufficiency usually produces less mineralocorticoid malfunction and lesspigmentation. C. Adrenal neoplasms l. Adrenal adenomas a. Clinical features. Adrenal adenomas are mostly asymptomatic and nonsteroidproducing. Steroid-producingadenomasmay produce Conn syndrome, Cushing syndrome, or virilization in women. They may also occur with multiple endocrine neoplasia(MEN) syndromes. b. Pathology. Adrenal adenomas are usually small and unilateral, yellow-orange on cut section, and poorly encapsulated.When adrenal adenomas are large, hemorrhage, rystic degeneration,or calcificationmaybe seen.Nonsteroid-producingadenomasare usually composedof lipid-filled cells;steroid-producingtumors are often mixed with lipid-filled cellsand compact cells. 2. Adrenal carcinomas a. Clinical features. Adrenal carcinoma is relatively rare and usually very malignant. Greaterthan 90oloare steroid-producing(often more than one steroid). b. Pathology. The tumors are often large and yellow with areasof hemorrhage, rystic degeneration,and necrosis. 3. Pheochromocytoma
Mnemonic TheRuleof losfor Pheochromocytoma . l0o/o extra-adrenal . l0o/o bilateral . l0o/o malignant . l0o/o affect children . l0o/o familial
270
a. Etiology. Pheochromocytomais a neoplasmof neural crest-derivedchromaffin cells that secretecatecholamines, resulting in hnrertension. b. Incidence. The highest incidenceis in children and in adults age 30-50. Ten percent are familial, i.e.,are associatedwith MEN IIa and MEN III (aka IIb), neurofibromatosis,or von Hippel-Lindau disease. c. Clinical features are related to catecholaminerelease.Parorysmal or constant hlpertension is the most classicsymptom. Also, sweating,headache,arrhythmias,palpitations, and nervousnessmay be seenin any combination. d. Laboratory values show elevated urinary catecholamines and catacholamine metabolites (e.g.,homovanillic acid, HVA, and vanillylmandelic acid,VIvIA).
Pathology
e. Pathology. Ten percent of tumors are extra-adrenal,l0o/o are bilateral, and 10oloare malignant. Tirmors are well defined and fibrous, creatinga lobulated appearance.The cut surface is light brown, often with areasof hemorrhage and necrosis.Cells are stained with chromium salts (chromaffin reaction) and have a basophilic cytoplasm with secretorygranules. 4. Neuroblastoma is the most common malignant extracranial solid tumor of childhood. Amplification of the N-myc oncogene is a characteristicof neuroblastoma.The more copiesof the oncogene,the more aggressive the tumor.
NoIe Youaremuchmorelikely to seea pheochromocytoma case ontheUSMLE than youeverareto seeonein yourclinical practice.
a. Clinical features. Ttrmors grow rapidly, metastasizewidely (especiallyto bone), and produce elevatedurinary catecholamines.The prognosis is better if patients are less than 1 year old. Tumors may regressin young infants. The presenceof ganglion cells also improvesprognosis. b. Pathology. Neuroblastomaoccurs most frequently in the adrenal medulla but may also arise in the cervical,abdominal, and thoracic sympatheticchain. The tumors are lobulated with a gray cut surface,showing areasof necrosis,hemorrhage,and calcification. Microscopically, malignant small cells are often seen in a rosette pattern around nerve fibrils.
THYROID GTAND A. Overview of hyperthyroidism 1. Etiology. Hyperthyroidism may be seenmost often in Gravesdisease,toxic multinodular goiter, and toxic adenoma.Thyroiditis, thyroid carcinoma,and iodine ingestion are less frequent causes. 2. Pathogenesisis due to increasedcirculating levelsof the thyroid hormones triiodothyronine (Tr) and thyroxine (Tr), causinga hnrermetabolic state. 3. Clinicat features a. Cardiacsymptoms include tachycardia,cardiacpalpitations,cardiomegaly,occasional cardiac arrhythmias (usually atrial fibrillation), and cardiomyopathy. b. The skin is warm, flushed,and moist due to vasodilatation. c. The eyesshow a wide starewith upper lid retraction and lid lag. Exophthalmos is characteristicof Gravesdisease,due to swellingof extraocularmusclesand periorbital tissues. d. Patients also show increasedsweating,heat intolerance,hyperactivity, nervousness, tremor, weight loss,diarrhea,oligomenorrhea,and myopathy. e. Propranolol, a nonselectivebeta blocker, may be given to alleviatethe sympathetic nervous systemsymptoms.
Clinical Correlation Clinical diagnosis of hyperthyroidism maybe difficultin pregnancy, whichis anintrinsically hypermetabolic stateandisoftenassociated withmilddegrees of thyromegaly. Inaddition, the increase inTBGthatresults fromthehighestrogen levels elevates thetotalserum T4, butnotthefreeserum T4.
f. Thyrotoxic storm is a severehypermetabolic state characterizedby tachycardia,fever, cardiacabnormalities,and coma.Twenty-fivepercentof casesare fatal. 4. Diagnosis is basedon low TSH and elevatedTn. Low TSH is most important. B. Overview of hypothyroidism 1. Etiologies a. Congenitalthyroid dysplasiaor hypoplasia b. Hypothalamic or pituitary disease
271
Endocrine System
c. Thyroid conditions causing goiter including iodine deficiency and Hashimoto (autoimmune) thyroiditis d. Surgicalor radiation destruction of gland e. Peripheralresistanceto thyroid hormone 2. Clinical features depend on the age group.
Note Incontrast toprimary hypothyroidism, secondary (pituitary gland failure) and (hypothalmic tertiary failure) hypothyroidism have low (ornormal) TSH levels.
a. Infants lacking sufficient thyroid hormone develop cretinism. The major effects are on skeletaland CNS development (i.e., short stature,retarded bone age,epiphyseal dysgenesis, and mental retardation).Once apparent,the syndromeis irreversible.The initial presentation includes failure to thrive, feeding difficulties, constipation, and somnolence.Children developprotuberant abdomens,wide-set eyes,dry rough skin, broad nose, and delayedepiphysealclosure.Neonatal screeningfor elevatedTSH is essentialfor early detection. b. Older children show short stature, retarded linear growth, and delayed onset of puberty. c. In adults, hypothyroidism causeslethargy, weakness,fatigue, decreasedappetite, weight gain, cold intolerance, hair loss, dry skin, constipation, apathy, myopathy, psychosis,metrorrhagia (irregular uterine bleeding), and acceleratedatherosclerosis with elevated serum cholesterol. Mpredema, a syndrome associatedwith severe hypothyroidism, showsperiorbital puffiness,pale doughy skin due to accumulationof hydrophilic mucopolysaccharides, sparsehair, cardiac enlargement,cardiomyopathy, pleural effrrsions,anemia,and thickened facial features. 3. Diagnosis of primary hypothyroidism is basedon an elevatedTSH and low To. C. Graves disease 1. Incidence. Gravesdiseasepeaksin the third and fourth decadesand is five times more common in women. There is a familial predisposition, and it is associatedwith other autoimmune diseases,such as pernicious anemia and Hashimoto thyroiditis. The incidenceof Gravesdiseaseis increasedin HLA-DR3- and HlA-B8-positive individuals. 2. Pathogenesis is autoimmune, resulting from production of thyroid-stimulating immunoglobulin (TSI) and thyroid growth immunoglobulin, two autoantibodies that causeglandular hyperplasiaand hormone production by binding to TSH receptors. 3. Clinical features are present in varying combinations. a. Thyrotoxicosis has symmetric glandular enlargement. b. Ophthalmopathy is characterizedby lid lag, retraction of the upper lid, proptosis, periorbital edema,and stare.It results from inflammatory infiltration and edema of extraocular musclesand periorbital tissues.It does not alwaysrespond to antithyrotoxicosistreatment. c. Dermopathy is characterizedby thickened edematous nodules or plaques on the lower extremitiesand is presentin 10oloof Gravespatients. 4. Pathology a. Grossly,there is a diffi.rse,moderatesymmetrical enlargementof the gland. b. Microscopically, hypercellulariry producing small follicles with little colloid and papillary infoldings into the lumen, is seen.The stroma exhibits increasedvascularityand variable lymphocytic infiltrate. These changesare not associatedwith an increased incidenceof thvroid cancer.
272
Pathology
D. Hashimoto thyroiditis is a chronic lymphocytic thyroiditis featuring goitrous enlargement of the thyroid gland produced by lymphocytic and plasma cell infiltrates, with the eventual development of hypothyroidism. 1. Etiology is autoimmune. There may be autoantibodies to the TSH receptor, T' Tn, microsomes,and thyroglobulin. 2. Incidence. Hashimoto thyroiditis is the most common type of thyroiditis and is the leading causeof goitrous hypothyroidism in the United States.The highest incidenceis in middleagedwomen, and there is a higher incidencein patientswith a family history of Hashimoto or other autoimmune diseases(e.g., Graves disease,Sj6gren syndrome, systemic lupus erythematosus).The incidence of Hashimoto thyroiditis is increasedin HLA-DR5 and HLA-BS individuals. 3. Clinical features include painless goiter. Hypothyroidism develops,along with malaise, fever,a decreasedTn, and elevatedTSH. 4. Pathology. The gland is enlarged,usually symmetric, and firm. It contains a lymphocftic and plasma cell infiltrate with occasional germinal centers.Acini are partly atrophic, with little colloid and variable fibrosis, increasing as the diseaseprogresses.Follicular epithelium is transformed into Htirthle cells characterizedby an eosinophilic granular cytoplasm.
E. Diffrrse nontoxic goiter is used to describe diffirse enlargement of the gland in euthyroid patients. 1. Incidence a. Endemic goiters havea high incidencein certain geographicregions (e.g.,mountainous regions or regions far from the ocean). They are causedby iodine-deficient diets or increasedintake of goitrogens (e.g.,calcium, fluorides).
In a Nubhell Hyperhyroidism l-lypdyroidlsn (J TSH, (t TsH,J Ty t T3, 1rJ JTJ
I
V
I V
.lHR
. Getrnism inchildren
. Skinmoi$ andflushed
. Lethargy inaduh
. Lidlag
. Fatgue
. Sweating
. Weight gain
. Heat . Cold intolerance intolerance . Weight los
b. Sporadic simple goiter is lesscommon. The incidencein women is much greaterthan in men. 2. Pathogenesis.There arevariableabnormalitieswith thyroid hormone synthesis,resulting in compensatoryhypertrophy and hyperplasiaof follicular epithelium. 3. Pathology. The gland becomeshyperplastic, then accumulatescolloid asymmetrically. Multinodular goiter developsfrom chronic diffirse goiters; it may be toxic or nontoxic and may become very large (Figure III-4-2).
275
Endocrine System
lP*" i
: ,;;TW'',
.:%ili
Et',-
ru
u'rr,,i
Figure lll-4-2.Thyroid:multinodular goiter, microscopic.
1. Clinical features. Glandular enlargement may causestridor, dysphagia,and even superior vena cavasyndrome (masseffect).Fifty percentproduce thyrotoxicosis.Thesetumors must be differentiated from thyroid cancer,particularly asymmetric tumors in euthyroid patients. 2. Pathology. Glands may be as large as 2 kg and nodular with areasof hemorrhage, scarring, and calcification. They are usually asymmetric with areasof colloid-filled acini. G. de Quervain granulomatous subacute thyroiditis 1. Etiology is probably viral. 2. Incidence. It is the second most common form of thyroiditis with the incidence in women greaterthan in men. The diseasepeaksin the secondto fifth decades. 3. Clinical features. Symptoms often begin following a viral syndrome, most commonly mumps and coxsackievirus.The courselasts severalweekswith a tender gland, a goiter in 30o/oof patients, fevet malaise,and dysphagia.Early in the course, the patient may have mild symptoms of thyrotoxicosis; latet patients are usually euthyroid, and the diseasefollows a self-limited course. 4. Pathology a. Grossly, there is moderate irregular enlargementof the gland. b. Microscopically, degeneration of follicular epithelium causesleakageof colloid from follicles, which initiates an inflammatory responsewith foreign body giant cells,histiocytes,and granuloma formation. The degenerationof epithelial cellsis presumably due to a viral infection, but a specificetiology is usually not demonstrated. H. Riedel thyroiditis is a rare diseasecharacterizedby connective tissue proliferation, causing destruction of the thyroid gland and fibrosis of surrounding structures. 1. Incidence is greatestin middle age,and greaterin women than in men. 2. Ctinical features. Fewer than 50oloof patients are hlpothyroid. They may present with stridor, dyspnea,dysphagia,or a painlesslump.
274
Pathology
3. Pathology a. Grossly, the gland is firm and hard, nodular, and irregular; sizevaries. b. Microscopically, complete fibrous replacementof the gland is seen.It may mimic carcinoma. I. Congenital thyroid conditions 1. Agenesis or dysgenesisare frequent causesof cretinism. 2. Thyroglossal duct or cyst may communicate with the skin or base of the tongue. It is formed from nests of incompletely descendedmidline thyroid tissue. 3. Ectopic thyroid nests are usually at the base of the tongue. Prior to removal, it must be documented that the patient has other functioning thyroid tissue.
\ Tumors. Thyroid nodules are very common (F7o/o adults in the U.S.), but thyroid cancer is uncommon (lessthan 2 casesper 1,000nodules).There is a higher incidenceof neoplasiain solitary nodules and in younger patients. 1. Adenomas. Follicular adenoma is the most common. a. Clinical features. Adenomas may causepressuresymptoms, pain, and, rarely, thyrotoxicosis. b. Pathology. There are usually solitary lesions lessthan 3 cm in diameter that are well encapsulatedand compressadjacent thyroid parenchyma. There is a sharp demarcation from surrounding thyroid with a variable amount of colloid, interstitial connective tissue,and acinal size. 2. Cysts make up lV25o/o of solitary nodules and usually represent rystic degenerationof follicular adenomas. 3. Carcinomas representneoplasia of follicular cells (i.e., papillary, follicular, or anaplastic cancer) and/or parafollicular cells (i.e., medullary cancer).Risk factors include radiation and a geneticpredisposition. a. Papillary carcinoma is the most common type. The incidence is higher in women. (1) Pathology. Grossly, there is a papillary branching pattern, which may be rystic or solid. Microscopi..lly, there is a singlelayer of tumor epithelium on a fibrovascular stalk. Nuclei have a characteristicground-glass appearance.Forty percent of tumors contain psammoma bodies. (2) Clinical features. Spread to local nodes is common. Hematogenous spread is rare. Resectionis curative in most cases.Radiotherapywith iodine tlt (131I)is also effective for metastases. b. Follicular carcinoma makes up 20o/oof thyroid cancersand is more malignant than papillary cancer. (1) Patholog''. Tumors are occasionallyencapsulated,with penetration through the capsule.They show an adenomatouspattern with developmentof acini or folliclesthat are lined by large cells compared to those lining normal follicles. Colloid is sparse. (2) Ctinical features. Local invasion and pressure causes dysphagia, dyspnea, hoarseness, and cough.Hematogenousmetastasisto lungs or bonesis common. The prognosis depends on the extent of metastases.The overall 5-year survival is 60010.
In a Nutshell . Papillary carcinoma + lymphnodemetastases . Follicular carcinoma + hematogenous meta$ases
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System Endocrine
and has a poor prognosis.It is relc. Anaplastic carcinoma is rapid growing, aggressive, atively uncommon and affectsolder patients (60-80 yearsold). (1) Pathology. Tumors are usuallybullq and invasive.They are composedof undifferentiated,anaplastic,and pleomorphic cells.
Note in LabAbnormalities Primary Hyperparathyroidism . tPTH . t ca,r . J Phosphate . t Alkaline phosphatase
(2) Clinical features are early, widespread metastasis and death within 2 years. d. Medullary carcinomas arise from parafollicular cells (C cetls).They are uncommon, and a minority are associatedwith MEN IIa and MEN III (IIb) syndromes.They are composed of nests of cells in an amyloid stroma made of calcitonin. The tumors secretecalcitonin.
PARATHYROID GLANDS A. Primary hyperparathyroidism 1. Etiology
ClinicalCorrelate
a. Parathyroid adenoma is the most common cause,usually involving a single gland.
fibrosa cystica, also Osteitis known asvonRecklinghausen disease of bone, occurs asa primary result ofchronic ism.Cy$ic hyperpa rathyroid changes inboneoccur dueto o$eoclastic resorption. Fibrous replacement ofresorbed bone "brown mayleadto a tumor," a non-neoplastic tumormass.
b. Parathyroid hyperplasia shows diffrrse enlargement of all glands, usually composed of chief cells. c. Parathyroid carcinoma is very rare. It is characterizedby a high mitotic rate, local invasion,and metastases. d. MEN I and MEN IIa include tumors or hyperplasiasof the parathyroids. 2. Clinical features. Patients with elevated serum calcium are often asymptomatic. They may presentwith bone abnormalities secondaryto elevatedparathyroid hormone (e.9., osteomalacia,osteitisfibrosa cystica,subperiostealresorption). Hypercalcemiamay cause metastaticcalcification (e.g,kidney stones). B. Secondary hyperparathyroidism
Note in LabAbnormalities HyperparaSecondary thyroidism .tPTH . J Car. . I Phosphate . t Alkaline phosphatase ClinicalCorrelate DiCeorge isalso syndrome withabsence associated ofthe thymus dueto a common embryologic defect. Tetany occurs shortly afterbirthdue to congenital absence ofthe parathyroid glands. Cardiac structural defects andimmunodeficienol arealsonoted. 276
1. Etiology. Secondaryhyperparathyroidismis usually causedby chronic renal failure, leading to decreasedCa2+ absorption, which in turn results in a feedback loop and increased PTH. Vitamin D deficiencyand malabsorption are lesscommon causes. 2. CLinical features show soft tissue calcification and osteosclerosis.Mild-to-moderate hypocalcemiais characteristic. C. Hypoparathyroidism 1. Etiology. Common causesare removal of glands during thyroidectomy, idiopathic, radioactiveiodine therapy for Gravesdisease,metastaticcancer,and DiGeorgesyndrome. The idiopathic form may be familial and autoimmune. 2. Clinical features include hypocalcemia,hyperphosphatemia, irritabiliry anxiefy, neuromuscular excitability,tetany, intracranial calcifications,lens calcification, dental abnormalities, and cardiacconduction defects. D. Pseudohypoparathyroidism i. Etiology. Pseudohypoparathyroidismis an autosomal recessivedisorder resulting in a kidney unresponsiveto circulating PTH. 2. Clinical features include skeletal abnormalities such as short stature, and shortened fourth and fifth carpalsand metacarpals.
Pathology
E. Hypercalcemia is defined as a persistentserum calcium over 10.4m/dl. 1. Etiology. Hlpercalcemia may be causedby metastaticdiseaseto bone, such as myeloma or epithelial neoplasm, vitamin D intoxication, sarcoidosis,primary or secondary hlperparathyroidism, the milk alkali syndrome,or Pagetdiseaseof bone. 2. Clinical features.Renal stones are often seen;hlperparathyroidism is alsousually associated with hypercalciuria and with hypophosphatemia. Alkaline phosphataseactivity is usually elevated.Patientsmay experiencean altered sensorium, often first noticed as drowsiness. 3. Pathologic features in bone range from obvious metastases to osteoclasttunneling through bony trabeculaein hyperparathyroidism.
Mnemonic (MISHAP) Hypercalcemia Malignancy !ntoxication 5arcoidosis Hyperparathyroidism Alkali syndrome lagetdisease
(rSrETS ENDOCRTNE PANCREAS OFLANGERHANS) A. Diabetes mellitus is causedby inadequate or abnormal insulin secretion,causing impaired glucose utilization, irnd resulting in hyperglycemia, glycosuria, and characteristic systemic pathology. 1. Types a. Insulin-dependent (tt'pe l) diabetes mellitus (IDDM). There is an abrupt onset with patientsprone to ketoacidosis,insulin dependence,and severemetabolic derangements. b. Noninsulin-dependent (t)"e 2) diabetes mellitus (NIDDM). This diseaseconstitutes most casesof idiopathic diabetics.It is characterizedby peripheral insulin resistanceand later,abnormal insulin secretion.Most patientshavecentral obesitywith an onset of diseaseusually after age40. Thesepatients are not prone to ketoacidosis. c. Secondarydiabetes may be causedby destruction of pancreaticislet cellsfrom inflammation, hemochromatosis,tumor, surgery or hormonal disease. 2. Pathogenesis a. IDDM shows a marked, absolute insulin deficienry resulting from diminished p-cell mass. It it therefore characterizedbylowserum insulin levels.There are three etiologic theories;in many casesof IDDM, all three mechanismsmay be operative. (l) A viral infection (e.g.,mumps, coxsackievirusB, rubella, CMV mononucleosis) may lead to destruction of B cells.A subgroup of adult-onset diabeticswith islet cell antibodies and HIA-DR3 are at increasedrisk to becomeinsulin dependent. (2) There is clearly a genetic predisposition becauseof increasedsusceptibility with certain HLA haplotypes. (3) Autoimmune response.Eighty percent of patientswith IDDM haveanti-islet cell antibodies. Relativesof patientswith IDDM often havesimilar antibodies,and this increasestheir risk of developing the disease.Autoantibodies to islet cells may precedethe developmentof the disease. b. MDDM is characterizedby mild-to-moderate insulin deficienry and is not associated with a specificHLA haplotype. There are two theories: (1) Insulin resistance,the impaired ability of tissuesto react to circulating insulin, results from a decreasein the number of cell-surface insulin receptors, for unknown reasons. (2) Delayed or inadequate insulin secretion may develop, probably due to islet exhaustion.
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Endocrine System
3 . Clinical features a. Predisposingfactors are obesiry pregnancy,trauma, infections,and stress. b. Presentation. Both IDDM and NIDDM may present with polydipsia, polyuria, polyphagia, weight loss, and muscle weakness.Laboratory values may show hnrerglycemia, glycosuria, and hyperlipidemia. c. Acute metabolic complications (1) Diabetic ketoacidosis(DKA) may occur in insulin-dependentdiabetics.It leadsto an oversupply of glucose,fueled by high rates of protein catabolism,lipolysis in adiposetissue,and fatty acid oxidation in liver. The acceleratedrate of fatty acid oxidation producesacetyl-CoAfasterthan it can be burned by the TCA cycle,and the liver conservesthe excessacetyl-CoA by synthesuing ketones.Metabolic acidosisresultsfrom the accumulation of the ketones.The high level of blood glucose leads to dehydration via an osmotic diuresis.Tieatment with insulin normalizes the metabolism of carbohydrate,protein, and fat. Fluids are given to correct the dehydration. (2) Hyperosmolar nonketotic coma occurs in patients with mild adult-onset diabeteswhen blood glucoselevelsexceedapproximately600 mg/dl. It is not clear why ketoacidosisdoes not occur in these patients,but it appearsthat lipolysis occurs to a much lesserextent than in DKA, thereby producing fewer ketones. The treatment of hyperosmolar nonketotic coma is identical to the treatment of DKA. d. Late complications of diabetes. Patientswith long-standing diabetesof either type may developa seriesof long-term complications. ( I ) Atherosclerosis causesstrokes,myocardial infarcts, and gangrene,frequently of the toes. (2) Nephropathy causesproteinuria, hypertension,and edema,and it may lead to renal failure.
ClinicalCorrelate Diabetics arealsoa high-risk group forthefollowing infections:
(3) In the Kimmelstiel-Wilson syndrome, intercapillary glomerulosclerosis with hypertensionand edemalead to proteinuria, beginning approximately20 years after the onset of disease. (4) There is a predispositionto infections (tuberculosis,pyelonephritis,pneumonia, skin infections).
. Klebsiello pneumonia
(5) Neuropathy is usuallya distal,symmetric polyneuropathy("stocking-glove"distribution) but may be a mononeuropathy.In addition to this peripheral neuropathy, diabetics can also have autonomic neuropathy.
. Sinus mucormycosis
(6) Retinopathy may lead to blindness.
. Malignant otitisexterna (Pseu dononosoerug inoso) . Chronic osteomyelitis
4 . Pathology is characterizedby a thickening of basementmembranesby homogeneousor laminated periodic acid-Schiff (PAS)-positive hyaline. Microangiopathy occurs with thickening of capillary basement membranes, causing increased leakage of plasma proteins. a. In the pancreas,visible abnormalitiesmay or may not be present.They may include: ( 1) Decreasein number and sizeof islets (2) Islet-cellhyperplasiaearly in IDDM (3) Lymphocytic infiltrate of islets
278
Pathology
(a) Hyalinization of islets (5) Glycogenaccumulation and degranulationof B cells b. Atherosclerosisbegins within 5 yearsof onset,regardlessof age.Widespreadlesions are prone to calcification,ulceration, and overlying thrombosis, and lead to ischemia (stroke,myocardialinfarction) or aneurysms. c. Arteriolosclerosis is characteized by a severethickening of arteriole walls in every tissue,frequently by hyaline material. d. Kidneys show severeinvolvement, leading to renal failure. Pathologic findings are characterizedbyarteriolosclerosis,glomerular pathology (diffrrseglomerulosclerosis, nodular glomerulosclerosis,exudativelesions),and bacterial infection (pyelonephritis, papillitis). e. Peripheral neuropathy, the most common defect, affectsboth motor and sensory nervesas a result of damageto Schwanncells and myelin, mainly in the lower extremities. It is often associatedwith autonomic neuropathy, causingbladder and bowel dysfunction, gastric atony, impotence, cardiac arrhythmias, and, possibly, sudden death. f. Retinopathy is relatedto duration of disease.Diabetic retinopathy is the fourth leading causeof blindness. (1) Nonproliferative retinopathy is characterizedbymicroaneurysms,with leakage resulting in exudates,edema,and hemorrhage;such a finding is diagnostic of diabetes.Hard protein exudatesare seenin deepretinal layers,and "cotton wool" spots appeardue to microinfarcts in the superficialretina. (2) Proliferative retinopathy is characterizedby neovascularization.It may cause traction bands resulting in retinal detachmentand vitreous hemorrhage. g. Diabeticxanthomas areyellow nodules on the elbowsand kneesresultingfrom lipidfilled macrophagesin the dermis. 5. Prognosis a. NIDDM decreases life spanby approximately8 years.There is a much higher mortality from IDDM. b. Causesof death in decreasingfrequencyare: (1) Myocardial infarction (2) Renalfailure (3) Stroke (4) Ischemicheart disease (5) Infections B. Islet-celltumors (FigureIII-4-3) 1. B-cell tumors. Insulinomas most commonly occur betweenthe agesof 30 and 60. a. Pathogenesis.B-cell tumors produce hlperinsulinemia, causinghypoglycemia. b. Clinical features.Patientsexperienceepisodesof alteredsensorium (i.e., disorientation, dizziness,diaphoresis,nausea,tremulousness,coma) that are relievedby glucoseintake.
279
Endocrine System
c. Pathology. Most tumors are solitary, well-encapsulated,and well-differentiated adenomasof various sizes.Ten percent are malignant carcinomas.
Bridgeto Gastrointestinal Zollinger-Ellison syndrome is discussed in greater detail in theCastrointestinal Pathology chapter ofthisbook.
Figure lll-4-3.lslet-cell adenoma (microscopic).
2. Zollinger-Ellison syndrome is due to a gastrinoma and is often associatedwith MEN tfpe I. a. Pathogenesis.Tumors of pancreaticislet cells secretegastrin, causinggastric hypersecretionof acid. b. Clinical features include intractable peptic ulcer diseaseand severediarrhea. c. Pathology. Sixty percent are malignant. Most tumors are located in the pancreas,with 10oloin the duodenum.
In a Nutshell . MEN| + anterior pituitary, parathyroids, adrenal cortex, pancreas and . MENlla+ adrenal medulla (pheochromorytoma) and parathyroids . MENlll -+ adrenal medulla (pheochromocytoma), (medullary thyroid carcinoma), andmucosal neur0mas
(MEN) MUTTTPTE ENDOCRTNE NEOPTASTA Multiple endocrine neoplasiashowsfamilial, autosomal dominant inheritance with incomplete penetrance.It is characterizedbybenign and malignant tumors of the APUD (amine precursor uptake and decarborylation) cell system. A. MEN I featurestumors of the parathyroids,adrenal cortex, pituitary gland, and pancreas, and is associatedwith peptic ulcersand Zollinger-Ellison syndrome. B. MEN IIa featurestumors of the adrenalmedulla (pheochromocFtoma),medullary carcinoma of thyroid, and parathyroid hyperplasiaor adenoma. C. MEN III (also calledMEN IIb) featuresmedullary carcinoma of the thyroid, pheochromocftoma, and mucosalneuromas. D. Clinical features show varied presentationsthat may include peptic ulcerations, hypoglycemia,hyperparathyroidism,hypertension,and Cushing syndrome.
OVARY ANDTESTIS The pathology of theseendocrine organsis discussedin the ReproductivePathologychapterin this book.
280
Endocrine Pharmacology
Manysynthetic andsemisynthetic hormones andhormone antagonists areusedfordiagnosis and treatment of endocrine andnonendocrine disorders. Thischapter willdiscuss theseimportant endocrine drugs.
HYPOTHALAM IC-PITU ITARYHORMON ES The hypothalamic-pituitary systemis important for regulating the secretion of peripheral hormones,which control growth and development,metabolic function, and reproduction. A. Hypothalamic hormones 1. Growth hormone-releasing hormone (GHRH) stimulates somatotrophs in the anterior pituitary to secretegrowth hormone. a. Indications for use. GHRH is available for diagnosis and therapeutic use in patients with growth hormone deficienry and is effective in specific types of dwarfism. b. Side effects and toxicity.It causespain at the injection site. 2. Somatostatin (growth hormone release-inhibitinghormone, GHIH) is produced in the hypothalamus,in other areasof the central nervous system (CNS), pancreas,gastrointestinal tract, and thyroid.
Note groMh Somatostatin, hormone release-inhibiting (CHIH), hormone and somatotropin release(SRIH) inhibiting hormone areallnames forthe same hormone.
a. Physiologic effects (1) Somatostatin reduces the secretion of growth hormone, gastrin, secretin,vasoactive intestinal peptide, cholecystokinin (CCK), glucagon, insulin, calcitonin, parathyroid hormone (PTH), renin, and thyroid-stimulating hormone (TSH). (2) It acts through cell membrane receptors to reduce calcium influx into the cells. b. Indications for use. Somatostatin's duration of action is too short to be clinically usefrrl.Octreotide, a synthetic somatostatin analog, is longer acting; given subcutaneously, it controls excessivehormone secretion in acromegaly glucagonoma, and insulinoma.
ClinicalCorrelate isusedclinically Octreotide to treatga$rointestinal bleeding andintractable diarrhea.
In a Nutshell
3. Thyrotropin-releasing hormone (TRH) a. Physiologic effects. TRH increasesthe secretion of TSH (thyrotropin) and actson cell membrane receptorsto increasethe activity of adenylateryclase. b. Regulation of secretion. Secretionis regulatedby levelsof thyroid hormones in a negative-feedbackloop.
TRHstimulates thesecretion of thyroid hormones by increasing cyclic adenosine (cAMP). monophosphate
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Endocrine System
4. Corticotropin-releasing hormone (CRH) a. Physiologic effects. CRH acts on the anterior pituitary to increasethe secretion of adrenocorticotropic hormone (ACTH). It binds to cell membrane receptors to increaselevelsof cyclic adenosinemonophosphate(cAMP). The releaseof ACTH is calcium dependent.CRH also stimulatesthe releaseof B-endorphin. b. Indications for use. A synthetic CRH is available for diagnostic studies of pituitary function. 5. Gonadotropin-releasinghormone (GnRH or LH-RH) is produced in the arcuatenucleus of the hypothalamus,which controls the releaseof follicle-stimulatinghormone (FSH) and luteinizinghormone (LH).
Note Leuprolide canbeusedto inhibit FSH andLHrelease.
a. GnRH (gonadorelin), when administered in a pulsatile manner (similar to endogenous secretionpatterns),stimulatesreleaseof FSH and LH and is useful in the diagnosis and treatment of hypogonadism. b. Continuous dosing. When administeredin continuous, steadydoses,gonadotropin releaseis inhibited. Leuprolide and other GnRH analogs (i.e., nafarelin, goserelin, histrelin) are given in continuous dosesto produce a chemical castration in adults with prostatecancer,polyrystic ovary syndrome,uterine fibroids, and endometriosis. Leuprolide is given subcutaneouslyor intramuscularly. Patientsusually worsen slightly before improving becausehormone levels(e.g.,testosterone)initially increaseduring the first week of therapy. 6. Prolactin-inhibiting hormone (PIH)
Bridge to Neruous System Nervous SeetheCentral Pharmacology Sy$em chapter of Organ Systems BookI the flolumelll)to review roleof bromocriptine in thetreatment of Parkinson disease.
