Management of Gastrointestinal Diseases in the Elderly

Management of Gastrointestinal Diseases in the Elderly Editors Alberto Pilotto, San Giovanni Rotondo Francesco Di Mari...

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Management of Gastrointestinal Diseases in the Elderly Editors

Alberto Pilotto, San Giovanni Rotondo Francesco Di Mario, Parma

9 figures and 11 tables, 2007

Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Singapore • Tokyo • Sydney

S. Karger Medical and Scientific Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Singapore • Tokyo • Sydney

Disclaimer The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

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Vol. 25, No. 2, 2007

Contents

111 Editorial Pilotto, A. (San Giovanni Rotondo); Di Mario, F. (Parma) 112 Basic Mechanisms of the Aging Gastrointestinal Tract Salles, N. (Pessac) 118 Mechanisms of Aging and Liver Functions Gagliano, N. (Milan); Grizzi, F. (Rozzano); Annoni, G. (Milan/Monza) 124 Usefulness of the Comprehensive Geriatric Assessment in Older Patients

with Upper Gastrointestinal Bleeding: A Two-Year Follow-Up Study Pilotto, A. (San Giovanni Rotondo); Ferrucci, L. (Baltimore, Md.); Scarcelli, C.; Niro, V. (San Giovanni Rotondo); Di Mario, F. (Parma); Seripa, D.; Andriulli, A. (San Giovanni Rotondo); Leandro, G. (Bari); Franceschi, M. (San Giovanni Rotondo/ Parma) 129 The Anorexia of Aging Di Francesco, V.; Fantin, F.; Omizzolo, F.; Residori, L.; Bissoli, L.; Bosello, O.; Zamboni, M. (Verona) 138 Liver Diseases in the Elderly: An Update Floreani, A. (Padova) 144 Intestinal Malabsorption in the Elderly Holt, P.R. (New York, N.Y.) 151 Diverticular Disease in the Elderly Comparato, A. (Parma); Pilotto, A. (San Giovanni Rotondo); Franzè, A. (Parma); Franceschi, M. (Parma/San Giovanni Rotondo); Di Mario, F. (Parma) 160 Bowel Care in the Elderly Spinzi, G.C. (Como) 166 Author Index/Subject Index

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Dig Dis 2007;25:111 DOI: 10.1159/000101513

Editorial

With the increase in the aging population, the study and care of gastrointestinal disorders in the elderly have become priority topics for both clinicians and researchers. In the last few years the medical literature has provided several studies on the changes that occur in gastrointestinal physiology as a function of advanced age, as well as on gastrointestinal diseases associated with aging. The aim of this Special Issue of Digestive Diseases entitled ‘Management of Gastrointestinal Diseases in the Elderly’ is to assemble the results of the more recent studies in geriatric gastroenterology and to review both basic research and clinical aspects of this field. The first two articles discuss an interesting point in geriatric gastroenterology, i.e. the effects of aging upon the physiology of the gastrointestinal tract and liver functions. Since the elderly patient may present with particularly unique variables, such as altered visceral function, which impact profoundly on the presentation, diagnosis and treatment of disease, a deeper understanding of these variables is critical to provide optimal diagnostic modalities and design specific treatment care plans for elderly individuals. The geriatric approach to gastrointestinal disorders is a crucial point in the clinical management of older patients with gastrointestinal disorders. Since these patients are likely to have multiple interacting problems that interfere with their daily function and complicate their treatments, a comprehensive multidimensional assessment is particularly important in managing older patients with chronic and disabling illnesses as well as with acute death-threatening diseases. In this issue, a special article reports a recent clinical experience evaluating the clinical usefulness of comprehensive geriatric assessment in older patients with gastrointestinal bleeding.

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A significant component of this special issue is devoted to identifying the physician’s clinical approach to the elderly with specific gastroenterological problems. Recent advances in pathophysiology, diagnostic tools and treatments of elderly patients with anorexia are reported in an updated article. Moreover, the physician’s approach to the management of disorders of the small intestine, colon, and liver is discussed, highlighting the specific aspects of such disorders in old age. Diagnostic testing becomes very important in old age since clinical features such as history and physical signs are frequently most difficult to interpret in older individuals. Clearly, both the course and the therapy of a disease may also be found to be altered in an older individual. Indeed, very frequently, clinical manifestations and the response to therapy may appear to differ because the older patient has several concomitant disorders that may distort the classic features of the primary gastrointestinal disease. For these reasons, the process of geriatric assessment often requires the involvement of a multidisciplinary team with experienced specialists as well as primary care physicians and/or community health workers focused on identifying functional problems and disabilities of older persons. A clear example of such a multidisciplinary approach to the older patient is described in the article on bowel care. We hope that this special issue will be useful for general physicians, specialists in geriatrics and gastroenterology, and all healthcare providers who are involved in planning care management of elderly people with gastrointestinal disorders. Alberto Pilotto Francesco Di Mario

Dig Dis 2007;25:112–117 DOI: 10.1159/000099474

Basic Mechanisms of the Aging Gastrointestinal Tract N. Salles Geriatric Department, Hospital Xavier Arnozan, Pessac, France

Key Words Geriatrics Gastrointestinal aging Motor and histological changes

Abstract The goal of this short review is to summarize recent data on gastrointestinal changes with aging, focusing on gastrointestinal motility disorders, and mucosal variations. First of all, this review focused on gastrointestinal motility disorders with aging, even though an increased prevalence of several gastrointestinal motor disorders (i.e., dysphagia, dyspepsia, anorexia, and constipation) occurs in older people, aging per se appears to have a minor direct effect on most gastrointestinal functions. Secondly, this review focused on histological changes with aging, i.e., regulation of gastrointestinal mucosal growth, gastrointestinal carcinogenesis, and gastric mucosal changes, especially changes in gastric acid secretion, bacterial overgrowth and its consequences on elderly patients. Copyright © 2007 S. Karger AG, Basel

Introduction

Relatively little work has been done to describe the gastrointestinal changes associated with normal aging in humans and in many instances normal data on which to base clinical comparisons are not available.

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The goal of this short review is to summarize recent data on gastrointestinal changes with aging, focusing on gastrointestinal motility disorders, and mucosal variations.

Aging and Gastrointestinal Motor Function

There seems to be an increase in gastrointestinal disorders of function and motility with aging. However, even though an increased prevalence of several gastrointestinal motor disorders (i.e., dysphagia, dyspepsia, anorexia, and constipation) occurs in older people, aging per se appears to have only a minor direct effect on most gastrointestinal functions, in large part because of the functional reserve capacity of the gastrointestinal tract. Esophageal Motility In studying patients in their 80 and 90s, several authors have reported a significant decrease in the amplitude of peristaltic pressures, but not duration and velocity, as well as an increased frequency of non-propulsive, often repetitive contractions [1, 2]. Morphological studies have shown an age-related loss of enteric neurons in the human esophagus. The number of neurons decreases after 70 years of age, which is accompanied by an increase in the sizes of the neurons along the esophagus being most pronounced in its superior third at the junction with the pharynx [3]. There is also evidence of reduced

N. Salles Geriatric Department, Hospital Xavier Arnozan FR–33604 Pessac (France) E-Mail [email protected]

amplitude of peristaltic contractions in the lower esophagus of the elderly, consistent with the observation that esophageal clearance after gastroesophageal reflux is impaired in older individuals. Ferriolli et al. [4] confirmed that these motility abnormalities in the elderly impaired acid clearance by finding that duration of gastroesophageal reflux episodes was longer in older persons although the frequency of reflux episodes did not vary with age. Furthermore, age-related normality limits of esophageal pressures should be considered before realizing manometric explorations. In fact, results of a study performing manometric explorations in healthy persons showed that age correlated inversely with both lower and upper esophageal sphincter pressure and length, and peristaltic wave amplitude and velocity [5]. Gastric Emptying and Small Intestinal Transit The effect of aging on gastric motility has evoked some interest, but it is still controversial whether gastric emptying changes in advanced age. Madsen et al. [6, 7] determined gastric emptying and small intestine transit rates in older persons (mean age 180) using a gamma camera technique. They reported no influence in gastric emptying or small intestine transit rate with advanced age, no difference in post-prandial frequency of antral contractions, and motility variables were not affected by gender or body mass index. However, other studies showed that radiolabeled liquids or digestible solids emptied more slowly from the stomach in older patients, even though the magnitude of the changes were relatively small when comparing with younger patients. Shimamoto et al. [8] enrolled active and inactive elderly subjects to investigate gastric motility using electrogastrography and the 13Cacetate breath test. They showed that post-prandial peristalsis and gastric contractile force were reduced in the elderly, and the reduction was greater in the inactive group than in the active one. Nakae et al. [9] determined the effect of lipid on gastric motor function in healthy elderly persons. They reported that the delaying effect of lipid on gastric emptying is increased in the elderly, and that the administration of lipase accelerates the emptying of lipid from the stomach. Mechanisms leading to slower gastric emptying in older persons are still not defined. Research in the aging enteric nervous system (ENS) reported the phenomenon of age-related neurodegeneration of the ENS in three rodent species commonly used in enteric neurobiology (rat, mouse, guinea pig) [10, 11]. Beyond the general observation that significant numbers of neurons in the myenteric plexus of the gastrointestinal tract are lost as these Basic Mechanisms of the Aging Gastrointestinal Tract

animals age, comparatively little else is known. It is unclear whether cell death affects all classes of myenteric neurons non-selectively or is confined to specific phenotypes. Even if results of different studies are still conflicting, it seems that age-related cell loss in the myenteric plexus does not occur in nitrergic neurons and that the loss occurs exclusively in the cholinergic subpopulation of enteric neurons. In a recent study, Phillips et al. [12] reported that age-related cell loss in the small and large intestines of Fischer 344 rats occurs exclusively in the cholinergic subpopulation. Colonic Transit It is commonly assumed that complaints of chronic constipation or alterations in colonic functioning are natural consequences of the aging process. Some studies reported a tendency towards a longer mean colonic transit time in older patients. Madsen and Graff [6] reported a slower colonic transit time in healthy persons aged 180. The process of normal aging seems to reduce the propulsive efficacy of the colon. Age-related changes in both the neurons and the receptors of the ENS might be one of the explanations. Morphological data from human tissues suggest that the population of colonic enteric neurons begins to decline relatively early in life, with marked decreases in both submucosal and myenteric plexuses [13]. The mechanism of delayed colonic transit time in aging remains unclear, a reduction in the number of myenteric neurons suggests that there may be a reduction in the releasable pool of neurotransmitter substances as well as fewer neurons to respond to signals. Some hypotheses are reported in the literature data. Some authors have hypothesized that advanced age was associated with decreased expression of neuronal nitric oxide synthase (NOS) and concomitant reduction in synthesis of NO in the colon. Takahashi et al. [14] reported significant reduction of NOS-immunoreactive cells and NOS synthesis in the colonic myenteric plexus of aged rats. This may be one explanation of delayed colonic transit time observed in advanced age. Other studies reported an increased density of opioid receptors in the colon of aged guinea pigs. Culpepper-Morgan et al. [15] reported that when administered orally, specific opioid antagonists were able to reverse the gastrointestinal transit delay caused by orally administered - and -opioid agonists in a dose-dependent fashion in aged guinea pigs. These data confirm the enteric action of orally administered opioids and the presence of -opioid activity in the guinea pig ENS. Accordingly, specific opioid antagonists appeared to improve chronic constipation in geriatric paDig Dis 2007;25:112–117

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tients. Other studies reported reduced release of acetylcholine in response to electrical field stimulation in old rat colonic preparations, with a decrease by 50% with age. Roberts et al. [16] reported age-dependent reduction in acetylcholine release in the rat colon myenteric plexus that may, in part, be associated with decreased calcium influx via membrane calcium channels. Furthermore, Powell and Reddix [17] reported that colonic tissues from older animals diminished secretory responses to nicotinic agonists when comparing with the preparations from younger animals.

Aging and Gastrointestinal Histological Changes

Regulation of Gastrointestinal Mucosal Growth The gastrointestinal tract represents an organ system that is characterized by rapid proliferation, aging gastrointestinal tissues illustrate markedly different phenomena from aged post-mitotic cells. A state of hyperproliferation occurs in the epithelial cells of the stomach, the small intestine, and the large intestine of stable-fed, aged rodents when compared to young mature rodents [18]. In fact, the number of gastric and colonic mucosal cell undergoing apoptosis was found to be lower in older animals [19]. Furthermore, abnormalities of proliferative and differentiation responses become evident when gastrointestinal tissues are stimulated by injury, or by starvation and refeeding. Gastrointestinal mucosal cell proliferation is known to be under the regulation of nutritional factors. Holt et al. [20] demonstrated that a restriction of calories in aging rats was associated with a significantly higher apoptotic index in the jejunum and colon. These observations suggest that nutritional modulation of mucosal cell proliferation is affected by aging. Age-associated changes in gastrointestinal mucosal cell proliferation could also be secondary to alterations in hormonal influences, especially in the gastric mucosa. Majumdar [21] reported that responsiveness of the gastric mucosa to different peptides, i.e., gastrin, bombesin, epidermal growth factor, changes at different stages of life. For example, some results demonstrated an age-related decline in gastrin secretion that could partly be attributed to a higher ratio of somatostatin to gastrin cells in the antral mucosa. There is also a progressive loss of gastric mucosal responsiveness to both acid secretory and growth-promoting actions of gastrin. One explanation could be the loss of functional receptors of gastrin with age.