In a Nutshell Oxytocin stimulates uterine contractility to: . lnduce labor . Control postpartum bleeding
a. Physiologic and pharmacologic effects. Dopamine has been identified as a PIH. It is not usefulin the treatment of CNS abnormalitiesbecauseof the peripheral sideeffects and the failure of dopamine to crossthe blood-brain barrier effectively.It is also not used to alter prolactin secretion. b. Bromocriptine, a dopaminergic receptor agonist,is effectiveorally in the treatment of hlperprolactinemia, to treat breastengorgement,to inhibit lactation in the postpartum period, and to treat infertility associatedwith excessiveprolactin secretion. B. Posterior pituitaryhormones 1. Oxytocin is synthesizedin the paraventricularnuclei of the hypothalamusand is stored in the posterior pituitary. a. Indications for use. Oxftocin stimulates uterine contractions and is used intravenously to induce or maintain labor at term. It is also usedby intramuscular administration to control postpartum bleeding.It is availableas a nasalspray to causemilk secretionby contracting smooth muscle in the myoepithelial cells of the mammary gland. Dinoprostone, a prostaglandinEz (PGEz),is also used to induce labor. b. Uterine relaxants used to inhibit premature labor include ritodrine and terbutaline, both p2-adrenoceptoragonists. 2. Antidiuretic hormone (ADH) is synthesizedin the supraopticand paraventricularnuclei of the hypothalamusand is storedin the posterior pituitary. a. Physiologic effects (1) ADH increaseswater permeability and, thus, reabsorption of water in the collecting ducts of the kidney. This antidiuretic effect is produced by the action at V2 receptors,leadingto an increasein cAMP. (2) At high doses,ADH alsocausessmooth musclecontraction by stimulation of V1 receptors.
282
Pharmacology
b. Indications for use. The main use of ADH is in treatment of central diabetes insipidus. DDAVP (also called desmopressin),an analog of vasopressinwith no V1 effects,is used clinically to treat diabetesinsipidus. DDAVP is of no use in the treatInent of nephrogenicdiabetesinsipidus becauseof dysfunctionalADH receptors. C. Anterior pituitary hormones 1. Growth hormone (somatotropin) is secretedby anterior pituitary cells (somatotrophs). a. Regulation of secretion is by GH-RH and somatostatin.
ClinicalCorrelate DDAVP isalsouseful in treating orpreventing bleeding complications. lt promotes therelease ofvon Willebrand factor by endothelial cells.
b. Physiologic effects (1) Growth hormone has metabolic and anabolic effects that are mediated by somatomedins,peptidesproduced in the liver. It actson specificcell membrane receptorsto stimulate the releaseof the somatomedins.
(2) Growt*:iilin ("anticatab ") It olic ffi:. ffi ::,t',T#i:?i.:i-:*:::: (3) Its anti-insulin action promotes hyperglycemia;hence,it is diabetogenic. c. Pharmacokinetics. Growth hormone is given subcutaneouslyor intramuscularly and has a half-life of 20-30 minutes.A peak increasein somatomedinsoccurs in24 hours. d. Indications for use. It is used for replacement therapy in children with deficienry of growth hormone and for anaboliceffectsin burn victims. e. Side effects and toxicity. Adversereactions include gigantism in children, acromegaly in adults,and diabetes-likesymptoms. f. Bromocriptine, a dopaminergic receptor agonist, has been used as an adjunct to octreotide to lower plasma levelsof growth hormone in acromegaly.Adversereactions include nauseaand vomiting, arrhythmias,hypotension,and paranoia/psychosis. 2. Prolactin a. Regulation of secretion. The secretion of prolactin is inhibited by dopamine; TRH stimulates secretion. Drugs that increase prolactin secretion include antipsychotics (e.g.,chlorpromazine,haloperidol) and catecholaminedepletors(e.g.,guanethedine). b. Physiologic effects. Prolactin promotes milk production in the postpartum breast. High levelsof prolactin inhibit the releaseof gonadotropin, thus inhibiting ovulation. c. Bromocriptine suppressesprolactin secretion by stimulating dopaminergic receptors. It is usedto treat women with hyperprolactinemia-inducedamenorrheaor galactorrhea. It is also usedto treat pituitary adenomasthat secreteprolactin. 3. Gonadotropic hormones. Secretion of estrogens,progesterone,and testosteroneare under control of the pituitary gonadotropins,FSH and LH, which are regulatedby GnRH from the hypothalamus. GnRH, FSH, and LH are also under negativefeedbackcontrol of the gonadalhormones. a- Follicle-stimulatinghormone (FSH) is a glycoproteinhormone produced and secreted by gonadotropic cells of the anterior pituitary. Secretion is regulated by the concentrationsof reproductivehormones. It actsvia the secondmessengercAMP. (1) In women, FSH causesmaturation of the ovarian follicle; plasmalevelsincrease during the follicular phase of the menstrual cycle, decreaseslowly, and then increase at midcycle; the lowest levels occur during the luteal phase. Together with LH, it causesfinal maturation of the corpus luteum.
In a Nubhell Bromocriptine, a dopaminergic receptor agonisl hasbeenusedto: . Lower serumCHlevels . Lower serum PRLlevels . Inhibit lactation Adverse reactions include nausea, vomiting, arrhythmias, hypotension, andparanoia.
In a Nubhell Infemales, FSHcauses granulosa cellsto synthesize estrogen andcauses follicles to mature. ln males, FSH causes spermatogenesis.
(2) In men, FSH promotes spermatogenesis.
28t
Endocrine System
In a Nutshell . Infemales, theLHsurge triggers ovulation andLH stimulates thecorpus luteum to produce progesterone. . Inmales, LHstimulates testosterone synthesis by Leydig cells.
Note hCCissecreted bythe placenta, anditspresence is diagnostic of pregnanoT.
b. Luteinizing hormone (LH) is a glycoprotein hormone similar in structure to FSH. It is secretedby gonadotrophiccellsof the anterior pituitary. It actsthrough cAMP; LH action on the ovary may alsobe associatedwith increasedinositol 1,4,5-triphosphate(IP3). (1) In women, LH levels peak at midrycle to induce ovulation and the initial formation of the corpus luteum. This pulse is induced by the positive feedbackof estradiol. (2) In men, LH activatesinterstitial cellsto secretetestosterone. c. Human chorionic gonadotropin (hCG) is a glycoprotein hormone secreted by syncytiotrophoblastsof the fetal placenta.It promotes growth of the corpus luteum and preventsmenstruation.It is usedas a pregnancytest, detectableby immunoassay in urine or blood before the first missedmenstrual period. d. Specific agents related to the gonadotropins. Menotropins are a mixture of partially degradedFSH and LH given to infertile women to induce maturation of the follicle. It is usually followed by HCG to induce ovulation. Adversereactionsare due to overstimulation of the ovaries,producing multiple pregnancies,enlargementof the ovaries,and ovarian rysts.In infertile men, menotropins are given after HCG therapy to induce spermatogenesis. 4. Thyroid-stimulating hormone (TSH) is a peptide that binds to cell membrane receptors on the thyroid gland to increaseiodide uptake and the synthesisand secretionof thyroid hormones. Its secretion is enhancedby TRH and is reduced by negative feedback of thyroxine (Ta) and triiodothyronine (T3). a. Physiologic effects.Activation of the TSH receptor produces an increasein cAMR diacylglycerol,IP3, and intracellular calcium. b. Indications for use. TSH is availablefor diagnosisof thyroid function and to increase the uptakeof iodine 131 (13lI) in certaincasesof thyroid carcinoma. 5. Adrenocorticotropic hormone (ACTH, corticotropin) is synthesizedand secretedby the anterior pituitary. Its secretion is stimulated by CRH and is reduced by negativefeedback control of corticosteroids.
Flashback to Pathology primary ACIHcandistinguish fromsecondary adrenal insufficiency. Failure to respond toexogenous AC|Hindicates thattheadrenals themselves (primary). have failed
a. Physiologic effects. ACTH stimulates the human adrenal cortex to secretecortisol and, to a lesserextent, aldosteroneand androgens.ACTH binds to cell membrane receptorsto stimulate adenylatecyclase,leadingto an increasein activity of cholesterol esterase,which catalyzesthe rate-limiting step in steroid hormone synthesis.It also increasesthe cytochrome P-450 enryme system responsiblefor the production of pregnenolone.ACTH actsas a growth factor to the adrenalcortex. b. Indications for use. Usesof ACTH include the diagnosisof primary adrenal insufficiency,therapy of secondaryadrenal insufficiency,and nonendocrine illnesses,such as multiple sclerosis.Cosyntropin, an active synthetic analog, is lessantigenic and is preferred for the diagnosisof adrenalfunction.
THYROID ANDANTITHYROID DRUGS The thyroid gland secretesthree hormones: calcitonin, which is important in calcium homeostasis;and triiodothyronine (Tr) and thyroxine (Ta), which are important in growth and generalmetabolic function.
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Pharmacology
A. Thyroid drugs. Tn and T, are iodine-containing hormones that are analogsof tyrosine. 1. Regulation of thyroid function. Thyroid function is regulatedby TSH, which increases both the synthesisand secretionof thesehormones. TSH secretionis regulatedby negative feedback of the thyroid hormones; it is positively influenced by TRH from the hlpothalamus. 2. Thyroid hormone synthesis a. Iodide is necessaryfor thyroid hormone synthesis.Iodide is obtained from the diet (e.g.,seafood)and is absorbedfrom the gastrointestinaltract. It is taken up by the thyroid gland by an activecotransportprocessinvolving potassium. b. Once in the gl*d, iodide is oxidized via peroxidaseto an active iodine intermediate, which iodinates tyrosine residuesof thyroglobulin (a glycoprotein).An aerobiccondensation of iodinated tyrosine moleculesresultsin production of T, and Tn. Subsequently, proteolysisof thyroglobutin causesreleaseof thyroid hormones into the blood. 3. Kinetic properties. Over 99o/oof T, and T, are bound to plasma proteins, most to thyroid-binding globulin. The hormones are deiodinatedand conjugatedin the liver to form sulfatesand glucuronides.They are excretedin the bile and urine. Tn has a half-life of 6-7 days;T, has a half-life of I-2 days.Some of the circulating Tn is deiodinated to T' the more potent and rapidly acting form. 4. Mechanism of action. Most of the effectsof thyroid hormones stem from activation of nuclear nonhistone protein receptors attached to DNA. Binding of hormone to the receptorleadsto increasedtranscription of messengerRNA (mRNA), thus increasingthe synthesisof specific proteins. T, is ten times more potent for binding to the nuclear receptor.The hormone may also bind to receptorson cell membranesto increaseamino acid and glucoseuptake and to receptorson the inner mitochondrial membrane to regulate energy metabolism.
Flashbackto Physiology Refer backto Figure lll-3-7 to review hormone thyroid biosynthesis.
Flashback to Physiology . T, ismuchmore potent thanTo. . T, hasa shorter half-life thanTo. . T, isboundlessto TBCthanTo.
5. Physiologic effects.Thyroid hormones produce effectsin most major systems,including normal growth and development,increasedbasal metabolic rate, and activation of oxygen consumption. The hormones havea thermogeniceffect (increasedheat production), they causeincreasedplasmaglucoseand free fatty acids,and causea reduction in plasma cholesteroland triglycerides.Increasedcardiovascularactivity, increasedheart rate, and maturation of the CNS are also effectedby thyroid hormones. 6. Specific agents used in the treatment of hypothyroidism. Thyromimetic agents,from animal or synthetic sources,are indicated as replacementtherapy for the treatment of hypothyroidism and to suppressTSH secretion.The levo isomers are more potent in increasing basal metabolic rate. They are all available orally; levothyroxine is also available by injection. Once absorbed,their pharmacokinetic and dynamic properties are identical to endogenousthyroid hormones. Adversereactionsinclude hyperthyroidism (or symptoms of hyperthyroidism), cardiovasculartoxicity (tachyarrhythmias,angina, and infarction are possible),CNS stimulation, and insomnia. a. Levothyroxine sodium is the synthetic levo isomer of T4. It is available for oral or intravenousadministration. It is the preferred drug for treatment of hypothyroidism as a result of better standardizationand stability and long duration. The long half-life of Tn greatly facilitatesmaintenanceof a steadyphysiologic replacementof thyroid hormone. b. Liothyronine sodium is synthetic r-triiodothyronine. It is more difficult to monitor than Tn, is more expensive,and has a shorter duration of action. c. Liotrix is a combination of levothyroxineand liothyronine (at a ratio of 4:1). It hasno advantageover levothyroxine.
285
Endocrine System
B. Antithyroid drugs inhibit the formation of thyroid hormones and are used in the treatment of hyperthyroidism. 1. Iodine. Although small amounts of iodine (75-100 pglday) are required for hormone synthesis,high concentrations( 50+ mg/day) produce autoinhibition. a. Pharmacologic properties. Iodine blocks the uptake of iodide by the thyroid, inhibiting synthesisand releaseof thyroid hormones. It alsodiminishesvascularityof the gl*d. b. Indications for use.Iodine is used only preoperatively to shrink the gland in preparation for surgical removal of the thyroid gland, and in the treatment of thyroid storm. It is given as Lugol solution (iodine and potassiumiodide). Effectsare visible within 24 hours. It is no longer used in long-term therapy. c. Side effects and toxicity. Adverse reactions include hypersensitivity and dose-related effects,such as"head cold" symptoms,gastricirritation, and parotitis. Long-term use can lead to sudden disinhibition of hormone synthesis,producing acute hyperthyroidism.
Note Bothmethimazole andPTU inhibit incorporation of iodine intothyroid hormone precursors. However, only PTUinhibits theperipheral conversion ofTo+ Tr.
Clinical Conelate PTUispreferred to methimazole in pregnancy because it ismoreextensively protein-bound (80versus 8o/o formethimazole) andless likely to cross theplacenta.
2. Thioamides: propylthiouracil (PTU) and methimaz,ole a. Mechanism of action. These drugs inhibit the peroxidase enzymes catalyzing the oxidation of iodide and the coupling of iodinated tyrosyl groups, thus reducing the synthesisof thyroid hormones. PTU also inhibits the peripheral deiodination of Ta to T3. There is a delay in onset of clinical effectivenessuntil preformed hormones have been metabolized. b. Indications for use. These drugs are used for control of hyperthyroidism until surgery,in the suppressionof thyroid hormone synthesisuntil the effect of radioactive iodide begins, and in the long-term therapy of mild-to-moderate hyperthyroidism. The drugs are given orally. c. Side effects and toxicit''. Most common adversereactions include mild maculopapular rash, joint pain, headache,nausea,and loss of hair. Although extremely rare, the most serious side effect is agranulocytosis.The drugs cross the placenta and enter breast milk, which can lead to hypothyroidism in the fetus and nursing infant. 3. Radioactiveiodine (t3t1, a. Pharmacologic properties. Given orally or intravenously, l3l1 ir rapidly taken up by the thyroid gland, where it is incorporated into thyroglobulin. With proper doses, 131Ileadsto partial or total destruction of the gland by emission of beta particles. Damageto surrounding tissueis minimal.
Note
b. Indications for use. 131Iis used in the treatment of hyperthyroidism.
Radioactive iodine isvery effective in treatment of hyperthyroidism because the iodine in selectively takenup bythegland's follicular cells.
c. Side effects and toxicity. The major adversereaction due to overdosageis a delayed incidenceof hypothyroidism. 1311r6on1dbe avoidedduring pregnancy.
286
4. Propranolol and other p-adrenergicreceptorblockersare usedasadjuncts in the treatment of hyperthyroidism. They reduce the symptoms of the disease(e.g.,tachycardia,anxiety) until the antithyroid drugs can take effect.Propranol alsoinhibits the peripheral conversion of Ta to T3 via 5'deiodinase.
Pharmacology
DRUGS A1TERING HOMEOSTASIS CALCIUM A. Calcium 1. Physiologic effects a. Calcium concentrationin blood is maintained within narrow limits. Calcium existsin three forms: 50o/oionized, 40o/obound to protein (especiallyto albumin), and 10o/o complexed to anions. Approximately l0-20o/o of. daily intake is absorbed from the proximal intestine, with an equal amount excretedby the kidney. Calcium levels are regulatedby calcitonin, PTH, and vitamin D (TableIII-5-1). Thble III-5-1. Effect of calcitonin, parathyroid hormone (PTH), and vitamin D on calcium homeostasis. Intestinal Absorption of Calcium
Calcitonin J Postprandial
Renal Excretion of Calcium
t
PTH
t Indirectdueto J increase in 1,25(oH)2D3
Vitamin D
t
I (minor)
Bone
Effect on Plasma Calcium
t Mineralization J Resorption
J
l Resorption
1
t Mineralization t Resorption
t
b. Calcium is vital for many cellular functions, including: ( 1) Developmentof bone and teeth (2) Control of enzyme activity (3) Blood coagulation (4) Excitability of nerve and muscle,including cardiac muscle (5) Excitation-contractioncoupling (6) Tiansmembranesignaling/neurotransmitterrelease (7) Cardiovascularfunction 2. Specific agents a. Calcium chloride contains 25o/ocalcium. It is given slowly. High concentrations can causesyncopewith vasodilatationand hypotension.Becauseof the salt, it is not the drug of choicein renal insufficienry. b. Calcium gluconate, containing 9o/ocalcium, is available for oral or intravenous administration. It is used for severetetany. It is also usefrrl for treating severehyperkalemia. c. Calcium carbonate, calcium lactate, and tricalcium phosphate are all used in the treatment of hypocalcemiaand in the prevention and treatment of osteoporosis.
287
Endocrine System
B. Phosphate 1. Physiologic effects. Phosphatehelps maintain acid-baseequilibrium, buffers and allows for renal H+ excretion,helps regulatecalcium metabolism,and is an activeintermediate of energymetabolism.Approximately 670/oof an oral doseis absorbedfrom the intestine. Excretion is via the kidney. 2. Indications for use.Various preparationsof sodium phosphateare availablefor a cathartic action and in the treatment of hypercalcemiaand hypophosphatemia. 3. Sideeffectsand toxicity. The major adversereactionof intravenousinfusion for the treatment of hypercalcemiais metastaticcalcificationof soft tissues. C. Parathyroid hormone (PTH) is synthesizedby the parathyroid gland as a preprohormone. 1. Regulation of secretion. Secretionis regulatedby Ca2+concentration in the blood; low freeCa2+stimulatesan increasein PTH secretion. 2. Mechanism of action involves the binding to cell membrane receptors, leading to increasedcAMP. PTH increasesCa2+concentrationbv: a. Increasingcalcium resorption from bone b. Enhancing renal tubular reabsorption of calcium c. Indirectly increasinggastrointestinalabsorption of calcium by enhancingthe production of the activeform of vitamin D 1,25(OH),D? 3. Indications for use a. PTH is a peptide and, thus, must be given parenterally.
ln a Nutshell Calcitonin . Lowers serum calcium . lnhibits boneresorption by osteoclasts . Blocks andphosphate Ca2* release frombone
b. Human PTH is not used clinically becauseadministration of vitamin D and calcium to raise calcium concentrationis safer.A synthetic human hormone is used diagnostically to distinguish between hypoparathyroidism and pseudohypoparathyroidism. Patientswith pseudohypoparathyroidismdo not respond to the synthetichormone. D. Calcitonin is secretedby the parafollicular (C cells) of the thyroid gland. High blood calcium levelsreducethe secretionof calcitonin. 1. Physiologic effects. In general, calcitonin has opposite effects of PTH: it decreasesthe concentration of serum calcium, inhibits bone resorption, and increasesrenal calcium excretion.Although it hasno major effecton the gastrointestinaltract, it may inhibit postprandial calcium absorption. 2. Indications for use include hypercalcemia,hyperparathyroidism, vitamin D toxicity, Paget disease(to reduce bone turnover), bone tumors, and osteoporosis.Human and salmon preparationsare available. 3. Sideeffectsandtoxicity. Adversereactionsinclude hypersensitivityreactionand hypocalcemia. E. Vitamin D 1. Synthesis.Vitamh D, (cholecalciferol) is produced in skin from 7-dehydrocholesterol and requiresthe presenceof ultraviolet light. In the liver, vitamin D, is hydroxylatedto 25-hydroxy-D, (calcifediol),which is convertedin the kidney to 1,25(OH)rD, (calcitriol), the most activeform of the vitamin. PTH increasesthe activity of the hydroxylaseenzyme responsiblefor the final step. 2. Mechanism of action. Calcitriol actsby binding to nuclear receptorsto alter gene expression and initiate protein synthesis.
288
Pharmacology
3. Physiologic effects. Vitamin D stimulates intestinal absorption of calcium and phosphate, increasesbone resorption and mineralization, and increasesrenal reabsorptionof calcium and phosphate.The net effect is to increase plasma calcium and phosphate. 4. Indications for use include hypocalcemiadue to rickets,hypoparathyroidism,and osteomalacia. 5. Side effectsand toxicity. The major adversereaction is hypercalcemia. 6. Specific agents. Preparations available orally include: calcitriol, calcifediol, cholecalciferol, dihydrotachysterol (vitamin D2 analog), and ergocalciferol (vitamin Dz). The choiceof agentdependson the causeof the disorder. F. Other agents 1. Glucocorticoids reduce calcium absorption from the gastrointestinaltract and increase renal calcium excretion.They are used in the treatment of hypercalcemia. 2. Diphosphonates (etidronate disodium, pamidronate disodium) are analogs of pyrophosphate used in the treatment of hypercalcemiaof malignancy, Paget disease, osteoporosis,and hyperparathyroidism.They bind to hydroxyapatitecrystals,reducing their formation, growth, and dissolution,thereby reducingbone turnover. 3. Plicamycin (mithramycin) is a cytotoxic antibiotic that inhibits osteoclastfunction and bone resorption by inhibiting DNA-directed RNA synthesis,thereby reducing plasma calcium. It is used to treat Pagetdiseaseand hypercalcemiasecondaryto malignancy. 4. Fluoride stimulatesbone formation when administeredwith calcium. It is accumulated by bones and teeth and stabilizesthe hydroxyapatitecomplex.Fluoride is substitutedfor the hydroxyl group. It is used in the treatment of osteoporosis.Adversereactionsdue to the ability of fluoride to bind calcium include nausea,vomiting, arthralgias,and arthritis. Extreme overdosecan causecardiovascularcollapseor respiratory failure by inducing hypocalcemia. 5. Estrogens inhibit bone resorption and are used in the treatment of postmenopausal osteoporosis. The pharmacology of estrogen is described in the Reproductive Pharmacologychapter of this book.
ISTS ANTAGON ANDTHEIR CORTICOSTEROIDS The term corticosteroidsdesignatessteroid hormones normally secretedby the adrenalcortex; these include glucocorticoids(cortisol), mineralocorticoids(aldosterone),and androgens ( dihydroepiandrosterone, DHEA). A. Glucocorticoids are natural and syntheticsteroidsthat alter glucosemetabolism. 1. Regulation of secretion. Cortisol is the principal naturally occurring hormone in humans, which is synthesizedin the zona fasciculata.Plasmaconcentrationsare highest between6-8 e.v. Synthesisand releaseare stimulated by ACTH, via a negativefeedback mechanism. 2. Mechanism of action. Glucocorticoidsenter target cellsby simple diffrrsion and bind to cytosolicreceptors.The steroid-receptorcomplex is translocatedinto the nucleus,where it regulatesthe synthesisof specificproteins. 3. Physiologic effects a. Glucocorticoidsinfluence carbohydrateand fat metabolismto ensureadequatedelivdecreaseperipheral use of ery of glucoseto the brain: they increasegluconeogenesis, (increased lipolysis). glucose,and increasefree fatty acids
ln a Nutshell bone inhibit Diphosphonates (major of store turnover serum decreasing calcium), levels. calcium Note for Fluoride substitution groups in hydroxyl this makes hydroxyapatite boneandtoothmineral to degradation. resistant ClinicalCorrelate isthe Estrogen replacement preventive for therapy favored Calcium osteoporosis. oftengivenin supplements D withvitamin combination risk reduce thefracture further dueto boneloss. Flashbackto Histology cortex Adrenal outside I | I I I I I V inside
zonuglomerulosa -+ aldosterone (salt) -+ Zonafasciculata (sugar) glu.ocorticoids Zonareticularis --+androgens (sex)
289
Endocrine System
b. They decreaseabsorption of calcium from the intestineand increaserenal excretionof calcium. c. Glucocorticoidsproduce redistribution of fat from the extremitiesto the trunk and face (buffalo neck). d. Glucocorticoidsfavor protein breakdown and help mobilize amino acids to the liver for gluconeogenesis.
ln a Nutshell Clucocorticoid effects include: . Anti-inflammatory actions . t Serum glucose (enhance gluconeogenesis) . Protein catabolism . lmmune suppression
e. Glucocorticoids have anti-inflamnatory and immunosuppressant activity. They increasecirculating levelsof neutrophils by interfering with adhesion,and they decrease eosinophils,lymphocytes,and monocytes.They decreaselocal edema,fibrin deposition, capillary dilatation, leukocyte migration, and phagocytic activity. Glucocorticoids indirectly inhibit phospholipaseAr-mediated arachidonic acid releaseby increasing the synthesisof lipocortins. The end result is decreasedproduction of prostaglandins, thromboxanes,and leukotrienes. f. Glucocorticoids may also alter mood, sleeppatterns, and EEG activity. 4. Specific agents. Preparations are available for oral, topical, and injectable routes of administration. A comparison of clinically useful corticosteroidsis presentedin Table tII-s-2. ?able lll- 5-2. Commonly used corticosteroids.
Note
Corticosteroids
Cortisone andcortisol have somemineralocorticoid activity, butmuchlessthan aldosterone. Prednisone is activated bytheliverto prednisolone. Beclomethasone potent isa long-acting, glucocorticoid.
Glucocorticoids Short-acting Hydrocortisone (cortisol) Cortisone Intermediate-acting Prednisone Prednisolone Methylprednisolone Triamcinolone Long-acting Dexamethasone
Biologic Half-Life 8-12 hours
18-36 hours
36-54 hours
Mineralocorticoid Fludrocortisone Available as aerosol for treatment of bronchial asthma Beclomethasone Flunisolide
5. Indications for use. In general,drugs with mixed glucocorticoid and mineralocorticoid activity (e.g.,cortisol) are used in replacementtherapy.Intermediate-actingdrugs with minimal mineralocorticoid effect (e.g., prednisone, prednisolone) are used as antiinflammatory and immunosuppressantagentswhen long-term therapy is needed.Doses are gradually reducedwhen the patient is to be taken off the drug. Long-acting,potent steroids (e.g.,dexamethasone)are used mostly for acute,severeconditions. Therapeutic usesof corticosteroidsinclude: a. Replacementtherapy for adrenalinsufficiency
290
Pharmacology
b. Treatmentfor: (1) Allergic disorderssuch as anaphylacticreactionsand statusasthmaticus (2) Collagen vascular disorders and other autoimmune conditions, including systemic lupus erythematosus,rheumatoid arthritis, scleroderma,polymyositis, dermatomyositis, polyarteritis nodosa, polymyalgia rheumatica, myasthenia gravis,multiple sclerosis,and temporal arteritis (3) Hematologic disorders,including immunologically mediated aplastic anemia, thrombocytopenicpurpura, acutelymphoblasticleukemia,chronic lymphocytic leukemia, Hodgkin disease,and multiple myeloma (4) Cerebraledema (5) Dermatologic disease (6) Gastrointestinaldisorders,such as inflammatory bowel disease (7) Hypercalcemia (8) Renal disease,including nephrotic syndrome, membranous nephropathy,and focal sclerosis (9) Respiratorydisorders,such assarcoidosis,chronic obstructivepulmonary disease (COPD), hypersensitivity reactions, pneumonitis, and idiopathic pulmonary fibrosis c. Diagnosisof Cushing disease(dexamethasonesuppressiontest) d. Cancerchemotherapy 6. Side effects and toxicity. Adverse reactions depend upon the route of administration (topical versussystemic),dose,and duration of therapy. a. Metabolic disorders, such as hyperglycemia, glycosuria, negative nitrogen balance, fat redistribution, and mineralocorticoid effects (sodium and water retention, hypokalemia,metabolic alkalosis)
ln a Nubhell of Cofticosteroids SideEffects . Hyperglycemia . Hypertension
b. Hypertension (from sodium and water retention and increasedplasmarenin)
. Easy bruising
c. Endocrine disorders,such as suppressionof hypothalamic-pituitary-adrenal axis (leading to adrenalinsufficiency),atrophy of adrenalcortex (from which it may take a year to fully recover),growth retardation in children, and secondaryamenorrhea
. Cataracts
d. Dermatologic disorders,such as hirsutism, skin thickening, poor wound healing, acne, and purpura e. Ocular disorders,such ascataracts(from hyperglycemia)and glaucoma(from salt and water retention)
. Osteoporosis . Myopathy . Dysphoria/psychosis . Cushingoid habitus
f. Gastrointestinaldisorders,such as peptic ulceration, pancreatitis,and perforation of colonic diverticula g. Musculoskeletal disorders, such as myopathy, osteoporosis,and aseptic necrosis (osteonecrosis) h. CNS reactions,including psychiatricsymptoms (elation, mania, psychosis)and pseudotumor cerebri (benign intracranial hypertension) i. Increasedsusceptibilityto infection
291
Endocrine System
In a Nutshell Adverse effects of chronic use of syste mic glucocorticoids stemfrom: . Suppression andatrophy of pituitary corticotrophs and adrenal fasciculata and reticularis zones . Symptoms associated with glucocorticoid excess systemic effects These adverse effects canbe minimized by:/) Using topical applications, not possible; systemic, whenever 2) lf systemic useisrequired: . Usea short(<2weeks) high-dose course rather thana longer low-dose c0urse . Civethehighest amount of glucocorticoids inthen.rr,r. . Civetheglucocorticoids on alternate days, if possible . Groduolly increase and decrease thedailydoses during thecourse, allowing theadrenal axis timeto compensate
Clinical Correlate . Exogerrous injected insulin doesnotcontain theCpeptide. Endogenous insulin contains cosecreted C-peptide. . C-peptide measurements areusedto determine if hypoglycemia isdueto surreptitious insulin (noelevation administration of C-peptide) or endogenous insulin (elevation of C-peptide).
292
B. Corticosteroid antagonists 1. Ketoconazole,an antifungal agent, inhibits steroid synthesisby the adrenal cortex and testes.It is availablefor treatment of Cushing diseaseand prostatecancer. 2. Spironolactone is an aldosteronereceptor antagonistused in the treatment of hyperaldosteronism.Its usesas a diuretic are discussedin the Renal Pharmacologychapter of Organ SystemsBook 1 (Volume III). C. Mineralocorticoids promote sodium reabsorptionand potassiumexcretionin the distaltubules. 1. Aldosterone is the most important natural mineralocorticoid, synthesizedin the zona glomerulosa of the adrenal cortex. Production and releaseare controlled by the reninangiotensin system and plasma potassium; its secretionis also transiently increasedby ACTH. Aldosteroneis not availablefor therapeuticuse. 2. Fludrocortisone, a synthetic steroid analog,has strong mineralocorticoid and relatively mild glucocorticoid effect.It is availablefor oral or parenteraladministration and is used in conjunction with cortisol in the treatment of adrenalinsufficiency.
PANCREATIC HORMONES ANDORAIHYPOGLYCEMIC AGENTS A. Insulin is a protein hormone, manufacturedin the beta cells of the pancreas.It containstwo polypeptide chainslinked by disulfide bonds. 1. Regulation of secretion a. Insulin is synthesizedas a prohormone in a single polypeptide chain. Proinsulin is cleavedto insulin. C peptide,a blproduct of cleavage, has no known physiologicfunction. Insulin is secretedat a low basalrate of 5-15 pU/ml plasmaand a high stimulated rate of 60-90 FU/ml. b. Synthesisand secretionare stimulated by food products (particularly glucose),gastrointestinalhormones'(e.g.,CCK, gastrointestinalglucagon),and neurotransmitteranalogs (e.9., pz-adrenergicagonistsand muscarinic agonists).Secretionis inhibited by o2adrenergicagonists. c. Glucoseis taken up by pancreaticcellsand metabolized,increasingproduction of ATP, which leads to blockade of potassium efflux. This causesdepolarization, calcium influx, and releaseof insulin. 2. Mechanism of action a. Insulin actsby binding to specificreceptorson the cell membrane.The receptor is a heterotetramericmembrane protein, containing two alpha and two beta subunits, linked by disulfide bonds. Insulin binds to the alpha subunits.The beta subunits span the membrane and contain tyrosine kinase activity. The binding of insulin causes autophosphorylation and begins a cascadeactivating protein kinases and phosphatases.Sometarget enzymesare activated,while others are inhibited. b. Insulin also promotes the translocation of glucosetransporter proteins (e.g.,GLUT 4 in skeletalmuscle) from intracellular pools to the plasmamembrane. c. The insulin receptor complex is then internalized. 3. Physiologic effects a. Anabolic effectson liver include increasedsynthesisof proteins and lipids, decreased ketogenesis,increasedglycogensynthesis,decreasedgluconeogenesis, and decreased glycogenolysis, decreasedfat oxidation.
Pharmacology
b. Anabolic effectson adiposetissueinclude increasedglucoseand potassiumuPtake, increaseduptakeof ftee fatty acids,incr€asedstorag€of triglycerides,and decreased lipolysis.
Note
c. Effectson skeletalmuscleinclude increaseduptakeof glucose,potassium,and amino acids'
. Increases glucose use
d. Insulin deffciency leadsto hyperglycemia,glycosuria,tissuewasting,hyperlipemia, in ."u"r" .ur"r, polpria, pruritus, vur.ut* .o-plii"tlons, pe'ripheralneuroputttn "ttal ketoacidosis.Shortenedlife exPectancyis due to rnyocardialinfarction, stroke,and renalandvasculardisease. 4. Specificagents.Thereareseveralinsulin preparationsavailablefrom bovine,porcine,and DNA) souc€s.lnsulin is preparedeitherwith protaminein phoshuman(recombinant in acetatebuffer to providedifferenltime phatebuffer or variouszinc concentralions of action(seeTableIII-5-3). courses
a'fedstate": Insulin signals
. Enhances Drotein svnthesis ' lncreases glycogen synness . Enhances K*uotake intocells . lnrrpa
5. Indications for use a. Insulin preparationsare usedin the control of insulin-dePendent,or type 1, diabetes mellitus(NIDDM). or q'pe2, diabetes mellitus(IDDM) andnoninsulin-dependent, b. Intravenousinsulin is usedin the tr€atmentof diabeticketoacidosisor hyperosmolar hyperglyc€micnonketoticcoma. TableIII-5-3, Insulin preparations Preparation*
Onset
Time to Peak
Duration
Regularcrystalline
0.25-1 hour
L-3 hours
5-7 hours
Lispro
0.25-0.5hour
1-2 hours
3-4 hours
NPH insulinand knte insulin zinc suspensron Extendedinsulin zinc suspension (ultralente)
1-2 hours
8-10 hours
18-24hours
2-4 hours
8-16 hours
24-36hours
zinc insulin
*All preparationsaregivensubcutaneousadministration.Regularand Lispro iruulin canalso and usedin an insulin pump. be givenby intravenousadministration (in emergencies)
6. Sid€effectsand toxicity a. Hypoglycenia with s)'mptomsranging from hunger,sweatinS,and tachycardiato confusion,coma,and conrrlsions can occur. b. Hypers€nsitivitywith local reactions(more commonwith animalsources)mayoccur; is rare. anaphylaxis mayoccurat the siteofinjection. c. Lipodystrophy
Cliniol Correlate B-blockenbluntthe of hYPoglYcemia, symPtoms particularly thetachycardia, andaretherefore to beused cautlously in diabetics'
B. Oral hypoglycemicagents(tolbutamide, clrlorpropamide' glyburide, gliPizide) 1. Pharmacokin€tics.The sulfonylureasareall effectivefollowing oral administration.They vary in the rate and extentof metabolismard time courseof action:tolbutamidehasthe shortestduration of action,while chlorpropamidehasthe longestduration of action.
29t
Endocrine System
2. Pharmacologic properties. All oral hypoglycemic agentsare sulfonylurea analogs,which lower blood glucoseby stimulating the pancreatic beta cells to secreteinsulin. They bind to receptor sites near the potassium channel to reduce potassium efflux, thus causing depolarization,which increasescalcium influx, leading to insulin secretion.On chronic administration, sulfonylureasalso reduce serum glucagon and potentiate the effect of insulin on targettissues.
ln a Nutshell Sulfonylureas enhance insulin secretion onlyin 2 diabetes. Vpe
3. Indications for use. The sulfonylureas are used in the treatment of type 2 NIDDM. Becausesulfonylureasenhanceexisting pancreaticability to produce and secreteinsulin, they are not usefi.rlin the treatment of type I IDDM. 4 . Side effects and toxicity a. Hypoglycemia is more likely with long-acting drugs (chlorpropamide) and highpotenry drugs (glyburide and glipizide). b. Adversereactionsinclude skin rashes,gastrointestinalupset,and hypothyroidism. c. A disulfiram-like reaction with ethanol (especiallychlorpropamide) may occur. C. Antihyperglycemic agents are another group of drugs used in the therapy of NIDDM. As opposed to the more traditional oral hypoglycemicagents(sulfonylureas),these drugs do not enhanceinsulin release,rather they increaseglucose utilization through biochemical mechanisms.Thesedrugs include metformin (a biguanide) and acarbose. a. Acarbose inhibits o-glucosidaseof the intestinebrush border, preventing absorption of glucose,thereby decreasingpostprandial glucose and insulin requirement. Side effectsare primarily gastrointestinal discomfort. b. Thiazolidinediones: pioglitaz.one and rosiglitazone. These drugs bind to nuclear peroxisome proliferator-activating receptors (PPARS) involved in transcription of insulin-responsivegenes.Overall, they increasethe sensitivity of tissuesto insulin. Side effectsinclude weight gain and edema. c. Metformin, euglycemicdrug with poorly characterizedmechanism of action. May increaseinsulin sensitivity and decreasehepatic gluconeogenesis. Lactic acidosiscan be a side effect, but the agent does not causehypoglycemia. d. Repaglinide is a new generation of sulfonylurea-like drugs which stimulates insulin releasefrom B cellsof the pancreas. D. Glucagon is a polypeptide hormone secretedby the alpha cells of the pancreas. It is a physiologicantagonistto insulin, resulting in glycogenolysis,gluconeogenesis,lipolysis, and formation of ketone bodies. It stimulates the secretion of growth hormone, insulin, and pancreatic somatostatin.It acts by increasing activity of adenylateryclase.Clinical uses include the treatment of severehypoglycemia in diabetics and the decreaseof intestinal motility for x-ray studies.
294
lv sEcTloN
System Reproductlve
Embryology Reproductive genitalia-is andexternal of gonads, ducts andtheirderivatives, Thegenital system-consisting anindifferent stage, thecomponents ofthissystem fromallthreegermlayers. Following derived phenotype. isgenetically determined Thesexoftheembryo intoeither themaleorfemale develop However, embryonic inthefertilizing sperm. bythepresence orabsence oftheY chromosome gonads weekof development. untiltheseventh donotappear asmaleorfemale
FORMATION OFGONADS Primordial germ cells arise in the yolk sacearly in development.When this part of the yolk sac is incorporated into the hindgut, the germ cellsmigrate by amoeboid movement along the dorsal hindgut mesentery.By the sixth week,they lie beneath the coelomic epithelium medial to the mesonephros.The germ cellsinduce proliferation of the overlying epithelium, and the resulting sex cord cells penetrate the mesenchyme,forming the genital ridge.
IN THEMAIE DEVETOPMENT A. Gonads 1. Under the influence of the Y chromosome,the primitive sex cords give rise to the testis cords,which separatefrom the coelomic epithelium by proliferation of mesenchyme. a. This mesenchymecondensesto form the fibrous connective tissue capsule of the testis,the tunica albuginea. b. The testiscords are composedof primitive germ cells,which give rise to spermatogonia, and sex cord cells,which differentiate into Sertoli cells. 2. During the fourth month, the testiscords becomeU-shapedand form the precursorsof the seminiferous tubules, which remain assolid cords until puberty. The ends of the seminiferous tubules form the straight tubules, which join near the hilum of the testesto form the labyrinthine rete testis. The rete testisbecomescanalizedand joins remnants of the mesonephric tubules, which form the efferent ductules. 3. Mesenchymebetween the seminiferoustubules givesrise to the testosterone-producing interstitial cells of Leydig. 4. The gubernaculum testis consistsof remnants of the urogenital mesenteryand fibers that run from this mesenteryto the scrotal swelling. a. The processusvaginalisis a coelomicefiension into the scrotalswellingthat carrieswith it extensionsof the body wall to form the inguinal canalduring the descentof the testes.
297
Reproductive System
b. During the secondmonth of development,rapid body growth resultsin movement of the testesbelow their level of origin in the dorsal body wall. c. In the seventhmonth, the testesbegin to descendbehind the processusvaginalisand arrive in the scrotal sacsat the time of birth. The processusvaginalisforms the coverings of the spermaticcords and testes. B. Ducts. The efferent ductules empty into the Wolffian (mesonephric) ducts, which, except for their most cranial portion, persistin the male. l. The cephalicportion of eachof theseducts becomesthe extensivelycoiled epididymis. 2. The caudal end forms the thick-coatedductus deferens,which continuesin the prostate and opensinto the prostatic urethra as the ejaculatory duct. 3. The terminal portions of the ductus deferensevaginateto form the seminal vesicles. 4. The prostatic urethra givesrise to the prostate gland. C. External genitalia 1. Mesenchymecells of the primitive streak migrate around the cloacalmembrane during the third week of developmentand form the cloacalfolds. Thesefolds unite the cranial and cloacalmembranesto form the genital tubercle.By the sixth week,the genital folds appearon eachside of the cloacalmembrane. 2. Another pair of elevations,the genital swellings,soon becomevisible on eachside of the genital folds. 3. Developmentof the male externalgenitalia is under the influence of androgenssecreted by the fetal testis.At the seventhweek,the genital tubercle elongatesto form the phallus, which developsan extendedend, called the glans.This elongation pulls the genital folds forward to form the lateral walls of the urethral groove. 4. By the end of the third month, the genital folds fuse over the urethral plate to form the penile urethra, which opens at the end of the penis asthe urethral meatus.The two genital swellingsmove caudallyand form the two halvesof the scrotum.
DEVETOPMENT IN THEFEMATE A. Gonads 1. In the femalegonad,primitive sexcordsarebroken up into clustersof primitive germ cells by proliferating mesenchyme,which forms the ovarian medulla. Surfaceepithelium proliferatesto form the cortical cords,which penetratethe mesenchymeby the seventhweek. In the fourth month, thesecords split into cell clustersthat surround one or more of the primitive germ cells.
Bridgeto Physiology
2. The germ cellsdifferentiateinto oogonia, which undergo mitotic divisions in the ovarian cortex to form primary oocytes.The primary oocytesare surroundedby a singlelayer of epithelial cells, which differentiate into follicular cells. The primary oocyte and surrounding follicular cellscomprise a primordial follicle.
Thehormonal control of B. Ducts sexual differentiation is discussed intheReproductive l. Miillerian (paramesonephric)ducts appearasinvaginationsof coelomicepithelium into Physiology chapter of the underlying mesenchymeof the posterior abdominal wall of the embryo during the thisbook. sixth week.Eachparamesonephricduct is divided into three anatomic regions:
298
Embryology
a. A cranial vertical part, which forms the upper portion of the oviduct and opensinto the coelom cavity b. A middle horizontal part, which forms the lower portion of the oviduct c. A caudalverticalpart, which fuseswith the correspondingportion on the oppositeside to form the uterine canal and differentiatesinto the uterus and part of the vagina 2. Oviduct (fallopian tube). In the fourth and fifth months, the oviduct elongatesand becomescoiled. Fimbriae develop at its cranial end, and differentiation of muscle and mucous membranesgivesrise to the infundibulum, ampulla, and isthmus portions of the oviduct. 3. Uterus. The fused paramesonephricducts give rise to the body and cervix of the uterus. The myometrium forms from the surrounding mesenchyme,and the perimetrium is derived from the peritoneal covering. 4. Vagina. The upper one-third of the vagina is derived from the uterine canal.The lower two-thirds of the vagina originatesfrom two outgrowths of the posterior urogenital sinus wall, called the sinovaginal bulbs. Cells of the sinovaginal bulbs proliferate to form the vagrnal plate, which extendsaround the caudalend of the uterine canal.The vaginalplate canalizesin the fifth month. The lumen of the vagina remains separatedfrom that of the urogenital sinusby a thin tissueplate,the hymen, which is derived from the vaginal plate and the urogenital sinus. 5. Ligaments a. As the paramesonephricducts descendthrough the pelvis, they pull a transverse fold of coelomic epithelium and mesenchymetoward the midline. This fold, which extendsfrom the lateral side of the uterine canalto the wall of the pelvis,is known as the broad ligament. b. The caudal end of the ovary is connectedto the genital swelling by a strip of mesenchyme,known as the gubernaculum. The part of the gubernaculumthat connects the ovary and uterus becomesthe round ligament of the ovary. The part that extends from the uterus through the inguinal canal into the labia majora becomesthe round ligament of the uterus. c. The ovary is suspendedfrom the posterior surfaceof the broad ligament by the mesovarium, or suspensory ligament of the ovary. C. External genitalia. The genital tubercle elongatesslightly to form the clitoris, and the genital folds remain unfused and differentiate into the labia minora. Labia majora are formed from the genital swellings.
299
Reproductive System
Table IV-l-f . Derivatives of embryonic genital structures. Embryonic Structure
Male
Female
Indifferent gonad
Testis
Ovary
Cortex
N/A
Ovarian follicles
Medulla
Seminiferous tubules Rete testis
Medulla Rete ovarii
Urogenital mesentery
Mesorchium
Mesovarium
Gubernaculum
Gubernaculum testis
Ovarian ligament Round ligament of uterus
Mesonephrictubules
Ductuli efferentes Paradidymis Aberrant ductules Ductus epididymis Ductus deferens Ureter, pelvis, calyces,and collecting tubules
Epoophoron Paroophoron Duct of epoophoron Duct of Gartner lJreter, pelvis, calyces, and collecting tubules
Mesonephricduct
Epididymis Ductus deferensand seminalvesicle
N/A
Paramesonephric duct
Appendix of testis Prostaticutricle
Hydatid (of Morgagni) Oviduct (fallopian tube) Uterus Vagina (upper)
Urogenital sinus
Urinary bladder (except trigone)
Urinary bladder (excepttrigone) Urethra Urethral glands Greater vestibular glands Vagina (lower)
Urethra (exceptpenile portion) Prostategland Bulbourethral glands
500
Genital tubercle
Glanspenis
Clitoris
Urogenital folds
Ventral (under) aspectof penis-penileurethra (medium raphe)
Labia minora
Labioscrotal swellings
Scrotum
Labia maiora
Embryology
ES ITAIABNORMATITI CONGEN A. Gonadal agenesis.Germ cellseither do not form or do not migrate,and in their absence,the gonads do not develop. The duct systemsand external genitalia differentiate along female lines until birth. B. Truehermaphroditism is the presenceof one ovary,one testis,and externalgenitaliaof both sexes;it rarely occurs. C. Pseudohermaphroditism is the presenceof gonadsand the karyotype of one sex,but secondary sexcharacteristicsof the other. 1. Male pseudohermaphrodites are XY but have a female phenotype. They may or may not have testes. An example of male pseudohermaphroditism is testicular feminization syndrome, where the individual has female external genitalia but an XY phenotype. 2. Femalepseudohermaphrodites are XX but have a male phenotype. They may or may not have ovaries. An example is the adrenogenital syndrome with masculinization of the external genitalia but an XX genotype. D. Cryptorchidism is characterized by undescended testis, unilaterally or bilaterally. This condition is due to abnormalities in androgen production and gubernaculum shortening. Mature spermatozoaare not produced in the undescendedtestisbecauseof the higher body temPerature. E. Congenital inguinal hernia is an incomplete closure of the inguinal canal, which allows intestinal loops to enter the scrotal sac. Obliteration of the passagewaymay be irregular, allowing the formation of hydroceles(watery rysts) along its course. F. Hypospadias is characterizedby an abnormal opening of the penile urethra on the inferior side of the penis, due to failure of the urethral folds to close.A similar defect in females occurs:the urethra opens into the vagina. G. Epispadiasis an abnormal opening of the penile urethra on the superior side of the penis. It is due to faulty positioning of the genital tubercle. H. Duplication of the uterine canal. Lack of fusion of the paramesonephricducts and sinovaginal bulbs results in a double uterus or vagina, respectively. I. Atresia of the uterine canal. Complete or partial atresiaof the paramesonephricducts and sinovaginalbulbs resultsin atresiaof the uterus or vagina,respectively. l. Ovarian hypoplasia is found in patientswith Ttrrner syndrome (XO).Primordial germ cells migrate toward the undifferentiatedgonad but primary follicles fail to develop.Germ cells eventuallydegenerate.The gonad producesno hormones after birth, and sexcharacteristics remain infantile.
501
MaleReproductive Histology Themalereproductive system reproductive organs, thetestes, consists of theprimary andthe genital glands, including secondary organs, a complex series of excurrent ducts, theaccessory and glands Thetestes thepenis. arepaired organs thatfunction bothasexocrine to produce glands spermatozoa in a process to produce called spermatogenesis, andasendocrine malesex hormones, theprimary Thischapter willreview onebeing testosterone. thedifferent tissue types foundinthetestes, aswellasthose foundintheaccessory andglands. ducts
TESTES The testesare composedof many serniniferoustubules, which contain a germinalepithelium wherespermatogenesis occurs.The tubulesareheld togetherby an extensiveconnectivet€sticular stromg which contain the androgen-secreting kydig cells. A. Testicularstroma consistsof the following components. 1. Eachtestisis coveredby a densefibrous capsulecalledthe tunica albuginea. 2. Projectinginward on the posterior border of the testis,the tunica albugineathickensto form the rnediastinumt€stis. 3. From the mediastinum,t}lin connectivetissueseptadivide the testisinto lobules. a. The pfititions betw€enthe lobulesareincomplete. b. Eachlobule containsone or more highly convolutedseminiferoustubules,which collectivelyrepresentthe exocrin€compartment of the testis. 4. Beneaththe tunica albugineais a loos€r conn€ctivetissuelayerwith many blood vessels calledthe tunica vasculosa. a. This layeris continuouswith a highly vascularlayerof delicateint€rstitial connectiv€ tissuelocatedbetweenthe serniniferoustubules' b. The interstitial conn€ctivetissuecontainsthe steroidogenicIeydig cells,which collectively representthe €ndocrine compartm€nt of the testis. B. Seminiferoustubules, the site of spermatog€n€sis, are lined by a complexstratified germinal epithelium composedof two cell types:supportingSertolicellsand spermatogeniccells. 1. Sertoli cells areirregular columnarcellstlat extendftom the basallamina to the lumen andproyide structuralorganizationto the tubr:le.The largeeuchromaticnuclei of Sertoli cellsarehighly folded and containprominent nucleoli.
t:U-!!S!*"[ = seminiferous tubures comDlex stratified eoithelium ,/ Sertoli cells
\ Spermatogenic cells
505
Reproductive System
a. Sertoli cellssynthesizetesticularandrogen-bindingprotein, which helpsto maintain the high androgenlevelswithin the seminiferoustubules necessaryfor spermatogenesis.
Note Theblood-testis barrier is (butnot functionally structurally) to the similar blood-brain barrier.
b. Multiple tight junctions betweenadjacentSertoli cellsform the structural basisfor the blood-testis barrier, which divides the seminiferous tubules into a basal compartment and an adlumenal compartment. ( 1) The basalcompartment containsthe spermatogonia. (2) The adluminal compartment provides germ cellswith an ideal environment for their development.It isolatesthe germ cellsfrom the rest of the body, including the immune system,which could potentially recognizethem as foreign cells. c. Sertoli cellsare alsoresponsiblefor phagocytosisof residualcytoplasmdiscardedduring the maturation of spermatids.
Note Thedevelopment of germ cellsisdependent onpituitary follicle-stimulating hormone (FSH) andontesticular testosterone.
2. Spermatogeniccells are the germ cells located betweenthe Sertoli cells;they consistof spermatogonia,primary and secondaryspermatocytes,spermatids,and spermatozoa. a. In the sexuallyimmature testes,only spermatogonia (i.e., primitive germ cells) and Sertoli cellsare presentin the seminiferouscords. b. At the onsetof maturity, spermatogeniccellsare presentin all stagesof differentiation and are more or lesslayered. c. The spermatogonia,by repeatedmitosis, give rise to primary spermatocytes. d. Primary and secondaryspermatocftes (1) Primary spermatocftes are adjacentto and are larger than the spermatogonia. (2) Eachprimary spermatocyteproducestwo secondaryspermatocytes. (3) Eachsecondaryspermatocytealmost immediatelydividesto form two spermatids. e. Spermatidsare adjacentto the lumen of the seminiferoustubules and are recognizable by their small size.Thesecellsundergo no further division, but becometransformed into mature spermatozoathrough the processof spermiogenesis. C. Spermatogenesisis divided into three components: spermatocytogenesis, meiosis, and spermiogenesis. 1. Spermatocytogenesisbeginswith the spermatogoniacontaining 46 chromosomes,or 23 pairs.After severalmitotic divisions,the cellsdifferentiatewithout division into primary spermatocytes. 2. Meiosis is a unique type of nuclear division that occurs only in germ cells.It is a reduction processthat reducesthe diploid condition of spermatocytesto the haploid condition of sperm. a. First meiotic (reduction) division occurswhen the paired chromosomesbecomeseparated.Primary spermatocytesdivide to form secondaryspermatocytes.
Note Intermsof DNAcontent, primary spermatocytes havefourtimesasmuch asspermatids.
(1) This division is different from ordinary mitotic divisions in that it doesnot consist of separationof sisterchromatids after DNA replication but rather involves the separationof previouslypaired,homologous chromosomes. (2) Meiosis allows for transposition of genetic information; prior to the division (during prophaseof meiosisI), crossing over occursbetweenthe chromatids of the tetrad. (3) After crossingover,each germ cell has a different geneticcomposition than the original spermatogonia.
504
Histology: Male
b. Second meiotic division is a division of the secondary spermatocytesthat results in four spermatids,eachcontaining the haploid number of chromosomes. 3. Spermiogenesisis a di:fferentiationor maturation processin which spermatidsdo not divide but mature to form spermatozoa. a. The spermatidsare envelopedby cytoplasmicprocessesof the Sertoli cellsfrom which they receivenourishment. b. Spermatid vacuoles containing small proacrosomal granules fuse to form a large vacuole,which contains the large acrosomalgranule.As the acrosomalvesicleincreases its zone of contact with the nucleus, it forms a cap over the nucleus known as the acrosomal cap. c. Concurrently,the centriolesmove to the caudalpole of the nucleusto function as the basalbody for the formation of the flagellum of the sperm. d. This processis followed by a posterior redistribution of cytoplasm and by a movement of mitochondria toward the proximal portion of the developing tail of the sperm. e. The posterior cytoplasmis extruded and digestedby the Sertoli cell.
D. Spermatozoa 1. There are approximately 60,000 spermatozoa per cubic millimeter of seminal fluid, or 20M00 million in a single ejaculation. 2. The mature spermatozoaconsistsof a head and a tail. a. The head of the spermatozoonis pear-shaped,and chromatin is enclosedwithin the nuclear envelope. b. The tail piece of the spermatozoonconsistsprimarily of microtubules for the flagellum and mitochondria for the energyof motion.
E. Interstitial cells of kydig are locatedbetweenthe seminiferoustubules in the interstitial connectivetissue.They are epithelioid connectivetissueelementsthat synthesizeand secretetestosterone. 1. The Leydig cells arise from fibroblast-like mesenchymalcells.They have all of the characteristicsof steroid secretorycells:abundant smooth endoplasmicreticulum (SER),mitochondria with tubular cristae,and numerous lipid dropletscontaining cholesterolesters. 2. They occur in groups and are large and polygonal in shape.They contain large,eccentric nuclei. Their eosinophilic cytoplasmis vacuolatedas a result of the large amount of lipid presentfor the production of testosterone. 3. The activity of the interstitial cellsdependsupon the production of luteinizing hormone (LH) by the anterior pituitary gland. 4. Testosteroneis responsiblefor developmentand maintenanceof sexaccessoryorgansand for the appearanceof secondarysexualcharacteristicsin males.
In a Nutshell Spermatogonium (primitive sperm cell)(2n)
I
I mrtosts
t
(2n) 1"spermatocytes
/
\."',,
2" spermatocyte2" spermatocyte (n) (n) r\ /\
tul I \ t"iotit \
snermaid spermatid \ \ spermatid spermatid (n) (n) wheren isdefined asthenumber of chromosomes, andchromosomes cancontain eitheroneortwo chromatids
ln a Nutshell isthe Spermiogenesis differentiation of round spermatids intoelongated spermatozoa: . Formation ofacrosome . Condensation and elongation of nucleus . Development offlagellum . Lossof rytoplasm
Bridgeto Physiology Cholesterol + pregnenolone -+ progesterone -) l7a-0H progesterone + androstenedione + testosterone
505
Reproductive System
EXCURRENT GENITAL DUCTS The system of excurrent ducts provides a conduit for the external transmission of sperm and glandular secretionsduring ejaculation.Some ducts also serveas sitesfor the maturation and storageof sperm. A. Terminal portions of the seminiferous tubules converge toward the mediastinum of the testes. 1. As the tubules approachthe mediastinum of the testes,the germ cellsdisappearfrom the epithelium,leavinga short segmentlined onlyby Sertoli cells.This terminatesin a valvelike structure that prevents reflux back into the seminiferous tubules. The continuous production of testicular fluid by Sertoli cells helps to move the gametesout of the seminiferous tubules. 2. Theseone-way valvesopen into the tubuli recti, which are short, straight channelslined with a simple cuboidal epithelium that connect the seminiferous tubules with the rete testis. B. Rete testis is composed of anastomosinglabyrinthine channelswithin the mediastinum. 1. It is lined with a simple epithelium. Some of the epithelial cells may possessa single flagellum. 2. The passageways of the rete testis convergetoward the efferent ductules. C. Efferent ductules are lined with an epithelium that is pseudostratified. 1. Cilia are present on many of the epithelial cells and may aid in the transport of sperm by beating in the direction of the epididymis. 2. The efferent ductules open into the ductus epididymis at the head of the epididymis. D. Ductus epididymidis is a single, elongated,tortuous duct that may be 6 meters or more in length. 1. The epithelium of this duct is pseudostratified;surface cells contain long microvilli called stereocilia. 2. As the sperm slowly move through the epididymis, they undergo maturation and develop increasedmotility and fertilizing capacity. E. Ductus deferens (vas deferens) is connected with the ductus epididymidis proximally and the urethra distally. 1. The proximal portion of the ductus deferensis somewhatcoiled,but it straightensout as it passesinto the abdominal cavity to terminate in the prostatic urethra. 2. Beforereachingthis point, however,the ductus deferensforms a spindle-shapeddilation, the ampulla. The ampulla gradually narrows to form the ejaculatory duct, which penetratesthe prostategland and emptiesinto the urethra. 3. The ductus deferensconsistsof three layers. a. The mucosa consists of pseudostratifiedepithelium, like that of the ductus epididymidis, and an underlying lamina propria rich in elasticfibers. b. The muscularis is the thickestcoat.It consistsof three smooth musclelayersarranged longitudinally in the inner and outer layers and circularly in the intermediate layer. c. The adventitia is a fibroelastictissuewith numerous blood vesels,nerves,and scattered bundles of smooth muscle.
506
Histology: Male
F. Urethra is the final common pathway of the reproductive and urinary systemsin the male. 1. The urethra extendsfrom the bladder to the end of the penis and consistsof a prostatic portion and a penile portion. 2. The epithelium varies from transitional in the prostatic portion to stratified or pseudostratified in the proximal penis to stratified squamous in the distal penis. G. Sperm storage occurs in the efferent ductules, epididymis, and proximal ductus deferens. 1. Sperm passesrapidly through the straight tubules and rete testis into the storage ducts and are thus rarely seenin the straight tubules and rete testis.
In a Nutshell Urethral Epithelium . Prostatic = transitional . Proximal penis= stratified or pseudostratified . Distal = stratified poflis squam0us
2. The maturation and survival of the sperm in theseducts is aided by a secretion from the epithelium, which, in turn, is dependent upon testosteroneproduction. 3. Following epididymal maturation, sperm is stored primarily in the tail of the epididymis and in the ductus deferens.
ACCESSORY GTANDS Accessoryglands provide the fluid secretionsthat mix with the sperm to form semen.They serve as substratesfor the metabolism of sperm and lubricate the excurrent ducts during ejaculation. A. Seminal vesicles are elongated, convoluted sacsthat lie near the ampullae of each ductus deferensand empty into the junction of the ampulla and the ejaculatory duct. They possess a well-developed muscularis, consisting of inner circular and outer longitudinal smooth muscle fibers. 1. The mucosa is folded, and the epithelium is pseudostratified. 2. They secretea slightly alkaline, viscous fluid into the semen that is rich in fructose and servesas an energy source for the sperm. 3. While spermatozoaare occasionally seen in the seminal vesicles,they are not a storage organ for sperm per se. B. Prostate gland is an aggregationof approximate$ 3f50 small, branched tubuloalveolar glands. 1. The epithelium of the glands is pseudostratified with cuboidal or columnar surfacecells. 2. The ducts leading from these glands to the urethra are lined by a cuboidal epithelium, which changesat the distal end to the transitional epithelium of the urethra.
Clinical Correlate
3. Concretions occur normally in most prostate glands.Theseare sphericalbodies, roughly 250 mm in diameter, which are composed of protein and carbohydrate.Normally, they increasein number with age.
Benignpro$atichypertrophy (BPH) ishyperplasia ofthe glands mucosal thatcanlead to clinically significant ob$ruction oftheurethra.
4. Normal prostatic secretion is rich in citric acid, lipids, zinc, acid phosphataseactiviry and PSA (prostate specific antigen)-a serine protein. C. Bulbourethral (Cowper) glands are two small glands located closeto the baseof the penile urethra. They are surrounded by strands of smooth and skeletalmuscle. 1. The glands are of the tubuloalveolar type. They are lined by a simple epithelium, which rangesfrom columnar to cuboidal. 2. Most of the cells are mucus secreting.The gland secretesa viscous alkaline fluid into the urethra for lubrication prior to ejaculation.
,07
Reproductive System
PENIS This organ is made up of three rylindrical bodies of erectiletissue:two dorsal corpora cavernosa and a singleventral corpus spongiosum.The corpus spongiosum surrounds the urethra and terminates distally as the glans penis. A. Corpora cavernosa consist of a system of irregular vascular channels,or cavernousspaces, separatedby trabeculae. 1. The trabeculae consist of a dense fibrous connective tissue that contains bundles of smooth musclefibers. a. Their surfacesare coveredwith the endothelium that lines the venous spaces. b. In the flaccid penis,the spacescontain little blood and thus appearascollapsedclefts. 2. Each of the dorsal cavernousbodies is surrounded by a thick, resistantfibrous capsule called the tunica albuginea. The inner surface of the tunica albuginea has a plexus of small veins that drain the cavernousspaces. B. Corpus spongiosum exhibits a similar arrangement of erectile tissue. l.
Its fibrous tunic is thinner than that of corpora cavernosa.
2. This body doesnot attain the samerigidity as the corpora cavernosaduring erection. C. The trabeculaeof erectile tissue contain branchesof the deepartery of the penis,which end in small arteries that open directly into the cavernousspaces.
508
Female Reproductive Histology Thefemale reproductive system consists oftheovaries, fallopian tubes(oviducts, uterine tubes), genitalia, glands. uterus andcervix, vagina, andmammary Theovaries arepaired organs external (oogenesis) glands gametes thatfunction bothasexocrine to produce thefemale andasendocrine glands to produce Thissystem a suitable thefemale sexhormones. alsoprovides environment for parturition. fertilization, embryonic, andfetaldevelopment, anddelivery oftheconceptus at The glands glands mammary areimportant compound tubuloalveolar thatproduce theexocrine secretions usedbytheneonate.
OVARIES A. Structural overview. The stroma and parenchyma of eachovary is organized into two zones that blend into one another. 1. The cortex is a broad outer layer that is covered by a visceral peritoneum called the germinal epithelium. The tunica albuginea is a white fibrous connective tissue layer located beneath the germinal epithelium. The cortex contains ovarian follicles and cellular connective tissue. 2. The medulla, or zona vasculosa, is the central deeper layer that consistsprimarily of a looseelasticconnectiveframework and contains many large blood vesselsand nerves. B. Ovarian follicles and follicular development 1. Overview. Ovarian follicles are located in the cortical stroma and are composed of oocytes surrounded by follicular (granulosa) cells. a. Approximately 400,000 follicles are present in the newborn ovaries. Only a small percentageof the oocftes (approximately 450) reach maturity in the adult (i.e., 13 rycles per year x 35 reproductive years). The remaining follicles eventually degenerate through a process called atresia. Atresia may occur at any stage of follicular development. b. Follicular development in preparation for ovulation involves maturational changesin the oocytes and granulosa cells. 2. Primordial follicles consist of an oocyte surrounded by a single layer of flattened follicular cells. a. The primordial follicles are inactive reserve follicles that contain primary oocytes, that is, oocytes arrested in prophase of their first meiotic division. b. As maturation continues, the primordial follicle becomesa primary follicle.
r09
Reproductive System
3 . Primaryfollicles are relatively small and spherical with a central oocyte and one or more layersof cuboidal-like follicular cells. a. The central oocyte has a deeplystaining nucleusand a rather indistinct nucleolus. b. During the growth of the primary follicle, there is a proliferation of follicular cells,an increasein the sizeof the oocfte, and formation of a connectivetissuecapsulearound the follicle by the follicular cells. c. Soon thereafter,small spacesbegin to appearin the follicular mass,which fuseto form the follicular cavity, or antrum. Once the antrum develops, the follicle is termed a secondary follicle. 4 . Secondary (vesicular) follicles continue to enlarge, become more ovoid, and are displacedinto the deeperregionsof the ovary. a. As a result of the continued mitosis of the follicular cells and the increasein the sizeof the antral cavity,the oocfte is pushed to one side of the follicle. b. The oocyte becomes surrounded by a hill of follicular cells known as the cumulus oophorus, and the cells adjacent to the oocyte are referred to as the corona radiata. c. At the sametime, the connectivetissuesurrounding the follicle developsinto a follicular sheath,or theca, with internal and external layers. (l ) Although the entire sheathderivesfrom connectivetissue,the theca interna has epithelioid characteristicsand a prominent vascularbed. The theca externa is more fibrous and lessvascular. (2) The theca interna is separatedfrom the follicular cellsby a follicular basement membrane.Thecacellsproduce androgens,which are convertedinto estradiolby granulosacells. 5 . Zona pellucida. As the oocyte grows, its nucleus becomes large, vesicular, and euchromatic with a large, deeply staining nucleolus.Yolk accumulatesin the cytoplasm,and a thick membrane, known as the zolnapellucida, forms around the outer surface of the oocyte directly beneaththe corona radiata.The zona pellucida is rich in polysaccharides and thus stainsPAS-positive. 6. Graafian follicle is the mature follicle that extends through the entire cortex and bulges out at the ovarian surface. a. Antral fluid continues to accumulateand appearsbetween the cells of the cumulus oophorus. This weakensthe attachment of the oocfte and the corona radiata to the follicular wall and facilitates ovulation. b. The amount of antral fluid continuesto increaserapidly, causingan increasein pressure on the wall of the follicle and on the thin layer of ovarian tissue at the surface of the ovary. c. The follicle eventuallyruptures and the ovum, alongwith its coronaradiata,passesout of the ovary in a processknown as ovulation.