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Aging and Gastrointestinal Carcinogenesis One of the most consistent pathological observations in senescent animals is the increased incidence of many types of malignancies, including gastric and colorectal cancers. In elderly patients the incidence of digestive cancers increases subsequently with peak incidence occurring in the seventh decade. Many reasons including altered carcinogen metabolism and long-term exposure of cancer-causing agents have been offered for the age-dependent rise in malignancies. Carcinogenesis results from the accumulation of mutations during progression from normal epithelium to carcinoma. For colon cancer, studies reported that the loss or inactivation of the tumor suppressor gene APC (adenomatous polyposis coli) initiated genomic instability which produced phenotypic appearance of an adenoma. With the inactivation of the tumor suppressor APC, additional alterations in tumor suppressor (p53, DCC) and oncogenes may accumulate and lead to the development of an adenomatous polyp and eventually to a carcinoma [22]. Recently, Majumdar [21] reported a higher incidence of mutations of several tumor suppressor genes, specifically APC, DCC and p53 in the gastric mucosa of older patients. Gastric Changes with Aging Between 1920 and 1980, many studies reported a significant reduction in gastric acid secretion with age. The majority of these studies were retrospective and did not take into account the presence of possible gastric atrophic lesions. More recent studies including old patients 180 without gastric atrophic lesions showed that gastric acid secretion remained normal with age, 90% of the patients had normal acid secretion [23]. Haruma et al. [24] reported that advancing age had no influence on gastric acid secretion in Helicobacter pylori-negative patients, while it decreased with age in H. pylori-positive patients. The decline in gastric acid secretion in H. pylori-positive patients depended on both increasing prevalence of fundic atrophic gastritis and inflammatory cytokines, i.e., IL-1 and TNF-, which are known to inhibit parietal cells. Epidemiological studies reported an increase prevalence of atrophic gastritis in elderly patients, with rates ranging between 50 and 70% in patients 180 [25]. A series of studies, mainly from Japan, has focused on the longterm effects of H. pylori infection and its role in the development of the histological changes that occur with aging, i.e., atrophic gastritis [25]. In a large multicenter trial, authors reported that both atrophic gastritis and intestinal metaplasia were strongly associated with H. pylori infection and not with aging per se [26]. Salles

As a result of atrophic gastritis, there is decreased acid secretion which may lead to two consequences in the elderly: bacterial overgrowth in the proximal intestinal tract and gastrointestinal malabsorption. Parlesak et al. [27] performed a study to determine the prevalence of small bowel bacterial overgrowth in older adults using a hydrogen breath test. They also tried to assess whether it was associated with abdominal complaints and nutrient intake. Their results showed a 15.6% prevalence of small bowel bacterial overgrowth. They showed that intake of inhibitors of gastric acid production contributed significantly to the high prevalence of a positive breath test in older adults, which was associated with lower body weight, lower body mass index, lower plasma albumin concentration, and higher prevalence of diarrhea. In geriatrics, malnutrition is one of the clinical consequences of bacterial overgrowth, and antibiotic treatment may lead to improve anthropometric parameters of these patients [28]. Gastric malabsorption may be another consequence of reduced acid gastric secretion. In fact, malabsorption of food-bound cobalamin may be due to reduced gastric acid production in elderly patients, combined with bacterial overgrowth. Decreased gastric acid production may lead to reduced release of free vitamin B12 from food protein [29]. Also, hypochlorhydria causes intestinal bacterial overgrowth, which interferes with vitamin B12 absorption. There are contradictory data in the literature on the effect of atrophic gastritis on vitamin B12 status in the elderly. Van Asselt et al. [29] found no significant difference in vitamin B12 absorption (free or protein-bound) between subjects !64 years and those 665 years (median 75 years). In contrast, Scarlet et al. [30] demonstrated that a reduction with age in dietary vitamin B12 absorption was related to elevated serum gastrin levels, which indicates hypochlorhydria. Kaptan et al. [31] reported in 77 H. pylori-positive patients with low serum vitamin B12 levels a normalization of cobalamin levels in 40% after H. pylori eradication. Moreover, previous studies have demonstrated that treatment of patients with a regimen of antibiotics, including tetracycline, can increase food-cobalamin absorption and correct low serum vitamin B12 levels. Atrophic gastritis may also affect calcium ferric iron and calcium absorption. Both calcium and ferric iron are kept soluble, and hence, absorbable in the intestinal milieu through the acidifying effects of gastric acid. In summary, atrophic gastritis is strongly associated with chronic H. pylori infection, and this may induce hypochlorhydria with bacterial overgrowth and malabsorp-

tion. Chronic infection may also lead to chronic gastritis with chronic inflammation in the gastric mucosa. This may have several consequences such as an increased production of reactive oxygen species (ROS) [32]. There is increasing evidence that ROS play a key role in the processes of tissue damage and aging [33]. In the stomach mucosa, ROS might directly damage or kill epithelial cells, and thereby contribute to atrophy. However, more complex mechanisms of action are conceivable. ROS may lead to a heightened sensitivity of the aging stomach to proinflammatory stimuli, and may damage DNA, thereby leading to mutations and cancerogenesis. The molecular sources of ROS that contribute to the aging process are still a matter of debate. ROS generation by mitochondria has been consistently implied, but more recently the role of the NOX family of superoxide-generating NADPH oxidases is receiving increased attention. Previous studies on expression of NADPH oxidases in gastric mucosa have mainly been performed in guinea pigs. In this system, NOX1 (an NADPH oxidase with its main localization in the colon) was found and proposed to be involved in the regulation of the inflammatory response and/or cell proliferation [34]. Chronic inflammation in the gastric mucosa may also affect expression of gastric satiety inducible peptides such as leptin or ghrelin, which may play a role in the regulation of food intake. Recent evidence supports the view that in humans and rats, leptin is secreted not only from adipose tissues but also from the gut [35]. Studies reported that gastric inflammation induced by H. pylori infection raised gastric leptin expression which induced satiety and lower body mass index [36]. Ghrelin is a recently discovered peptide which is produced mainly in the stomach, and which has been implicated in the control of food intake and energy homeostasis in both humans and rodents. A recent study, authors reported that cure of H. pylori infection increased plasma ghrelin, which in turn may lead to increased appetite and weight gain [37]. Chronic gastric inflammation may, thus, induce variations of expression of both leptin and ghrelin and may play a role in the physiopathology of anorexia in elderly patients.

Basic Mechanisms of the Aging Gastrointestinal Tract

Dig Dis 2007;25:112–117

Small Bowel Changes with Aging Conflicting reports have been published regarding intestinal mucosa. While studies in rodents have suggested an age-related loss of both villous and enterocyte height, most studies in humans have not shown any age-related changes in the small intestinal architecture. No changes were observed when looking at the surface areas of the small intestine, crypt depth, villous height, crypt-to-vil115

lus ratio, enterocytes, brush border, and Brunner glands [38]. Age-related changes in intestinal absorption have been studied. Authors reported a decreased absorption of Dxylose in aging humans. This may be explained by two mechanisms: poor renal function and the presence of bacterial overgrowth [39]. In fact, D-xylose excretion is dependent on renal function, frequently impaired with aging. When excluding patients with impaired renal function, results show only a modest reduction in xylose absorption associated with aging. In addition, bacterial overgrowth of the small intestine may induce falsely positive breath tests results. Anaerobic bacteria can produce proteases that reduce carbohydrate absorption. When regarding lipid absorption, results are contradictory [40]. In animals, results show a reduced gastric lipase and bile acid secretion, decreasing lipid solubilization and thus decreasing lipid absorption. In humans, a study of only healthy aged showed no correlation between age and 72 h fecal fat excretion. Other studies in humans reported that

absorption of fat may take longer in the elderly, and that post-prandial serum bile acid levels may be reduced with aging. The prolonged absorption of fats in elderly may induce post-prandial satiety, reducing overall intake in the elderly. Studies in animals reported an impaired adaptive response of the aged intestine. In time of stress, like dietary restriction initiated in aged rats, results show dramatic weight loss without stabilization after reintroduction of normal diet. The intestine of the animals was atrophied and ileal hydrolase activity was decreased. Following a period of stress, like illness or injury, it has been shown that elderly patients continued to underfeed themselves for 10–15 days while younger patients increased their energy intake [39]. Elderly patients may have decreased functional reserve of the intestine and may become undernourished more rapidly during acute hospitalizations, and may require an extended period of intensive nutritional monitoring because of reduced adaptive responses.

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31 Kaptan K, Beyan C, Ural A, et al: Helicobacter pylori : is it a novel causative agent in vitamin B12 deficiency? Arch Intern Med 2000;160:1349–1353. 32 Pignatelli B, Bancel B, Plummer M, et al: Helicobacter pylori eradication attenuates oxidative stress in human gastric mucosa. Am J Gastroenterol 2001;96:1758–1766. 33 Lenaz G, Bovina C, D’Aurelio M, et al: Role of mitochondria in oxidative stress and aging. Ann NY Acad Sci 2002 959:199–213. 34 Teshima S, Kutsumi H, Kawahara T, et al: Regulation of growth and apoptosis of cultured guinea pig gastric mucosal cells by mitogenic oxidase 1. Am J Physiol 2000; 279: G1169–G1176. 35 Bado A, Levasseur S, Attoub S, et al: The stomach is a source of leptin. Nature 1998; 394:790–793.

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36 Azuma T, Suto H, Ito Y, et al: Gastric leptin and Helicobacter pylori infection. Gut 2001; 49:324–329. 37 Nwokolo CU, Freshwater DA, O’Hare P, et al: Plasma ghrelin following cure of Helicobacter pylori. Gut 2003;52:637–640. 38 Corazza GR, Frazzoni M, Gatto MR, et al: Aging and small-bowel mucosa: a morphometric study. Gerontology 1986;32:60–65. 39 Woudstra T, Thomson ABR: Nutrient absorption and intestinal adaptation with aging. Best Pract Res Clin Gastroenterol 2002; 16:1–15. 40 Holt PR, Balint JA: Effects of aging on intestinal lipid absorption. Am J Physiol 1993; 264:G1–G6.

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Dig Dis 2007;25:118–123 DOI: 10.1159/000099475

Mechanisms of Aging and Liver Functions Nicoletta Gagliano a Fabio Grizzi b Giorgio Annoni c, d a

Department of Human Morphology, University of Milan, Milan; b Laboratories of Quantitative Medicine, Istituto Clinico Humanitas IRCCS, Rozzano; c Chair of Geriatrics and School of Specialization in Geriatrics, University of Milan-Bicocca, Milan; d S. Gerardo Hospital, Monza, Italy

Key Words Aged liver, stress response Aging liver Liver regeneration Mast cells

Abstract Background/Aims: Morphofunctional studies suggest that the liver, compared with other organs, ages fairly well. Its success is ascribable to its lasting ability to regenerate, even if the potential of the cells to replicate progressively declines with age. The aim of this study was to analyze some aspects of the early phases of liver regeneration, its capacity to mount a stress response, and the inflammatory response in the early stage of an acute injury. Methods: Rats aged 2, 6, 12 and 19 months received a single intraperitoneal injection of CCl4, and morphological, biochemical and molecular evaluations were done 2 and 24 h later. Results: AST and ALT, starting at age 12 months, were significantly higher than in the younger rats after CCl4. Histological modifications were already detectable after 2 h in rats aged 12 and 19 months, thereafter becoming more diffuse and marked, whereas they become evident only 24 h after the intoxication in rats aged 2 and 6 months. Albumin, c-fos, c-myc, hepatocyte growth factor, transforming growth factor- and HSP70 mRNA levels decreased 24 h after CCl4 starting at age 12 months. Mast cell density was higher in the young rats than the old ones. Conclusion: Our results point to: (a) a basically

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preserved regenerative response of the aged liver, although somehow weaker and slower, with reduced ability to counteract agents inducing cell necrosis; (b) a decrease in the HSP70 response suggesting a reduction in homeostatic capacity, and (c) a lower inflammatory response during aging. Copyright © 2007 S. Karger AG, Basel

Aging affects organs, tissues and cell functions to different extents, resulting in a decline in the capacity of the whole organism to cope with its environment. Morphofunctional studies suggest that the liver, compared with other organs, ages fairly well [1]. This concept, for a long time more anecdotal than scientifically proven, was firmly demonstrated several years ago by means of a rat transplant model [2]. Livers from young (5 months) and old (28 months) syngeneic BN/ BiRij rats were transplanted into young recipients, and there were no differences in the survival curves. Analysis of the transplanted aged livers showed reduced weight of the organ, hepatocyte degeneration, bile duct proliferation, pigment deposition, and mild to moderate fibrosis [2, 3]. All these features were perhaps well known, but certainly not the unexpected ability of the liver to survive far beyond the rats’ maximum life span [2]. More evidence comes from the finding that under physiological

Prof. Giorgio Annoni DIMEP, Building U8, Via Cadore 48 IT–20054 Monza (Italy) Tel. +39 0392 333 458, Fax +39 0392 334 358 E-Mail [email protected]

conditions the liver’s overall functions do not appear seriously affected by aging, as suggested by a full analysis of serum tests in subjects of different ages [4]. However, wide interindividual variability is the main characteristic of aged people [1, 4]. The successful aging of the liver is probably ascribable to its relatively well-preserved ability to regenerate, even though the potential of the cells to replicate progressively declines with age [5]. This statement is based on the observation that partially resected livers in old animals need longer to regain their original volume, compared to the young. This can also be elicited experimentally by an acute chemical treatment with CCl4 [6–8], providing a useful model to investigate aspects such as: (a) the triggering mechanisms in the early phase of regeneration; (b) the capacity to mount a stress response to a noxious stimulus, and (c) the inflammatory response in the early phase of an acute injury. Here we report and review these aspects in the in vivo model of a single intraperitoneal injection of CCl4 to young (2 months), adult (6 and 12 months) and aged rats (19 months). All the evaluations, biochemical, morphological and molecular, were done 2 and 24 h after liver intoxication, in comparison with age-matched untreated animals.