Bridgeto Physiology
(1) The ovum briefly entersthe peritonealcavity and passesinto the fimbriated funnel of the fallopian tube. (2) The ovum must be fertilized within 24 hours or it degenerates.
iscontrolled bythe Ovulation cyclic release of LHandFSH. Themidcycle surge ofLH triggers ovulation.
5r0
(3) Fertilization usually occurs in the upper third of the fallopian tube. The fertilized ovum begins to undergo cleavagealmost immediately as it moves through the fallopian tube to the uterus,where it arrivesapproximately 3 daysafter ovulation.
Histology: Female
(a) Implantation in the endometrium of the uterus occurs approximately 6 days after ovulation. 7. Follicular changes after ovulation result in the formation of the glandular corpus luteum. a. The cellsof the follicle and the thecainterna cellsenlargeand becomeepithelioid.The thecalutein cellssecreteestrogen. b. The cytoplasm of the granulosalutein cells contain yellow pigment and lipid droplets. Thesecellssecreteprogesterone. c. If the ovum is not fertilized,the corpusluteum reachesits maximal developmentapproximately 7 daysafter ovulation and then beginsto degenerate. d. If the ovum is fertilized, the corpus luteum increasesin size for approximately 3 months. The corpus luteum persistsuntil the third trimester before degenerating,and is maintainedby hCG secretedby the placentaltrophoblast of the developingembryo. After day40 of pregnanry,the placentaproducesthe progesteronenecessaryto maintain pregnancy. 8. Changesafter fertilization. The first meiotic division is normally completed within the ovary just prior to ovulation. Therefore,it is a secondary oocyte that is ovulated. Sperm penetration during fertilization activatesthe secondaryoocyte to completethe secondmeiotic division. The final result is a single,mature ovum, albeit with a male pronucleus.Most of the cytoplasm of the primary oocyte ends up in the ovum. The other two cellsresulting from meiosis,which contain very little cytoplasm,are discardedaspolar bodies.
In a Nutshell (2n) l" oocyte
(meiosisr)
/\
2ooocyte lst polarbody
t\ | \
(meiosis ll)
Y\
(n) 2ndpolarbody Oocyte
I
V
Ovum(n)
FAIIOPIAN TUBES The fallopian tubes (uterine tubes, oviducts) are muscular tubes approximately 12 cm long that open to the peritoneal cavity at their ovarian ends and into the uterine cavity at the opposite ends.The function of the fallopian tube is to receivethe oocyte,provide an appropriateenvironment for its fertilization, and transport the zygote to the uterus for implantation. A. Fallopian tube wall is richly vascularizedand consistsof a mucosa, a muscularis,and a serosa. 1. Mucosa consistsof a simple columnar epithelium and a lamina propria of loose connective tissue.TWotypes of cellsoccur in the epithelium. a. Ciliated cells beat toward the uterus. b. Secretory cells produce components of the tubal fluid, which provides nutrients for the zygoteand participatesin the activation of sperm.
In a Nutshell Oogenesis vs.Spermatogenesis . One . Four functional functional ovumand spermatozoa twopolar areproduced bodies are produced . Allprimary . Primary oocytes are spermatorytes present atbirth areproduced throughout lifeafter puberty
2. Muscularis is alayer of smooth muscle that is irregularly arrangedas inner circular and outer longitudinal fibers. 3. Serosaconsistsof a layer of connectivetissuecoveredwith visceralperitoneum. B. Regions of the fallopian tube 1. Infundibulum is the funnel-shapedend that is open to the peritoneal cavity. a. Ridgesof its mucosa extend from the open end like a fringe of branched processes called fimbriae. Fimbriae are coveredwith ciliated cellsthat beat toward the mouth of the tube.
5tl
Reproductive SySem
b. Before ovulation, estrogensinduce engorgement of blood vesselsin the fimbriae, which expandsthe fallopian tube toward the surfaceof the ovary. Estrogenssimilarly induce growth and activity of the cilia as well as enhancement of the peristaltic contractions of the fallopian tube. 2. Ampulla is the thin-walled longest region of the oviduct. Fertilization usually occurs in the ampulla. This is also the most frequent location of ectopic pregnancy. 3. Isthmus is a narrow, thick-walled segmentnearestto the uterine wall. 4. Uterine (interstitial) segment is the portion of the tube that traversesthe uterine wall.
UTERUS The uterus is a pear-shaped,6.5-cm-long organ composed of an upper fundus, a dilated body, and a lower cylindrical portion called the cervix. The cervix bulgesinto the vaginal lumen at the external os. A. Uterine wall is relatively thick and is formed by three coats: an inner mucosa called the endometrium, a thick (12-15 mm) muscular layer called the myometrium, and an outer serosallayer called the perimetrium. 1. Endometrium is lined by a simple columnar epithelium composedof ciliated and nonciliated cells. a. The lamina propria contains numerous fibroblasts.Many tubular glands,consisting mainly of columnar secretorycells,extend into the endometrium. b. Different layers of the endometrium are distinguishable. (1) The basalis,the deeperlayer,is relativelythin and is not dischargedduring menstruation. Its glands changevery little during the menstrual rycle. (2) The functionalis, the superficial layer,undergoesthe cyclic ovulatory changesof the menstrual cycleand is lost at menstruation. 2. Myometrium is composedmostly of smooth muscle,connectivetissue,and prominent blood vessels.During pregnancy,the myometrium undergoestremendousgrowth in size due to cell division and growth. a. Four layersof the myometrium are distinguished: the innermost and outermost layers are mainly longitudinal, while the middle layers contain circular and longitudinal fibers. b. The innermost middle layer, called the stratum vasculare, contains many blood vesselsand mostly longitudinal fibers. 3. Perimetrium is a serousmembrane that forms the peritoneal layer of the broad ligament and coversthe body of the uterus and part of the cervix. B. Cyclic endometrial changes occur monthly in preparation for ovulation and fertilization of the ovum. In preparation for pregnancy,the endometrium undergoeshlpertrophy of its glandular, vascular, and interstitial components. If the ovurn becomes fertilized and the embryo implants, this hypertrophy continues. If the egg is not fertilized, the endometrium breaks down and the tissue,as well as some blood, is dischargedas menstrual fluid. The first day of the menstrual rycle is, by convention,the first day of the menstrual flow. There are four stages through which the endometrium passesduring the menstrual rycle. The average menstrual cvclelasts28 davs.
tl2
Histology: Female
1. Menstrual stage occupiesthe first 3-5 daysof the cycle and is characterizedby menstrual flow. 2. Proliferative (estrogenic) stagebegins during the later stagesof menstrual flow and continues through the 13th or 14th day of a typical 28-day cycle. This stageis characterized by the regrowth of endometrium from what remains after menstruation. a. The epithelial cells of the glandular structures remaining after menstruation migrate and proliferate to cover the new mucosal surface. b. Spiral arteries also grow into the regeneratingendometrium. c. Significant edema develops by the end of the proliferative stage and continues to develop during the secretoryphase. d. During proliferation, the endometrium increasesin thicknesssix-fold. 3. Secretoryphasecontinuesthe hlpertrophyof the endometrium. a. Mitosis has ceasedby this point. The tissue expandsby cellular hlpertrophy and by an increasein vascularity and edema.At the same time, the spiral arteries continue to grow toward the mucosal surface. b. At the beginning of the secretorystage,glycogen,mucigen, and various lipids accumulate rapidly in the glandular cells of the functionalis. c. During the second half of the secretoryphase,the secretionsmove from the basal region of the glandular cells to the apical region. d. Once the glycogen,mucin, and lipid secretionsappearin the lumina of theseglands, the secretorystagehas ended. 4. Premenstrual phase consists mostly of changes in the spiral arteries that lead to the breakdown of the functionalis. a. Constriction of the spiral arteriesleadsto anoxia and ischemia.The glands degenerate along with their endometrial surface,and blood and tissue debris appear in the uterine lumen. b. Menstrual blood is fibrinolytic and, therefore, does not clot. C. Uterine changesin relation to the ovary. Cyclic changesof the uterus are closely associated with cyclic changesof the ovary. 1. The onset of menstruation correspondsto the involution of the corpus luteum. 2. The proliferative phaseof the uterus correspondsto the preovulatory period of follicular maturation. 3. Ovulation normally occurs at the end of the proliferative phase. a. Ovulation occurs 14 daysbefore menstruation begins. b. It may occur anytime between the 8th and the 20th day of the cycle,but most commonly, occurson the llth, 12th, or 13th day. 4. The secretoryphaseis associatedwith the luteal phaseof the ovary. 5. Estrogen is necessaryfor the proliferative phase,and progesteroneis necessaryfor the secretoryphase. a. The appearanceof estrogenprecedesthat of progesteroneand is responsiblefor the appearanceof progesteronelater on in the menstrual cycle.
In a NuBhell Fourstages of endometrial changes duringthe menstrual cycle: (l) Menstrual (days I to 3-5) . Menstrualflow . Coincides withinvolution of corpus luteum (2) Proliferative (endof men$rualflowtillday13or 14) . Regrowth of endometium . Coincides withdevelopmentof ovarian follicles production andestrogen . Ovulation occurs atend ofthisphase (5) Secretory (l5thto 2sthday) . Occurs afterovulation . Depends onprogesterone fromcorpus luteum, whichstimulates glandcellsto secrete glycoprotein (4) Premenstrual . Breakdown offunctional layer of endometrium
tr!
Reproductive System
b. If the ovum has not been fertilized, the degenerationof the corpus luteum 12 days after ovulation leads to a rapid drop in progesteroneand estrogenlevels.The funcand menstrual flow commencesbecausethe endometrium is no tionalis degenerates, longer being maintained under the direction of thesehormones.
D. Uterine changesin relation to fertilization 1. If the ovum is fertilized, the developing embryo implants in the endometrium on approximately the sixth day after ovulation. 2. Once the developingembryo implants, its chorionic membrane proliferatesinto a trophoblast, which eventually completely coversthe embryo. a. Irregular spacesthen appearin the trophoblast,which are eventuallyfilled with maternal arterial blood from the spiral arteriesthat supply the developingembryo.
Flashback to Principles General Fertilization isreviewed in detail intheEmbryology section oftheCeneral 2 (Volume ll). Principles Book
b. The trophoblast layer changesthroughout pregnanry. 3. The original, inner cellular layer of the trophoblast givesrise to an outer, syncytiallayer on approximatelythe 1lth day of pregnancy. a. Thesetwo layerspersistthrough the first half of pregnancy,after which time the inner cytotrophoblast layer slowly beginsto decreasein size,becoming inconspicuousand leaving only the outer syncytiotrophoblast layer. b. Underneaththe two layersof trophoblast,the embryonic mesenchymedevelops. 4. Villi with a core of mesenchymegrow from the trophoblastic surfaceand becomechorionic villi. In the connective tissue core, branches of the fetal blood vesselsappear. Eventually,thesevilli attach to the chorion and form the chorionic plate. 5. There are two tnres of chorionic villi: anchoring and floating. a. Anchoring villi anchor the decidua of the endometrium to the chorionic plate. b. Floating villi arebranchesof the anchoringvilli. They traversethe spacesbetweenthe chorionic plate and the deciduain which maternal blood circulates. 6. At the same time that the embryo developschorionic villi and the chorionic plate, the endometrium forms the decidua basalis, which consistsof differentiated stromal cells called decidual cells.
E. Placenta. The placenta developsin the uterus during pregnancy,and has both fetal and maternal components. The function of the placentais to allorv for exchangeof nutrients and wasteproductsbetweenthe maternal and fetal circulations.While the maternal and fetal circulationsare completelyseparate,they passvery closeto eachother, allowing for exchange of materials.
ln a Nutshell
1. The fetal component consistsof the chorionic plate and villi. It lies adjacentto the spaces near the endometrial deciduathrough which the maternal blood circulates.
Placenta consists of:
2. The maternal component of the placentais the deciduabasalis.
. Fetal portion (chorionic plate andvilli)
3. The maternalblood vesselsfrom the deciduapassinto the intervillous spacesof the placenta, where floating villi are present.
. Maternal portion (decidua basalis)
a. Maternal blood is separatedfrom fetal blood by severallayersof tissue (i.e., cftotrophoblast, syncytiotrophoblast,a basementmembrane,little or no fetal mesenchyme and fetal capillary endothelium). b. The proximity of the floating villi to the maternal blood allows for the exchangeof nutrients (from maternal) and wastes(from fetal) betweenthe two circulations.
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Histology: Female
c. The placenta is selective; not all substancescan be transmitted to the fetus from the mother. F. The cervix contains a thick muscular wall, which is a continuation of the corpus of the uterus. 1. The mucosa,which doesnot undergo cyclic changes,containsdeep transversefolds. 2. The surfaceand glandular epithelia are composedof simple columnar mucus-secreting cells,whose product fills the lumen of the cervix.
ClinicalCorrelate Thecervical $romaisoften infiltrated withinflammatory cells, whichappear in response to microorganisms.
3. Ovarian hormones, especially estrogens, influence cervical stromal growth. The Pap smear,developedby Papanicolaou,screensfor any cervical abnormalities.
VAGINA The vagina is a flexible tubular organ that extends from the vestibule of the external genitalia to the cervix. There are no glands in the vagina, and the mucus lubricating it originates from the glands of the cervix and the vestibular glands.The fibromuscular wall consistsof a mucosa, muscularis,and adventitia. A. Mucosa consistsof severaltransversefolds, or rugae. 1. It is composedof a stratified squamousepithelium, a basementmembrane,and an underlying lamina propria. 2. Vaginal epithelium is rich in glycogen,which increasesthroughout the menstrual rycle as estrogenlevelsincrease. a. During the estrogenic(i.e.,follicular, preovulatory) phaseof the menstrual rycle,vaginal fluid has a lower pH than during the rest of the cycle as a result of the formation of lactic acid by bacteria from the carbohydratesin the vaginal epithelium. b. The drop in estrogenand therefore in glycogen causesan increasein vaginal pH and thus an increasein the likelihood of infection.
In a NuBhell
c. Lymphocytes and polymorphonuclear leukocytes are commonly found beneath the epithelium, especiallyduring menstruation, when they also appear as free cells in the lumen of the vagina. B. Muscularis of the vagina consistsmostly of longitudinal bundles of smooth muscle,with an inner circular layer. C. Adventitia is composed of denseconnective tissue and attachesthe vagina to the surrounding structures.
VaginalWall -+ Outside Inside -+ Adventitia Mucosa-+ Muscularis JJV Stratified Smooth Dense squamous muscle connective epithelium tissue
EXTERNAT GENITATIA The external genitalia (or vulva) of the femaleincludesthe clitoris,labia minora,labia majora, and vestibularglands. A. Clitoris is an erectilestructure homologous to the dorsal portion of the penis. 1. It is composedof two corpora cavernosa,containing erectiletissueenclosedin a fibrous membrane. 2. The clitoris is lined by stratified squamousepithelium.
5t5
Reproductive System
B. Labia minora are two small folds of skin containing a spongy connective tissue core. 1. The epithelium is keratinized,stratified squamous,and contains cellswith melanin. 2. Sebaceous and sweatglandsare numerous on both sidesof the folds. C. Labia majora are two prominent folds of skin containing a large quantity of adiposetissue and a thin layer of smooth muscle. 1. The inner aspectis similar in composition to the labia minora. and the outer aspect is coveredwith skin and coarse,curly hair. 2. Sebaceous and sweatglandsare numerous on both sidesof the folds. D. Vestibular glands (of Bartholin) are similar in structure to the bulbourethral glands in the male. The secretionsof the vestibular glands help to lubricate the vagina, which lacks glands of its own. 1. Thesemucous glandsare two small round bodies situatedon eachside of the vestibulum (i.e.,the cleft betweenthe labia minora). 2. Minor vestibularglandsthat secretemucus are alsopresent.
MAMMARY GTANDS The mammary glands are modified sweat glands that respond to hormonal changes.They secretevarious componentsof milk by merocrine and apocrine mechanisms. A. Mammary gland structure consistsof secretory alveoli and a compound duct system that opens onto the surface of the skin at the mammary papilla, or nipple. 1. Eachmammary gland consistsof approximately15--20lobes. a. Eachlobe is an independentcompound gland, drained by a separatelactiferous duct that opensat the nipple. Dilations of the lactiferousducts, before they open onto the surfaceof the nipple, are called lactiferous sinuses. b. The lobesare enclosedin a layer of denseconnectivetissueand are surroundedbv adiposetissue. c. Eachlobe is subdividedinto lobules,and within the lobules,ducts and alveoli are supported by loose reticular connectivetissue. 2. The lactiferousduct is lined by stratified squamousepithelium and branchesinto terminal ducts entering each lobule as an intralobular duct. a. The epithelium lining the smaller ducts is simple cuboidal and becomesstratified squamousnear the opening to the cutaneoussurface. b. Myoepithelial cells are at the baseof the smaller ducts. 3. The secretory alveoli begin to develop at puberty, when the immature mammary gland comesunder the influence of estrogenand progesterone. a. True secretoryalveoli are not presentuntil pregnancy. (1) Early secretions that are rich in protein and poor in lipids are known as colostrum. Colostrum is availableto the newborn in the first few days.It contains many antibodies that help protect the newborn. (2) Protein and relatedcomponentsare secretedby a merocrine mechanism,whereaslipid componentsare secretedby an apocrine mechanism.
5t6
Histology: Female
b. Myoepithelial cells with extensivecontractile filaments in their cytoplasm occupy the spacebetweenthe secretorycellsand their basementmembranes. B. Nonlactatingmammaryslurd
The glandular tissueof a mature, nonpregnant woman is scanty.
1. The glands are grouped together as lobules and appearnarrow as a result of the lack of mammary secretions,which, if present,would distendthe lumina of the glandsand ducts. 2. The mammary glands lack a capsule,but an extensiveinterlobar connectivetissue contains abundant adiposetissue. C. Mammary gland during pregnancy. The inactive glands form buds that expand to form alveoli. 1. The alveoli are lined by a simple cuboidal epithelium with a thin basementmembrane. 2. During gestation,there is continuous production of both estrogen and progesterone, which results in the full development of the mammary glands. a. The production of milk components is called lactation. It requires prolactin, a polypeptide synthesizedand releasedby the adenohypophysis. (1) Milk is a proteinaceousfluid (consistingof casein,lactose, and salts)in which the milk lipids are suspended. (2) Milk is alsorich in calcium, an element necessaryfor the growing infant. b. If the mammary gland is primed by estrogen,progesterone,corticosteroids,and insulin, then prolactin stimulatesmilk secretion. 3. Oxytocin, produced by the hypothalamusand stored and secretedby the posterior pituitary, causesthe contraction of the myoepithelial cells. These cells surround the alveoli and subsequentlycausethe ejection of milk. The stimulus of suckling on the nipple area sendsneural impulses to the hypothalamus,initiating oxytocin secretion,and, in turn, milk secretion, or let-down. D. Mammary gland after menopause. The mammary glands atrophy, with the lobules and ducts becoming obliterated. The connectivetissue becomesincreasinglydense,occupying the spacewhere the lobules and ducts were formerly present.
Note Attheendof pregnancy, lymphorytes andplasma cells increase in number inthe intralobular connective tissue glands. ofthemammary This leads to secretion of lgA, passive whichconfers immunity onthenewborn.
In a Nubhell . Prolactin + milkproduction (anterior phuitary) . Oxytocin + milksecretion (etiown)(po$erior pituitary)
tl7
Anatomy Reproductive Thisbriefchapter reviews oftheexternal andinternal organs of boththemale thegross anatomy andfemale reproductive systems. Thearterial supply, venous andlymphatic drainage, and innervation of reproductive organs arealsodiscussed.
PERINEUM The perineum is the diamond-shapedareabetweenthe thighs; it supports the external genitalia. The perineum is divisible into two triangles (Figure IV-4-1).
Clitoris Bulbospongiosus muscle lschiocavernosus
muscle
Crus of clitoris
Vestibularbulb Bartholingland
Superficial transverse perineal muscle
lschialtuberosity
Externalanal sphinctermuscle Levatorani muscle Anococcygealligament Coccyx
Figure lV-4-1.Theperinium in the female.
A. Urogenital triangle 1. Superficial pouch contains the cavernous bodies (corpora cavernosa and corpora and bulbospongiosus)in both spongiosa)and their associatedmuscles(ischiocavernosus men and women.In women, the superficialpouch alsocontainsthe vestibular(Bartholin) glands.
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Reproductive System
2. Deep pouch consistsof the urogenital diaphragm, which is a sheet of muscle, and the superior and inferior perineal fasciae.The muscular portion includes the sphincter urethrae in men and the sphincterurethraeplus the sphinctervaginaein women. In men, the deep pouch also containsthe bulbourethral (Cowper) glands. B. Anal triangle
ClinicalCorrelate
1. External anal sphincter
Anabscess oftheischiorectal fossa mayspread fromone sideto theotherthrough the communicating anterior recesses. These infections generally poorly respond to antibiotic therapy.
2. Ischiorectal fossais a bilateralwedge-shapedspacebound by the pelvic diaphragm medially and the obturator internus laterally.This spaceis filled by the ischiorectalfat pad. The anterior recessesof the ischiorectal fossaeextend forward superior to the urogenital diaphragm and are continuous acrossthe midline.
MATEREPRODUCTIVE VISCERA
l'I
ti
Retrovesical pouch
Urinarybladder Ductusdeferens
Seminal
Ejaculatory duct
n.;
Prostategland Medianlobe (M) Anteriorlobe (A) Posteriorlobe (P) Urethra
Urogenital diaphragm
;-
Penis
Bulbourethral gland
Figure lV-4-2.Male pelvis. A. Testis.The male gonad originatesfrom the posterior wall of the abdomen,not in the pelvis. The testesdescendthrough the inguinal canal to the scrotum. l. Tunica vaginalis is a double-layeredderivative of the peritoneum. Its visceral surface coversthe testis. 2. Scrotum is a cutaneoussacderivedfrom the anterior abdominal wall. It housesthe testes and providesan environment a few degreesbelow body temperature,which is suitablefor sperm development. 3. Spermatic cord consists of ductus deferens,nerves, blood vessels,and fascial layers externalto the tunica vaginalis.
,20
Anatomy
4. Blood supply. The major arterial supply is from the testicular artery, which is a branch to of abdominal aorta.Venousdrainageis from the pampiniform plexus, which coalesces form the testicular vein. 5. Lymphatics. The scrotum drains to the superficialinguinal nodes,and the testisdrains to the para-aorticnodes. 6. Innervation. The genital branch of the genitofemoral nerve suppliesmotor fibers to the cremastermuscle.The ilioinguinal nerve suppliesthe skin of the scrotum and the medial thigh with sensoryfibers.
ClinicalCorrelate by torsion iscaused Testicular along thetwisting ofthetestis cord. theaxisofthespermatic spontaneously, It usually occurs by andcanoftenberesolved anduntwisting manipulating thecord.
B. Epididymis is a paired tubular structure that conveyssperm from the efferent ductules of the testisto the vas deferens(ductus deferens).Sperm must spend time within thesestructures to becomeviable. C. Vas deferens is a paired muscular duct that carries sperm to the prostatic urethra via the ejaculatoryduct. D. Seminal vesicle is a paired gland located posterior to the urinary bladder that produces a viscous,alkaline component of semen.The ducts of the seminal vesiclesjoin with the vas deferensto form the ejaculatoryducts. E. Prostate gland is a single structure that lies inferior to the bladder and transmits the prostatic urethra. Prostaticsecretionsenter the urethra through minute ducts. l. Blood supply. Arterial blood to the prostate comes from branchesof the internal iliac artery.Venousdrainageis from the prostatic venousplexus,which drains to the internal iliac veins and communicateswith the vertebralvenousplexus. 2. Lymphatics. The lymph of the prostatedrains mostly to internal iliac nodes. F. Penis 1. Structure
ClinicalCorrelate to mayspread Prostatic cancer andCNS thevertebral column venous viathevalveless ofthe interconnections prostatic plexus with venous plexus. venous thevertebral
a. Root of the penis is locatedin the superficialpouch. It containsthe bulb and the crura of the penis. b. Body of the penis (1) Corpus spongiosum is located ventrally; it transmits the penile (spongy) urethra. Its terminal portion is the glans. (2) Corpora cavernosaare paired, dorsallylocatedbodies of erectiletissue. 2. Arterial supply. The penis is suppliedby branchesof the internal pudendal artery,which is a branch of the internal iliac artery. 3. Venous drainage. The deep dorsal vein, which drains the sinusoidal spacesof the cavernousbodies,joins the prostaticvenousplexus.The superficialdorsalvein drains superficial layersand joins the superficialexternalpudendalvein. a. Lymphatics. Most of the penis drains to the superficialinguinal nodes. 5. Innervation. The musclesof the superficialpouch are suppliedby motor branchesof the pudendal nerve,which is derived from sacralspinal nerves2,3,and 4. Erection of the penis is under parasympathetic control (pelvic splanchnic nerves), and ejaculation involvesboth sympatheticand parasympatheticstimulation.
tzl
Reproductive System
FEMATE REPRODUCTIVE VISCERA
Oviduct
Ureter
Uterus
Suspensory ligament
f ne.tout*in.
Round ligament
I pouch(pouch
I
of Dougtas)
Vesicouterine pouch
Posterior fornix
Urinary bladder
Cervix Vagina
Urethra Clitoris
"'o''" ---,,.. --"-,_ri;r,r..,
Urogenital diaphragm
Figure lV-4-3.Female pelvis.
A. Vulva 1. Structure a. Labia majora are the skin swellingsthat lie lateral to the labia minora and vestibule. They are homologousto the scrotum in men. b. Labia minora are the thin, mucosalfolds that flank the vestibule. c. Vestibule is the central areathat contains openingsfor the urethra, vagina,and ducts of the vestibular (Bartholin) glands.
ClinicalCorrelate Anepisiotomy isanincision made during childbirth to facilitate deliveryof the infant's head. lt isperformed either in plane themedian or mediolaterally ghthe throu perineal bodyto avoidtearing of theexternal analsphincter.
d. Clitoris is a mass of erectile tissue located anterior to the vestibule.Its structure is similar to that of the penis. e. Perineal body is locatedposterior to the vestibuleand is a massof fibrous tissuethat separatesthe vagina from the anal area. 2 . Blood supply. The arteriesof the superficialperineal areain women are mostly branches of the internal pudendal artery.The labia majora are supplied by the external pudendal arteries.Venousdrainageof the areais via branchesof the internal pudendal vein, which drains to the internal iliac vein, and the externalpudendal veins,which drain to the great saphenousvein. 3 . Lymphatics. Skin and fascia of the vulva drain to superficial inguinal nodes, and the clitoris drains to the internal iliac nodes. 4 . Innervation. Motor branchesof the pudendal nerve supply the musclesof the superficial pouch, and the cutaneousareasreceivesensorysupply from the ilioinguinal and pudendal nerves.The clitoris,like the penis,is supplied by autonomic and sensoryfibers.
t22
Anatomy
B. Ovary. The femalegonad,like the testis,descendsfrom the posterior wall of the abdomen but remains in the pelvis and does not enter the inguinal canal.A portion of the gubernaculum, the ligament that extendsfrom the gonad through the inguinal canal in both sexes,remains as the round ligament of the uterus in women. 1. Ovarian ligament is the proximal remnant of the gubernaculum, which attachesthe ovary to the uterus. 2. Suspensoryligament of the ovary attachesthe ovary to the lateral pelvic wall and conveysthe ovarian vessels. 3. Cuboidal epithelium is a specializedsurface epithelium that is continuous with peritoneal mesothelium.This epithelium allows the egg to rupture into the peritoneal cavity following ovulation. 4. Blood supply. Arterial blood reachesthe ovary from the ovarian artery, a branch of the abdominal aorta.Venousdrainageis through the ovarian veins. 5. Lymphatics. Lymph vesselsfollow the courseof the ovarian artery and vein. They drain to the lumbar para-aortic nodes. C. Fallopian tubes (uterine tubes,oviducts) 1. Pairedstructuresthat receivethe ovum following ovulation. 2. Ferttlizationnormally occursin the ampulla (outer one-third) of the tube. D. Uterus is a muscular,hollow organ. 1. Fundus is the dome-shaped,upper portion of the uterus. 2. Body is the major part of the uterus. 3. Cervix is the narrow inferior neck of the uterus that protrudes into the vagina. 4. Supports of uterus. The levator ani muscle and the round and broad ligaments offer variable support to the uterus. Additional support comes from the transversecervical (cardinal) ligaments(of Mackenrodt) and the sacrouterineligaments. 5. Blood supply. Arterial supply to the uterus is derived primarily from the uterine branch of the internal iliac artery.Venousdrainageis mostly through the correspondinguterine vein. 6. Lymphatics. The lymphatic drainageis multiple through the para-aortic nodes,the external and internal iliac nodes,and the superficialinguinal nodes (from the round ligament in the inguinal canal). E. Vagina is a muscular tube extending from the uterine cervix to the vaginal opening of the around the cervix. perineum. Fornices (anterior and posterior) are the vaginal recesses 1. Arterial supply. The vaginal artery is a branch of the internal iliac artery.There is also a vaginal branch of the uterine artery. 2. Venous drainage. Vaginalveins drain to the internal iliac vein. 3. Lymphatics. Lymph from the vaginadrains to the externaland internal iliac nodesaswell as to the superficialinguinal nodes.
ClinicalCorrelate pregnancies Tubal ectopic of intheampulla usually occur Thetube tube. thefallopian willrupture atapproximately causing 12weeks of gestation, acute, lower severe, pain. lf left abdominal of thereisa danger untreated, to death. bleeding ClinicalCorrelate directly Theureterpasses artery, to theuterine inferior lateral to thebodyofthe with uterus nearitsjunction ("water flowsunder thecervix a During thebridge"). the hysterectomy, therefore, (instead oftheuterine ureter artery)maybeinadvertently ligated. ClinicalCorrelate pouch Therectouterine (ofDouglas) isthemost partofthe inferior peritoneal inwomen. cavity a to obtain Culdocentesis fluidisa of peritoneal sample performed viatheposterior fornixofthevagina.
4. Innervation. The vagina is supplied by nervesderived from the pelvic splanchnicnerves and the hypogastric plexus, and in its lowermost portion by somatic fibers from the pudendal nerve.
t2!
Reproductive System
F. Breast l. The breast (mammary gland) is a subcutaneousglandular organ of the superficialpectoral region. It is a modified sweatgland, specializedin women for the production and secretionof milk. A variable amount of fat surrounds the glandular tissueand duct system and is responsiblefor the shapeand sizeof the femalebreast.
ClinicalCorrelate Breast cancer develops most frequently intheupper outer (superolateral) quadrant, where thereisa preponderance of glandular tissue.
a. The nipple containsthe openingsof the lactiferousducts. It is located approximately at the level of the fourth intercostalspacein nulliparous women and in men. It contains circular,smooth musclefibers that contract during emission (let-down) of milk from the ducts. b. The areola is a variable areasurrounding the nipple. It containssebaceousglands. c. There are 15-20lactiferous ducts, each of which drains a glandular lobule of breast tissue.The ducts radiate outward from the nipple. The terminal portion of eachduct, the lactiferous sinus, is dilated. d. Cooper ligaments are suspensoryligaments,which attach the mammary gland to the skin and run from the skin to the deep fascia. 2. Arterial supply. Most of the blood supply to the breast is derived from branchesof the internal thoracic (internal mammary) artery. However, the lateral thoracic and thoracoacromialbranchesof the axillary arlery and the intercostalarteriesalso contribute to the blood supply. 3. Venousdrainage.Venousblood from the breastdrains primarily to tributaries of the axillary vein. 4. Lymphatic drainage. Most of the lymph of the breastdrains to axillary nodes (pectoral group). Lymphatics from the deep surfacedrain to the apical group of axillary nodes. From the medial surface,lymph drains to the parasternalnodes,which accompanythe internal thoracic vessels.It may passto the parasternalnodes of the oppositeside. 5. Innervation. Sensoryfibers from the breast contribute to intercostalnerves2-.6.These nervesalso carry sympatheticfibers,which supply the smooth muscleof the areolae.
t24
Physiology Reproductive intothe secreted primarily of hormones balance physiology bya delicate isgoverned Reproductive leadto thedesired putintomotion thateventually of events a sequence hormones blood.These thedifferent among theinterplay willdiscuss Thischapter tissues. bythetarget response pregnancy, and play gametogenesis, reproduction, in hormones aswellastherolethey reproductive aswellasthe differentiation of sexual control thehormonal lt alsoreviews thepuerperium. to oldage. frompuberty development rolein reproductive hormonal
HORMONES REVIEW OFSTEROID A. C2l steroids-pregnenes (pmgestins, corticoids). These steroid hormones are either involved with pregnancy (progestational, progestins) or rnade by the adrenal cortex (corticoids). The major progestin, progesteron€, is made in the greatest quantities in the ovary. B Cl9 steroids-androgens. Androgens are male sex steroids that are synthesizedin both men and women. They are produced in the testes,ovaries, and t}te adrenal corter
Fhshba*
to End'Gdne
TheLeydig cells cannot
MA1EREpRODUCIION A. Androgen s€cretion 1. Production of the predominantandrogen,testosterone,is via a s),ntheticpathwaythat (or$n)' ana dehydroepiandrosterone includespregnenolone,17-hydrory-prelnenolone, Leydig cells ofthe testis in both the This synthesis occurs asintermediates. androstenedione andthe adrenalgland.
svnthesizeslucocorticoi mineralocorticoids because theYdo not haglFhydroxylaseor I I Flrydroxylase'
2. Dihydrotestosterone (DHT) is a metabolic product of testosterone'Conversion to DHT is catalyzedby So-reductase.This conversionis a necessarystep for androgen actionin manytissues. Oscillationsfollow an 3. There are biologicallyimPortant small oscillationsof Gstosterone. and LH from the pituitary' hlpothalarnus equalnumberof pulsesof GnRHsecretionby the 4. Thereis a natural declinein androgensecretionwith agingin bot}l malesand fema.les.
,25
Reproductive System
Gholesterol ACTH stimulates---* | chotesterol desmolase thisreaction V 17,20-lyase 17u-hydroryrase ' - l7-hydroxyPregnenolone > Dehydropregnenolone 3p-hydrorysteroidI epiandrosterone dehydrogenase (DHEA) Y Zona Progesterone 1 sB-hYdrory- Reticularis 21 B-hydroryla"" lsteroid dehy/ \ fdrogenase 17,20-lYase I \ ll-Deorycorticosterone l7-Hydrcxyprogesterone-* Androstenedione I 21 p-hydrorylase | p-hydrorylase | 11 | (mostcommon Iesfes Y V Y deficiency) and Corticosterone 11-Deorycortisol Testosterone I Angiotensinll --->l atdosterone Ovaries p-hydrorylase | 11 stimulates sVnthase { V V thisreaction Aldosterone Estradiol Cortisol Zona Glomerulosa
Zona Fasciculata Figure lV-5-1. Pathways in steroidogenic cells.
Note No,it'snotyourimagination: you Thisisthesame chart reviewed intheEndocrine Physiology chapter.
B. Transport of androgens in blood. Testosteronecirculates bound to sex hormone-biodiog globulin (SHBG).SHBG binds testosterone,DHT, and estradiol.At least90oloof testosterone is bound. Androgens suppressliver production of SHBG. Therefore,compared to females, males have lower levels of SHBG and higher levels of free androgens. C. Metabolism of androgens. The half-life of testosterone is approximately 90 minutes. Testosteroneis activated in specific target tissuesto DHT, which is more potent in some tissues. D. Mechanism of action of androgens.In prostate, hair follicles, and external genitalia, testosterone is activatedto DHT in order for action in that tissueto occur. The active molecule then binds directly to the nuclear androgenreceptor and activatesmRNA transcription. E. Physiologic effects of androgens 1. Fetal. The physiologic effectsof androgenson the fetus are so profound that an entire section on sexualdifferentiation is included later in this chapter. 2. Spermatogenesis a. The sertoli cells participate in the initiation of spermatogenesis when FSH binds to receptorson the sertoli cell. Testosteronefrom the Leydig cells entering the seminiferous tubules is also necessiuyfor spermatogenesis. This intratesticularaction of testosterone on spermatogenesis is an exampleof paracrine effect. b. The spermatogenictubules are surrounded by a lymphatic sinus that bathes the tubules in high concentrationsof testosterone. c. Testosteronealso actson the Sertoli cellsand stimulatesthe production of androgenbinding protein (ABP).ABP carriesandrogensin the spermatogenictubules toward the epididymis. While some ABP enters the circulation, it is not the major plasma androgen-bindingprotein. As noted earlier,SHBG is the major carrier of androgens in the plasma. d. The Sertoli cell also secretesinhibin. Inhibin inhibits FSH secretionby the pituitary gland (seefollowing sectionon control).
526
Physiology
3. Internal ducts and organs a. Epididymis. High levelsof testosteroneare essentialfor epididymal function. These levelsare derived from transport from the testis inside the duct system.Circulating levelsof testosteroneare inadequatefor epididymal support. b. Vas deferens.Circulating levelsof testosteronesupport function of the vas deferens. Testosteroneis essentialfor optimal function of both the muscular componentsof the vas as well as its epithelial lining. c. Seminal vesicles.Testosteroneis essentialfor the production of seminalvesiclefluid, a major component of seminalfluid. d. Prostate.The prostatemust convert testosteroneto DHT before activiry can occur.In a condition where the enryme 5c-reductase(the enzymethat convertstestosteroneto DHT) is greatly reduced or absent,the prostate gland never develops.DHT causes growth and secretionin the prostategland. Growth becomesa problem in older men who developbenign prostatic hypertrophy (BPH). As the prostategland enlarges,it can occludethe urethra and causea characteristicconstellationof symptoms,including urinary frequenry,urgency,and nocturia. 4. External genitalia a. Scrotum. During and after puberty,DHT is responsiblefor the thinning and development of folds (rugation) of the scrotum. This greatlyincreasesthe surfaceareaof the scrotum and allows for heat transferto keep the testescool. The lower temperatureis essentialfor normal sperm production, as well as optimal testosteroneproduction. DHT is alsoresponsiblefor scrotumpigmentation.
Bridgeto Pharmacology with BPHcanbetreated thatblockthe drugs of testosterone conversion finasteride). to DHT(e.g.,
b. Penis.DHT is essentialfor enlargementof the penis at puberty. 5. Pubic and axillary hair. DHT is essentialfor developmentof pubic and axillary hair in both males and females.DHT alsoincreasesbeard growth (this is counteractedby estrogensin females)and is responsiblefor the temporal pattern of balding seenin males(also counteractedby estrogensin females).If 5u-reductaseis absent,males have very scant facial,pubic, and axillary hair and temporal balding patternsdo not appear. 6. Larynx. At puberty, androgensincreasethe sizeof the larynx in both malesand females, deepeningthe voice. 7. Sebaceousglands. Sebaceousgland activity increasesin responseto androgens.During the pubertal transition phase,this activity leadsto acne (mi1d to severeforms). 8. Behavior a. Androgens are responsiblefor maintenance of the libido in males and probably females.Cultural and psychologicalaspectsalso greatlyinfluence sexualbehavior. Although there is b. Androgens are also thought to be responsiblefor aggressiveness. is still forthproof definitive hypothesis, this to support much anecdotalevidence coming. 9. Anabolic actions of androgens a. Effect on muscle. Testosteroneis the most potent anabolic steroid. Syntheticanabolic steroids(the legaland illegalvarieties)are all essentiallymodificationsof the basicC19 androgen.Testosteroneincreasesprotein synthesis in musclesand increasesthe overall in muscle,and testosterone(not DHT) muscle mass.There is very little 5cr-reductase appearsto be the predominant effectorof androgenactivity.
527
Reproductive System
b. Growth spurt. At puberty, both males and females have an acceleration of linear growth. Testosteroneis presumably the major factor in males,and probably synergizes with estrogenin females.The mechanismmay be direct (there are androgenreceptors in the end platesof long bones) or indirect by stimulating growth hormone secretion, which then stimulatesIGF-1 production. c. Epiphyseal maturation. Androgens have paradoxical effects on bone. They causethe acceleration of long bone growth, but they also stimulate the closing of the epiphyseal plates (end plates).Thus, androgenslimit growth. This is regulatedby the total amount of androgensthat the long bones are exposedto. Thus, adding exogenous androgens(such astaking anabolicsteroids)would result in premature closureof the long bones and a decreasedadult height. F. Control of testosterone secretion (Figure IV-5-2)
CNS Hypothllamus
I
GnRHI
+
gonadotrophs Pituitary
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\t.l
FSH
/\ Leydigcells
ti/
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/ \t*r
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Figure lV-5-2. Control of testosterone secretion.
l.
GnRH from the hypothalamusis secretedin ryclesof l2-24bursts per 24hours. It stimulatesthe pituitary gland to synthesizeand releaseLH and FSH.
2. LH stimulates the Leydig cell to synthesizeand secretetestosterone. 3. FSH stimulatesthe Sertoli cell to synthesizeand releaseABP and inhibin. 4. Testosteronestimulates the seminiferous tubules and synergizeswith FSH to initiate and maintain spermatogenesis. Testosteronealso feedsback at both the hypothalamus and pituitary gland to slow production of GnRH and block synthesisand secretionof LH. 5. Inhibin feedsback to the pituitary gland to block synthesisand secretionof FSH. However, the importance of inhibin in male reproduction is still not completely understood. 6. Input from higher centersin the central nervous system (CNS) can either stimulate or inhibit hypophysealsecretion of GnRH. G. Regulation of penile erection 1. Erection is mediated by the parasympatheticnervous systemand ejaculation is mediated by the sympathetic nervous system. a. The autonomic neurons that stimulate erection have been termed nonadrenergic, noncholinergic (NANC) autonomic neurons and they release nitric oxide (NO).
528
Physiology
b. The NO is releasedat a myoneuraljunction on the vascularsmooth musclecellsof the corpus cavernosum.The NO binds to the iron in the heme molecule of guanylate ryclase and activatesthe ryclase to form cGMP. This, in turn, results in a decreasein intracellular calcium and subsequentsmooth muscle relaxation and vasodilatation in the corpus cavernosa,resulting in erection. 2. The initial stimulation for erection is usually through the central nervous system. Androgen action in the central nervous systemis essentialfor normal libido and erection to occur. Androgens are also necessaryto maintain normal amounts of nitric oxide synthase,the enzymethat synthesizesNO. Thus, androgensare essentidboth in the CNS and in the penis for normal erection to occur. H. Sperm transport
Clinical Correlate Sildenafil citrate isthefirst FDA-approved oralmedication forthetreatment of erectile dysfunction. Sildenafil inhibits thephosphodiesterase inthe corpus cavernosum that converts The cCMP to CMP. potentiates increased cCMP thevasodilatation responsible forerection.
1. Tiansport from testis to epididymis. Sperm are shed from seminiferous epithelium along with fluid that is constantlysecretedinto the lumen. The fluid is moved with the sperm in suspension.The sperm are not motile or fertile at this stage.Contractile elements in the tubules and lamina propria along with the tunica albugineapropel the fluid forward. Additionally, fluid absorption in the ductule efferentescausesa decreasedpressure downstream and thus a hydrostatic pressure differential that drives the fluid forward. There is a high concentrationof testosteronein this fluid. 2. Transport within the epididymis a. Becauseof fluid absorption (up to 90o/o)in the efferent ductules,the sperm are concentratedupon entry into the head of the epididymis. b. Sperm can stayin the epididymis and survive up to 40 days.Sperm are transported to the body of the epididymis by peristalsisand move to the tail of the epididymis by continued peristalsis.In the tail, a protein is formed called forward motility factor. The interaction of this factor plus testosteroneon the sperm allow the sperm to become motile. They are still, however,not fertile (not able to fertilize an ovum). 3. Transport from epididymis through the urethra a. The muscle-to-lumenratio of the vas deferensis greaterthan in any other tube in the body. Major muscular contractions in the vas deferensdrive the sperm through the rest of the male reproductive tract. It is possiblethat the muscular contractions are facilitated by oxytocin and prostaglandins. b. At the sametime that the vas deferensis contracting during ejaculation,fluid (from the prostategland and the seminalvesicles)is emitted. ( 1) Prostaticfluid is alkaline and helps neutralizethe acid pH of the vagina. (2) Most of the seminal fluid is from the seminal vesicles.Fluid from the seminal vesiclescontainsfructoseand prostaglandins.The fructoseprovidesan oxidative substratefor sperm, while the prostaglandinsmay be involved in induction of contractionsin the uterus to help propel the sperm forward. c. When the seminal vesiclesexpel their fluid, the rush of fluid past the opening of the terminal portion of the vas deferensdraws sperm out of the vas deferens. I. Testosterone insensitivity syndrome (testicular feminization). This genetic anomaly which results in a male genotypewith a female phenotype is due to inactive or improperly formed testosteronereceptorson cells.As a result, individuals are incapableof responding to any testosteronestimulation. Suchpeople are in many respects"perfect" females,lacking any testosterone-inducedcharacteristics.
t29
Reproductive System
a. Due to the presenceof the Y chromosomethey lack a uterus and ovariesand harbor internal testes. b. The condition is usually detectedat the age of puberty with a chief complaint of amenorrhea. c. Becausesuch individuals are physicallyappearing and psychologicallyfemale,treatment usually involvessurgeryto: (1) Remove the ineffective testes (which at internal abdominal temperaturesare likely to becomemalignant) (2) Enlargeand extend the blind vagina to accommodatesexualintercourse d. Although relativelyuncommon, the syndromeis a sourceof confusion for the understanding of testosteroneaction. (1) Thesewomen undergo a growth spurt at the ageof puberty and are usuallytaller than the averagewoman and are frequently thought to be quite beautifrrl. They are often found working asfashion models.Their long-bone growth cannot be acceleratedby testosterone,nor can their epiphysealplatesbe prematurelyclosed. (2) They have libido despiteno effectivetestosteroneaction and they describethe urge to have children which, of course,can be satisfiedonly by adoption. (3) Sinceneither the hypothalamusnor pituitary can respond to testosterone,there
;T:#:*:i:f :"1*;:,Hli;*il:ii#fi':i::J#:"x#:1Jl
promotion of protein synthesis and the production of hormone-binding globulins (TBG, CBG, SHBG) and all the generalizedactionsof estrogensnot involving the primary sexorgans.
FEMATE REPRODUCTION A. Synthesis of ovarian hormones 1. Pathway in theca interna-androgen synthesis. Cells in the theca interna have receptors for LH. LH binding to its receptor on the cell membrane stimulates the conversion of cholesterol to pregnenolone. Pregnenolone is converted in a series of steps to androstenedione,an androgen.Androgensare secretedfrom thecal cellsand are carried to the granulosacellsaswell asto the blood.
In a Nutshell Estrogen formation is synthesized viaa two-cell process. Androgens (androstenedione, primarily) produced are inthetheca interna cellandconverted to estrogens inthegranulosa cell.
550
2. Pathway in granulosa cells-<strogen synthesis. The granulosa cell contains receptors for FSH. FSH binding to its cell membranereceptorhas two functions. First, it stimulates aromatase to convert androstenedione to estrone, which is then converted to estradiol. Second,FSH stimulatesthe production of new LH receptorson the granulosacells. 3. Pathway in corpus luteum-estrogen and progesterone synthesis. Corpus luteum cells are derivedfrom both theca interna cellsand granulosacells. a. Thecainterna cellshavevery little aromataseenzymeand thus do not make estrogens. As the cell luteinizes, aromatase enzymes develop and thus, LH stimulates the cells to produceestrogens.Progesterone, which is alreadyin the pathwayfor the production of androgens,is also secreted. b. As noted, granulosa cells already possessthe enrymes necessaryfor conversion of androgensto estrogens.FSH induces LH receptorsin this cell and as it luteinizes,it develops the enzymes necessaryto convert cholesterol to androstenedione. Progesterone, from the cholesterolto androstenedionepathway,is alsosecreted.
Physiology
c. Thus, both types of luteal cells(those derived from theca interna cellsand those derived from granulosacells) havethe ability to make androgens,estrogens,and progestins. B. Hormone transport l.
Estradiolbinds to SHBG,the samebinding protein that carriestestosteronein the blood.
2. Progesteronebinds to corticosteroid-binding globulin (CBG). Although it is a sex hormone, progesteroneis structurally closerto the glucocorticoidsthan to the androgensor estrogens(it is a 21-carbon steroid rather than 19- or 18-carbonsteroid). Thus, it binds to the glucocorticoid-binding protein rather than the sexhormone-binding protein. C. Hormone metabolism and mechanism of action 1. Estrogensand progesteroneare metabolized by sulfonation in the liver and kidney. The sulfates make these compounds water soluble and they can then be excretedin bile or urine. 2. Progesteroneis also metabolized to dihydroprogesterone.This is catalyzedby the same enzymethat convertstestosteroneto dihydrotestosterone( 5o-reductase). 3. Thesesteroidsexert their mechanism of action by binding to a cytoplasmic receptor. The hormone-receptor complex migrates to the nucleus and promotes transcription. The recent discoveriesof the estrogen cr and B receptors has given new insight into estrogen action and allowed the developmentof new estrogenicdrugs that have specificestrogen actionswhile being devoid of other estrogenactions. D. Physiologic effects 1. Estrogen effects on sex characteristics a. Estrogensare the primary hormones responsiblefor breast growth. b. Estrogenis necessaryfor ovulation. c. Estrogen stimulates contraction of the fallopian tubes. It acts by increasing oxytocin receptors in the fallopian tubes. Estrogensalso increasethe size of the epithelial cells lining the tubes and increasesthe rate of beating of the cilia in those cells. d. Estrogenshave many effectson the uterus. (1) Promote endometrial growth (both hypertrophy and hyperplasia)of endometrial cells (2) Increaseboth the length and number of the endometrial glands (3) Increaseblood flow to the uterus (4) Increasethe length of the coiled arteries (5) Increasethe amounts of actin and myosin in the myometrium (6) Increasethe spontaneousmuscular activity of the uterus,probably by increasing oxytocin receptors (7) Increasethe concentrationof estrogenand progesteronereceptors e. Estrogensmake the cervical mucus thin and watery. f. Estrogensthicken the mucosallining of the vagina.During sexualexcitation,estrogen stimulates vaginal epithelial cells to produce a transudate secretion (called vaginal sweating). g. Estrogens(possibly in combination with androgens)causean increasein labial and clitoral growth.
551
Reproductive System
h. Estrogensmay play an indirect role in the libido of females (as in the male, libido is probably increasedprimarily due to androgens). 2. Generalized actions of estrogens a. Estrogens,like androgens, are anabolic. They promote growth and, in combination with androgens,are probably responsiblefor the growth spurt at puberty and epiphysealclosure. b. Estrogenspromote protein synthesis.One classof proteins that are of specificimportance is the hormone-binding globulins (TBG, CBG, SHBG). Estrogensstimulate the liver to increaseproduction of thesebinding globulins. Estrogens also increase highdensity lipoproteins (HDL) and decreaselow-density lipoproteins (LDL). c. Estrogenspromote salt and water retention. This is most readily observed in the uterus. d. Estrogensare responsiblefor fat deposition. This is seen most prominently in the breasts,hips, and skin. e. Estrogensare responsiblefor inhibiting bone resorption. This is one of the primary reasonspostmenopausalwomen are given estrogenreplacementtherapy. 3. Progesterone effects. Progesteroneprepares the uterus for pregnancy. a. It causesfurther proliferation of the endometrium after estrogen has had an initial stimulation. b. It counteractsthe action of estrogenin sensitizingthe uterus for muscular contraction. Progesteroneprobably accomplishesthis by blocking the action of oxytocin, not by blocking the synthesisof oxytocin receptors. c. Progesteroneand dihydroprogesteroneincreasebasalbody temperature. 4. Androgen effects. Androgens are secreted by the ovary in very significant amounts, though clearly not to the same levels as in males. The role of androgens in the female is understoodto a much greaterextent than the role of estrogensin males. a. Androgensare responsiblefor pubic and axillaryhair growth in femalesaswell asmales. b. While estrogensinhibit bone resorption,evidenceis rapidly accumulatingthat androgensstimulate deposition of new bone. c. Androgens are also responsiblefor the basal levels of libido in both male and female.
E. Menstrual cycle (Figure IV-5-3). Although almost all schematicrepresentationsof the menstrual cyclehave a starting and ending point, it must be remembered that this is a cycle with no fixed beginning or end. We have arbitrarily chosento begin with the start of menstruation. The cycle representedis 28 days long. This is the averagehuman female cycle,not the normal cycle.TWostandard deviations from the mean givesan approximate range of normal rycle length from 2l*35 days. 1. Follicular phase a. Declining progesteronelevels from the previous menstrual cycle releaseits negative effect on the pituitary gland and hypothalamus.As progesterone falls, the cyclicity of GnRH increases,i.e.,there are more spikesper 24 hours. This stimulatesFSH secretion. b. FSH stimulates the follicle to grow and produce more estrogen. Estrogen has a positive effect on the GnRH cyclicity and increasesthe number of spikes per 24 hours. Increasingestrogenlevels then feedbacknegativelyto suppressFSH. LH levels are essentiallyconstantduring this phase.
ttz
Physiology
60 -
Folliclestimulating hormone - - - Luteinizing t l hormone tt ll
ll
50
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l l
t l
t l
-r 40 €
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-200
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Figure lV-5-3. Monthly cycles of FSH, LH, estrogen, and progesterone.
2. Midcycle. As estrogenincreasesrapidly at the end of the follicular phase,this createsthe positive feedback of estrogen on the hypothalamus and pituitary gland and increases the number of GnRH spikesper 24 hours, causinga surgeof both FSH and LH. It is probably the rate of estrogenrise,not the actuallevels,that inducesthis positivefeedback.The surge of LH, in combination with the high estrogen levels, induces ovulation.
3 . Luteal phase a. After ovulation, the cellsfrom the Graafianfollicle collapseinto the antrum and form luteal cells.Progesteroneis secretedin greatlyincreasedquantitiesascomparedto the follicular phase. it is not being driven by any parallelincreasesin LH. b. Note that asprogesteroneincreases, of the corpusluteum, essenThe increasein progesteroneis due to neovascularization tially providing a greatersurfaceareafor transport of progesteroneinto the blood. c. Although LH doesnot rise, its presenceat low levelsis essentialfor normal luteal cell function. d. Progesteroneslows the cyclicity of GnRH. Although estrogenis also increased,the effect of progesteroneis greaterand the GnRH surgesare much lessfrequent. e. LH and FSH levelsare essentiallyconstant. f. The corpus luteum then undergoes luteolysis and progesterone and estrogen levels decrease.The exacttriggering mechanismfor luteolysisis not known. When levelsof progesteroneand estrogenare decreasedto low enough levels,the lining of the uterus is no longer hormonally supported and the cellsundergo apoptosis. g. With the cells dying, the lining of the uterus shedsand the menstrual period begins. The suppressiveeffectof progesteroneon the hypothalamusis removedand the number of GnRH spikesper 24 hours increases.We are now back at the beginning of the follicular phaseand the cyclerepeats. 4. Basalbody temperature (BBT). Note that the basal body temperature rises after ovulation during the luteal phase of the cycle. This changeis probably due to the action of dihydroprogesteroneon the temperatureregulation centersin the hypothalamus.
ltT
Reproductive System
5. Inhibin. The ovary, like the testis, secretesinhibin. Inhibin inhibits FSH secretion. However,regulation of FSH in the female is more complex than in the male becauseestrogensalsoinhibit FSH secretion.Inhibin appearsto play only a minor role in the female. 6. Regulation of uterine activity and ovum transport during the menstrual cycle a. Follicular phase. During the follicular phase there is an increased estrogen/progesterone ratio. This ratio is usedto predict the effectson uterine activity.When the estrogen/progesteroneratio is increased,the oxFtocin receptors increase and uterine and fallopian tube motility is increased. Under oxftocin stimulation, the fimbriae of the oviduct start to sweepover the ovary in order to "capture" any eggthat is ovulated. b. Midcycle. The estrogen/progesterone ratio remainshigh and at midcycle,the fimbriae achieve maximum sweeping frequenry over the ovary. As the egg is released,it is picked up by the fimbriae and beginsits travel down the oviduct. The oviduct itself is moving in segmentalwavesand the rate at which the cilia lining the fallopian tube beat toward the uterus increases.As the ovum (which is surrounded by the corona radiata cells) moves towards the uterus, it travels through the ampullary portion of the fallopian tube. At the junction betweenthe ampulla and isthmus of the fallopian tube (ampullary-isthmic junction), the contractionsbecomeso frequent that the junction essentiallygoesinto tetany and constricts,therebyblocking passageof the ovum. The ovum remains at this point of the fallopian tube to await fertilization. Most fertilization occurs at the ampullary-isthmic junction or in the ampulla. c. Luteal phase. During the luteal phaseof the cycle,the estrogen/progesterone ratio is decreased,and the contractions of the fallopian tube and uterus decrease.This also relaxesthe ampullary-isthmic junction, allowing the possibly ferttlized ovum (now a morula) to be releasedand travel toward the uterus.Rememberthat during the follicular phase,estradiol increasedthe numbers of progesteronereceptorsso that now, during the luteal phasewhen progesteronelevelsare increased,progesteroneactivity is potentiatedand the action of oxytocin is inhibited (via a postreceptormechanism). Now that the uterus is calm, the blastocystcan implant in the endometrium. F. Sperm transport in the female reproductive tract 1. Sperm activity in the vagina a. When sperm are depositedin the vagina,they are not able to fertilize the ovum. They must undergo capacitation. Seminal fluid contains decapacitationfactors that keep the sperm from gaining the ability to fertilize. If sperm stay in the female reproductive tract for several hours, they acquire the capacity to fertilize an ovum. However, if freshly ejaculated sperm are washed in culture medium, they quickly gain the ability to fertilize. Thus, there are factors normally in sementhat keep the sperm decapacitated.Once sperm are capacitated,they havea shorter life span (2 daysmaximum). In the decapacitatedstate,they live longer (possiblyone week). b. The prostaticand seminalvesicularsecretionsare alkalineand help neutralizethe acid media of the vagina.The vaginalenvironment is neutralized.toa pH of 7.0-7. ,which is optimal for sperm motility. 2. Major impediments to sperm transport a. Cervical mucus. During most of the menstrual cycle,the cervical mucus is thick and not easilypenetratedby sperm. The sperm move via flagellar motion but have difficulty traversing the cervical mucus plug. During midcycle, the cervical mucus becomes thin and watery due to the action of estrogen (an increased estrogen/progesterone ratio). The mucin strands,which are normally coiled and tangled with one another, straighten out and actually form channelsof mucin strands that are approximately the
t!4
Physiology
width of a sperm head. The sperm are then able to quickly swim up the channel and enter the uterine lumen. b. Uterus (1) Travelof sperm through the uterus is not well understood.This processcannot be flagellar becausethe sperm move through the uterus and oviduct much too quickly to be attributed to flagellar motion alone. Some form of active uterine transport must be present. (2) Overall, the pH of the uterus is not good for sperm motility. The contractions ratio is high so contractions are induced at midcycle (estrogen/progesterone most frequent) are oppositein direction to the direction the sperm are traveling. c. Uterotubal junction. The uterotubal junction is highly folded and estrogen stimulation causesswellingof the tissueso that much of the lumen is occluded. G. Regulation of uterine activity during pregnancy and labor 1. Pregnancy.If pregnancyoccurs,the corpus luteum continues to grow and secreteprogesterone.Therefore,the estradiol/progesterone ratio is low. Progesteronelevelscontinue to rise throughout pregnancy,thus keeping the ratio low. Sincethe ratio is low, the uterus remainscalm. 2. Labor. The mechanismfor the actual initiation of labor is still unknown. It appearsthat it is probably causedby the fetal hypothalamic-pituitary-adrenalaxis. The most comratio changes. monly acceptedtheory is that just before term, the estrogen/progesterone However,the mechanismof this changealso has at leasttwo explanations. a. The first is that maternal progesteronelevelsfall in responseto elevatedfetal cortisol levels.Elevatedfetal cortisol doeshavespecificknown effects,suchaslung maturation. If progesteronefalls while estrogenremains constant,then the estrogen/progesterone ratio increasesand the uterus can now respondto oxytocin. b. The other possible explanation is that estrogenincreasesin relationship to progesterone.This can alsobe accomplishedby activatingthe fetal adrenalgland to produce more DHEA. The DHEA is then easilyconvertedto estradiol by the placentaand the ratio increases.Rememberthat estradiol maternal circulating estrogen/progesterone also increasesoxftocin receptors so that the uterus, at the end of pregnancy,has approximately 100 times the concentration of oxytocin receptorsas compared to the non-pregnant state.Thus, without changing the oxytocin concentration, the action of oxftocin is still amplified becauseof the increasedconcentration of the receptors. 3. Delivery. As the uterus beginsto contract at the beginning of labor, the head of the fetus is pusheddown againstthe cervix.This causessome cervicalstretch.As the cervix stretches,neural stretch receptorstransmit information to the hypothalamusfor new synthesis and secretionof oxftocin. Circulating oxftocin rises,causinga greatercontraction of the uterus and further expulsion of the fetus. The upward spiral (positive feedback)of this neuroendocrinereflex continuesuntil the fetus is expelled.Contractionswill continue for a short time after the fetus is delivered and are helpfirl in shutting down blood vesselsin the uterus and expelling the placenta.Once the placenta is expelled,positive feedback ceasesand oxytocin levels fall. H. Placental hormones and the endocrinology of pregnancy 1. Polypeptidehormones a. Human chorionic gonadotropin (hCG)
555
Reproductive System
(l) hCG is similar in structure to LH, FSH, and TSH in that it has both alpha and beta chains.The alpha chain is the sameas that of LH, FSH and TSH. The beta chain is different and confersthe specificityof hCG and makesit biologically different from the other hormones. (2) hCG binds specificallyto LH receptorsand is a potent LH agonist.hCG stayson the LH receptor for a longer time than LH does and this accounts for its increasedpotenry.
ClinicalCorrelate ln additionto pregnancy, hCC levels arealsoelevated in women withchoriocarcinoma moles. andhydatidiform
(3) hCG is synthesizedin the syncytiotrophoblast and secretedinto both the fetal and maternal circulations. hCG is manufactured in very high amounts and secretedinto the urine of pregnant women. Measurementof hCG in the urine is the basis of the home pregnanry tests.Circulating hCG (specifically,the beta chain) is usually measuredby the physicianto confirm pregnancy. (4) During the first trimester, HCG is responsiblefor stimulating the corpus luteum to produce estradioland progesterone. b. Human placental lactogen (hPL; human chorionic somatomammotropin [hCS]). hPL is similar in structureand function to prolactin and growth hormone (GH). hPL is secretedby the syncytiotrophoblastinto both the fetal and maternal circulations.It does not function like prolactin in the pregnant woman (i.e., for milk production) becausethe breast is not preparedfor the production of milk. Milk production will come after pregnancy,when hPL is no longer present.hPL is more like GH and binds to the GH receptor aswell as to the prolactin receptor.
2. Steroid hormones a. Progesterone (1) Progesteroneis initially manufactured by the corpus luteum (stimulated by hCG). The corpus luteum of pregnanry does not undergo luteolysis like the corpus luteum during the menstrual cycle.At 8 weeksof gestation,the corpus luteum of pregnancystartsto decline in function and by 10-12 weeksof gestation the placenta takes over the production of progesterone. (2) Progesteroneis formed in the placentavia the normal steroid pathway.The placenta does not contain any l7a-hydroxylase,so it cannot hydroxylateand cannot cleavethe side chain betweencarbons 17 and 20. Thus, progesteroneis the end product of this steroid biosyntheticpathway. b. Estrogens (1) Estrone and estradiol. Eventhough the placentadoesnot contain 17cr-hydroxylase,it is able to form androgensand estrogensfrom DHEA-sulfateprovided by the maternal and fetal adrenalgland. DHEA-sulfateis desulfatedto DHEA. (2) Estriol. Estriol production, like estrogenand androgenproduction, dependson functional fetal and maternal adrenalglandsand a functional placenta.The one differenceis that estriol production also dependson a functional fetal liver. 3 . Function of hormones during pregnancy a. hCG. The primary role of hCG is to keep the corpus luteum functioning and producingprogesterone. hCG declinesto much lower levelsafter the deterioration of the corpus luteum of pregnancy. b. hPL. hPL primarily functions like GH. It is glucosesparing and makesglucoseavailable from the mother for the fetus.Like prolactin, hPL increasesestrogenreceptorsin the breast.
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Physiology
c. Progesterone. The primary function of progesterone is to calm the uterus. Progesteroneblocks oxytocin receptor activation by u postreceptor mechanism. Progesteronealsoactsasan immunosuppressantand blocks cellular-mediatedimmunity at a very local level. Specifically,the very high levelsof progesteronein the placentakeepthe fetus from being rejected.The circulating levelsof progesteroneare not high enough (although they are higher than at any other time in life) to be immunosuppressive. d. Estrogens.All three estrogensrise throughout pregnancy. (1) Estrone and estradiol help keep the endometrium functional during pregnancy so that the placentaand fetus are well maintained. Estrogensalso stimulate breast tissue during pregnancy and increase the blood flow to the uterus. Estrogensthat passto the fetus are inactivatedby a fetal protein called alphafetoprotein. This protein binds estrogensso tightly that very little, if any, free estrogenis available.However,it doesnot bind androgensat all. (2) Estriol is a very weak estrogen; it binds very weakly to the estrogenreceptor. However,estriol is very good at increasinguterine blood flow and thus may keep the uterus well supplied with blood without hyperestrogenizationin other aspects. I. Preparation for lactation prior to birth 1. Function of estrogens.Estrogensincreaseseveralparametersthat will be essentialfor milk formation after pregnancy. a. During pregnancy,estrogensare continually rising and sensitizethe pituitary to secretemore prolactin. b. The rising estrogenlevelsalso increasethe total number of estrogenreceptorsin the breast. c. Estrogenalsoincreasesthe number of progesteronereceptorsin the breast. d. Estrogensstimulate ductal elongation in the breast. e. High estrogenlevelsinhibit milk formation. 2. Function of progesterone.Progesteronecombined with estrogencausesalveolargrowth. High levelsof progesteronemay alsobe inhibitory to milk formation. 3. Function of prolactin and hPL a. Prolactin (which increasesduring pregnancy due to increasingestradiol levels) and hPL increaseestrogenreceptorsin the epithelium of mammary glands. b. Although the breastis being preparedfor lactation, no milk is produced (due to very high levelsof estrogenand possiblyprogesterone).Toward the end of pregnanry and the beginning of the period right after pregnancy(the puerperium), the alveoliare full of colostnun, a thin, watery fluid that is rich in antibodies.During the first few days after delivery,colostrum is the fluid that the newborn usesfor nourishment. L Hormonal regulation of milk production and secretion 1. Estrogens and progesterone. After birth, estrogen and progesterone levels decline. However,it takesseveraldaysbefore the levelsare low enough to allow lactation to begin. Estrogenand progesteronelevelsdo not go to zero; some estrogenand progesteroneis required for lactation.