Under physiological conditions the liver is a largely quiescent organ in terms of cell proliferation since only a very small percentage of hepatocytes undergoes mitosis at any given time. Cell necrosis or surgical resection induces the hepatocytes to proliferate and replicate, thus restoring the previous functional capacity as well as the original mass [9]. Cell death caused by CCl4 drives hepatocytes through two main steps: a ‘priming’ phase that gives them replicative competence, and a ‘progression’ phase in which primed cells undergo DNA replication [6, 9]. This transition requires the expression of some genes whose products regulate key events during the G0 and G1 phases. Among these early genes, c-fos and c-myc [6, 10] act as transcription factors, encoding nuclear phosphoproteins believed to function as regulators of cell proliferation. Regeneration is strictly governed by growth factors and cytokines, as suggested in vitro and in vivo [11] and, in this context, up-regulation of hepatocyte growth factor (HGF) and transforming growth factor (TGF)- exert a positive control [6, 10] acting, respectively, in an auto-

crine and paracrine fashion. The whole process ends once the liver mass reaches a species- and age-specific fraction of total body mass, indicating that negative regulatory influences are needed and, in fact, a stop signal is encoded by the TGF-1 gene [12]. All this machinery in the senescent phenotype has been comprehensively investigated by analyzing serum transaminases, liver histology, GSH content, albumin, cfos, c-myc, HGF, TGF- and TGF-1 gene expression [13]. AST and ALT levels, biochemical markers of hepatic injury, are not affected by aging per se, but are significantly higher than in young rats after CCl4, starting at age 12 months and more in the oldest rats, since there is more cell necrosis. The histological findings indicate a very similar morphological appearance in control rats, but treated rats have localized cell necrosis in the central region (zone 3) with an inflammatory reaction, the portal tracts being almost spared. Hydropic degeneration, with a clear cytoplasm, vacuolization or ballooning, and fatty changes from few droplets to diffuse involvement, are the main features in the pericentral zone (fig. 1). These findings are evident 24 h after the intoxication in rats aged 2 and 6 months, but are already detectable after 2 h in those aged 12 and 19 months, thereafter becoming more diffuse and marked. All this points to a lower capacity to counteract the free radical toxicity subsequent to CCl4 metabolism. The reduced GSH content of aged livers probably explains the susceptibility to oxidative stress [13, 14]. However, the recent finding of changes in the sinusoidal endothelium and spaces of Disse, termed ‘pseudocapillarization’, that restrict the availability of oxygen and other substrates [15], also marks the lower energy status of the aged liver as a major determinant of impaired xenobiotic detoxification. At the molecular level this model discloses several features of the aging process. In both young and aged animals there was a clear reduction of albumin gene transcription 24 h after CCl4 intoxication but, 2 h after the treatment, this was true only in the old rats, since this gene was up-regulated in the young ones, pointing to a more efficient transcription machinery [13, 16]. Analysis of the c-fos and c-myc gene offers information on the entry of the priming quiescent hepatocytes into the cell cycle and of the better ability of young and adult cells, compared to senescent one, 2 h after CCl4 (fig. 2a). The persistence of c-fos transcripts for 24 h only in 6-month-old rats might correspond to a second round of replication, because only hepatocytes of this age are able to replicate through more than one cell cycle

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Liver Regeneration

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logical changes in liver tissue. Two-monthold control rat (a), or 2 h (b) and 24 h after CCl4 (c); 19-month-old controls (d), or 2 h (e) and 24 h after CCl4 (f). Sections were stained with hematoxylin and eosin. Orig. magnif. !200.

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pressed as optical densities normalized on GAPDH gene expression. Values are means 8 SEM (4 animals per age and treatment group). * p ! 0.05 vs. 6 months old, CCl4 2 h; #p ! 0.05 vs. 12 months old, CCl4 2 h; ** p ! 0.05 vs. 2, 6 and 12 months old, CCl4 2 h.

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[9]. At the same time, the fact that c-myc mRNA levels were highest in young-adult rodents (fig. 2b) suggests some facilitation of proliferation, either by enhancing the responsiveness of growth factors [17] or by shortening the cell cycle, accelerating the G0-G1 transition [18]. All together the c-fos and c-myc data show that senescent hepatocytes are triggered for a delayed, weaker regenerative response because they are blocked in G1 phase, as already demonstrated in fibroblasts [19]. In this experimental context, the HGF gene transcript was always more abundant in the old animals, possibly because of their more limited ability to maintain homeostasis, as suggested by a positive relationship between plasma HGF levels, hepatic necrosis and systemic inflammation [20, 21]. The involvement of TGF- seems different from that of HGF: TGF- mRNA levels were increased after 24 h in rats aged 2, 6, and 12 months, but not in the old animals (fig. 2c). One of the most powerful stop signals to liver growth is exerted by TGF-1 [12]. Again, in this model, the tendency to a progressive age-dependent decrease of its transcripts suggests that the aged liver takes longer to complete regeneration, as also indicated by the longer cell proliferation phase after treatment with a neutralizing TGF-1 antibody [22].

unbalanced with increasing age and thus may explain, at least in part, the increased susceptibility of aged livers to stress- and age-associated diseases. Furthermore, the knowledge of the highly integrated and complex responses of aged organisms to environmental stress will provide a basis for developing therapies related to aging-associated pathophysiological conditions.

Inflammatory Response

The heat-shock response is a highly conserved defense mechanism against noxious agents, including high temperature, alcohol, heavy metals, xenobiotics, oxidants, and radiation, and is mediated by the transient transcription of genes belonging to the family of heat-shock proteins (HSP) [23]. This provides a state of increased cell resistance, because HSP form transient complexes with other cellular proteins, promoting their folding into the correct secondary structures thus preventing denaturation. As described by several authors [24–27], aging is associated with a decrease in HSP70 response, and this is assumed to be one of the main features of aging, which involves a reduction in homeostatic capacity. Therefore, it is not surprising that 2 h after CCl4, HSP70 mRNA levels were raised only in young-adult rats, and almost undetectable in the oldest ones (fig. 2d). Induction of the gene still persisted at 24 h only in the adult animals (6 months). The ability to produce the protective HSP70 is

Inflammation involves a complex set of interactions among soluble factors and cells, and identifies a finelytuned local protective response, because its deficiencies or excesses may cause morbidity and shorten life span [28]. This response is modified in the elderly, where both function and phenotype of pivotal cells, i.e. monocytes and granulocytes, are affected [29]. Much attention has focused on the recruitment of leukocytes from the blood. However, a rapid response requires sentinel cells pre-stationed in the tissues, such as macrophages and mast cells (MC) [30]. MC are a heterogeneous family of cells containing different enzymatic proteins, such as tryptase, chymase, vasoactive amines, neutral proteases, carboxypeptidase and cathepsin E, whose content depends on the animal species and stage of development. MC maturation can be induced by a wide range of stimuli, including multivalent antigens (allergens), neuropeptides, growth factors, complement components (serum glycoproteins) and various drugs [31– 34]. Their activation results in degranulation, with secretion of preformed mediators stored in the cytoplasmic granules, synthesis of pro-inflammatory lipid mediators, and the synthesis and secretion of cytokines and chemokines [35]. All these events lead to both immediate and late-phase responses. Recently, Nguyen et al. [36] have suggested the ability of prostaglandin E2 (PGE2) to initiate MC degranulation changes in the aging animal, and therefore elevated PGE2 levels might provide an important pathway by which MCs are engaged in inflammatory responses in the elderly patient. MCs are critical effectors in many pathological conditions, including acute liver injury and, since their tissue accumulation can change significantly in the course of the inflammatory response, they have been assigned a role as an early indicator of this process. MCs have recently been studied to investigate their involvement in the mechanisms leading to age-related chronic diseases [37, 38]. In the experimental model described, MCs were evaluated as a quantitative parameter

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Stress Response of Aged Livers

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Fig. 3. a Localization of mast cells (MC) in rat liver: MCs are mainly recognizable in the connective tissue near the portal tracts and centrolobular veins. These cells are usually histochemically stained with toluidine blue, which metachromatically stains the glycosaminoglycans of MC granules (toluidine blue, !40; inset, !100). b MC densities in rats aged 2 and 19 months, untreated and 2 and 24 h after CCl4. MC density was considerably raised in young rats 2 and 24 h after CCl4 : the difference between untreated rats and treated 2-month-old rats 24 h after intoxication was significant (p ! 0.0001). In the 19-month-old rats, MC density increased less than in the young rats, but there were significant differences between the untreated rats and the treated rats 2 h after CCl4 (p = 0.032), and between the densities after 2 and 24 h (p = 0.037).

of acute inflammation, in order to detect any age-dependent changes of their density in the liver [37, 38]. Histological analysis (fig. 3a) showed that although MCs were mainly located in the connective tissue near the portal tracts and centrolobular veins, there were no real differences between the various zonal arrangements of the hepatic cells and the microcirculatory system. MC density rose considerably in young rats 2 and 24 h after CCl4 intoxication, whereas this increase was less marked in the old animals. The changes in MC density in rats aged 6 and 12 months fell between those in the rats aged 2 and 19 months (fig. 3b). These findings, confirming a role for MC as a marker of acute liver inflammatory reaction, show that there is higher and faster recruitment of these cells in injured tissue in young rats, suggesting that this inflammatory response is lowered during aging.

Conclusions

These findings point to a basically preserved regenerative response of the aged liver, though somewhat weaker and slower than in younger rats. This was coupled with a reduction in the ability to counteract agents promoting cell necrosis. From a clinical point of view, these results provide further evidence that: (1) acute liver failure is definitely more severe in old than young subjects; (2) the progression to chronicity and the clinical course of chronic viral hepatitis is worse in aged patients when the infection arises late in life; (3) nevertheless, livers of donors aged 165 years, when carefully evaluated, could offer a substantial source of organs, helping satisfy the increasing number of patients listed for liver transplant.

References 1 Schmucker DL: Aging and the liver: an update. J Gerontol 1998;53:B315–B320. 2 Sakai Y, Zhong R, Garcia B, Zhu L, Wall WJ: Assessment of the longevity of the liver using a rat transplant model. Hepatology 1997; 25: 421–425.

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3 Gagliano N, Arosio B, Grizzi F, Masson S, Tagliabue J, Dioguardi N, Vergani C, Annoni G: Reduced collagenolytic activity of metalloproteinases and development of liver fibrosis in the aging rat. Mech Ageing Dev 2002; 123:413–425.

4 Tietz NW, Shuey DF, Wekstein DR: Laboratory values in fit aging individuals sexagenarians through centenarians. Clin Chem 1992;38:1167–1185.

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5 Beyer HS, Sherman R, Zieve L: Aging is associated with reduced liver regeneration and diminished thymidine kinase mRNA content and enzyme activity in the rat. J Lab Clin Med 1991;118:101–108. 6 Fausto N, Mead JE: Biology of disease. Regulation of liver growth: protooncogenes and transforming growth factors. Lab Invest 1989;60:4–13. 7 Michalopulos GK: Liver regeneration: molecular mechanisms of growth control. FASEB J 1990;4:176–187. 8 Pessole Biondo-Simoes ML, Fouto Matias JE, Montibeller GR, Dalledonne Siqueira LC, Da Silva Nunes E, Grassi CA: Effect of aging on liver regeneration in rats. Acta Chir Brasil 2006;21:197–202. 9 Fausto N: Liver regeneration. J Hepatol 2000; 32:19–31. 10 Thompson NL, Mead JE, Braun L, Goyette M, Shank PR, Fausto N: Sequential protooncogene expression during rat liver regeneration. Cancer Res 1986;46:3111–3117. 11 Webber EM, Fitzgerald MJ, Brown PI, Bartlett MH, Fausto N: Transforming growth factor- expression during liver regeneration after partial hepatectomy and toxic injury, and potential interactions between transforming growth factor- and hepatocyte growth factor. Hepatology 1993;18: 1422–1431. 12 Braun L, Mead JE, Panzica M, Mikumo R, Bell GI, Fausto N: Transforming growth factor- mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation. Proc Natl Acad Sci USA 1988;85:1539–1543. 13 Gagliano N, Arosio B, Grizzi F, Vergani C, Annoni G: Acute liver CCl4 intoxication causes low HSP70 gene expression and a delayed transition through the cell cycle in aged rats. Exp Gerontol 2002; 37:791–801. 14 Stio M, Iantomasi T, Favilli F, Marracchini P, Lunghi B, Vincenzini MT, Treves C: Glutathione metabolism in heart and liver of the aging rat. Biochem Cell Biol 1994; 72:58–61. 15 Le Couteur DG, Cogger VC, Markus AMA, Harvey PJ, Yin Z, Ansselin AD, McLean AJ: Pseudocapillarization and associated energy limitation in the aged rat liver. Hepatology 2001;33:537–543.

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16 Panduro A, Shalaby F, Shafritz DA: Liverspecific gene expression in various pathophysiologic states. Hepatology 1987; 7: 10S– 18S. 17 Sorrentino V, Drozdoff V, McKinney MD, Zeitz L, Fleissner E: Potentiation of growth factor activity by exogenous c-myc expression. Proc Natl Acad Sci USA 1986;83:8167– 8171. 18 Karn J, Watson JV, Lowe AD, Green SM, Vedeckis W: Regulation of cell cycle duration by c-myc levels. Oncogene 1989;4:773–787. 19 Smith JR, Pereira-Smith OM: Replicative senescence: implications for in vivo aging and tumor suppression. Science 1996; 273: 63– 67. 20 Tomiya T, Ogata I, Fujiwara K: Transforming growth factor- levels in liver and blood correlate better than hepatocyte growth factor with hepatocyte proliferation during liver regeneration. Am J Pathol 1998; 153: 955– 961. 21 Shiota G, Wang TC, Nakamura T, Schmidt EV: Hepatocyte growth factor in transgenic mice: effects on hepatocyte growth, liver regeneration and gene expression. Hepatology 1994;19:962–972. 22 Armendariz-Borunda J, Katai H, Jones M, Seyer JM, Kang AH, Raghow R: Transforming growth factor- gene expression is transiently enhanced at a critical stage during liver regeneration after CCl4 treatment. Lab Invest 1993;3:283–294. 23 Lindquist S: The heat-shock response. Annu Rev Biochem 1986;55:1151–1191. 24 Fargnoli J, Kunisada T, Fornace AJ, Schneider EL, Holbrook N: Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats. Proc Natl Acad Sci USA 1990;87:846–850. 25 Heydari AR, Wu B, Takahashi R, Strong R, Richardson A: Expression of heat shock protein 70 is altered by age and diet at the level of transcription. Mol Cell Biol 1993; 13: 2909–2918. 26 Wu B, Gu MJ, Heydari AR, Richardson A: The effect of age on the synthesis of two heat shock proteins in the HSP70 family. J Gerontol 1993;48:B50–B56.