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Reproductive System
2. Permissivehormones. In addition to the necessityof low levelsof estrogenand progesterone,other "permissive"hormones are alsonecessaryat low levelsfor lactation to occur. Thesehormones are insulin, thyroxine (or triiodothyronine), and cortisol. 3. Prolactin. In the presenceof the hormones mentioned above,prolactin stimulatesmilk production. The feedbacksystemthat regulatesthe secretionof prolactin is a neural feedback, not hormonal. Prolactin synthesis and secretion is under tonic inhibition by dopamine (prolactin-inhibiting hormone). The primary neural feedback for prolactin secretion is nipple stimulation. Nipple stimulation suppressesdopamine release and thus removes the inhibition of prolactin secretion. 4. Oxytocin a. Oxytocin causes contractions of the myoepithelium, resulting in milk let-down. Oxytocin doesnot stimulatemilk production like prolactin does.This is another neuroendocrine loop. The suckling stimulus sendsa neuronal impulse to the hypothalamus that releasesoxytocin into the bloodstreamfrom the posterior pituitary. b. Other stimuli will also result in oxftocin secretion.Psychologicstimulation will causea releaseof oxytocin. The two primary psychologicsituations that induce oxFtocin release are the mother hearing the ba\ crylng and mental sexualstimulation. fu was pointed out for the situation for labor, stretching of the cervix induces oxytocin stimulation. Additionally, stimulation of the external genitalia resultsin oxytocin stimulation. K. Return of hormonal cyclicity after birth. The return of hormonal cyclicity after birth is dependenton the recoveryof the profound suppressionof LH and FSH presentduring pregnancy and lactation. During pregnancy,the high levelsof estrogenand progesteronehave kept the hypothalamic-pituitary axis suppressed. At the end of pregnansy,levelsof estrogen and progesteronefall to low levelsbut prolactin continuesto remain high if nursing occurs. High levelsof prolactin will also suppressLH and FSH. Thus, the longer nursing continues, the longer the suppressionof LH and FSH.
HORMONAT DIFFERENTIATION CONTROT OFSEXUAT A. Genetic sex. Genetic sex is determined at the instant of fertrlization. If the embryo is XX, it will develop into a female; if the embryo is XY, it will develop into a male. 1. A true hermaphrodite is an individual that is both XX and XY and possessesall of the sexual structures of both femalesand males.This is extremely rare in nature. 2. Nomenclature for describing abnormalities of sexualdifferentiation alwayscompare back to the genetic sex of the individual. a. A phenotypic female that is genetically XY is called a male pseudohermaphrodite. b. A phenotypic male that is genotypically XX is called a female pseudohermaphrodite. B. Gonadal sex. The primitive gonads arise bilaterally from a region near the developing adrenalglands.The primitive gonad consistsof a cortex and a medulla. 1. In an XX genotypefemale,the cortex grows and the medulla atrophies.Thus, the cortex becomesthe adult ovary. 2. In an XY genotype male, the medulla expandsand the cortex atrophies,with the medulla forming the precursor of the adult testis. The medulla secretesa substancecalled "testis determining factor," which is coded for on the Y chromosome. This factor causesregression of the cortex and induction of the medulla.
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Physiology
C. Development of internal duct systems 1. Wolffian ducts (mesonephric ducts). The Wolffian ducts will develop into the adult male internal duct systemconsistingof the epididymis, vas deferens,and seminal vesicles.The prostategland and the urethra developfrom the urogenitalsinus.The ducts are present in both males and femalesuntil approximately 8 weeksof age. a. At this point in the female, the Wolffian duct begins to degenerate,starting at the gonad and progressingtoward the urogenital sinus. The ovary during this period is quiescentand is not producing steroids. b. In the male,testosteronsslaSilizestheWolffian duct. Testosteronewill stabilizeall of the structuresof theWolffian duct asthe hormone drains toward the urogenitalsinus. However,as it reachesthe prostate gland, it must be convertedto DHT in order to induce prostatic outgrowth of the urogenital sinus.The prostatic and penile urethra are also DHT dependent. 2. Miiilerian ducts. The Mtillerian ducts develop lateral to the Wolffian ducts. They are also presentin both sexesuntil actedupon by a protein from the Sertoli cellsof the fetal testis called anti-Miillerian hormone (AMH). a. In males,AMH causesthe active degeneration of the Miillerian ducts. b. In females,there is no AMH and the Mtillerian ducts continue to proliferate and become the adult female internal duct structures.This includes the fallopian tubes (oviducts),the uterus,and the upper two-thirds of the vagina.The lower one-third of the vagina is of ectodermalorigin and is produced by the infolding of ectoderm. D. Development of external genitalia. The external genitalia begin in an indifferent stagethat is identical in both sexes.Development into the male structures is entirely DHT dependent. If no hormones are present (as is the casewhen an ovary has developed)the female structures develop.
ln a Nutshell Early in development, both maleandfemale fetuses have bothsetsof internal duct systems, theWolffian ducts andtheMUllerian ducts. The produces testis twomajor hormones, testosterone and AMH.Thetestosterone stabilizes theWolffian ducts, thereby stabilizing themale reproductive AMH tract. induces degeneration ofthe Mullerian ducts andtherefore getsridofthepotential female structures inthemale. lnthe developing female, the absence oftestosterone results ina failure to stabilize the Wolffian ducts andthemale ductsystem disappears. Since theovaryis notmakingAMH, theMullerian ductsystem remains into andproliferates theinternal female reproductive tract.
E. Neural differentiation. Male hormones appear to induce a male sexual brain, while the absenceof male hormones leadsto the developmentof a femalesexualbrain.
In a Nutshell
ANDAGING REPRODUCTIVE DEVETOPMENT: PUBERTY A. Prepubertal reproductive development 1. Birth to 6 months of age.In males,there is a postnataltestosteronesurgethat may have importance in future sexualbehavior. There is no concomitant estrogenor androgen surge in the female. 2. Early state of the hypothalamic-pituitary-gonadal axis. In the early prepubertal axis, gonadalsteroidsdo not feed back to the hypothalamusand pituitary gland. LH and FSH serum levels (reflecting diminished secretionby the pituitary gland) are low. Additionally, GnRH secretionis also minimal and noncvclic.
lf androgens arepresent and the5a-reductase enzyme is genitalia active intheexternal primordia, thenthefetus will genitalia. develop maleexternal Theabsence of hormones allows fordevelopment of genitalia. female external
B. Puberty 1. Underlying mechanisms regulating maturation of the hypothalamic-pituitarygonadal axis a. Sleep-associated hormone secretion.In the early prepubertal child, GnRH secretion is fairly constant.The very first sign that a child is entering puberty is sporadicspikes of GnRH that occur during sleep.This results in concomitant spikes in LH (FSH changesvery little at this time).
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b. Decreasing negative-feedback sensitivity. As puberty progresses,the feedbacksystem becomeslesssensitive.The very low levelsof gonadalsteroidsbecomecapableof suppressingGnRH and LH secretion.The hypothalamusseemsto be the primary organ that initiates puberty in that it now starts to becomelesssensitiveto the feedbackof the gonadalsteroids.The nocturnal spikesof GnRH becomemore frequent,occurring throughout the 24-hour day.LH, following the pattern of GnRH, stimulatesthe gonad in an oscillatorypattern. c. Development of positive feedbackin girls. One of the last phenomenaof puberty is the developmentof positive feedbackof estrogenon GnRH in females.The mechanism is not yet completelyunderstood. d. Adrenal gland. Another developmentthat occursat puberty is the processcalledthe adrenarche.The adrenalgland startsproducing greateramounts of androgensduring early phasesof puberry usually prior to the increasein serum gonadotrophin levels. This adrenal androgen secretion is probably responsiblefor the initial growth of pubic and axillary hair in both malesand females.Adrenarcheis not associatedwith any changesin CRH or ACTH; it appearsto be completely associatedwith spontaneous changesin the adrenalgland itself.
Note Youdon'tneedto knowthe Tanner fortheStepI Stages exam;you willneedto know themforStep2. ClinicalCorrelate Although theovary has stopped ovulating, thereare probably someovaleft(not many, butsome)inthe menopausal Thisfact ovary. hasbeenusedclinicallv to prime artificially postmenopausal females with hormones thatinduce ovulation, thereby enabling themto conceive atthisstage intheirlifecycle.
Clinical Correlate Hotflashes aretheprimary reason thatwomen initially intervention seekmedical with hormones aftermenopause.
2. Physical changes of puberty (Tirnner stages).The physical changesthat occur in breast developmentand pubic hair growth in femalesand in external genitalia and pubic hair growth in maleswere classifiedmany yearsago by Dr. Thnner,a pediatrician.Dr. Tanner classifieddifferent gradesof sexualdevelopment into five stages.Puberty is still classified accordingto the five Thnner stages. C. Aging.In both men and women, there is a diminution in gonadalfunction with age. l.
Females a. In women, reproductiveagingis very dramatic in that there is a specific,clearlynoticeable change,the cessationof menstruation. The processis somewhat gradual, with lengthened cycles preceding the actual cessation.This phenomenon is termed menopause and usually occurs between 45 and 55 years of age.Accompanying the cessationof menstruationis a cessationof ovulation.Menopausein humansis thought to be a gonadally mediated event, as opposed to puberry which is hypothalamically mediated. However, although the ovary probably initiates menopause,the resulting changesin the hormones that bathe the hypothalamus probably permanently resetthe hypothalamus aswell. b. When the ovary stops ovulating, follicles are no longer formed and estrogenproduction greatly diminishes. Since ovulation does not occur, a corpus luteum does not form and progesteroneproduction is greatly diminished. Basallevelsof LH and FSH rise, with FSH levelsrising much more than LH levels. c. A striking feature of menopausein many women is the occurrenceof hot flashes. Tieatment with estrogensuppresses theseflashes. d. Beneficialeffectsof estrogentreatment (1) Estrogen helps prevent bone resorption and osteoporosis. Calcium supplementation from early ages(right after puberty) is also recommendedto combat osteoporosis. e. Estrogentreatment after menopausemay increasethe risk of breastcancer.
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Physiology
2. Males a. Although males experience reproductive aging, there is no dramatic demarcation of loss of fertility as there is in the female. What is many times referred to as the "male menopause"usually refers to a psychologic event where the male is trying to "regain his youth." b. As men age,there is a gradual decreasein androgens.After the ageof 60, a rise in plasma LH levelscan be detectedand is much more pronounced between 65 and 70 years of age. Spermatogenesis continues throughout life. FSH may rise slightly as men reach 65 to 70 years of age,but it is much lessmarked than the rise in LH. c. One of the main changesthat accompaniesmale reproductive aging is an enlargement of the prostategland,termed benign prostatichyperplasia(BPH). Becausethe prostate gland is almost completely dependent on DHT rather than testosterone,BPH and prostate cancer treatment is currently being directed at inhibiting the conversion of testosteroneto DHT.
ClinicalCorrelate Oneoftheproblems that women occasionally complain of aftermenopause is growthof hair.A excessive thicker mustache orsomechin hairsmaybeapparent. The reason thatsomehirsutism isnoticed aftermenopause isthattheandrogenic activity isunopposed byestrogens.
Bfidgeto Pathology BPHisdiscussed in greater detail intheReproductive Pathology chapter in thisbook.
541
Pathology MaleReproductive pathology aresolidtumors ofthetestes, Themostcommon clinical findings in malereproductive prostate, cause of cancer in men.Since Prostate infact,isthemostcommon andpenis. carcinoma, to chemotherapy, radiation therapy, andrespond themajority ofthetumors arewelldifferentiated on in the course of the disease, it isimportant to beableto identify thetumors early orsurgery, andsymptoms. Thischapter tumormarkers, andclinical signs through theuseof screening tests, affect themale aswellasonotherdisorders thatcommonly willfocusonthese diseases, reproductive system.
TESTES A. Cryptorchidism 1. Clinical features. Cryptorchidism is the failure of normal descent of intra-abdominal testesinto the scrotum. It affectsapproximately lo/oof the adult male population, more often on the right side than the left, and may be unilateral or bilateral. Bilateral cryptorchidism can causeinfertility by elevatingtemperatureof the testesto a level that interMaldescendedtestesare also susceptibleto trauma, and have fereswith spermatogenesis. a greatlyincreasedincidenceof testicularcancer. 2. Pathogenesis.Cryptorchidism may be a mechanical,hormonal, or idiopathic congenital anomaly. B. Germ cell tumors. Approximately 95o/oof testiculartumors are germ cell tumors. They are the most common malignancy in men l5-34years of age.Although the reasonis unknown, cryptorchidism increasesthe likelihood of malignanry 14-fold.Infection,trauma, and genetic factors also influence incidence.Generally,germ cell tumors begin as a painlesstesticular enlargement,with potential for widespreaddissemination,usuallyvia the lymphatics to iliac and para-aorticnodes(TableIV-6-1).
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Reproductive System
Thble IV-6-f . Testicular tumors. Tirmor
Clinical Feature
Pathology
Radiosensitive
Bully and homogeneous
Germ cell Seminoma
Embryonal carcinoma Often metastatic
Hemorrhagic nodules
Choriocarcinoma
Cyto- and
Highly malignant; elevatedhCG'|'r'n''-:,'
Yolk sactumors
Infants and children;
syncytiotrophoblast Nonencapsulated
elevatedAFP Teratoma
Mature or immature
Variery of tissues
Nongerm cell Interstitial (Leydig)
May produce estrogens
Usually unilateral
cell tumors
or androgens
Sertoli cell tumors
May produce estrogens
Lymphoma
Older men
Usually unilateral
or androgens Often disseminated
1 . Seminoma a. Clinical features. Rare in infants, incidence increasesto a peak in the fourth decade. b. Pathology (1) Grossly, the tumors appear as a bu\, neouscut surface(FigureIV-6-1).
grey-white mass exhibiting a homoge-
(2) Microscopically, seminomasare composedof sheetsof uniform polyhedral cells, divided by fibrous septa of connective tissue; lymphocytes and multinucleated giant cells can also be present. Ten percent of all seminomas show increased mitosesand nuclear atypia,i.e.,"anaplasticseminomas"(Figure IV-6-2). c. Course and prognosis. With treatment, the 5-year survival rate exceeds90olo.The tumors are highly radiosensitive, and metastasesare rare.
2. Embryonal carcinoma a. Clinical features. Embryonal carcinomasoccur most commonly in the 20-30-year age group and are more aggressive than seminomas.Thesetumors presentwith testicular enlargement,and 30olohave metastatic diseaseat the time of diagnosis.Serum AFP is usually elevated. b. Pathology (1) Grossly, embryonal carcinomas form nodules with areas of hemorrhage and necrosis, often involving the epididymis, the spermatic cord, and the tunica albuginea. (2) Microscopically, embryonal tumors are comprised of pleomorphic epithelial cells,frequently exhibiting mitoses,hemorrhage,and necrosis.Cellular arrangements are varied in composition, including papillary, glandular, tubular, and alveolar cells.
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Pathology: Male
FigurelV-6-1.Seminomaof the testis(gross).
Figure lV-6-2.Seminoma of the testis (microscopic). c. Course and prognosis. The 5-year mortality rate is 650/o.Less radiosensitivethan seminomas,embryonal carcinomas often metastasizeto lymph nodes, lungs, and liver. Patientsmay require orchiectomy and chemotherapy. 3. Choriocarcinoma a. Clinical features. Most common in men 15-25 years of age,these highly malignant tumors may coincide with gynecomastiaor testicular enlargement. Laboratory studies typically show elevated serum and urine hCG levels. b. Pathology (1) Grossly, the picture is variable. Usually, small amounts of preserved tissue appearamidst areasof hemorrhageand necrosis.
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Reproductive System
(2) Microscopically, both cytotrophoblast and syncytiotrophoblast must be present,usually arrangedaround fibrous septaof connectivetissue.Hemorrhage is prominent. Choriocarcinomais often mixed with other germ cell tumors. c. Course and prognosis are poor. Thesetumors tend to disseminate hematogenously, invading lungs,liver, and brain, and are treatedwith orchiectomyand chemotherapy. 4. Yolk sac tumors a. Clinical features.Most common in children and infants, thesetesticulartumors are rare in adults.Thev can alsocoincidewith embryonal carcinoma.SerumAFP is elevated. b. Pathology (1) Grossly, yolk sac tumors are nonencapsulated,homogeneous,and whitish-yellow in appearance.
Note Yolksactumors maybe considered a variant formof embryonal carcinoma.
(2) Microscopically, there may be solid cords of cells or a papillary arrangement. The cytoplasmcontainseosinophilic globulesfull of AFP and u,-antitrypsin. c. Course and prognosis. Yolk sac tumors are very aggressive, exhibiting a 50o/o5-year mortality rate. 5. Teratoma a. Clinical features.Teratomascan occur at any age,but are most common in infants and children. This type of tumor appearsas a testicularmass. b. Pathology (1) Gross pathology is variable,often appearingas a whitish-grey matrix in which diverseelements(e.g.,bone, cartilage,cysts)can amalgamate. (2) Microscopically, teratoma cells may show differentiation into any of three germ layers:endoderm, mesoderm,or ectoderm.Mature teratomas tend to be well differentiated, exhibiting a variety of tissues,such as nerve, muscle, cartilage, and glands. Immature teratomas show incomplete differentiation with primativeappearingcells. c. Course and prognosis. Generally,teratomasexhibit benign activiry during childhood yet behave variably in adults. Overall, the 2-year mortality is 30olo.Tieatment is orchiectomy,followed by chemotherapyand radiation. 6. Tumor markers
Note Alpha{etoprotein isalsovery elevated inlivercancer; it can beless markedly elevated in nonneoplastic liver disease.
a. Alpha-fetoprotein is a protein synthesizedbythe fetus during the first year of life that can be produced by some germ cell tumors. b. Human chorionic gonadotropin is a glycoprotein synthesizedby placental syncytiotrophoblast.The B subunit of HCG has a unique amino acid sequence,making specific assaypossible.It is produced mostly by choriocarcinomas. c. Diagnosis and staging. Ttrmor markers may prove useful in diagnosis,staging,and follow-up; elevated markers following treatment can serve as early indicators of relapse.Stagingof germ cell tumors of the testisis as follows: ( 1) StageI is confined to the testis. (2) StageII spreadsto the nodesbelow the diaphragm. (3) StageIII is distant metastases.
546
Pathology: Male
7. Treatment plans vary according to characterization and stage of tumor. Surgery,radiation, and chemotherapymay all be used. C. Nongerm cell tumors 1. Interstitial (Leydig) cell tumors a. Clinical features. L.ydig cell tumors can produce androgens,estrogens,or corticosteroids. In children, they often present with masculinization or feminization and in adults with gynecomastia. b. Pathology (1) Grossly, interstitial tumors form large, brownish-yellow massesor small nodules.More than 90oloare unilateral. (2) Microscopically, tumor cells resemble normal L.ydig cells with round nuclei, eosinophilic cytoplasm, and lipid granules.Approximately one-half of these tumors contain cigar-shapedcrystalloids of Reinke. c. Course and prognosis. They are usually benign and only I0o/o are invasive.Surgery may be curative. 2. Sertoli cell tumors a. Clinical features. Sertoli cell tumors can produce small amounts of androgens or estrogens,but usually not enough to causeendocrinologicchanges.They may present with testicularenlargement. b. Pathology (1) Grossly, thesetumors causeenlargedtesticlesor may form small nodules in a normal-sizedtesticle. (2) Microscopically, they are composed of uniform tall or polyhedral cells, with clear cytoplasm,growing in cords resemblingspermatictubules. c. Course and prognosis. Over 90o/oof thesetumors are benign. 3. Lymphomas are the most common testicular cancerin elderly men. The tumors are rarely confined to the testes. D. Inflammatorylesions 1. Mumps a. Clinical features. Orchitis developsin approximately 25o/oof patients over age 10, usually within a week after parotid swelling. Orchitis is less common in patients under 10 yearsold. b. Pathology (1) Mononuclear inflammatory infiltrates predominatein the acutephase. (2) Atrophy is rare. c. Course. Mumps rarely leads to sterility. However, should atrophy follow, it may predisposepatientsto testicularneoplasm. 2. Gonorrhea a. Clinical features. A neglected urethral gonococcal infection may spread to the prostate,to the seminalvesicles,and to the epididymis,but rarely to the testes. b. Pathology. There may be purulent inflammation or abscesses.
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Reproductive System
3. Syphilis a. Clinical features. Acquired or congenital syphilis may involve the testes. b. Pathology. There are two forms: gummas or a diffuse interstitial/lymphocytic plasma cell infiltrate. c. Course.Syphiliscan leadto sterility; Leydig cell involvementcan causea lossof libido. 4. Tuberculosis a. Clinical features. TB usually spreadsfrom the epididymis; this is almost alwaysassociatedwith foci of TB elsewhere. b. Pathology. Caseatinggranulomata are the classicfinding, as with TB dissemination elsewhere. 5. "Nonspecific" inflammation is usually causedby Chlamydiatrachomatisspreadfrom the epididymis. E. Torsion 1. Clinical features. TWistingof the spermatic cord may compromise both arterial supply and venousdrainage.Torsion may be precipitatedby suddenmovement,trauma, or congenital anomalies. 2. Pathology a. Grossly, the testisis usually enlargedand can becomesoft and necrotic. b. Microscopically, the pathology is variable,dependingon the duration and severityof the insult. Findings rangefrom congestionto hemorrhagic infarct. 3. Course. If not surgically correctedearly,torsion may result in testicular infarction with resultant loss of function.
PROSTATE Note The"H"in BPHmore accurately represents hyperplasia thanhypertrophy, youmaysee although either termstillused.
A. Benign prostatic hyperplasia (BPH) 1. Clinicalfeatures. BPH is characterizedby the formation of large nodules in the periurethral region (median lobe) of the prostate,which may narrow the urethral canal to produce varying degreesof urinary obstruction. Patients often present with difficulty urinating. It is increasinglycommon after age 45, and the incidence increasessteadily with age (e.g.,90o/o of men after age70). 2. Pathogenesis.The mechanismis poorly understood,but blocking androgensreducesthe incidence. 3. Pathology
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Pathology: Male
Figure lV-6-3.Fibromuscular and adenomatous hyperplasia of the prostate (gross).
a. Grossly,the prostateis enlarged,and the nodules compresssurrounding prostatetissue(FigureIV-6-3). b. Microscopically, there are multiple patterns of nodular hyperplasia. Both glandular and fibromuscular stromal proliferation can occur in the samegland. 4. Course. The course can follow an asymptomatic pattern, or it could result in urinary symptoms and urinary retention, leading to secondarybladder changes,such as smooth musclehypertrophy.Currently, it is thought that this diseasedoesnot predisposeto prostatic carcinoma.
Clinical Correlate Theurinarysymptoms of BPH include frequency, nocturia, andproblems initiating and theurinary stream. stopping
B. Carcinoma 1. Clinical features. Prostatic carcinoma is the most common cancerin men. Prostatecancer usually occurs after age 50, and the incidence increasessteadily with age.In addition to clinically significanttumors, a high incidenceof small "incidental" or "latent" carcinomas is discoveredat autopsyin men over age50. The diseasemay presentwith urinary problems or a palpablemasson rectal examination. 2. Pathogenesisis unknown. The tumor is agerelated,associatedwith race (more common in African Americans than in Caucasians,relatively rare in Asians), and is under endocrinologic and environmental influences.
Note Whileprostate cancer ismore common thanlungcancer, is mortality fromlungcancer morethantwicethemortality fromprostate cancer.
3. Pathology a. Grossly, prostatecanceris found usually in peripheral tissueand is firm and "gritty" as a result of fibrosis. b. Microscopically, most are adenocarcinomas. Patternsrange from a well-differentiated glandular pattern with uniform epithelium, oval nuclei, pale cytoplasm,and rare mitotic figures, to a poorly differentiated glandular pattern that is hard to discern, where tumor cells grow in sheetsand may show mitoses and cellular atypia (Figure IV-6-4).
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Reproductive System
4. Course and prognosis
Clinical Correlate Anelderly manwith o$eobla$ic metastases visible onx-ray should beconsidered to havepro$ate carcinoma untilproven othenruise.
a. Staging of prostatic tumors depends upon the size of the tumor, the degreeof infiltration to local tissues,and the degreeof metastasis. b. Metastasesmay occur via the lymphatic or hematogenousroute; bone is commonly involved with osteoblastic metastases,typically in the pelvis and lower vertebrae. c. Tumor markers. PSA (prostate-specific antigen) is an enzyme produced by normal, hyperplastic,and malignant prostateglands.It is elevatedin both hyperplasiaand cancer, but usually more so in the latter (particularly when extracapsular efiension has occurred).The usual cutofffor serum PSA is 4 nglmlbelow age50. The normal range risesgraduallywith age.Levelsbetween4 and 10 ng/ml are in agray area.ElevatedPSA with an enlarged prostate on digital rectal exam is highly suggestiveof carci:".*;,1* d. Survival is correlated with stageand grade. Unfortunately, most patients present with advanceddiseaseand havea lO-yearsurvival rate of lessthan 30o/o. e. Treatment involves surgery,radiation, and hormonal modalities (orchiectomy and androgenblockade).
uuF
Figure lV-6-4.Well-differentiatedadenocarcinomaof the prostate (microscopic).
C. Infections 1. Acute prostatitis a. Clinical features. This condition usually results from a bacterial infection of the prostate.Pathogensare often organismsthat causeurinary tract infection. ^Esch erichia coli is the most common, followed by other Gram-negativerods, including Kebsiella, Proteus,Pseudomonas, Enterobacter,and Serratia.Infection may follow manipulation of the prostateor urethra (e.g.,rystoscopy,catheterization). b. Pathogenesis.Bacteriaspreadby direct extensionfrom the posterior urethra or the bladder.Lymphatic or hematogenousspreadcan also occur.
550
Pathology: Male
c. Pathology (1) Grossly, the gland is enlargedand boggy.Edema and congestion,multiple small or small areasof necrosismay all be seen. abscesses, (2) Microscopically, necrotic foci and a leukocytic infiltrate occur. d. Course. Appropriate antibiotic therapy is usually curative. 2. Chronic prostatitis a. Clinical features. Chronic prostatitis is a common causeof recurrent urinary tract infections in men. There are two types:bacterialand nonbacterial.Both forms may be asymptomaticor may presentwith lower back pain and urinary symptoms. b. Pathogenesis.Bacterial infection may be a sequelaof acute prostatitis; nonbacterial infections are most often causedby Ureaplasmaand Chlamydia trachomatis. c. Pathology ( 1) Grossly, there is usually an enlargedprostate. (2) Microscopically, the inflammatory reaction in the prostate is usually lymphocytic.
PENIS A. Congenitd malformations 1. Hypospadias and epispadias a. Clinical features. Theseare malformations of the urethral groove and canal. They are often associatedwith crlptorchidism and other congenitalanomalies. b. Pathology. In hypospadias,the urethra opensonto the ventral surfaceof the penis.In epispadias,the urethra opens onto the dorsal surface. c. Course. Both of thesemalformations may causeinfertility. 2. Phimosis. In this condition, the prepuce orifice is too small to be retracted normally. It interferes with hygiene, and can also predisposeto bacterial infections. If the prepuce is retracted over the glans,it may lead to painfirl swelling with subsequenturethral constriction, termed paraphimosis. Circumcision is indicated. B. Infections 1. Condyloma acuminatum a. Clinical features. This is a benign lesion of papillomavirus origin, which may occur on any mucous membrane. b. Pathology ( 1) Grossly,lesionsusually form on the inner surfaceof the prepuceor on the coronal suface.They are red papillary lesions a few millimeters in diameter, which may be sessileor pedunculated. (2) Microscopically, there is thick, hyperplastic squamous epithelium covering a branched connective tissue stroma. Maturation is orderly, but some mitotic figures are present."Fried egg" cells (a pyknotic nucleus in a clear cytoplasm) are visible,indicative of papillomavirus.
551
Reproductive System
2. Syphilis. Syphillis is a sexuallytransmitted or congenitaldiseasecausedby the spirochete Treponemapallidum. The acquiredform initially presentswith cutaneousmanifestations followed by widespreaddissemination.The diseaseoccursin stages. a. Primary syphilis has an average3-week incubation during which spirochetesspread throughout the body. Painlesschancre sores form and heal within 1-3 months. ( 1) Grossly,chancresusuallyoccur on the glanspenis in men and the vulva or cervix in women. Occasionally,they appear on other mucous membranes,such as the oral cavity.They appearas single,firm, red papulesthat may ulcerate. (2) Microscopically, there is a mononuclear infiltrate with obliterativeendarteritis. Plasmacellsare very prominent. Specialstainsmay show treponemes. b. Secondaryslphilis usually develops1-2 months after the primary stage.There is a local or generalizedrash lasting 1-3 months. The rash can involvethe palms and soles as well as mucous membranes.Condyloma lata can appearon the penis. (1) Grossly, condyloma lata are flat, brown-red papules on the penis or other mucous membranes.They may form large plaquesor ulcerate. (2) Microscopically, there is an obliterative endarteritis and plasma cell infiltrate. Treponemesare present. c. Tertiary slphilis developsin one-third of untreatedpatients.It may affect the central nervous system (CNS), heart, and skin. Neurosyphilis has a varied presentation, including meningovascular,tabesdorsalis,and generalparesis.CNS gummas are rare. An obliterative endarteritis can occur,involving the vasavasorum of the aorta,which can leadto the formation of an aneurysm. Elasticstainsshow destructionof fibers. In other tissuesthe characteristiclesion is the gumma. ( 1) Grossly,gummas may be singleor multiple. They haverubbery,necrotic central focusthat is variablein size.They are most common in the liver,testes,and bone. (2) Microscopically, gummas are composedof mononuclear cells surrounding a center of coagulative necrosis. Gummas resemble caseatinggranulomas but usually do not have multinucleated giant cells and do not have any stainable acid-fastorganisms.Tieponemesare rare. d. Serologic tests for slphilis (1) VDRI tests for nonspecific antibodies evoked by spirochetal infection; these antibodiesreactwith cardiolipin, a lipoid substancefrom beef heart. The VDRL becomespositive a few weeks after primary infection and may remain persistently elevated."Falsepositives" *uy occur in many acuteillnesses,aswell as in chronic mononucleosis,leprosy,hepatitis,and autoimmune disorders.
Note Chancroid isnotcaused by thesameetiologic agent as chancre Chancroid Gyphilis). iscaused byH.ducrei, whereas chancre iscaused byT.pollidum.
T,:fl TTl,',:?":T,'ff; "'i*".:ffi:ilit.T::l1T'L:,1:!,.il'i.;fi",:l'# 3. Chancroid a. Clinical features. This is a sexually transmitted infection causedby Haemophilus ducreyi. Patients have a painfrrl chancre and regional lymphadenopathy. b. Pathology (l) Grossly, patients presentwith a soft chancre,usually on the penis. It is initially macular,becomespapular,and then ulcerates. (2) Microscopically, inflammation and granuloma formation occur. There are no treponemes.
,52
Male Pathology:
4. Lymphogranulorna venereurn (I,GV) a. Clinical features. LGV is a sexually transmitted disease caused by Chlamydia trachomais, lt is rarc in t}Ie United Statesbut common in tropical areas.IGV can present with genital or anorectal lesions or regional l1'rnphadenopatly. b. Pathology (1) Grosdy, I,GV causesa painless ulcer on the penis, mouth, anus, or rectum. (2) Microscopically, tlere is a neutrophilic exudate. Lymph nodes show hlaerplasia and granuloma formation in small necrotic centers, which may coalesceto form stellateabscesses. c. Course. Scarring and fibrosis can follow chronic infection. Subsequent lymphatic obstruction can Lad to edemaand elephantiasisofthe lower extremitiesand external genitalia.
Glinkal Corelate HSVI usuallyappearsabove the wai$line;HSVll typically appearsbelow Theyshare genes,andeithercanappear anYwhere
5. Genital herpes a. Clinical features. There are two subtypes: herpes simplex (HSV I) and herPes genitalis (HSV II), causing an overlapping spectrum of disease. b. Pathology (1) Grossly,HSV I and II causevesicleson the externalgenitaliaand mucous membranes; ulcerations can also develop. (2) Microscopically, epithelial cells show cytopathic changes (Cowdry type A acidophilic intranuclear inclusions) and slightly increased cellular and nuclear size' Cell fusion leads to giant cells or polykaryons, which can be seen on a smear of blister fluid or Tlanck smear' c. Course. HSV inf€ctions tend to recur. The virus can remain latent in nerve ganglia' Acyclovir may prevent or d€creasetie ftequenry of recurrences. 6. Granulorna inguinale a. Clinical features. Granuloma inguinale is a chronic' sexually transmitted disease causedby the bacterltm Calymmatobacteiumdonovani.It is common in India and New Guinea but rare in the United States.It Presentswitl ulcerating granulomas of genital skin and mucous membranes. b. Pathology (1) Grossln there are multiple ulcerating papules on t}re skin and mucous membranes. Lymph nodes are not involved. (2) Microscopically, there are granulation and microabscesses.Macrophages contain Donovan bodies, which are diagnostic. c. Course. Granuloma inguinale generally remains localized. C. Carcinoma l. Bowen disease is carcinoma in situ and can be associatedwith visceral malignancy' It usually occurs in men or women over age 35. In men, it tends to involve the shaft of the penis and the scrotum. a. Grossly, a thick, ulcerated plaque appears. b. Microscopicalln apPearance.
there is squamous cell carcinoma in situ. Nuclei may be bizarre in
555
Reproductive System
Note Squamous cellcarcinomas, particularly those associated withpapilloma viruses, showa markedly higher incidence in HIVinfection. ltsconfiguration isoftenpapillary. Patients can alsohaveperianal carcinomas orpapillomas. Papillomaviruses (types l6 and lB)aremostoftenassociated withsquamous carcinoma.