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27 Zhang HJ, Doctrow SR, Oberley LW, Kregel KC: Chronic antioxidant enzyme mimetic treatment differentially modulates hyperthermia-induced liver HSP70 expression with aging. J App Physiol 2006; 100: 1385– 1391. 28 Tracey KJ: The inflammatory reflex. Nature 2002;420:853–859. 29 De Martinis M, Modesti M, Ginaldi L: Phenotype and functional changes of circulating monocytes and polymorphonuclear leucocytes from elderly persons. Immunol Cell Biol 2004;82:415–420. 30 Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G: Inflamm-aging. An evolutionary perspective on immunosenescence. Ann NY Acad Sci 2000;908:244–254. 31 Metcalfe DD, Baram D, Mekori Y: Mast cells. Physiol Rev 1997;77:1033–1079. 32 Okayama Y, Kawakami T: Development, migration, and survival of mast cells. Immunol Res 2006;34:97–115. 33 Gurish MF, Boyce JA: Mast cells: ontogeny, homing, and recruitment of a unique innate effector cell. J Allergy Clin Immunol 2006; 117:1285–1291. 34 Franceschini B, Ceva-Grimaldi G, Russo C, Dioguardi N, Grizzi F: The complex functions of mast cells in chronic human liver diseases. Dig Dis Sci 2006;51:2248–2256. 35 Kawakami T, Galli SJ: Regulation of mastcell and basophil function and survival by IgE. Nat Rev Immunol 2002;2:773–786. 36 Nguyen M, Pace AJ, Koller BH: Age-induced reprogramming of mast cell degranulation. J Immunol 2005;175:5701–5707. 37 Grizzi F, Franceschini B, Barbieri B, Gagliano N, Arosio B, Chiriva-Internati M, Annoni G, Dioguardi N: Mast cell density: a quantitative index of acute liver inflammation. Anal Quant Cytol Histol 2002;24:63–69. 38 Grizzi F, Franceschini B, Gagliano N, Moscheni C, Annoni G, Vergani C, Hermonat PL, Chiriva-Internati M, Dioguardi N: Mast cell density, hepatic stellate cell activation and TGF-1 transcripts in the aging Sprague-Dawley rat during early acute liver injury. Toxicol Pathol 2003; 31:173–178.

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Dig Dis 2007;25:124–128 DOI: 10.1159/000099476

Usefulness of the Comprehensive Geriatric Assessment in Older Patients with Upper Gastrointestinal Bleeding: A Two-Year Follow-Up Study Alberto Pilotto a Luigi Ferrucci e Carlo Scarcelli a Valeria Niro a Francesco Di Mario c Davide Seripa a Angelo Andriulli b Gioacchino Leandro d Marilisa Franceschi a, c a

Geriatric Unit and Gerontology & Geriatrics Research Laboratories, and b Gastroenterology Unit, IRCCS ‘Casa Sollievo della Sofferenza‘, San Giovanni Rotondo, c Gastroenterology Department, University of Parma, Parma, and d Gastroenterology Unit, IRCCS ‘Saverio De Bellis’, Castellana Grotte, Bari, Italy; e National Institute on Aging, Longitudinal Studies Section, Harbor Hospital Center, Baltimore, Md., USA

Key Words Comprehensive geriatric assessment Multidimensional prognostic index Upper gastrointestinal bleeding, diagnosis

Abstract Background: The potential usefulness of standardized comprehensive geriatric assessment (CGA) in evaluating treatment and follow-up of older patients with upper gastrointestinal bleeding is unknown. Aim: To evaluate the usefulness of the CGA as a 2-year mortality multidimensional prognostic index (MPI) in older patients hospitalized for upper gastrointestinal bleeding. Materials and Methods: Patients aged 665 years consecutively hospitalized for acute upper gastrointestinal bleeding were included. Diagnosis of bleeding was based on clinical and endoscopic features. All patients underwent a CGA that included six standardized scales, i.e., Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Short Portable Mental Status Questionnaire (SPMSQ), Mini Nutritional Assessment (MNA), Exton-Smith Score (ESS) and Comorbity Index Rating Scale (CIRS), as well as information on medication history and cohabitation, for a total of 63 items. A MPI was calculated from

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the integrated total scores and expressed as MPI 1 = low risk, MPI 2 = moderate risk, and MPI 3 = severe risk. The predictive value of the MPI for mortality over a 24-month follow-up was calculated. Results: 36 elderly patients (M 16/F 20, mean age 82.8 8 7.9 years, range 70–101 years) were included in the study. A significant difference in mean age was observed between males and females (M 80.1 8 4.8 vs. F 84.9 8 9.3 years; p ! 0.05). The causes of upper gastrointestinal bleeding were duodenal ulcer in 38.8%, gastric ulcer in 22.2%, and erosive gastritis in 16.6% of the patients, while 16.6% had gastrointestinal bleeding from unknown origin. The overall 2-year mortality rate was 30.5%. 18 patients (50%) were classified as having a low-risk MPI (mean value 0.18 8 0.09), 12 (33.3%) as having a moderate-risk MPI (mean value 0.48 8 0.08) and 6 (16.6%) as having a severe-risk MPI (mean value 0.83 8 0.06). Higher MPI grades were significantly associated with higher mortality (grade 1 = 12.5%, grade 2 = 41.6%, grade 3 = 83.3%; p = 0.001). Adjusting for age and sex, the prognostic efficacy of MPI for mortality was confirmed and highly significant (odds ratio 10.47, 95% CI 2.04–53.6). Conclusion: CGA is a useful tool for calculating a MPI that significantly predicts the risk of 2-year mortality in older patients with upper gastrointestinal bleeding. Copyright © 2007 S. Karger AG, Basel

Alberto Pilotto Unità Operativa di Geriatria, Ospedale ‘Casa Sollievo della Sofferenza’ Istituto di Ricovero e Cura a Carattere Scientifico IT–71013 San Giovanni Rotondo (Italy) Tel./Fax +39 088 241 0271, E-Mail [email protected]

Introduction

Comprehensive geriatric assessment (CGA) is a multidimensional, usually interdisciplinary, diagnostic process intended to determine an elderly person’s medical, psychosocial, and functional capacity and problems with the objective of developing an overall plan for treatment and long-term follow-up. It is particularly useful in dealing with frail elderly, since such patients are likely to have multiple and interacting problems that interfere with daily functioning and complicate treatment, all of which can be better understood and addressed through the comprehensive assessment process. The process of geriatric assessment can range in intensity from a limited assessment by primary care physicians or community health workers focused on identifying an older person’s functional problems and disabilities (screening assessment), to more complete evaluations of these problems usually coupled with therapeutic plans by a multidisciplinary team with geriatric training and experience (comprehensive geriatric assessment). Indeed, an older patient presenting with a gastrointestinal problem typically has a multitude of other disease conditions and age-related disorders that complicate the diagnostic and therapeutic options and make the comprehensive assessment approach particularly valuable [1]. A large number of studies support the effectiveness of geriatric assessment programs in a variety of settings [2, 3]. However, no data on the use of the CGA in older patients with upper gastrointestinal bleeding have been reported. The aim of this study was to evaluate the usefulness of the CGA as a 2-year mortality multidimensional prognostic index (MPI) in older patients hospitalized for upper gastrointestinal bleeding.

Materials and Methods Subjects The study was conducted according to the Declaration of Helsinki and the guidelines for Good Clinical Practice and was approved by our Institution Ethics Committee. Written informed consent was obtained from the patients or from relatives of critically ill or demented patients prior to participation in the study. All patients aged 665 years consecutively admitted from January 1 to December 31, 2004, to the Geriatric Unit of the Casa Sollievo della Sofferenza Hospital (IRCCS, San Giovanni Rotondo, Italy) for acute upper gastrointestinal bleeding were screened for study inclusion. Inclusion criteria were: (1) age 665 years; (2) diagnosis of upper gastrointestinal bleeding; (3) complete

CGA in Older Patients with Upper Gastrointestinal Bleeding

CGA during hospitalization, and (4) availability of mortality/survival information at the date of study completion. At baseline, demographic and clinical parameters were defined by structured interview, clinical evaluation and review of records from the patients’ general practitioners: date of birth, gender, clinical history, current pathologies and medication history. Vital status up to December 31, 2005, was assessed by directly contacting the participants or consulting the Registry Offices of the cities where the patients were residents at the time of hospital admission. Dates of death were identified from death certificates. Diagnosis of Upper Gastrointestinal Bleeding Endoscopic diagnoses for esophageal, gastric and duodenal lesions were based on the criteria of Cotton and Williams [4]. Upper gastrointestinal tract bleeding was diagnosed on the basis of clinical signs (hematemesis, melena or anemia with a loss of 13 g of hemoglobin) and endoscopic stigmata of a recent hemorrhage defined according to Laine and Peterson [5] as a flat pigmented spot (red, purple, brown or black), an adherent clot, a visible vessel or active bleeding. Patients with bleeding from esophageal varices and/or coagulation diseases were excluded. Comprehensive Geriatric Assessment CGA was carried out including assessment instruments that are widely used in geriatric practice. Functional status was evaluated by the Activities of Daily Living (ADL) index [6], which defines the level of dependence/independence of 6 daily personal care activities including bathing, toileting, feeding, dressing, urine and bowel continence and transferring (in and out of bed or chair) and by the Instrumental Activities of Daily Living (IADL) scale [7], which assesses independence in 8 activities that are more cognitively and physically demanding than ADL, including managing finances, taking medications, using the telephone, shopping, using transportation, preparing meals, doing housework and washing. Cognitive status was assessed by the Short Portable Mental Status Questionnaire (SPMSQ), a 10-item questionnaire that assesses orientation, memory, attention, calculation and language [8]. Comorbidity was examined using the Cumulative Illness Rating Scale (CIRS) [9]. The CIRS uses 5-point ordinal scales (score 1–5) to estimate the severity of pathology in each of 13 systems, including cardiac, vascular, respiratory, eye-ear-nose-throat, upper and lower gastroenterological diseases, hepatic, renal, genitourinary, musculoskeletal, skin disorders, nervous system, endocrine-metabolic and psychiatric behavioral problems. Based on the ratings, the two following scores are derived: (a) the Comorbidity Index (CIRS-CI) score, which reflects the number of concomitant diseases, and is derived from the total number of categories in which moderate or severe levels (grades from 3 to 5) of disease are quoted (range from 0 to 13), and (b) the Severity Index (CIRS-SI), which reflects the overall severity of diseases, and the average rating of 13 disease categories, excluding psychiatric behavioral problems (range from 1 to 5). Nutritional status was explored with the Mini Nutritional Assessment (MNA) [10], which includes information on (a) anthropometric measures (body mass index, BMI: body weight/height 2, mid-arm circumference in cm, MAC, calf circumference in cm, CC, and weight loss); (b) lifestyle, medication and mobility;

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Table 1. Patient characteristics divided according to gender

Age (mean 8 SD), years Age, range Education level (mean 8 SD), years ADL score (mean 8 SD) IADL score (mean 8 SD) SPMSQ score (mean 8 SD) Exton-Smith score (mean 8 SD) CIRS comorbidity score (mean 8 SD) MNA score (mean 8 SD) Drugs, n (mean 8 SD) Low-dose aspirin/NSAID, n (%) Warfarin, n (%) PPI, n (%) MPI (mean 8 SD) score Mortality, n (%)

(c) number of meals, food and fluid intake, autonomy of feeding, and (4) self-perception of health and nutrition. The Exton-Smith Scale (ESS) was used to evaluate the risk of developing pressure sores. This 5-item questionnaire determines physical condition, mental condition, activity, mobility and incontinence. For each item, a score from 1 to 4 is assigned [11]. Medication use was defined according to the Anatomical Therapeutics Chemical Classification code system (ATC classification) [12] and the number of drugs used by patients at admission was recorded. Patients were defined as drug users if they took a medication of any of the above-described classes at the moment of admission. Social aspects include household composition, home services, and institutionalization. Multidimensional Prognostic Index The MPI was calculated by aggregating data from specific questionnaires (ADL, IADL, SPMSQ, CIRS-CI, MNA, EES) as well as additional data on medication and cohabitation status, for a total of 63 items. All scales were arbitrarily reduced to three values, i.e., 0 = no problems, 0.5 = minor problems, and 1 = major problems based in part on data from the literature and a general discussion among the members of the team that occurred prior to any data analysis. The sum of the calculated scores from the above-reported eight domains was divided by 8 to obtain a final MPI score from 0 to 1. Three levels of risk were arbitrarily identified: MPI 1 = low risk, range 0.0–0.33; MPI 2 = moderate risk, range 0.34–0.66, and MPI 3 = severe risk, range 0.67–1.0 as previously reported [13]. Statistical Analysis All analyses were performed using the SPSS Version 13 software for Windows (SPSS Inc., Chicago, Ill., USA) [14]. Continuous variables are shown as mean 8 SD and comparisons between men and women were defined using the Mann-Whitney U-test. The Kruskal-Wallis analysis of variance was used to compare mortality rate across MPI groups.