,54
2. Squamous cell carcinoma a. Clinical features. Squamouscell carcinoma of the penis accounts for |o/oof cancersin men in the United States,usually age 40-70. Circumcision decreasesthe incidence. Human papilloma virus infection is closelyassociatedwith the development of squamous carcinoma. b. Pathology ( I ) Grossly, squamouscarcinoma presentsas a plaque progressingto an ulcerated papule or fungating growth. (2) MicroscopicallS a papillary invasive, ulcerating squamous cell carcinoma appears. c. Course and prognosis. Squamouscarcinoma is usually slow growing and nonpainfi.rl; patients often delay seekingmedical attention. Metastasescan go to local lymph nodes. The prognosisdependson the degreeof advancementof the tumor.
Pathology Reproductive Female including states, disease to specific issusceptible system reproductive inthefemale organ Each majority of large for a account malignancies Cynecologic infection. and hyperplasia, benign cancers, in the in women death of cancer leading cause isthesecond cancer inwomen:breast cancers disorders manySynecologic Because cause. isthesixthleading cancer andcervical States, United or bleeding vaginal nonmenstrual irregularities, of menstrual present symptoms withsimilar one differentiate features that the recognize able to pain, to be pelvic it is important and discharge, the risk will highlight and disorders on these focus will Thischapter fromanother. state disease them' thatdistinguish features andpathologic andclinical factors
UTERUS A. Endometrium 1. Endometritis a. Acute endometritis is relatively uncommon. It is causedby bacterial infection of the endometrium, usually following childbirth or abortion. It may be related to retained productsof conception.The usualpathogensaregroup A p-hemolytic streptococciand staphylococci,producing a nonspecific interstitial inflammation with neutrophils. b. Chronic endometritis may occur postabortion or postpartum but is also relatedto the use of intrauterine devices(IUDs), tuberculosis(TB), or pelvic inflammatory disease (PID). There is a chronic inflammatory infiltrate with plasma cells in the interstitium. 2. Endometriosis a. Clinical features. Endometriosis refers to ectopic endometrial tissue outside the uterine cavity, most often in the ovaries, uterine ligaments, rectovaginal septum' pelvic peritoneum, postlaparotomy scars,vagina, vulva, and appendix. It occurs in women of reproductive age and is rare over age 50. It is commonly associatedwith infertility. Depending on the location of ectopic tissue,it may causedysmenorrhea, pelvic pain, dyspareunia,pain on defecation,dysuria,and an inability to conceive. b. Pathogenesis is a debated issue. Possibilities include metaplasia,implantation of abnormal epithelium at the time of menses,or lymphatic or hematogenousspreadof benign endometrial cells that can nonethelessattract a blood supply and grow at a new site.
Nole ischaracterized Endometriosis fromthe bleeding bycyclic tissue, endometrial ectopic "chocolate cysts"in resulting spaces. blood{illed brown,
c. Pathology (1) Grossly, endometriosis forms blue-red or brown-yellow nodules, 1-2 cm in diameter.They may causefibrosis and adhesions.
555
Reproductive System
(2) Microscopically, two of the following must be present: glands, stroma, or hemosiderin pigment. Cyclic menstrual changesmay be seen. d. Course and prognosis. Infertility may result from fibrosis and scarring of tubes and ovaries.
Note Inpostmenopausal women, endometrial hyperplasia is oftendueto exogenous estrogen administration. Occasionally, welldifferentiated adenoca rcinoma arises inthissetting. lt regresses whenestrogen therapy isstopped.
3. Endometrial hlperplasia a. Clinical features. Hyperplasia may occur in both perimenopausal and postmenopausalwomen. It may presentwith abnormal or excessive uterine bleeding,often associatedwith statesof elevatedestrogenproduction (e.g.,prolonged estrogentherapy,adrenocorticalhyperfunction, certain ovarian tumors). It may be a precancerous lesion. b. Pathology is variable. ( 1) Mild hyperplasia (cystic) consistsof many glandsof multiple sizes(often rystic) with scant mitoses,dilatation of glands, and the appearanceof a proliferative endometrium, including increased stromal elements, all leading to a "Swiss cheese"appearance. (2) Moderate hnrerplasia (adenomatous)producesa thick, gray mucosa.There are irregular glands,a hyperplasticepithelium, and papillary projections.There may alsobe increasedstromal mitoses. (3) Atfpical hyperplasia is grosslysimilar to adenomatoushyperplasia,but microscopic study may show crowding of glands, disorganizedepithelium, cellular atypia, closely packed glands, and frequent mitoses. This may resemblewelldifferentiatedadenocarcinoma. c. Course andprognosis. Although cystichyperplasiais benign, adenomatousand atypical hyperplasia are consideredpremalignant and are associatedwith an increased incidenceof endometrial carcinoma. 4. Endometrial polyps a. Clinical features. These are most common in perimenopausalor postmenopausal women. They usually present with uterine bleeding. b. Pathology ( I ) Grossly, polyps may be single or multiple and are usually lessthan 3 cm. They are often sessilebut may be pedunculated. (2) Microscopically, there are two types: functional endometrium and hyperplastic (rystic or adenomatous)endometrium. c. Course and prognosis. Malignant transformation is rare.
ClinicalCorrelate Riskfactorsfor endometrial carcinoma: . Prolonged estrogen stimulus . Obesity . Diabetes . Hypertension
556
5. Endometrial carcinoma a. Clinical features. This diseaseprimarily occurs in the postmenopausalage group. It is associatedwith obesity,diabetes,hypertension,and infertility. It may be asymptomatic or presentwith abnormal uterine bleeding/discharge. b. Pathogenesisis thought to be the result of prolonged estrogen stimulation. There is a correlation with prolonged estrogen therapy, estrogen-secretingneoplasms,and endometrial hyperplasia(which may alsobe a result of estrogenstimulation). c. Pathology (1) Grossly, tumors are either polypoid or diffirse and may become fungating and necrotic.
Female Pathology:
(2) Microscopically, one seesprimarily adenocarcinomas,showing glandular patterns with varying degreesof differentiation. Other conlmon types include adenoacan-
*ffi J:liil:il:'l:il:#*|;}ru"'ffi ililTil:T:*.ill,adenosquamous d. Course and prognosis. There is early spread by contiguous growth through the myometrium, into the broad ligament, and then to nearby portions of the gastrointestinal and urinary tract. Later,lymphatic and hematogenousspreadoccur. Survival dependson the stageat diagnosis.Tieatment is usually surgery,with or without radiation. B. Myometrium 1. Leiomyoma (fibroids) a. Clinical features.Theseare benign smooth muscle neoplasmsrepresentingthe most common tumor in women and occurring generallyin the third and fourth decades. Incidenceis increasedin African American women. There is a possiblerole of estromenstrualbleeding,abnorThey may presentwith excessive gensin the pathogenesis. mal uterine bleeding,pain, infertility, or urinary symptoms. b. Pathology (1) Grossly, tumors are whitish-gray, discrete,myometrial masses,often multiple, and varying in size.They are usually in the corpus of the uterus but may arisein the cervix or lower uterine segment(Figure IV-7-1). Common descriptiveterms are: (a) Intramural, or embeddedin the myometrium (b) Subserosa, or beneaththe coveringserosa (c) Submucosal,or closeto the endometrium
Note the wereamong Leiomyomas to be firstneoplasms to be demonstrated glucosebyusing monoclonal dehydrogenase 6-phosphate (C6PD) In isoenzymes. the women, heterozygous isotype, only one have tumors whiletheadjacent hasboth. normal myometrium
Figure lV-7-1.Leiomyoma of the uterus (gross).
t57
Reproductive System
*v ,, : *.&!r
Figure lV-7-2.Leiomyoma of the uterus (microscopic). (2) Microscopically' tumors are composedof bundles of smooth muscle cellswith increasedfibrous elementsvisible on a trichrome stain (FigureIY-7-2). c. Course and prognosis. Malignant transformation is rare. They may require surgical removal for bleeding or infertility. 2. kiomyosarcomas a. Clinical features. Leiomyosarcomasare arare myometrial malignancy.They may arise in a pre-existingleiomyoma,but this is so rare that it is reportable.Tlrmors may occur before or after menopause. b. Pathology (1) Grossly, there are two patterns: bulky invasive (growing into the wall) or polypoid (growing into the lumen). (2) Microscopically, there are variable degreesof atypia. To make the diagnosis, there must be more than 10 mitosesper high-power field (a00x), and over half of these mitoses must have cellular atypia. The tumor must be searchedextensivelybecauseatypia and mitotic rates are not constant throughout the tumor. The worst fields establishthe diagnosis. c. Course and prognosis. Leiomyosarcomasare highly malignant, and 5-year survival is only 40o/o.They metastasizewidely and tend to recur after removal.
FAttoptANTUBES (UTER|NE TUBES, OVIDUCTS) A. Inflammation 1. Pelvic inflammatory disease(PID) a. Clinical features. Inflammation begins in the vulva or accessoryglands (Bartholin's glands or Skeneducts) and may spreadupward throughout the reproductivesystem. The most common organism is N. gonorrhoeae,butStaphylococcus, Streptococcus, coIiforms, Clostridiumperfringens,Mycoplasma,Chlamydia,and anaerobesmay be seen. PID may occur spontaneously,postabortion, or postpartum. Presentationsinclude abdominaUpelvicpain, menstrual irregularities,dysmenorrhea,and fever.
558
Female Pathology:
b. Pathogenesis.For gonococcalPID, the initial inflammation of the accessoryglandsis followed tn l-2 weeks by inflammation of the fallopian tubes. In children, vulvovaginitis may develop;it is rare in adults. c. Pathology (l) Grossly, there is a suppurative salpingitis (lumen of tube filled with pus).
and salpingo-oophoritis to the ovary,causing adherent
ii*:':irffl,3:."me (2) Microscopically, inflammation is present in the mucosa and submucosaand may involve the serosa. d. Course and prognosis. Complicationsare severeand include sepsis,peritonitis, adhesions with intestinal obstruction, and infertility from tubal scarring or tubo-ovarian Early diagnosisand appropriateantibiotic therapy are essential. abscess. B. Tirmors in the fallopian tubes are rare.
cERVIX A. Inflammation 1. Acute and chronic cervicitis a. Clinical features.Various forms of cervicitis are common and are of variable clinical Escherichia Enterococci, significance.The most common pathogens areStreptococctts, olhers include gonococci, Trichomonasvaginalis,Candida, coli, and Staphylococcus; and herpes (usually HSV II). Infection may follow intercourse,childbirth, and gynecologic instrumentation. Predisposinginfluences include high estrogens,alkaline mucus, and congenitalanomalies. b. Pathology (1) Grossly, one observesa swollen,edematouscervix. (2) Microscopically, there are two phases.The acute phaserevealsstromal edema and a neutrophilic infiltrate. The chronic phaserevealsinflammation or cervical glands,with a mononuclear infiltrate leadingto cysticdilatations,which are due to duct obstruction. c. Course and prognosis. Cervicitis may be asymptomatic or present with a vaginal discharge.It is important to distinguish it from cervicalcancer,usuaily by Pap smear or biopsy. B. Tumors 1. Cervical polyps a. Clinical features. Polyps are common in the fourth and fifth decades.They may present with irregular vaginal bleeding. b. Pathology (l) Grossly, polyps are usually single, arise in the endocervicalcanal, and maybe sessileor pedunculated. (2) Microscopically, they are composedof hypertrophic glands with rystic dilatation and fibromyxomatousstroma; they may have chronic inflammation. c. Course and prognosis. They may be removedby curettage.
559
Reproductive System
ClinicalCorrelate Risk factors forcervical carcinoma: . Early sexual activity . Multiple partners sexual . Lower socioeconomic gr0up
2. Squamous cell carcinoma of the cervix a. Clinical features. This is the sixth most common causeof cancer death in women. It may occur at any age from the seconddecadeonward, but it is most common in the fourth and fifth decades. b. Pathogenesis.There is an increasedrisk associatedwith early onsetof sexualrelations and multiple sexualpartners.Human papillomaviruses, particularly types 16 and 18, are clearly associatedwith squamous carcinoma. Other types are associatedwith benign papilloma. In patients infected with HIV cervical cancer due to papillomavirusesis increasingin incidence. c. Pathology
ClinicalCorrelate Nowthatweappreciate the importance of papillomaviruses ascausative agents of cervical cancer, in situhybridization studies for specific viralDNAmaybe doneonsuspicious lesions. ClinicalCorrelate Therecommended frequency of Papsmears isunder discussion. Sexually active probably women should have year. a Papsmear every Sexually inactive women may onlyneeda smear every 3 years. Women withsuspicious findings should haverepeat perhaps Papsmears asoften asevery 3-6 months. Repeatedly suspicious or positive smears should leadto cervical biopsy fordefinitive diagnosis.
( 1) Grossly,advanced,invasivecervicalcancermay be fungating,ulcerating,or infiltrative. (2) Microscopically, koilocytosis and squamous vacuolizations are seen. Cervical canceris viewed as the end stageof progressionof atypia in cervicalepithelium, or cervical intraepithelial neoplasia(CIN). Premalignantsquamousepithelium begins to show atypical features (pleomorphism, loss of polariry frequent mitoses,and increasednuclear/cytoplasmicratio), but maintains differentiation in the upper cell layers.Atypia is gradedon a scalefrom I to III, basedon the proportion of epithelium that is involved: involvement of less than one-third of epithelium is CIN I, one-third to two-thirds is CIN II, and greaterthan two-thirds is CIN III. Full-thicknessinvolvement is carcinoma in situ (Figure IV-7-3). Atypia usually begins at the squamocolumnar junction (transition zone). d. Course and prognosis. Cervical cancer spreadsby contiguous growth to involve urinary structures and bowel. Lymphatic or hematogenousdissemination may occur. Mortality is declining asa result of early recognition of the precursordysplasticcervical epithelium via the Pap smear, which should be a part of every woman's yearly physicalexamination from reproductive age onward. The cure rate for carcinoma in situ may be as high as l00o/o.More advanceddiseasehas a much lower cure rate ( 10-15o/oif metastasishas occurred) and may require both surgeryand irradiation.
W
@*i1i "*'
Figure lV-7-3.Gervical carcinoma in situ (microscopic).
560
'*
Pathology: Female
VAGINA A. Congenital anomalies 1. Gartner duct cysts a. Clinical features. These cystsmust be distinguished from tumor masses. b. Pathology (1) Grossly,l-2 cm submucosalrysts on the lateral vaginal walls are present. (2) Microscopically, the cystsmay have cuboidal, columnar, transitional, or a mixed epithelial lining. There is no atypia. B. Inflammation may be due to various pathogens. l. Trichomonas vaginalis is a flagellatedprotozoan.It typically causesa "strawberry red" vaginal mucosaand microscopic,suppurativeinflammation. 2. Candida albicans (monilia) causesa thick, white exudate. 3. Herpes simplexvaginitis may accompanyvulvar infection. It may lead to neonatal infection during delivery.The organism is usually herpessimplex virus (HSV) II. 4. Gonococcusmay causevulvovaginitis in children, as well as adults. C. Tumors 1. Squamous cell carcinoma a. Clinical features. This tumor is quite rare, comprising lessthan lo/oof female genital cancers.It may presentwith irregular bleeding,spotting, or dischargebut is occasionally asymptomatic until advanced. b. Pathology (1) Grossly, the tumor starts as a thickened epithelium, progressingto a large plaque. (2) Microscopically, theseare usually well-differentiatedsquamouscarcinomas. c. Course and prognosis. Squamouscarcinomaof the vagina spreadsby local extension to the cervix,rectum, and bladder.Latelymphatic or hematogenousspreadmay occur. 2. Adenocarcinoma a. Clinical features. Adenocarcinoma is very rare; of the vaginal cancers,95o/oare squamous and 5o/oare adenocarcinoma.It is much more common in young women whose mothers were treatedduring pregnancywith diethylstilbestrol (DES).BecauseDES is no longer usedto treat threatenedabortion, this causeof adenocarcinomahas almost disappeared. b. Pathology (1) Grossly, tumors usually appear in the upper one-third of the anterior vaginal wall and may arise in the cervix.
Clinical Correlate DES in pregnant therapy women increases theincidence intheir ofvaginal neoplasms adenosis is daughters. Vaginal a benign condition thatis thought to bea precursor of in clear celladenocarcinoma women. these
(2) Microscopically, the classicpicture is a "clear cell" carcinoma,resulting from vacuolated cells containing glycogen. c. Course and prognosis. Tirmors grow by contiguous spread; later, they grow by lymphatic or hematogenousspread. Treatment includes surgery with or without radiation. DES-relatedtumors have an 80o/o5-vearsurvival.
56r
Reproductive System
3. Sarcomabotryoides a. Clinical features. This is a rare vaginal rhabdomyosarcoma most common under age5. b. Pathology (1) Grossly, polypoid tumors, protruding from the vagina and resembling clusters of grapes,are present. (2) Microscopically, tumors are composedof small, crowded cellswith oval nuclei and a teardrop shape,constituting malignant rhabdomyoblasts.One may haveto searchdiligently for cross-striations. c. Course and prognosis. Sarcomasspread by local invasion. Treatment is usually surgerywith or without chemotherapy.
Note BRCAI, a geneimplicated in premenopausal early, breast cancer, isalsoimplicated in someovarian carcinomas.
OVARIES A. Overview. The most common ovarian lesions are cystsand tumors. Ovarian canceris the fifth most common cancerin women, accountingfor 60/oof all female cancers.Eighty percent of ovarian tumors are benign. The benign tumors tend to occur earlier (in the third through the fifth decades),whereas the malignant tumors are more common in older women (in the fifth through the seventhdecades).Familyhistory, earlymenarche, and nulliparity are risk factors.There is an increasedincidencein children with gonadaldysgenesis. Tumors are often asymptomatic until large; then, they may presentwith abdominal pain, distension,vaginal bleeding,and gastrointestinalor urinary symptoms.Ovarian tumors are classifiedinto four groups: surfaceepithelial tumors, germ cell tumors, sex cord/stromal tumors, and metastatictumors involving the ovary. B. Surface epithelial tumors
Note Surface epithelial tumors of theovaryincrease in incidence withthenumber of ovulations a woman experiences. Thus, pregnancy andbirthcontrol pillsareprotective. Repeated tearing andregroMh ofthe epithelium isapparently a riskfactor.
t62
1. Overview. Sixry percent of ovarian tumors arisefrom surfaceepithelium. There are variable presentations. In addition to abdominal discomfort, vaginal bleeding, and gastrointestinaVgenitourinarysymptoms,patients may presentwith malignant ascitesfrom peritoneal seedingor with an acuteabdomen from torsion of a large tumor or rupture of a ryst. Unfortunately, theseslow-growing tumors are often asymptomatic until the diseaseis far advanced. 2. Classification is accordingto epithelial cell type: five groups are commonly recognized. a. Serous neoplasms are characterizedby serous,fluid-filled cysts lined with ciliated columnar epithelium. They are most common in the third through sixth decades. Most are malignant. (1) Benign serouscystadenomais clinically benign and usually cured by oophorectomy. It is usually composedof unilateral, thin-walled, fluid-filled rysts, with a smooth, glistening surface.Cysts are lined with ciliated cuboidal epithelium without afypia. (2) Borderline serous tumor may present with an adnexal mass.TWenty-fivepercent are bilateral and composedof small papillary growths, protruding through the serosa.Microscopically,two to three layersof stratified epithelium line the rysts, forming papillary projectionswith variable atypia.Psammomabodies are present in approximately 25o/oof cases.Of utmost importance is the fact that there is no stromal invasion. Peritonealimplants are common, but patientshave a 90o/olO-yearsurvival. Treatmentis bilateral salpingo-oophorectomy,hysterectomy, and removal of the omentum to remove microscopicimplants.
Pathology: Female
(3) Serous cystadenocarcinoma is the most common malignant ovarian tumor. It is usually bilateral. Tumors may be solid masseswith hemorrhagic and necrotic areas, or they may be primarily cystic. Microscopically, there are papillary growths with multiple layersof epithelium, frequent psammoma bodies, marked cellular atypia, and stromal invasion. These tumors spread via peritoneal implants, contiguous growth, or lymphatic or hematogenousdissemination. There is only a 20o/o5-year survival rate becausepatients generally present with local spread and metastases.Treatment is bilateral salpingo-oophorectomy, followed by chemotherapy,radiation, or both. b. Mucinous tumors are most common betweenpuberty and menopause.Most are large, unilateral, and benign. They are composed of nonciliated, columnar, mucus-secreting cells. (1) Benign mucinous cystadenomas are unilateral in 95o/oof cases.They have a smooth surface,and they form large massesthat may contain multiple mucusfiIled cysts. The epithelium is well-differentiated columnar with no atypia and a mucin-filled cytoplasm.Oophorectomy is curative. (2) Borderline mucinous cystadenocarcinomas are moderately aggressivetumors that form multiloculated rysts, lined by a papillary growth of layered epithelial cellswith some atypia. Peritoneal implants may occur, and therapy is surgical (as it is for seroustumors of the samegrade). (3) Mucinous cystadenocarcinomas are malignant tumors that form solid masses with hemorrhageand necrosis.They are composedof papillary arrangementsof epithelium with cellular atypia and stromal invasion. Mucinous cystadenocarcinomas may spreadvia implants, contiguousgrowth, or lymphatic or hematogenous routes. Tieatment includes surgery,radiation therapy, or both. (4) "Pseudomproma peritonei" is a term used to describe a peritoneal cavity filled with mucinous material derivedfrom a tumor that hasruptured or metastasized. It is associatedwith a small percentageof ovarian mucinous tumors and with rupture of an appendicular carcinomatous mucocoele. Multiple mucinous implants on serosalsurfacesin the peritoneal caviry which may causeinteradherance of viscerae,are present. Tumor cells form a nonciliated, columnar, mucus-producing epithelium. Prognosisis very poor. Tieatment is surgical,but recurrencesare frequent. c. Endometrioid tumors ( 1) Clinical features. Most are malignant. They contain glandular structures resembling endometrium, and they maybe accompaniedby endometrial carcinomaor by ovarian endometriosis. (2) Pathology. Grosslp cysts are embedded in a solid matrix, usually unilateral. Microscopically, the structure resemblesthe endometrium: glandular structures in a connective tissue stroma. (3) Course and prognosis. Five-year survival is approximately 50o/o.Bilateral involvement usually indicates spreadbeyond the reproductive tract. d. Clear cell adenocarcinomas are rare and are almost alwaysmalignant. (1) Ctinical features. They may be associatedwith ovarian endometriosis or endometrioid carcinoma.
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Reproductive System
(2) Pathology. Thmors may be solid or cystic.Microscopically, there are sheetsof tubules of clear cells in solid tumors. In cystic tumors, atypical columnar cells line fluid-filled cysts. (3) Course and prognosis. There is a 50oloS-year survival. Treatmentcombines surgery radiation, and chemotherapy. e. Brenner tumors (1) Clinical features. These are rare, comprising only 2o/oof ovarian neoplasms. They can be seenat all ages,with a peak incidencefrom the fifth through eighth decades.Most are benign. (2) Pathology.Grossly, tumors are usually unilateral and are variable in size (1-20 cm). They are usually solid but may be rystic. Microscopically, solid nests of transitional epithelium in ovarian stroma are present.The malignant type shows atypia and invasion. (3) Course and prognosis. These tumors may have endocrine activity. Surgery is usuallycurative.
C. Germ cell tumors l. Overview. These comprise l5-20o/o of all ovarian neoplasms;most (over 95o/o)arc benign cystic teratomas. They occur primarily in young women and children. Presentationsvary. Germ cell tumors are divided into four groups:teratomas,dysgerminomas, endodermal sinus (yok sac) tumors, and "other," a group that includes choriocarcinoma,embryonal carcinoma,polyembryoma,and mixed germ cell tumors. 2. Teratomas a. Mature (benign) teratomas are also called dermoid cysts becausethey are lined by skin and adnexaeand are often filledwith keratin and hair. There is a high incidence in women of reproductiveage.They may presentwith an abdominal mass,pain, and gastrointestinalor menstrual abnormalities. (1) Grossly, they are usually unilateral, small, unilocular cyststhat may have a mixture of hair, tooth structures,and bone (Figure IV-7-4).
&
w
w 4
w W Figure lV-7-4.Dermoid cyst of the ovary (gross).
til
Pathology: Female
(2) Microscopically, they are usually composed of cysts,lined by stratified squamous epithelium and structuresderived from multiple germ layers, including endoderm,mesoderm,and ectoderm(FigureIV-7-5).
Figure lV-7-5.Dermoid cyst of the ovary (microscopic).
(3) The courseis usuallybenign. Surgicalresectionleadsto cure.Torsion may occur. b. Immature (malignant) teratomas are rare, containing embryonic elementsderived from all three germ layers. (1) Grossly, they form smooth, large massesthat are primarily solid but may have rystic spaces.Necrosis and hemorrhage are common. As with the benign tumors, malignant teratomasmay contain hair and bone. (2) Microscopically, they are composed of immature tissues differentiating into nerve, muscle,bone, and a variety of other tissues.The characteristicof malignancy is undifferentiatedareas. (3) These tumors are fast-growing and invasive with both lymphatic and hematogenousspread. Grading is based on degree of maturity of cells and presenceof neural tissue:The more immature the cells and the more neuroepithelium, the higher the grade and the worse the prognosis. 3 . Dysgerminoma a. Clinical features.This tumor is analogousto testicularseminoma.It is rare and usually occurs in the secondthrough third decades.Patientsmay presentwith abnormal menstrualbleeding.Elevatedlevelsof hCG should raisesuspicionof a focus of choriocarcinoma. b. Pathology. Dysgerminomasvary in sizeand are usually unilateral and solid. They are composedof sheetsof large cellswith clear cytoplasm and regularnuclei in a fibrous stroma.There are variable degreesof atypia. c. Course and prognosis. One-third are aggressiveand all are very radiosensitive.The 5-vearsurvival is 70-90o/o.
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Reproductive System
4. Endodermal sinus (yok sac) tumor a. Clinical features. These tumors are rare and usually produce o-fetoprotein (AFP) and, occasionally,c,-antitrypsin. They occur in young women and children, and present with a pelvic massand abdominal pain. b. Pathology ( 1) Grossly, they usuallyform a large,smooth tumor with areasof hemorrhageand necrosis. (2) Microscopically, there are papillary:rrangements of immature epithelium around blood vessels.Intracellular and extracellularhyaline droplets containAFP. c. Course and prognosis. They are rapid growing and aggressive.Surgery and chemotherapyprolong survival and occasionallyproduce a cure. 5. Other germ cell tumors a. Choriocarcinoma may arise as an ovarian germ cell tumor. These tumors produce elevatedhCG levelsin serum and are usually widely metastatic. b. Embryonal carcinoma is an aggressiveovarian carcinoma, resembling testicular embryonal carcinoma. c. Polyembryoma may contain "embryoid bodies."Thesestructures show all three germ layers,just as in normal embryologic development. d. Mixed germ cell tumor may combine elements of other germ cell tumors. It is usually composed of dysgerminoma, combined with yolk sac tumor, and immature teratoma. D. Sexcord-stromal tumors 1. Overview. Thesetumors comprise only 5-10o/oof ovarian neoplasms.They occur at all ages,and produce steroid hormones that may lead to endocrinologic syndromes. The three most important groups of these tumors are granulosa-thecacell, fibroma, and Sertoli-Leydigcells. 2. Granulosa-theca cell tumors
ln a Nutshell Granulosa CellTumors . Usually estrogen-secreting . Call-Exner bodies . Associated withendometrial hyperplasia and endometrial carcinoma
a. Clinical features. These usually occur in postmenopausalwomen. They contain granulosaand theca cells in variable ratios. b. Pathology. They are usually unilateral with a yellow hue. They may be small or large, solid or cystic. Histology is variable. Some contain only granulosa cells,which are small polygonal follicle cells in sheetsor strands,which may be filled with acidophilic material (Call-Exner bodies). Others are pure thecomas; these cells are cuboidal/spindle-shapedwith lipid droplets.Many are mixed. c. Course and prognosis. Thesetumors may secreteestrogens.They are associatedwith rystic hyperplasia/carcinomaof the endometrium and breast cancer.Some granulosa tumors make androgens with resultant virilization. Thecomas are benign. Granulosa cell tumors may be malignant (5-25o/o).Surgerymay be curative. 3. Fibromas a. Clinical features. Fibromas comprise 5o/oof ovarian neoplasms.They presentwith pain and a pelvic mass;ascitesis common, and hydrothorax (usually right-sided) may occur. b. Pathology
566
Pathology: Female
(1) Grossly, they are usually unilateral, solid, hard, grey masses,5-10 cm in diameter, with an intact serosa. (2) Microscopically, they are composed of well-differentiated fibroblasts with rare mitoses.If thecal elementsare present,the tumor is a "fibrothecoma." c. Course and prognosis. The triad of ovarian tumor, hydrothorax, and ascitesis called "Meig syndrome." This triad may occur with other ovarian neoplasms,but it is most common with fibromas. It doesnot imply pleural or peritoneal metastases. 4. Sertoli-Leydig cell tumors (androblastoma, arrhenoblastoma) a. Clinical features. Theseare most common in the secondand third decades.They may produce masculinization, anovulation, and sterility.
ln a Nubh-gll MeigSyndrome . Ovarian fibroma . Hydrothorax . Ascites
b. Pathology. Tumors are usually unilateral, solid, and whitish-gray. Microscopy is variable. They may be well differentiated with easily identifiable Sertoli or Leydig cells; they may have immature tubules with large L.ydig cells;or they may appear sarcomatous with no Leydig cells. c. Course and prognosis. The course is benign. Manifestations range from defeminization (breastatrophy,amenorrhea)to frank virilization (hirsutism, male hair pattern). 5. Other sex cord-stromal tumors a. Lipid cell tumors are often virilizing and are composed of large, vacuolated cells. TWenty-fivepercent are malignant. b. Stromal luteoma is composed of pure lutein cells that may produce estrogensand androgens.(Normal corpus luteum cells produce large amounts of progesterone.) Thesetumors are benign. c. Hilus cell tumors (pure L.ydig cell tumors) causemasculinization. They are usually unilateral. Cells contain lipochrome pigment and Reinke crystals. They follow a benign course. d. Gonadoblastoma is rare, occurring in young patients with abnormal sexual development. It may causeamenorrheaand virilization. Cells resembleimmature Sertoli and granulosacells. E. Tirmors metastatic to the ovary. The most common sitesof origin are other pelvic organs, upper gastrointestinal tract, and breast. Iftukenberg tumor is bilateral, metastatic, mucinproducing adenocarcinoma(usually signet-ring cellsderived from the stomach). F. Cysts 1. Follicular cysts a. Clinical features. These are often asymptomatic cysts, originating in unruptured or resealedfollicles. b. Pathology (1) Grossly, thesecystsare usually in the cortex, multiple, filled with clear fluid, and approximately 1 cm in size. (2) Microscopically, granulosalining cells may be identified in cystswith little fluid; with large amounts of fluid, pressurecausesatrophy of lining cells. c. Course and prognosis. These cysts generally remain small. Some may produce estrogensand causeendometrial hyperplasia.
' t67
Reproductive System
2. Lutealcysts a. Clinical features.Thesebenign cystsare lesscommon than follicular rysts. b. Pathology ( 1) Grossly, cystsare usually approxim ately2 cm and yellow. (2) Microscopically, the rystic lining is luteal tissue,comprised of large cells filled with smooth endoplasmicreticulum (like normal corpus luteum cells). Thble lV-7-1. Ovarian neoplasms. Tirmor Tirmors of surface epithelium Serous Serouscystadenoma Borderline seroustumor Serouscystadenocarcinoma
Clinical Features
Pathology
Usuallybenign Adnexal mass,moderately aggressive Most common malignant ovarian tumor
Usuallv unilateral Twenty-fivepercent bilateral Usually bilateral
Mucinous Mucinous rystadenoma Benign Borderline mucinous tumor Moderately aggressive Mucinous cystadenocarcinoma Malignant
Usuallv unilateral Multiloculated rysts Hemorrhagic/necrotic
Endometrioid carcinoma Clear cell adenocarcinoma Brenner tumor
Usually malignant Rare,malignant Rare,usually benign
Glandular structures Solid or rystic Usually unilateral
Germ cell tumors Teratomas Mature (dermoid cyst)
Usually benign
Immature Dysgerminoma Endodermal sinus tumor Choriocarcinoma
Rare,invasive Rare,radiosensitive Rare,producescr-fetoprotein ElevatedhCG
Usually unilateral, mixture of hair/teeth/bone Immature tissues Usually unilateral Hemorrhagic, necrotic Often metastatic
Sexcord-stromal tumors Granulosa-thecacell Fibroma Sertoli-Leydig Gonadoblastoma
May elaborateestrogens or androgens Meig syndrome Masculinizing in some cases Rare
Usually unilateral Usuaily unilateral Unilateral Immature Sertoli/ granulosacells
3. Polycystic ovaries a. Clinical features. Polycysticovariesmay be associatedwith three clinical syndromes: virilism; excessivemenstrual bleeding; or the Stein-Leventhal syndrome, which is characterizedbysecondaryamenorrhea,obesity,hirsutism, infertility, and bilaterally enlarged,polycystic ovaries.They are most common in young women in the second and third decades.
568
Pathology: Female
b. Pathology ( 1) Grossly,theovariesareenlarged, with a thick,whiteoutercovering andmultiple cysts, (2) Microscopically,cystsarelined with granulosatleca cells.
Ina Nu! hell lolycystic Ovaries . Occur mainly inyoung women
c. Pathogenesisinvolveshyperinsulinismand insulin resistance, increasedftequencyof GnRH pulses,and dysregulationof androgensecretionin ovariesand adrenals.
. Asociated with:
d. Course and prognosis, Wedgeresection(by removing cystsand tleca cells) may restorenormal mensesand fertility.
- Infertility
- Amenorrhea
- Obesitv
PLACENTA
- Hirsutrsm
A Gestationaltrophoblastic neoplasmsare derivedftom trophoblastictissueassociated with pregnancy.
- t LHsecre,tion
1. Hydatidiform mole a. Clinical features. Hydatidiform mole occurs in l/2,000 pregnanciesin the United States;it is more common in Asia.The highestincidenceis in older pregnantwomen in the fifth and sixth decade.Molesmaypresentin the fourth and fifth month of pregnancywith a uterusthat is largefor datesand vaginalbleeding.No fetusis detectable by examinationor ultrasoundlThe "embryo" co-nsists of a 46lof karyotype derived exclusivelyfrom the father. Theremaybe elevatedblood and urine (hCG) levels. b. Pathology ( I ) Grossly,molesareusualJy in the uterusbur maybe ectopic.The urerusis larger than expected,and the .unity i, fil.d rnrith-ultiple grapi-like cysticstructurls. A collapsedamniotic sacmaybe presenl. (2) Microscopicallt one seesa hydropic,cysticswellingof chorionicvilli with epithel.ialhyperplasiaand anaplasia;epitheliummaycontainboth cyto- and syncftiotrophoblast.
Note A partialhydatidform molecontains anembryo thatistriploidortebaploid lt isthoughtthatthisis dueto tlvoor moresperm fertilizingthe ovum'
c. Courseand prognosis. Moles canbe gradedby degreeof atypia and differentiation. Eighty percentare benign. Somemay be precursorsof malignant choriocarcinoma. Therapyis removal by curettagewith periodic monitoring of hCG levels. 2. Invasivernole (chorioadenomadestruens) a, Clinical features. Thesemoles causeencessive, irregular uterine enlargementand vaginalbleedingin pregnantwomen.hCG is elevated. b. Pathology ( i ) Grossly,thereis a hydropicmasswithin the uterinecayity,which mayinvadeand perforatethe wall. (2) Microscopicalln one seesthe c)'sticvilli with proliferation of cyto- and qrrcytiotrophoblast.Microinvasioncanbe demonstrat€d. c. Course and prognosis. Invasive moles may spread by local invasion or distant embolization.They do not grow at thes€distant sites;henc€,they arenot true metastases. Uterine rupture may be a lethal complication. The tumor responds to chemotherapy.
569
Reproductive System
3. Choriocarcinoma a. Clinical features. This is an uncommon trophoblastic malignancy that may be pre(22o/o), cededby a hydatidiform mole (50olo),abortion (25o/o),pregnancy or other con(3o/o). Patientsgenerallypresent with bloody vaginal discharge.hCG levels are ditions markedly elevated. b. Pathology (1) Grossly,pale necrotic areas,hemorrhage,and rysts occur. (2) Microscopic findings vary. Epithelial cells or atypical cuboidal and syncytial cells may occur but no villi. Invasion is obvious. c. Course and prognosis. Choriocarcinoma metastasizes*id"ly to the lungs, vagina, brain, liver, and kidney. Tieatment includes surgery and chemotherapy, which may have dramatic results and cure some patients.
BREAST A. Acute mastitis 1. Clinical features. Fissuresin nipples during early nursing or from skin disorders may predisposeto bacterial infection of the breast.Usual pathogens are Staplrylococcusaureus and Streptococcus. 2. Pathology. Mastitis is usually unilateral, with pus in the ducts. Necrosis may occur. 3. Course. Antibiotics and surgical drainagemay be adequatetherapy,but necrosisand subsequent fibrosis of a localized areaof breast tissue may occur. B. Mammary duct ectasia (plasma cell mastitis) 1. Clinical features. This disorder generally occurs in the fifth decade in multiparous women. It presentswith pain, redness,and swelling around the areola. 2. Pathology. Involvement is usually unilateral, causing a thickened, indurated area of the breastwith thick secretions. 3. Course. Skin fixation, nipple retraction, and axillary lymphadenopathy may occur and must be distinguished from malignanry. C. Fibrocystic disease(cystic hyperplasia) 1. Clinical features. This is the most common breast disorder; it is responsiblefor 50oloof breast surgery,affecting approximately I0o/oof women. It usually developsduring reproductive life and representsa distortion of the normal breast changesassociatedwith the menstrual rycle. Patients often have lumpy, tender breasts. 2. Pathogenesisis thought to be due to high estrogenlevels,e.g.,estrogentherapy,or estrogensecretingneoplasm,coupled with progesteronedeficienry. 3. Pathology. Severalmorphologic patterns are recognized. a. Fibrosis usually affectswomen 3549 years of age and is not premalignant. (1) Grossly, fibrosis is usually unilateral, most often in the upper outer quadrant, forming a dense,rubbery mass. (2) Microscopically, there is an increase in stromal connective tissue, which may compressducts and lobular buds. Cystsare rare.
,70
Pathology: Female
b. Cystic disease usually affects women 45-55 years of age and may predispose to malignanry. (1) Grossly, rystic diseaseis usually multifocal but is often bilateral. It causesgross rysts and a nodular, firm breast to palpation. Cysts are filled with serous fluid, which may be hemorrhagic, and are easily aspirated. (2) Microscopically, cysts are lined by cuboidal/ columnar or flattened epithelium and may have papillary projections or piled up massesof cells. Occasionally, there are large, polygonal cells with round, dark nuclei and eosinophilic cytoplasm,representingbenign apocrinemetaplasia.There may be an accompanying stromal lymphocytic infiltrate ("chronic rystic mastitis"). c. Sclerosing adenosis usually affectswomen 3545 years of age and probably does not predisposeto cancer. (1) Grossly, this diseaseis usually unilateral, often focal, and is most often found in the upper outer quadrant. It causesa palpable,ill-defined, firm area. (2) Microscopically, there are glandular patterns and nests of cells in a fibrous stroma. Adenosis (closely aggregatedglands) may be difficult to distinguish histologically from cancer becausethe mixture of epithelial and stromal cells suggestsan invasive,epithelial malignanry (Figure IV-7-6).
ffi
Figure lV-7-6.Sclerosing adenosis (microscopic).
d. Epithelial hyperplasia occurs in women over 30 yearsof age (usually 3545) and representsan increasedcancer risk. (1) Grossly, findings are variable. Hyperplasia may be accompaniedby adenosis, fibrosis,and rysts that produce ill-defined masses. (2) Microscopically, the duct epithelium is multilayered and producesvariable morphologies:glandular structures(cribriform patterns) or papillary configurations (ductal papillomatosis).There are often increasedmitoses(atypicalhyperplasia).
t7l
Reproductive System
4. Course and prognosis. Fibrorystic diseaseis clinically important, becauseit may be mistaken for cancer,and it may predisposeto cancer,particularly the epithelial hyperplasia variant. ThbleIV-7-2lists the featuresthat differentiate the two diseases. Thble lV-7-2. Features distinguishit g fibrocystic diseasefrom breast cancer. Fibrocystic Disease
Breast Cancer
Often bilateral May have multiple nodules Menstrual variation Cyclic pain and engorgement May regressduring pregnancy
Often unilateral Usually single nodule No menstrual variation No cyclic pain or engorgement Does not regressduring pregnancy
D. Gynecomastia 1. Clinical features. Gynecomastiais an enlargement of the male breasts that occurs in various clinical situations (e.g.,Klinefelter syndrome;testiculartumors [particularly SertoliLeydig cell tumors], puberry or old age) and is associatedwith increasedsensitivity to estrogens(e.g.,in hepatic cirrhosis,the liver cannot properly metabolizeestrogens). 2. Pathology a. Grossly, it may be unilateral or bilateral,but it is most often unilateral. b. Microscopically, there is ductal epithelial hyperplasia and adjacent edema of the periductular stroma. 3. Course dependson the etiology.Gynecomastiamay be an important signal to the clinician that the patient has a high-estrogenstate. E. Thmors 1. Fibroadenoma a. Clinical features. This is the most common benign breast tumor. It occurs in women of reproductiveage,generallybefore age30, and may be relatedto increasedestrogen sensitivity.Fibroadenoma presentsas a single movable breast nodule, not fixed to the skin. b. Pathology (1) Grossly, there is a small,freely movable nodule, often in the upper outer quadrant. Sizemay range up to 10 cm. The tumors are usually round and encapsulatedwith a grey-whitecut surface(FigureI\f-7-7).
t72
Pathology:Female
ss**g*3# Figure aV-7-7. Fibroadenoma(gross).
(2) Microscopically, fibroadenomas form glandular epithelial-lined spaceswith a fibroblastic stroma. Stromal proliferation may collapsegland lumina, or alternatively,glandular proliferation may predominate with scantyconnectivetissuestroma. Usually,there is a network of ducts within a proliferated, edematousstroma (FigureW-7-8).
.\. +"
a4 .t
.9,
h
Figure lV-7-8. Fibroadenoma(microscopic).
c. Course. Fibroadenomasmay show menstrual variation and increasedgrowth during pregnancy.Postmenopausalregressionis usual. Surgery is required for definitive diagnosis.
77t
Reproductive System
2. Cystosarcoma phyllodes (Phyllodes tumor) a. Clinical features. Theseare fibroadenoma-like tumors that have become large, cystic, and lobulated. They are distinguished from fibroadenomas by the nature of the stromal component. When hypercellular,the term "cellular fibroadenoma" is used.When the stroma is both hypercellular and highly atypical, the tumor is called a sarcoma. b. Pathology ( 1) Grossly, thesetumors form an irregular mass,often fungating or ulcerated. (2) Microscopically, there is a mlaroid stroma with increasedcellulariry anaplasia, and increasedmitoses.Malignant fibrous, cartilaginous, and bony elementsmay be present. c. Course. The tumor is initially localized but may spread latet usually to distant sites but not to local lymph nodes. 3. Intraductal papilloma a. Clinical features. This forms a solitary lesion within a duct or ryst and is most common in women 20-50 years of age.It may present with nipple discharge (serous or bloody), nipple retraction, or as a small subareolarmass. b. Pathology (1) Grossly,lesionsare small (lessthan 1 cm) and are usually closeto the nipple in major ducts. They may be sessileor pedunculated. (2) Microscopically, there are multiple papillae.
In a Nutshell RiskFactors for Breast Cancer . Increasing age(40+) . Nulliparity . Family history . Early menarche . Latemenopause . Fibrocystic disease . Previous history of breast cancer . Obesity . High{at diet
c. Course. Current evidence suggeststhat single intraductal papillomas are benign, but multiple papillomas are associatedwith an increasedrisk of cancer. 4. Carcinoma of the breast a. Incidence. Breastcarcinomais the most common causeof cancerin women, although lung cancercausesmore deaths.It is rarely seenin women under age25. b. Etiology. Risk factors include increasing age (particularly after 40), nullipariry family history (especiallyin premenopausalcancer),early menarche/latemenopause,fibrorystic disease(especiallyepithelial hyperplasia), and a previous history of breast cancer.The lifetime risk of breast cancer for the averagewoman with no family history is 8-l0o/o. c. Clinical features ( 1) Locationsof breastcarcinomaare:50% in the upper outer quadrant,20o/oin central area,and 10o/oin other quadrants. Ninety percent arise in ductal epithelium, while 10oloarise in the lobules. Carcinoma is slightly more common in the left breast( 110:100);it is bilateral or sequentialin 4o/oof cases. (2) Most patients presentwith a breast massdiscoveredeither by self-examination or on a routine physical examination by a physician. (3) Dependingon the sizeand invasiveness of the tumor, other clinical patternsmay occur. The tumor may grow into the thoracic fasciato become fixed to the chest wall; it may extend into the skin, causing dimpling and retraction; it may cause obstruction of subcutaneouslymphatics, causingan orange-peelconsistencyto skin called "peau d'orange"; or it may invade Cooper ligaments within ducts to causenipple retraction.
t74
Pathology: Female
d. Pathogenesis is multifactorial: genetic (e.g., family history), environmental (e.g., radiation), and viral (e.g., mammary tumor virus in mice) influences may be involved.A possiblehormonal role has been intensivelystudied,yielding the finding that "unopposed estrogen" over prolonged periods may lead to ductal hyperplasia and malignant transformation.
Note
e. Noninfiltrating intraductal carcinoma ( 1) Grossly,there is a focus of increasedconsistenryin breasttissue.Intraductal carcinomas, called "comedocarcinomas I' are so named becausecheesy,necrotic tumor tissuemay be expressedfrom ducts. (2) Microscopically, typical duct epithelial cellsproliferate and fill ducts,leadingto ductal dilatation.They rarely have a papillary pattern (i.e., intraductal papillary carcinoma). f. Infiltrating ductal carcinoma is the most common breast cancer. (1) Grossly, thesetumors typically have a rock-hard, cartilaginousconsistenryand are usually 2-5 cm in diameter. They may be fixed to the chest wall with nipple retraction and skin dimpling. Foci of necrosis and calcification are common, aiding discoveryon mammography. (2) Microscopically, anaplasticduct epithelial cellsappearin masses,nests,glands, cords, and tubes, invading the stroma. A fibrous reaction is responsiblefor the hard, palpablemass. g. Medullary carcinoma with lymphoid infiltration. Thesehave a better prognosis than infiltrating ductal carcinoma. (1) Grossly, medullary carcinoma forms fleshymasses,often 5-10 cm in diameter. There is little fibrous tissue.Foci of hemorrhageand necrosisare common. (2) Microscopically, there are sheets of large, pleomorphic cells with increased mitotic activity and a lymphocytic infiltrate that separatesthe epithelial cells from eachother. h. Colloid (mucinous) carcinoma occurs in older women. It is slow growing and has a better prognosisthan infiltrating ductal carcinoma. ( 1) Grossly,theseare soft, large,gelatinoustumors. (2) Microscopically, there are islandsof tumor cellsfloating in a seaof mucin. Some may resemblewell-differentiated,mucin-producing adenocarcinomas.
genesTwotumorsuppressor BRCAI onchromosome l7q andBRCA2 onchromosome 13q-have recently been discovered. BRCAI hasbeen cloned, andspecific mutations in high-incidence families have beencharacterized. Essentially, protein allcause synthesis termination, leading to the absence of geneproduct. Patients carrying mutated BRCAI areatextremely high (almost l00o/o) lifetime riskfor breast cancer, oftenoccurring inthethirdandfourth patients decades of life.Some arealsoatincreased riskfor ovarian carcinoma, andmen maybeatincreased riskfor prostate cancer, although data onthissubject arenot conclusive. Mutated BRCA2 doesnotincrease the incidence of ovarian cancer in women butdoesincrease the incidence of breast cancer in bothwomen andmen.
i. Lobular carcinoma arisesfrom terminal ductules.Ttrmors are multicentric and usually haveestrogenreceptors. (1) Grossly, the lobular carcinomasare rubbery and ill-defined as a result of their multicentric nature. (2) Microscopically, tumor cells are small and may be arranged in rings around ducts. In lobular carcinomain situ, tumor cellsare confined to lobules.In infiltrating lobular carcinoma,there is stromal infiltration, often showing malignant epithelial cellsin single file.
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Reproductive System
Figure lV-7-9.Paget disease of the breast (gross). j. Paget disease of the breast is a form of intraductal carcinoma that involves the areolar skin and the nipple. It occurs in older women and has a poor prognosis. (1) Grossly, the skin of the nipple and areolaare ulceratedand oozing. There may be a superimposedinflammation or bacterialinfection (Figure IV-7-9). (2) Microscopically, there is ductal carcinoma aswell aslarge,anaplastic,hyperchromatic "Pagetcells,"i.e.,tumor cellsinvadingthe epidermis(FigurefV-7-10).
w
#
*, *
," &,
,# , glF *r
,
ry'+,.#
Figure lV-7-10.Paget disease of the breast (microscopic).
Note TheAmerican Cancer Society recommends annual mammography forall women over40.
,76
k. Metastatic tumors to the breast are rare. The most common are leukemia, lymphoma,lung cancer,and melanoma. l. Diagnosis. Mammography, a radiologic evaluation of the breast, is part of the clinical investigationof a breastmass.Sixty percentof breastcancershavefoci of calcification (FiguresIV-7-11 and lV-7-12).
Pathology: Female
Figure lV-7-11.Carcinoma of the breast (gross).
T?*n ,
m.&^" Figure lV-7-12.Carcinoma of the breast (microscopic)
m. Metastases.Most breastcancersdisseminatevia lymphatic or hematogenousroutesto axillary, supraclavicular,and internal thoracic nodesor the nodes of the contralateral breast. The direction of spread depends on the anatomic location and lymphatic drainageof the primary tumor. n. Staging of breast carcinomas is basedupon the sizeof the tumor and the degreeto which the tumor has spreadto the surrounding tissues. ( 1) StageI refersto a tumor lessthan 5 cm, with no metastasesor nodal involvement. (2) StageII tumors are lessthan 5 cm and havelocal, moveable,nodal involvement, but not distant metastases. (3) StageIII tumors have local nodal, pectoral, and/or skin involvement, but no distant metastases.
t77
Reproductive System
( ) StagefV tumors may or may not have local involvement,but are characterized by the presenceof distantmetastases.
Note Prognosis isalso heavily influenced by histologic type.
o. Prognosis dependson many factors,including the type and stageof the carcinoma. Overall S-yearsurvival is 50%; a breakdown by stageis summarizedin ThbleIV-7-3. Thble lV-7-3. Breast cancer 5-year survival rate by stage. Stage I II III IV
5-Year Survival 80-95o/o 65-85o/o 40-50o/o l0-20o/o
p. Treatment (1) Surgery. Segmental mastectomy (can be local excision, quadrant excision, partial removal of breast tissue,or "lumpectomy"), where only the tumor and its surrounding tissueis removed.Simple mastectomy is the removal of breast tissue; modified radical mastectomy is the removal of the breast tissue, axillary nodes, and pectoralis fascia; and radical mastectomy is the removal of breast tissue, axillary nodes, pectoralis fascia, and pectoral muscles.Therapy usually includes some combination of surgery, radiation, and chemotherapy. (2) Estrogen receptors. The presenceof cytoplasmic estrogenreceptorsmay be a useful predictor of responseto "hormonal therapy."Approximatelytwo-thirds of breast cancersare estrogen-receptorpositive; most of these will regresswhen patients are given antiestrogencompounds such as tamoxifen. In fact, patients who are both estrogen- and progesterone-receptorpositive have the best response to tamoxifen. Adjuvant chemotherapy is clearly of benefit in postmenopausalcancerbut not in premenopausalcancer.
!78
Reproductive Pharmacology
progestins, Thereproductive orsexhormones consist of estrogens, andandrogens. Synthetic hormone analogs andtheirantagonists areavailable forendocrine andnonendocrine abnormalities, including replacement therapy, fertility control, treatment of infertility, andcancer chemotherapy.
ESTROGENS The estrogensare steroid hormones produced predominantly by the ovaries, although the adrenals,placenta,and other organs may contribute. Estradiol is the principle ovarian estrogen.Other endogenousestrogensinclude estriol and estrone. A. Regulation of secretion. Synthesisand secretion are regulated by the hypothalamic-pituitary-ovarian axis.Synthesisby ovarian folliclesis stimulatedbyFSH, which increasescAMP in follicular cells.Estrogensprovide negativefeedbackto inhibit pituitary secretionof FSH and LH. However,the midrycle surge (or pulse) in estradiolstimulatesthe secretionof LH, which induces ovulation. Estrogensremain elevatedin the luteal phase. B. Mechanism of action. Estrogenswork via a steroid hormone mechanism,entering the target cells and binding to specific cytosolic receptors.The steroid-receptorcomplex is then translocatedto the nucleuswhere it altersgeneexpression. C. Physiologic effects l. Stimulate the development of uterus, fallopian tubes,vagina,breast,and secondarysex characteristics 2. Causeendometrial growth during the menstrual rycle 3. Decreaseserum cholesterol 4. Inhibit bone resorption 5. Estrogensincreaselinear bone growth with subsequentclosure of the epiphysealplate, effect a mild increaseon fluid and salt retention, increasehigh-density lipoproteins (HDLs), and decreaselow-density lipoproteins (LDLs). cr-Blood clotting factors II, VII, IX, and X are increased,and antithrombin III is reduced. B. Pharmacokinetics. Estradiol has low bioavailability following oral administration; analogs with better bioavailability are usually used. Estrogens are also available for topical, intramuscular,and transdermaladministration. They bind in the blood to sexhormone-binding globulin.
Bridge to MolecularBiology Steroid receptors areDNA proteins binding thathave a zincfinger structure allowing themto interfere withspecific enhancers inspacer DNAor introns of genes theyregulate expression of. ln a Nutshell Estrogens . Stimulate secondary sex characteristics . Inhibit bone resorption . Have procoagulant effects . Canincrease riskofendomewithout trialcarcinoma if given progestins Bridgeto Pathology Endometrial hyperplasia isa possible precursor to endometrial carcinoma andis generally withhigh associated exposure to estrogens.
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Cliniol Correlate ForDostmenoDausal Women whoseuterushasnol been removed surgiolly,both estrogen anda progestin are recommended. The combination reduces the risk of endometrial arcinoma asociated withunoooosed --l -. ,., "-"-qlmulanon enroSen
C. Indications for use 1. Oral contraceptives,in combinationwith progestins 2. Postn€nopausalrq acernenttherapy to reducesymptomssuchashot flashesandvaginal atrophy;aisoto decrease the risk of osteoporosisand coronaryartery dis€ase 3. Replacement therapyfor primary hypogonadismand hypopituitarism 4. Dysmenorrheaand dysfunctionaluterine bleeding 5. Palliativetreatmentof prostaticcarcinomato reducegrowth rat€ of metastases 6. Diethylstilbestml (DES),which canbe givento preventpregnancywhen administeredin high dose2,1-72hours after intercourse;it is th"refore knor,r,oasthe "morning-after pill." D. Specificagents l. Natur.l estrogensinclude estradioland conjugatedestrogens. 2. Synthetic estrogens include t}le oral preparations ethinyl estradiol and mestranol. Mestranolis convertedin the body to ethinyl estradiol. 3. Nonst€roid estrogenicagentsinclude DESand chlorotrianisene.
PROGESTINS Progesteroneis a steroidhorrnonesynthesized predominandyby the corpusluteum during the postovulatoryor luteal phaseof the menstrualcycle.During pregnancy,the placentatalcs over the production of progesteron€.Th€ adrenalcortex is also a sourceof small amountsof progesterone.Progestinsaredrugswith progesterone-like properties. A. Regulationof secretion.Synthesisby the corpusluteum is stirnulatedby LH, an effectmedirted by cAMP. B. Mechanisrnofaction. Progestins actlike estrogens to alterg€xre opressionandproteinsynthesis. C. Physiologiceffects 1. Producea secretoryvascularuterine endometriumin preparationfor implantation 2. Stimulatebreastdevelopmentin preparationfor lactation ). Maintain pregnancyby inhibiting the sloughingof the endometriallining GliniOl Gorrelate Clucose intolerance, decreased HDL,and ,--------;, ^; cnote$erol 1-;-,- -, tncreasec LUL areseenwithprogestin.
4. IncreasebodyGmperature(basaltemperatureis 0.5-1.0degreehigherin the postovulatory phase) 5. Alter carbohydratemetabolismand enhancefat deposition 6. Progestins arealsoandrogenic andantiestrogenic D. Pharmacokinetics.Progesteron€is largd metabolized(conjugated)by the liver and is, therefore,ineffectiveorally.Syntheticprogestinsareorally administered. E. Indications for use 1. Oral contracE tives (usuallyin combinationwith an estrogen) 2. The treatmentof dysrnenorrheaand dysfunctionaluterine bleeding 3. The treatment of endometriosis (a condition in which endometrialtissueis presentat someectopicsite) to suppressovarianfunction
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ORAIANDIMPIANTABLE AGENTS CONTRACEPTIVE A. Specific agents 1. Oral contraceptivesare availableaseither a combination of an estrogenand a progestin, or as progestinonly ("mini-pill"). The combination products may be biphasic or triphasic, in which the doseof progestin increasesduring the later daysof the month to mimic the natural menstrual cycle. 2. Progestin implants consist of levonorgestrel capsules, which are implanted under the skin of the upper arm, providing a slow releaseof progestin. Progestin implants are consideredan effectiveand reversiblecontraceptionfor up to 5 years. 3. Medroxyprogesteroneacetateintramuscular depot injection provides contraceptionfor 3 months. B. Mechanism of action 1. The estrogen component inhibits ovulation by negativefeedbackto inhibit the releaseof FSH and LH. 2. The progestin component may, but does not always, inhibit ovulation. The progestin reducesthe possibility of fertilization and implantation by effecting changesin fallopian tube motility, cervical mucus, and endometrium. C. Side effects and toxicity 1. Nauseaand vomiting, breasttenderness,increasedskin pigmentation, hypertension,and breakthrough bleeding correlate with the amount of estrogen given. Weight gain, depression,and hirsutism correlatewith progestincontent. 2. Headachesmay occur but are often transient;however,migraine headachesmay occur for the first time or be exacerbatedand associatedwith stroke.Oral contraceptivesare contraindicated in patientswith a history of migraine headaches. 3. There may be withdrawal bleeding. Excessivespotting and late cycle spotting may improve by decreasingestrogenand increasingprogestin. a. Vaginal infections may occur. 5. There may be effects from changes in serum proteins; specifically,increasedfibrinogen may increasethe erythrocyte sedimentationrate. 6. Cholestatic jaundice has been reported in patientstaking progestins.
Clinical Correlate SomeContraindications to Taking OralContraceptives . Thromboembolicdisease . History of migraine headaches . Smoking . Liver disease . Cerebrovascular disease . Estrogen-dependent neoplasms
7. Cardiovascular effects of combination oral contraceptives a. There may be thromboembolic disease. The risks of superficial and deep venous thrombosis and pulmonary embolism are related to estrogencontent. b. There is an increasedrisk of myocardial infarction that is related to estrogencontent, usually after prolonged use. The risk is increasedby cigarettesmoking, hyperlipoproteinemia,diabetes,hypertension,and a history of preeclampsia. c. Stroke may occur. There is an increasedincidenceof thrombolytic and hemorrhagic strokes,predominantly in women over 35 yearsold. 8. Sodium and water retention may occur. 9. Cancer risk a. DES useduring pregnancyhasbeen associatedwith vaginal and uterine carcinomain femaleoffspring.
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Reproductive System
b. Becauseprogestinsoppose estrogen-inducedcell growth, oral contraceptivesdo not increasethe incidenceof endometrial cancer.They actually decreasethe incidenceby 50o/o, an effectthat lasts l5 yearsafter the pills are stopped.Sirnilardata exist for the incidenceof ovarian cancer.The useof oral contraceptivesis not associatedwith a significant increasein breastcancer.The only cancerrisk is that of iiver adenoma.
ESTROGEN ANDPARTIAT AGONISTS ANTAGONISTS There are two drugs in this categorythat play an important role in therapy. A. Thmoxifen, a nonsteroidaldrug, is important in the treatment of estrogen-sensitivebreast cancer. l. Mechanism of action. Thmoxifen is a competitive antagonistto estrogenat receptorsin the breast;it may be a partial agonistat other estrogenreceptors(thus minimizing side effectsdue to estrogendeprivation). 2. Side effects and toxicity. The drug has a low incidence of adversereactions.Thesemay include hot flashes,nausea,vomiting, rash,menstrualirregularitiesand bleeding,infrequent depression, headache, hypercalcemia, edema,and blood dyscrasias. 3. Indications for use. The drug is successfulin reducing the recurrence of estrogenreceptor-positivebreastcancer,particularlyin postmenopausal women.
Note A partial hasefficacy agonist alone, butbehaves asa blocker inthepresence of a (e.g. fullagonist endogenous estrogens). Bridgeto Pathology
B. Clomiphene, a nonsteroidalestrogen,is used in treatment of infertility. 1. Mechanism of action. Clomiphene is a partial agonist at pituitary estrogenreceptors.It decreases the negativefeedbackof estradiol,leading to increasedreleaseof FSH and LH. 2. Indications for use. Clomiphene is used in women to improve follicular development and induce ovulation.It is usedin men to increasespermatogenesis. 3. Side effects and toxicity. Adversereactionsinclude hot flashes,headache,constipation, allergic reactions.Overstimulation of the ovariescan lead to ovarian cystsand multiplebirth pregnancies.
C. Raloxifenis used after menopauseto decreaseosteoporosis. Board-like scenario. Young woman onoralcontraceptives playing soccer drops during a ANTIPROGESTINS game witha ruptured liver A. Mifepristone (RU486)is a competitiveinhibitor of the progesteronereceptor.The drug can adenoma, causing also bind to the glucocorticoid receptor.It is used as an abortifacient to terminate early intraperitoneal bleedi ng. pregnancy.Drug administration is usuaily followed by a prostaglandin. B. Danazol is a partial or weakagonistat androgen,glucocorticoid,and progesterone receptors. It appearsto act centrallyto reduceovarianproduction of steroids.It is usedin the treatment of endometriosisand fibrocysticdiseaseof the breast.Adversereactionsare due to its weak androgenicproperties.
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Pharmacology
ANDROGENS ANDANABOTIC STEROIDS A. Regulation of secretion 1. Testosteroneis the principle androgen secretedby the testes(Leydig cells).Testosterone and other androgensare also secretedby the adrenalcortex and in small amounts by the ovaries.Once secreted,testosteroneis 99olobound to plasmaproteins, mostly to sexhormone-binding globulin. 2. Secretionof testosteroneis regulatedby the hypothalamic-pituitary system.LH stimulates the Leydig cells to synthesizeand secretetestosterone.Testosteroneand FSH act to increasespermatogenesis. Testosteroneprovides negativefeedbackto the pituitary. B. Mechanism of action. Testosterone,similar to other steroid hormones, binds to cytosolic receptors,which are translocatedto the nucleus where they regulate gene expression.In some organs (e.g., prostate), testosteroneis converted via 5cr-reductaseactivity to dihydrotestosterone,a more potent receptoragonist. C. Physiologic effects 1. Testosteroneis necessaryfor the developmentof secondarymale sex characteristicsand male sexualbehavior. 2. It is required for spermatogenesis. 3. Testosteronepromotes protein anabolism and growth and enhanceslinear bone growth and muscular development. 4. It causesan increasein the sizeof the larynx and deepensthe voice.It increasessebaceous gland activity,which may result in acne,and stimulateserythropoiesis(responsiblefor the higher hematocrit in men than in women). D. Indications for use 1. Androgensare used in replacementtherapy for hypogonadismand hypopituitarism.
ClinicalCorrelate
2. They are used to accelerategrowth and to promote anabolism.
Androgens havefallenoutof useforthetreatment of anemia since theadvent of recombinant erythropoietin.
3. In breastcancer,androgensare used as palliatives. 4. Androgens are also used in the treatment of angioneurotic edema and endometriosis (danazol). 5. Specific agents a. Compounds with androgenicand anabolic activity include testosteroneand methyltestosterone. b. Synthetic analogs with greater anabolic than androgenic properties include fluoxfmesterone, nandrolone, and oxandrolone. These"anabolic steroids" were first produced for treatment of patients with debilitating diseasesor prolonged immobilization to prevent negativenitrogen balance. E. Side effects and toxicity 1. Adverse reactions include masculinization in women and prostatic hypertrophy, priapism, and feminization in men. Testicularatrophy and gynecomastiaare problems in chronic users. 2. The most common adverse reactions are edema, jaundice, local irritation, urinary obstruction, and steroid fever. 3. Other adverseeffectsinclude premature epiphysealclosurein children,liver dysfunction, hypercalcemia,and alteration of serum lipids.
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Note
ANDROGEN ANTAGONTSTS
Spironolactone. analdosterone Rblocker, isusedfor its antiandrogenic effecblike Cyproterone acetate.
Androgenantagonistshavebeensl.nthesizedfor the treatmentof prostatecancerand benign prostatichyperplasia. A. GnRH analogs(e,g.,leupmlide). Long-termtherapyreducesthe secretionof FSHand LH, thus leducingtestosteroneproduction.Usedfor advancedprostatecanc€r. B. Flutamide is a nonsteroidcompetitiveantagonistat androgenr€c€ptorsusedin metastatic prostatecanc€rto block t€stosterone.
Gliniol Gorrelate Thecr'-blocker terazosin is alsousedinthetreatment of symptomatic 'prostatic Lrpa"frr"
C. Cyproterone acetateis an androgenreceptor antagonistwith progestin-likeactiyity. It is beingtestedfor the treatmentof hirsutism in women. D. Finasteride is an inhibitor of Scr-reductase and thus inhibits the production of dihydrotestosterone. It is us€din the treatmentofbenignprostatichypertrophyand malepattern baldness. E. Ketoconamle,an irnidazole-typeantifungal agent,inhibits steroid synthesisand is usedin mdrogenreceptor-positivecancertlerapy,
DRUGS OTHER A. Anastrozole is an aromataseinhibitor used in breastcancer. B. Danazol inhibits ovarian steroid synthesisand is used in endometriosis and breastfibrocvstic disease.
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