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All (n = 36)

Males (n = 16)

Females (n = 20)

p

82.887.9 704101 4.483.9 4.182.4 3.983.2 2.783.4 15.384.5 3.182.1 19.287.0 3.481.9 11 (30.6) 3 (8.3) 6 (16.7) 0.3980.26 11 (30.6)

80.184.8 70490 5.285.3 4.382.5 4.483.5 2.983.3 15.485.0 3.382.6 20.787.9 3.581.4 6 (37.5) 2 (12.5) 2 (12.5) 0.3680.27 3 (18.8)

84.989.3 704101 3.682.0 3.982.3 3.683.1 2.482.9 15.184.1 2.981.5 18.186.3 3.382.2 5 (25.0) 1 (5.0) 4 (20) 0.4080.25 8 (40.0)

0.03 0.426 0.481 0.386 0.808 0.445 0.854 0.180 0.539 0.656 0.840 0.881 0.560 0.156

The relationship between MPI score group and time-to-death was analyzed by an age- and sex-adjusted Cox proportional hazard regression model. Time to death was calculated as the time between admission and time of death or end of follow-up whichever came first. The proportionally of the hazard assumption was graphically checked by plotting log [–log(survival function)]. A p value of ! 0.05 was considered statistically significant.

Results

During the 1-year inclusion period, 52 patients with a diagnosis of upper gastrointestinal bleeding were consecutively admitted to our Unit. Eight patients were excluded because the CGA was not completed, 4 patients were excluded because information on their vital status at study conclusion was not available, and 4 patients were excluded because they refused to participate in the study. Thus, the final study population included 36 elderly patients: 16 men and 20 women with a mean age of 82.8 8 7.9 years, and a range of 70–101 years. Table 1 reports the characteristics of patients included in the study. A significant difference in mean age was observed between males and females (M 80.1 8 4.8 vs. F 84.9 8 9.3 years; p = 0.03). No differences were found between males and females for all other parameters (ADL, IADL, SPMSQ, MNA, ESS, CIRS-CI, drug use and cohabitation status). Table 2 shows the endoscopic diagnoses of patients: 38.8% had duodenal ulcer, 22.2% had gastric ulcer, 16.6% had erosive gastritis, and 16.6% had gastrointestinal bleeding from unknown origin. The overall 2-year mortality rate was 30.6%. Pilotto et al.

1.0 Group 1 (n = 18)

Cumulative survival

0.8

0.6 Group 2 (n = 12) 0.4

0.2

Group 3 (n = 6)

0 0

100

200

300

400

500

600

700

Days

Fig. 1. Survival curves of elderly patients

(n = 36) with three grades of MPI for 2-year mortality as derived from a CGA.

Table 2. Endoscopic diagnoses of bleeding patients (n = 36) in-

cluded in the study Diagnosis Esophageal ulcer Erosive gastritis Gastric ulcer Duodenal ulcer Duodenal angiodysplasia Unknown origin GI bleeding

Patients (%) 1 (2.8) 6 (16.6) 8 (22.2) 14 (38.8) 1 (2.8) 6 (16.6)

The mean MPI value in the total study population was 0.39 8 0.26. Overall, 18 patients, i.e., 50% of the total study population, were included in the MPI grade 1 group (low risk, MPI mean value 0.18 8 0.09); 12 patients, i.e., 33.3% of the study population, in the MPI grade 2 (moderate risk, MPI mean value 0.48 8 0.08) and 6 patients, i.e., 16.6% of the total population, in the MPI grade 3 (severe risk, MPI mean value 0.83 8 0.06). Higher MPI grades were significantly associated with progressively higher mortality: MPI 1 = 12.5% mortality, MPI 2 = 41.6% mortality, and MPI 3 = 83.3% mortality (p = 0.001). Adjusting for age and sex, the prognostic efficacy of MPI for defining the risk of mortality was confirmed and was highly significant (odds ratio 10.47, 95% CI 2.04–53.6). CGA in Older Patients with Upper Gastrointestinal Bleeding

Figure 1 shows the survival curves of patients with different grades of MPI: patients with a higher MPI demonstrated a significantly higher mortality rate (p = 0.001).

Discussion

In this study we demonstrated that a CGA can be used in the clinical setting to stratify patients 665 years hospitalized for an upper gastrointestinal bleeding according to their risk for 2-year mortality. Data obtained from a standardized CGA, including clinical, functional, cognitive, nutritional and social parameters, were used for calculating a MPI that was significantly associated with the risk of mortality in this population of older patients. Mortality was selected as an outcome because it is dichotomous, easily distinguishable, and unequivocal. The findings of this study demonstrate the importance of considering multidimensional impairment in prognostic systems for elderly hospitalized patients. Inclusion of group of parameters relating to multidimensional aspects of elderly patients, obtained from a standardized CGA, yielded a multidimensional index, i.e., the MPI, which proved excellent in identifying three groups of 2-year mortality risk as demonstrated by the three distinct and uncrossed survival curves. This MPI was calculated from conventional CGA data easily colDig Dis 2007;25:124–128

127

lected from hospitalized elderly patients. Unlike the CGA used in community-dwelling or institutionalized elderly people [15, 16], in the present study we used parameters that particularly characterize hospitalized elderly patients, such as comorbidity and the number of medications taken. As expected [17], a high number of patients with upper gastrointestinal bleeding were taking aspirin or NSAIDs (30.5%) and/or warfarin (8.3%). Moreover, of those patients who were taking these damaging drugs, only 2 were treated with proton pump inhibitors as preventative therapy, confirming the underutilization of pharmacological gastroprotection in older high-risk patients [18]. This multidimensional approach has been successfully used in hospitalized elderly patients for clinical [19] and, very recently, even for administrative purposes [20].

Indeed, a significant correlation was found between multidimensional impairments assessed by the CGA criteria and the all-patients-refined-(APR)-DRG system, which is an administrative tool useful in identifying elderly inpatients at high risk of high health-resource consumption. In conclusion, CGA is a useful tool for evaluating older patients with upper gastrointestinal bleeding. For the first time, we describe a CGA-derived MPI that is a clinically useful tool for stratifying older patients into three different grades of 2-year mortality risk. These findings suggest that opportunity does exist to consider CGA a prognostic instrument clinically useful for the short- and long-term management of older patients with upper gastrointestinal bleeding.

References 1 Rubenstein LZ, Rubenstein LV: Comprehensive geriatric assessment of older patients with gastrointestinal disorders; in Pilotto A, Malfertheiner P, Holt PR (eds): Aging and the Gastrointestinal Tract. Interdiscip Top Gerontol. Basel, Karger, 2003, vol 32, pp 12– 27. 2 Consensus Development Panel (Chairman: D Solomon): National Institutes of Health Consensus Development Conference Statement: Geriatric Assessment methods for clinical decision-making. J Am Geriatr Soc 2003;51:1490–1494. 3 Rubenstein LZ: Comprehensive geriatric assessment: from miracle to reality. J Gerontol Med Sci 2004;59A:473–477. 4 Cotton P, Williams CB: Practical Gastrointestinal Endoscopy, ed 3. Oxford, Blackwell Scientific, 1990. 5 Laine L, Peterson WL: Bleeding peptic ulcer. N Engl J Med 1994;331:717–727. 6 Katz S, Downs TD, Cash HR, Grotz RC: Progress in the development of an index of ADL. Gerontologist 1970;10:20–30. 7 Lawton MP, Brody EM: Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9:179–186.

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8 Pfeiffer E: A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. J Am Geriatr Soc 1975;23:433–441. 9 Linn B, Linn M, Gurel L: The Cumulative Illness Rating Scale. J Am Geriatr Soc 1968;16: 622–626. 10 Guigoz Y, Vellas B: The Mini Nutritional Assessment (MNA) for grading the nutritional state of elderly patients: presentation of the MNA, history and validation. Nestlé Nutr Workshop Ser Clin Perform Programme 1999;1:3–11. 11 Bliss MR, McLaren R, Exton-Smith AN: Mattresses for preventing pressure sores in geriatric patients. Mon Bull Minist Health Public Health Lab Serv 1966;25:238–268. 12 L’informatore farmaceutico 2004: OEMF International, Milan 2002. Guidelines for ATC Classification. NLN Publ No 16. Uppsala, Nordic Council on Medicines, 1985. 13 Pilotto A, Franceschi M, Leandro G, D’Ambrosio PL, Scarcelli C, Corritore M, et al: Frailty Index from a Comprehensive Geriatric Assessment: a new tool to evaluate frailty in hospitalized elderly patients. J Nutr Health Aging 2006;10:327. 14 SPSS Version 13 Instruction Manual. Chicago, SPSS Inc, 2002. 15 Carey EC, Walter LC, Lindquist K, Covinsky KE: Development and validation of a functional morbidity index to predict mortality in community-dwelling elders. J Gen Intern Med 2004;19:1027–1033.

16 Lee SJ, Lindquist K, Segal MR, Covinsky KE: Development and validation of a prognostic index for 4-year mortality in older adults. JAMA 2006;295:801–808. 17 Pilotto A, Franceschi M, Leandro G, Paris F, Niro V, Longo MG, et al: The risk of upper gastrointestinal bleeding in elderly users of aspirin and other non-steroidal anti-inflammatory drugs: the role of gastroprotective drugs. Aging Clin Exp Res 2003; 15: 494– 499. 18 Pilotto A, Franceschi M, Vitale DF, Zaninelli A, Masotti G, Rengo F on behalf of FIRI (Fondazione Italiana Ricerca suill’Invecchiamento) and the SOFIA Investigators: Upper gastrointestinal symptoms and therapies in elderly outpatients, users of non-selective NSAIDs or coxibs. Aliment Pharmacol Ther 2005;22:147–155. 19 Ellis G, Langhorne P: Comprehensive geriatric assessment for older hospital patients. Br Med Bull 2004;71:45–49. 20 Pilotto A, Scarcelli C, D’Ambrosio LP, Cascavilla L, Longo MG, Greco A: All patient refined diagnosis related groups: a new administrative tool for identifying elderly patients at risk of high resource consumption. J Am Geriatr Soc 2005;53:1–2.

Pilotto et al.

Dig Dis 2007;25:129–137 DOI: 10.1159/000099477

The Anorexia of Aging Vincenzo Di Francesco Francesco Fantin Francesca Omizzolo Luigi Residori Luisa Bissoli Ottavio Bosello Mauro Zamboni Department of Biomedical and Surgical Sciences, Geriatric Unit, University of Verona, Verona, Italy

… si mangiano i sospiri e un po’ di mele cotte i vecchi senza un corpo, i vecchi senza una carezza … ‘I Vecchi’, Claudio Baglioni 1981. (... they eat just their whispers and a bit of crumbled apples old people without a body, old people without a caress ... ‘The Elderly’)

Key Words Anorexia of aging Central hypothalamic hunger-satiety control Peripheric control of energy balance Taste and smell alterations Gastrointestinal motility

Abstract Malnutrition in the elderly is one of the greatest threats to health, well-being and autonomy, it is therefore crucial to understand and to contrast the causal factors of inadequate energy intake. This review focuses on the mechanisms of the so-called ‘anorexia of aging’. In recent years, it has been shown that elderly subjects have abnormal peripheral signal patterns and alterations in central hypothalamic control relays. Negative feedback from impaired gastric motility, exaggerated long-term adiposity signals (leptin, insulin) and postprandial anorexigenic signals (CCK, PYY) seem to prevail over the central feeding drive. If nutritional strategies of intervention are to be improved, these data need to be taken into account. Copyright © 2007 S. Karger AG, Basel

© 2007 S. Karger AG, Basel 0257–2753/07/0252–0129$23.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ddi

Introduction

Protein-energy malnutrition is a frequent condition in the elderly, it is associated with a reduction in the adaptive response to the physiological and pathological conditions of aging [1]. The pathogenesis of malnutrition is likely to be multifactorial. A low-calorie intake represents one of the main risk factors for malnutrition: this condition has been referred to as ‘anorexia of aging’ [2]. Many factors are involved with the pathogenesis of anorexia in the elderly. Both cross-sectional [3] and longitudinal [4, 5] observations have shown that energy intake is reduced in the elderly as compared to younger subjects. The mean calorie reduction between 20 and 80 years of age was 1,300 kcal/day for men and 600 for women [3], while from 40 to 70 years of age food intake was reduced by 25% [4]. At more advanced ages, energy intake declined constantly by 13 kcal/day/year in women and 25 in men [5]. The consistent reduction of food intake in the elderly is only partly balanced by reductions in energy expenditure, so old men and women mainly lose body weight [5].

Dr. Vincenzo Di Francesco, MD, PhD Dipartimento Scienze Biomediche e Chirurgiche Sezione di Geriatria, Ospedale Maggiore, p.le Stefani 1 IT–37126 Verona (Italy) Tel. +39 0458 123 577, Fax +39 0458 122 043, E-Mail [email protected]

Table 1. Drugs that may cause anorexia in

the elderly

Taste

Abnormal hunger and satiety control mechanisms

Cardiovascular

Amiodarone Furosemide Digoxin Spironolactone Theophylline

NCS

Levodopa Fluoxetine Lithium

Gastrointestinal

H2-antagonists, PPI Oils Psyllium

Antibiotics

Griseofulvin Metronidazole

Chemotherapies

Any

Anti-inflammation

Colchicine AINSD Penicillamine

Smell

Social problems

Energy expenditure Exercise

Diseases Anorexia

Drugs Depression

Malnutrition

Fig. 1. Mechanisms of malnutrition in the elderly: role of an-

orexia.

Many of the social, psychological and organic conditions which characterize aging are also recognized causes of reduced food intake and malnutrition (fig. 1). Among social factors, economic problems and isolation are the most frequent. Depression more frequently plays a role in weight loss in the elderly than in young people [2]. Dementia causes malnutrition, as meals are frequently ignored or refused. Ageusia of swallowing may also be recognized, particularly in postischemic dementia [2]. Several diseases which are frequently associated with the elderly lead to weight loss, mainly by elevating energy expenditure, but also because they depress hunger sensation. Patients with chronic obstructive pulmonary disease suffer from both the consequences of energy dispersion (due to respiratory inefficiency) and anorexia, caused by inflammatory mediators. Similarly, neoplasia and heart failure cause cachexia for higher energy requirement but also for anorexia. In these conditions, high concentrations of cytokines such as IL-6 and TNF- have a strong anorexigenic effect [6]. Dysphagia and poor mastication interfere with nutritional status either directly or indirectly, by reducing taste sensation. Many drugs, which are widely used in the elderly, may cause anorexia. Table 1 shows a list of the most common. Even when old and young people are compared in the same setting, in paired health and social con130

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ditions, energy intake has been reported to be lower in the elderly. A primitive alteration in the mechanisms regulating energy balance has been hypothesized [7]. Aging is associated with an impairment in the ability to regulate body weight. A study from Roberts et al. [8] demonstrated that after a few weeks of a hypocaloric diet both elderly and young subjects lost weight, however the elderly were unable to spontaneously regain weight by a compensative hyperphagia as was observed in young adults. On the contrary, after overfeeding only the young spontaneously reduced food intake and thus lost extra weight, while older subjects maintained excess weight [8]. Short-term regulation of food intake also seems to be impaired with aging. A preload with a snack (yogurt) was not compensated in a subsequent buffet meal and the older subjects showed a 10–30% excess in calorie intake [9]. Single food-specific sensory satiety contrasts the excessive intake of a single food even in a normocaloric meal. In the elderly this kind of satiety seems to be impaired thus facilitating monotonous single food intake [9]. Furthermore, a reduction in the hedonist component of eating and an elevated threshold of taste and smell restricts the pleasure of eating to only a few foods in the elderly. These conditions often lead to a poor alimentary Di Francesco et al.

Satiety Hunger

PVN LHA

Satiety

NTS

NPY/AgRP POMC/CART

ARC

Ghrelin

Fig. 2. Central hypothalamic energy bal-

Insulin

ance control and interrelationships with main peripheral signals. Full lines indicate stimulation, broken lines inhibition (see text for abbreviations).

Leptin

Mechanical/chemical stomach receptors

CCK

PYY

variety of choice which increases the risk of quantitative malnutrition due to low-calorie intake and qualitative low intake of single nutrients [10]. Malnutrition has a dramatic impact on health in the elderly; it impairs the immune system thus increasing the frequency and severity of infectious diseases. In fact malnourished old people have particularly low levels of CD4+ T-helper cells [11]. Malnutrition may cause anemia as well as cognitive decline, osteopenia, altered drug metabolism and sarcopenia. Malnourished elderly run a higher risk of hospitalization, delayed discharge from the hospital and mortality [12]. Unfortunately, malnutrition is a frequent condition at older ages. It has been reported that 17–65% of hospitalized older subjects and 5–59% of institutionalized suffer from malnutrition [13]. In many cases, reduced food intake caused by unbalanced hunger-satiety sensation appears to be the only cause of malnutrition. Control mechanisms and possible abnormalities of aging are described below.

Figure 2 summarizes the hypothalamic role in hunger-satiety control. The nucleus arcuatus (ARC) has neurons which release NPY (neuropeptide Y), the most common and potent orexigenic mediator, and AgRP (agoutirelated peptide), another hunger mediator. Axons from ARC neurons release NPY and AgRP in the paraventricular nucleus (PVN), referred to as the ‘satiety center’, and inhibit it. Other neural terminations from ARC reach the lateral hypothalamic area (LHA), known as the ‘hunger center’, and stimulate it. The net effect of NPY and AgRP tone is hunger stimulation and satiety inhibition leading to increased food intake [14]. Adjacent to orexigenic neurons in the ARC, other neurons express POMC (pro-opiomelacortin), the precursor of melanocortins, such as -MSH, that inhibit LHA and stimulate PVN. Other neurons with similar action express CART (cocaine-amphetamine-related

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peptide). MSH and CART are inhibited by NPY neurons [14]. Leptin produced by the adipose tissue and insulin from the pancreas rise in the blood as a long-term signal of adiposity (i.e., they refer the presence of a positive energy balance to the hypothalamus). CCK and peptide YY (PYY) produced after meals by the upper and lower intestine elicit short-term signal of satiety. Leptin, insulin, CCK and PYY inhibit NPY/AgRP neurons and stimulate POMC neurons, thus causing satiety [14, 15]. Ghrelin, a hormone produced by the stomach during fasting, stimulates NPY neurons in the ARC, potentiates hunger and triggers eating [16]. Along the vagal nerve, stimuli from stretching receptors of the stomach rise after gastric filling by food and reach the nucleus of the tractus solitarius (NTS). NTS evokes the sensation of satiety and contrasts excessive food ingestion. In the same neural way, CCK, produced by the intestine in the presence of lipids and amino acids in the lumen, also stimulates NTS and thus postprandial satiety. NTS receives inhibitory fibers from LHA and excitatory fibers from PVN. In this complex system hunger prevails in fasting conditions, satiety after meals [14, 15]. NPY is one of the most abundant peptides in the whole brain and is able to integrate the metabolic and behavioral systems [17] pushing towards the search and intake of food, as a potent survival instinct. NPY impairment may potentially be involved in the pathogenesis of anorexia in the elderly. Studying this system in humans is very difficult for obvious reasons, so most of the data have been obtained from observations in rats. Aged rats exhibited low drinking and eating responses when NPY was injected into the PVN [18]. Surprisingly however, when plasma and cerebrospinal NPY levels were evaluated in anorectic elderly, NPY was found to be high [19]. At the level of the CNS, endogenous cannabinoids stimulate hunger since they potentiate the pleasure of and desire to eat [20]. It has been postulated that in analogy with animal studies, endocannabinoid tone in the elderly may be diminished [21]. Although some authors found lower concentrations of plasmatic endocannabinoids in elderly as compared to young people [22], the opioid inhibitor naloxone showed the same suppressive action on hunger in both young and older subjects, suggesting that there is no difference in the basal endocannabinoid tone. On the basis of these findings, MacIntosh et al. [23] concluded that age is not associated with reduced opioid feeding drive.

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Peripheric Control of Energy Balance

Taste and flavor, but also the sight of pleasant food, enhance hunger by acting on the orexigenic mediators and by cortical integration of past experience. Ghrelin is the only orexigenic signal which comes from peripheral districts; it is produced in a pulsatile manner by the empty stomach. All other peripheral short- and long-term signals inhibit hunger and produce satiety. Anorexigenic signaling from the gastrointestinal tract counteracts food intake over digestive and absorption ability [24]. Adiposity signals from leptin and insulin indicate to the central system energy storage in the adipose tissue, thus they potentiate central satiety sensation. Long- and short-term signals interact so that insulin inhibits ghrelin and leptin enforces the CCK signal and vice versa [14]. Finally, nutrients themselves influence food intake, in particular blood levels of fatty acids and glucose, directly or indirectly, regulate hunger and satiety control centers [14, 19]. Taste and Smell Alterations The elderly have a reduced sensor-specific satiety. As a consequence they may consume a large amount of a single food, but, on the other hand, they may feel satiety for any food after a single food ingestion. For instance, a young person who has eaten a yogurt would avoid intake of further yogurt but not necessarily other kinds of food; an older subject would lose not only desire for yogurt but also for any other food [7]. The possible mechanism for reduced sensory-specific satiety could be impairment of taste and smell senses in the elderly. This latter condition also causes reduced food intake, since taste and smell normally potentiate the sensation of hunger [25]. Taste is impaired with aging. Fukunaga et al. [26] found higher thresholds for recognizing sweet, bitter, salty and acid in the elderly as compared with young controls. Oral taste receptors were not found to be reduced, since taste buds count was similar between the different age groups. However, impaired cell turnover and structural abnormalities have been reported with aging [27]. Olfactory deficit has been demonstrated in the elderly and this may also reduce hunger [28]. Food consumption increased when elderly subjects were offered food with flavor enhancement [29]. Difficulty in recognizing flavors may be the consequence of age-related modification of olfactory epithelium, receptors and neural pathways. Furthermore, several drugs, commonly prescribed to old patients, impair taste and smell sensitivity [25]. Di Francesco et al.

Both flavor and taste of food perception are involved not only in specific food recognition, but also in the pleasantness of food. For this reason age-related sensory impairment may affect the hedonistic enhancement of food intake and contribute to the anorexia of aging [2]. Unfortunately, instead of improving the flavor and taste of their food to make it more appetizing, older people often renounce with the pleasure of eating and choose a monotonous diet, increasing their risk of malnutrition. Gastrointestinal Motility Abnormalities in gastrointestinal motility may play a crucial role in the hunger/satiety unbalance observed with aging. In particular, delayed gastric emptying may cause prolonged postprandial satiety [30–35]. Studies on gastric motility in the elderly have shown controversial results, mostly due to differences in test meals and methods of evaluation. Scintigraphic observations with radiolabeled food showed delayed emptying of both liquid and solid components of food [31, 34], but in one study only liquid food emptying from the stomach was delayed [32]. Ultrasound studies extrapolate gastric volume modifications, and thus gastric filling and emptying, by measuring the area at the level of the antrum, in fasting conditions and at regular intervals after meals. Using this technique, liquid meal emptying was found to be accelerated in the early postprandial phase in elderly patients [33]. The authors hypothesized an age-related reduction adaptation of the stomach to the alimentary (liquid) bolus. Morley [2] demonstrated a reduced production of nitric oxide at the level of the fundus, leading to a loss of gastric compliance and more rapid antral filling, while another US study with a liquid meal failed to find any differences between younger and older subjects [35]. Under more physiological conditions where subjects were given a mixed solid-liquid meal, ultrasonographic antral dynamics demonstrated delayed gastric emptying in the elderly [30, 36]. A study conducted in our institution showed complete gastric emptying after an 800-kcal meal to be delayed by more than 2 h in the elderly [30]. Satiety consistently lasted longer and hunger was suppressed during the 4 h of postprandial observation; satiety was directly and hunger inversely correlated with gastric emptying time. Nonetheless, satiety remained high in the elderly even at the end of the observation, when only a small quantity of food was present in the antrum. This suggests a possible sensory hypersensitivity. Ultrasonography can only evaluate antral emptying and cannot study fundus filling or emptying, nor distinguish be-

tween the liquid and solid components of food. Nevertheless, complete gastric emptying time, extrapolated by ultrasound antral area dynamics, proved to be reliable when compared with ‘gold-standard’ scintigraphy [36]. Therefore, the use of ultrasound monitoring after physiological meals is probably the best non-invasive way of evaluating gastric motility at more advanced ages. Furthermore, in physiological conditions, antropyloric motility leads neurohormonal response to a meal, which regulates food intake and digestion, according to antral filling and nutrient delivery from the antrum to small intestine [37]. Reduced fundus compliance has been suggested in the elderly but, again, this may reduce food intake because of distension of the antrum due to earlier delivery of food [2]. Slower gastric emptying in elderly persons may be a consequence of a reduced digestive ability of the stomach; it could also be the consequence of an ‘ileal brake’ effect, caused by a neurohormonal response to the presence of nutrients in the small intestine over its digestive and absorptive ability. Furthermore, a primitive age-related decline of gastric motility might be involved. Finally, chronic gastritis or medications may cause hypochlorhydria, which further retards gastric emptying [38]. Altered gallbladder contraction has also been postulated in elderly persons. A recent study [30] shows minor postprandial gallbladder contraction in healthy elderly compared with young controls. Postprandial gallbladder volume was inversely correlated with satiety. Nevertheless, previous ultrasound studies [35, 39] failed to demonstrate any gallbladder contractility abnormality in elderly persons. In the experiment of Di Francesco et al. [30], the administration of a meal rich in calories (800 kcal) and lipids (45%), requiring a submaximal digestive response, probably unmasked the difference between younger and older participants. The approximate mean volume of bile reversed into the duodenum by the gallbladder in young controls and elderly subjects may be calculated by the percentage of volume reduction after the meal. Gallbladder bile volume output was nearly half in the elderly (7.5 vs. 14.5 cm3) [unpubl. data]. These findings seem to be in contrast with the high levels of CCK in elderly subjects, but CCK may maintain the role of anorexigenic signal and it may be less effective on gallbladder motility due to a CCK resistance [30]. Gastric and cholecystic emptying is coordinated after ingestion of a meal, and the gallbladder only starts to refill when the stomach is almost empty. Gastric emp-

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tying leads to gallbladder contraction by delivering nutrients into the small intestine where CCK is produced [40]. For this reason, slower gastric emptying coincides with reduced gallbladder contraction. Only one other study simultaneously evaluated gastric and cholecystic emptying by ultrasonography in elderly subjects [35]. However, Wedmann et al. [35] did not find any gastric or cholecystic motor abnormality after a lighter liquid meal. Abnormalities in gastric motility may cause early satiation due to reduced fundus compliance [2], and prolonged satiety caused by slower gastric emptying [30]. Using satiety scores, younger subjects crossed hunger sensation 2 h after their meal and had scores comparable to fasting values after 4 h. In their elderly counterparts, the sensation of satiety still prevailed over hunger 4 h after their meal. Satiety was directly and hunger inversely correlated with gastric emptying time. Gallbladder volume was inversely correlated with satiety [30]. Intestinal motility also influences the hunger/satiety balance at the level of colon-rectum, in particular colonic stasis delays gastric emptying by a colon-gastric reflex, indirectly prolonging the sensation of satiety [2]. Gastrointestinal motility in the elderly has received little attention, even though breath-H2 test orocecal transit time and radiopaque label transit time were found to be normal in healthy elderly subjects [41]. Constipation, which is a common finding in advanced ages, is an exclusion criteria for motility studies of this kind, but it should be taken into account as a possible cause of impaired motility along the whole gastrointestinal tract, and thus as a risk factor for anorexia. Role of Hormones CCK is the prototype of satiety hormones: it is released by the proximal small intestine in response to the delivery of nutrients from the antrum, particularly of lipids and proteins [24]. Several studies have demonstrated the presence of higher CCK concentrations in the blood of aged compared to young persons [30, 37, 39, 42]. Intraduodenal infusion of either glucose solution or lipid suspensions showed a greater difference between the age groups after lipid infusion [43]. Motor gallbladder sensitivity to CCK seems to be impaired with aging, but a CCK satiating effect sensitivity seems to be preserved [44]. High levels of CCK are probably among the major causes of the anorexia of aging as they were correlated to abnormally higher satiety sensation after meals [37]. In a recent study we confirmed higher fasting and postprandial CCK serum concentra134

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tion in the elderly [30]. At the end of the observation, when the antrum contained small volumes of food, the elderly group still had circulating CCK levels which correspond to high satiety and low hunger. CCK may have a primitive role in the genesis of anorexia and malnutrition, since higher CCK levels were found in malnourished aged subjects compared to wellnourished elderly [42]. PYY is released by the distal intestine in response to the presence of nutrients in the lumen. PYY inhibits the NPY-mediated appetite stimulus [44]. A previous study [37] on postprandial PYY did not find any differences between young and older people, but the observations were limited to 120 min after the meal. A recent observation showed a greater rise of PYY in late postprandial period in the elderly as compared to young controls [30]. In analogy with CCK, abnormally high postprandial PYY levels may inhibit the search for a second meal, thus leading to longer fasting intervals resulting in a risk of malnutrition in elderly persons. Both CCK and PYY are enteric peptides involved in gastrointestinal motility in response to eating, they provide a potent anorexigenic signals to the hypothalamus. They also mediate slowing of gastric emptying induced by the presence of nutrients in the small intestine [37]. Abnormally high levels of fasting and postprandial CCK and PYY may further and indirectly prolong satiety by slowing antral emptying. The glucagon-like peptide-1 (GLP-1) is an active byproduct from glucagon metabolism. GLP-1 is produced by the distal small intestine after food ingestion and carries a strong anorexigenic signal [45]. The role of GLP-1 in anorexia in the elderly needs to be further investigated since its concentrations after different stimuli have been shown to be similar in older and younger subjects [37, 42]. Insulin, a well-known regulator of glucose metabolism, is also a satiety hormone. Insulin probably acts indirectly by enhancing the leptin signal to the hypothalamus and by inhibiting the ghrelin orexigenic stimulus. Aging is characterized by reduced glucose tolerance and elevated insulinemia. This condition may facilitate anorexia [45]. Higher concentrations of plasma insulin may amplify the anorexigenic signal of leptin, since insulin stimulates central leptin action and sensitivity at the level of the ARC [46]. Hyperinsulinemia in the elderly could also be responsible for inhibiting ghrelin gastric expression and central sensitivity [47]. Di Francesco et al.

Leptin is another possible actor of anorexia in the elderly. This cytokine is a hormone which is mainly produced by adipose cells, whose main role consists in longterm energy balance, by giving the CNS a sign of energy storage. Low leptin levels signal loss of body fat and a need for energy intake, while high leptin levels testify the presence of adequate body fat and no need for further food intake [14]. Fasting leptin in healthy elderly subjects was found to be elevated when compared to young persons, even after adjusting for body fat mass [48]. Serum leptin was found to be significantly higher in the elderly group after a meal. Interaction was not significant, as well as the effect of time, so that mean values of leptin showed a flat line in both young and older persons; younger subjects showed lower mean values compared to older subjects [49]. These findings are in line with previous observations in adults, suggesting that leptin concentrations do not change significantly shortly after a meal [50] and confirming that leptin is more involved in long-term food control than in short-term modulation of food intake. Nevertheless, the authors hypothesized that elevated serum leptin may have facilitated a postprandial prevalence of anorexigenic signals. As already discussed, aging is characterized by high postprandial CCK concentrations [2, 30]. In this condition, leptin passes more easily through the blood-brain barrier, inducing an increase in hypothalamic sensitivity to leptin [51]. Other authors claim the contrary for higher central CCK sensitivity in the presence of high leptin levels [50]. In any case, leptin and CCK collaborate to amplify the inhibitory message to NPY feeding drive. Ghrelin is the only peripheral hormone known to stimulate appetite. Ghrelin is produced and secreted by the endocrine gastric mucosa to enhance food intake [16]. Ghrelin has a pulsatile secretion, with a maximal blood concentration just before the meal and a drop just after stomach filling. For these reasons, ghrelin is thought to be implicated in meal initiation. It has been suggested that ghrelin also encourages healing and growing. Therefore, hunger elicited by ghrelin could be considered as a warranty for energy surplus need in case of growth and tissue repair [14–16]. Ghrelin also seems to regulate long-term energy balance, and it rises under conditions causing negative balance such as anorexia nervosa, cachexia or hypocaloric diet; on the contrary, ghrelin secretion is suppressed in obese subjects with a positive energy balance [52]. Only relatively few data are presently available on ghrelin dynamics with aging. One study showed fasting The Anorexia of Aging

Opioids

? Smell Taste

Vague nerve Spinal nerves

Ghr Leptin

Insulin

PYY

CCK

Fig. 3. Age-related modifications of the hunger signals (in black) and satiety signals (in grey).

ghrelin elevated values in the elderly [53]. Two other observations showed no significant age-related difference even in the postprandial period [42, 49]. Postprandial ghrelin was not significantly different in young and old subjects. In both age groups ghrelin dropped after the meal and returned to basal values within 4 h. Nevertheless, hunger did not follow a postprandial ghrelin raise in the elderly. Concurrent high concentrations of leptin and insulin may have been responsible for the low sensitivity to ghrelin [47, 52]. Furthermore, ghrelin is produced by the stomach in two major molecular forms: an active acylated ghrelin that stimulates food intake, and a second desacyl ghrelin that was thought to have no hormonal action [54]. However, very recently, in animal models, it has been demonstrated that, in contrast with the acylated form, desacyl ghrelin decreases the intake of Dig Dis 2007;25:129–137

135

food [52]. The ratio of acylated to non-acylated ghrelin may have a role in different responses to ghrelinemia in the elderly and further studies are necessary in this direction.

Conclusions

In summary, the risk of malnutrition in the elderly is high even in the absence of clinical or social risk factors due to the primitive so-called ‘anorexia of aging’. In adult life we face the risk of overeating and gaining body weight due to the prevalence of hunger (mostly central) signals, warranting survival in the presence of small quantities of food. In the elderly there is a prevalence of both short- and long-term satiety signals (mostly peripheral), which contrast energy balance and cause malnutrition (fig. 3). In this case it seems that species survival prevails and less active (aged) people spontaneously consume less community food resources. Notwithstanding the presence of large amounts of food, at least in developed countries,

this mechanism leads to malnutrition and thus to higher morbidity, disability and mortality at older ages. A pharmacological approach to this problem does not seem to be realistic at this stage, but data coming from recent studies already suggest a possible intervention strategy in order to contrast anorexia and prevent malnutrition. For example, slow gastric emptying may be contrasted by fractioning food intake in small digestible meals. Improving taste and flavor of the dishes may enhance blunted hunger. Excessive CCK signal may be reduced by limiting the intake of CCK-stimulating foods such as fats and proteins. Finally, the large amount of recent data has not yet clarified all of the aspects of anorexia in the elderly. Many more peptides and mediators involved in energy homeostasis need to be tested in the elderly, the complex integration of peripheral and central circuits needs to be further studied in humans, little attention has been paid to the role of digestive and absorptive dysfunction with aging on hunger and satiety control. Basic scientific research but also on-the-road nutritional intervention protocols will help to clarify these issues.

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46 Doucet E, St-Pierre S, Alméras N, Mauriege P, Despres JP, Richard D, Bouchard C, Tremblay A, Quebec Family Study: Fasting insulin levels influence plasma leptin levels independently from the contribution of adiposity: evidence from both a cross-sectional and an intervention study. J Clin Endocrinol Metab 2000;85:4231–4237. 47 Murdolo G, Lucidi P, Di Loreto C, Parlanti N, De Cicco A, Fatone C, Fanelli CG, Bolli GB, Santeusanio F, De Feo P: Insulin is required for prandial ghrelin suppression in humans. Diabetes 2003;52:2923–2927. 48 Zamboni M, Zoico E, Fantin F, Panourgia MP, Di Francesco V, Tosoni P, Solerte B, Vettor R, Bosello O: Relation between leptin and the metabolic syndrome in elderly women. J Gerontol A Biol Sci Med Sci 2004; 59: 396– 400. 49 Di Francesco V, Zamboni M, Zoico E, Mazzali G, Dioli A, Omizzolo F, Bissoli L, Fantin F, Rizzotti P, Solerte SB, Micciolo R, Bosello O: Unbalanced serum leptin and ghrelin dynamics prolong postprandial satiety and inhibit hunger in healthy elderly: another reason for the ‘anorexia of aging’. Am J Clin Nutr 2006;83:1149–1152. 50 Romon M, Lebel P, Velly C, Marecaux N, Fruchart JC, Dallongeville J: Leptin response to carbohydrate or fat meal and association with subsequent satiety and energy intake. Am J Physiol 1999;277:E855–E861. 51 Barrachina MD, Martinez V, Wang L, Wei JY, Tache Y: Synergistic interaction between leptin and cholecystokinin to reduce shortterm food intake in lean mice. Proc Natl Acad Sci USA 1997;94:10455–10460. 52 Asakawa A, Inui A, Fujimiya M, Sakamaki R, Shinfuku N, Ueta Y, Meguid MM, Kasuga M: Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut 2005; 54:18–24. 53 Rigamonti AE, Pincelli AI, Corrà B, Viarengo R, Bonomo SM, Galimberti D, Scacchi M, Scarpini E, Cavagnini F, Muller EE: Plasma ghrelin concentration in elderly subjects: comparison with anorexic and obese patients. J Endocrinol 2002;175:R1–R5. 54 Hosoda H, Kojima M, Matsuo H, Kangawa K: Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 2000;279:909–913.

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Dig Dis 2007;25:138–143 DOI: 10.1159/000099478

Liver Diseases in the Elderly: An Update Annarosa Floreani Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy

Key Words Liver diseases in elderly Non-alcoholic fatty liver disease Hepatitis C virus infection Alcoholic liver disease Hepatocellular carcinoma Liver transplantation

Abstract Although there are no liver diseases specific to advanced age, the clinical course and management of liver diseases in the elderly may differ in several aspects from those of younger adults. During the last decade an explosion of new knowledge in liver disease has provoked increasing enthusiasm among hepatologists. On the other hand, the development of new emerging conditions (e.g. non-alcoholic steatohepatitis) and novel therapeutic approaches has made it increasingly difficult to validate and assimilate information to be applied in clinical practice. Some liver diseases in the elderly need to be revisited, particularly non-alcoholic fatty liver disease, chronic hepatitis C, alcoholic liver disease, and hepatocellular carcinoma. Moreover, some therapeutic approaches, especially antiviral therapy and liver transplantation, should be discussed also in selected groups of elderly patients. Copyright © 2007 S. Karger AG, Basel

Introduction

The specific subject of chronic liver disease in the elderly has generally received little attention from hepatologists, probably for several reasons. First of all, there

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are no specifically age-related liver diseases. Secondly, some of the liver diseases that can develop in old age, particularly primary biliary cirrhosis and autoimmune hepatitis, do not represent a different diagnostic tool in the elderly and can easily be treated with standard therapy. Moreover, autoimmune liver disease carries a good prognosis in the elderly, and very few patients have clinically aggressive conditions. Even when we consider chronic liver disease in the very elderly (180 years old), cirrhosis is the main risk factor affecting prognosis [1]. In dealing with elderly people, however, it is important to consider the increase in the number of deaths unrelated to the liver, especially pneumonia, when liver disease gradually deteriorates [1]. Hepatitis B virus (HBV) infection is declining in many countries. Infected elderly people often develop a subclinical or oligosymptomatic hepatitis with a low rate of HBV clearance, possibly due to their impaired immunological status. Chronic hepatitis and/or cirrhosis are generally inactive and progress slowly. However, it is undeniable that in recent years there has been an increasing interest in distinguishing between old and young people as regards clinical liver disease and its management. In fact, one of the most important problems lies in the increasing number of elderly patients with chronic hepatitis C infection. Epidemiological figures suggest that elderly people form a cohort whose infection was acquired many years earlier. Another problem is the recent acquisition of metabolic conditions specifically affecting old age (diabetes, dyslipidemia) as important factors correlated to chronic liver disease. Finally, it is important to bear in mind the

Prof. Annarosa Floreani Division of Gastroenterology Via Giustiniani, 2, IT–35128 Padova (Italy) Tel. +39 049 821 2894, Fax +39 049 876 0820 E-Mail [email protected]

Table 1. Interferon monotherapy in the

elderly

Group

>65 years

<65 years

Response (end of treatment)

p

Side effects

Bresci, 1993 [14] Van Thiel, 1995 [15] Horiike, 1995 [16]

22 25 19 (>60)

21 25 52 (<60)

62 vs. 57% 48 vs. 41% SR = 26 vs. 33%

NS NS NS

similar similar similar

SR = Sustained response.

increasing incidence of hepatocellular carcinoma (HCC) in old age, as a complication of end-stage liver disease. This chapter focuses on a few specific aspects of parenchymal liver disease that have recently been revisited in the elderly.

Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological spectrum of liver abnormalities ranging from steatosis to non-alcoholic steatohepatitis (NASH). Its prevalence varies depending on the diagnostic methods used, but about 25% of the general population in the USA is presumably affected. An Italian population survey based on ultrasound found steatosis in 16.4% of the general population, in 46.4% of heavy drinkers, in 75.8% of obese subjects, and in 94.5% of obese drinkers [2]. NASH is mainly related to metabolic disorders including obesity, insulin resistance, hyperlipidemia, nutritional disorders, inherited lipoprotein metabolism disorders, drug use and toxin ingestion. While prospective studies on the natural history of NASH are still lacking, approximately 10–15% of patients will progress to advanced fibrosis and cirrhosis [3]. It is now clear that a large proportion of cases with cryptogenic cirrhosis represent the end-stage liver disease of NASH [4]. In this light, cases of cryptogenic cirrhosis in old age may conceivably be due to metabolic risk factors developing in adult life. A combination of age 1 45 years with obesity, diabetes mellitus, and AST/ALT 11 has been identified as a predictor of liver fibrosis [5]. Liver failure is the main cause of morbidity and mortality in NASH-associated cirrhosis. The prognosis is either comparable with, or less severe than for hepatitis C virus (HCV) cirrhosis, except that HCC appears to be less common [6].

Liver Diseases in the Elderly

Hepatitis C Virus Infection

This is the most important clinical form in the elderly. Besides the epidemiological figures that indicate an increasing prevalence of anti-HCV with age [7], at the onset of infection or the diagnosis of chronic hepatitis, old age is clearly associated with more severe histological damage and the presence of cirrhosis [8]. Risk factors for elderly people acquiring HCV differ considerably from those of the younger generations. In fact, epidemiological studies suggest an epidemic of HCV infection during the Second World War and in the early post-war years. The epidemiological factors included blood transfusions, but the main culprits were non-disposable syringes [9]. In young people, on the other hand, HCV infection is mainly due to risk behavior, including tattooing, piercing, and sharing contaminated needles among intravenous drug users. The clinical spectrum of cases with active replication ranges from no biochemical or clinical signs of liver disease right up to decompensated cirrhosis, sometimes with superimposed HCC [10]. Treatment Strategies for Hepatitis C Asymptomatic carriers have mild histological changes and rarely develop advanced disease [11, 12]. The natural history of this group of patients appears to progress slowly, if at all. Experts differ on whether to biopsy and treat these patients [13]. In our opinion, antiviral treatment is not to be recommended for such elderly patients, whereas follow-up is, with liver function tests and -fetoprotein every 6 months and liver ultrasound annually. Elderly patients with chronic hepatitis C are generally considered poor candidates for antiviral treatment due to the predictably low rate of response and the high rate of adverse effects. Only three studies with interferon (IFN) as monotherapy have been published so far (table 1). Two controlled studies [14, 15] included a small sample of subjects (21 and 25, respectively) 165 years old, with an averDig Dis 2007;25:138–143

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Table 2. Side effects of IFN and ribavirin

therapy

Frequency

IFN-

Ribavirin

>30–50%

Fatigue, fever, arthralgia, headache

Hemolysis, dyspepsia

Mild depression Thrombocytopenia Leukocytopenia Anorexia Severe depression Diabetes Autoimmune diseases (thyroid dysfunction) Neuropathy

Anemia Pruritus Cough Rash Severe angina Gout Myocardial infarction

1–30%

age age of 68.8 years [14] and an age range of 65–81 years [15]. In both studies, the response at the end of the treatment did not differ significantly in the elderly group by comparison with younger patients, and the percentage of side effects was similar in the two groups. Any viremia was not investigated in these studies and the rate of sustained response is not reported. Horiike et al. [16] treated 19 patients 160 years old (average age 62.5 years) with IFN and compared the results with 52 younger adult patients (average age 44.1 years): the percentage of sustained response did not differ significantly in the two groups (26 vs. 33%, respectively). Older patients may be at risk of neurological side effects of IFN, e.g. confusion, lethargy, cognitive changes and depression, especially if they have a history of neurological and/or psychiatric disorders [17]. Selected individuals !70 years old might thus be candidates for antiviral therapy. The National Institute of Health Consensus Conference on hepatitis C defined IFN + ribavirin combination therapy as the new standard treatment for chronic hepatitis C [13]. More recently, the addition of a polyethylene glycol molecule to IFN has improved its pharmacokinetics, requiring its administration only once a week. Multiple side effects are common, and occasionally severe. Predosing with antipyretics, paying attention to hydration and ensuring adequate rest periods are also important. As elderly patients have a higher chance of side effects than younger patients, accurate patient monitoring is also necessary. The most common side effects are listed in table 2. A number of cost-benefit analyses have evaluated parameters for predicting response to combination therapy. In general, old age, genotype 1, high viral load and a high degree of histological fibrosis are associated with a low sustained response rate [18]. There are no reports available on controlled trials with IFN + ribavirin in elderly 140

Dig Dis 2007;25:138–143

patients, but we have recently enrolled 33 naive patients with a mean age 8 SD of 70.2 8 1.2 years to receive pegylated IFN-2b at a dose of 1.5 mg/kg weekly plus ribavirin for 6 (genotype 2 or 3) or 12 (genotype 1 or 4) months. Tolerance and efficacy were compared to those observed in a 1:2 adult group matched for sex, genotype, viral load, and grading/staging parameters [19]. The results of this study indicate that elderly patients have a higher likelihood of side effects and significantly lower rate of virological response at the end of treatment and 6 months afterward than younger adults. Cost-benefit analysis shows that only selected patients aged 65 and older should be treated. There is a general consensus that adult patients who have failed to respond, or have responded only temporarily to IFN alone, should be offered a combination of IFN + ribavirin, unless they have major contraindications to such therapy. There are no reports on retreatment with antiviral therapy in the elderly, or rather the number of older patients involved in any such studies has been too small to assess the tolerability of this combination in older people. In our opinion, retreatment is not to be recommended in elderly patients because of the high risk of side effects. There is only one published study using IFN + amantadine in patients 165 years of age whose prior treatment with IFN had failed to eradicate HCV infection [20]. In this trial, 165 patients were randomized into three groups and treated for 12 months: group A received amantadine 100 mg twice a day; group B received IFN- 6 MU every other day for 3 months followed by 3 MU, and group C was given the same dose of IFN- as group B plus amantadine 200 mg/day. The percentage of sustained response was 16.6% in group A, 23% in group B, and 25% in group C. Although the tolerability of this combination, this trial does not appear to substantially improve the sustained Floreani

response rate in elderly patients who have failed to become clear of HCV infection after IFN monotherapy. Amantadine alone is not effective in patients 170 years old with contraindications for antiviral therapy [21].

Alcoholic Liver Disease

Alcohol consumption is common in old age. In a study on community-dwelling people ranging from 60 to 92 years of age, 62% of the subjects were drinkers, and heavy drinking was reported in 13% of men and 2% of women [22]. However, the criteria commonly used to define alcohol abuse and dependence may be difficult to apply to older people, particularly when they have retired or have few social contacts [23]. Half of the elderly patients who develop cirrhosis die within a year of its diagnosis [24]. Alcohol abuse has been mentioned in many studies as contributing to the progression of HCVrelated liver disease. In a study including 800 patients with HCV infection, heavy drinking (150 g of ethanol a day) was associated with an increase in mean fibrosis (p = 0.01) [25]. However, on multivariate analysis in a cohort of patients with hepatitis C, none of the alcohol intake categories (light, moderate and heavy) correlated with the presence of steatosis in either genotype 3 and other genotypes [26]. The effects of alcohol may also be compounded in elderly patients by age-related pharmacological changes involving interactions between alcohol and medication. Alcohol withdrawal in elderly subjects should be supervised by a health care professional [27].

ever (nearly 5% per year in the HCV-related liver cirrhosis group) [1]. HCV and HBV coinfection is a condition particularly prone to malignant transformation [9]. Another emerging condition that contributes to the development of HCC in old age is NAFLD. Although prospective studies on this condition are lacking, several reports have identified cryptogenic cirrhosis as the end stage of liver disease due to metabolic factors underlying NAFLD-related cirrhosis. Moreover, the hypothesis that obesity and diabetes mellitus are important risk factors for cryptogenic chronic liver disease in patients with HCC is supported by the analysis of surgically-treated patients [30]: in a series of 18 patients who underwent liver resection for HCC developing on cryptogenic cirrhosis, 12 patients were 165 years of age. These observations have prompted the increasing interest in surveillance programs for cirrhotic patients, aiming to detect any HCC development as early as possible. The treatment of HCC in elderly subjects deserves some considerations. Hepatic resection can be safely done in cirrhotic HCC patients 170 years of age, but the prognosis for these patients is less favorable than for patients !70 years, even when curative resection is achieved [31]. Liver transplantation is an exceptional measure for elderly patients, due to many current data concerning the management of HCC. Many transplant centers restrict the waiting list for HCC for patients !65 years; moreover, the problem of the increasingly long waiting lists obviously restricts the life expectancy for patients with malignancies. Radiofrequency ablation, alcohol injection and transcatheter arterial chemoembolization are non-surgical treatment modalities for HCC that are currently performed in elderly patients.

Hepatocellular Carcinoma

HCC is the most common complication of liver cirrhosis affecting elderly people. The rate of HCC increases with age in cirrhotic patients [28]. A number of studies conducted in different groups of patients have established that, due to its long natural history, HCV infection contributes to the greater risk of HCC in the elderly. A recent prospective study carried out on a homogeneous cohort of 312 patients with initially compensated cirrhosis of viral etiology in the last 15 years has identified HCC as the most frequent and life-threatening complication, particularly in HCV-positive cases [29]. HCC often preceded the appearance of ascites and was the cause of death in 70.7% of the patients [29]. A relatively low carcinogenesis rate has been observed in extremely elderly patients, how-

Liver transplantation is considered an acceptable treatment for fulminant liver damage. According to the European Liver Transplant Registry, the proportion of adult liver recipients older than 60 years increased from 9% in 1990 to more than 16% by 1999. Moreover, more than 10.7% of recipients of a liver allograft in the USA in 2000 were 165 years old. Randall et al. [32] examined data from the Organ Procurement and Transplant Network for the last 10 years to determine whether it is justifiable to perform transplantation in older patients. For liver transplant recipients 165 years old, the annual death rate per 1,000 patients per year at risk rose from 49 in 1991 to

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185 in 2000. The total number of patients increased from 382 in 1991 to 3,181 in 2000, for a rate of 183.8 in 1991 and 85.5 in 2000. However, the survival rate, as reported in the European Liver Transplant Registry for more than 3,000 liver recipients 160 years of age, was significantly shorter than for a group of 11,762 recipients aged 45–60 years (p ! 0.001). The shorter survival in elderly patients is due to several comorbidity factors, such as cardiopulmonary disease and advanced kidney dysfunction [32]. The recipient’s age is particularly important as a predictive factor for survival among patients with hepatitis C [33]. On the other hand, the outcome of liver transplantation with a graft from a donor 165 years of age into an HCV-positive recipient shows a worse outcome than with organs from younger donors [34]. Generally speaking,

several studies report a decline in the survival rates of patients who receive organs from donors older than 45.5 or 60 years even in etiologies other than hepatitis C. In a recently published study, patient survival is lower when the donor is 130 years old, and hepatic graft survival is reduced at a cut-off donor age 125 years [35]. Obviously, organ donation cannot be limited for reasons of age because the number of donations would be insufficient. However, there are many other aspects of this topic warrant discussion and evaluation. One important point to make, for example, is that organs from older donors should be given to older recipients. Another important area of debate is whether it is ethical to consider healthy family members as donors for the elderly population.

References 1 Hoshida Y, Ikeda K, Kobayashi M, Suzuki Y, Tsubota A, Saitoh S, Arase Y, Kobayashi M, Murashima N, Chayama K, Kumada H: Chronic liver disease in the extremely elderly of 80 years or more: clinical characteristics, prognosis and patient survival analysis. J Hepatol 1999;31:860–866. 2 Bellentani S, Saccoccio G, Masutti F, Crocè LS, Brandi G, Sasso F, Cristianini G, et al: Prevalence and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000;132:112–117. 3 Angulo P: Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221–1231. 4 Neuschwander-Tetri BA, Caldwell SH: Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 2003;37:1202–1219. 5 Angulo P, Keach JC, Batts KP, Lindor KD: Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30:1356–1362. 6 Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, Hall P, Khan M, George J: Longterm outcomes of cirrhosis in non alcoholic steatohepatitis compared with hepatitis C. Hepatology 2003; 38:420–427. 7 Poynard T, Yen MF, Ratziu V, Lai CL: Viral hepatitis C. Lancet 2003;362:2095–2100. 8 Pagliaro L, D’Amico G, Puleo A: Meta-analysis as a source of evidence in gastroenterology: a critical approach. Ital J Gastroenterol Hepatol 1999;31:723–742. 9 Chiaramonte M, Stroffolini T, Vian A, Stazi MA, Floreani A, Lorenzoni U, Lobello S, Farinati F, Naccarato R: Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 1999; 85:2132–2137.

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10 Marcus E-L, Tur-Kaspa R: Chronic hepatitis C virus infection in older adults. Clin Infect Dis 41:1606–1612, 2005. 11 Puoti C, Castellacci R, Montagnose F, Zaltron S, Stornaiuolo G, Bergami N, Bellis L, Precone D, Corvisieri P, Puoti M, Minola E, Gaeta GB: Histological and virological features and follow-up of hepatitis C virus carriers with normal aminotransferase levels: the Italian prospective study of the asymptomatic C carriers (ISACC). J Hepatol 2002; 37:117–123. 12 Hoofnagle JH: Management of hepatitis C: current and future perspectives. J Hepatol 1999;31(suppl 1):264–268. 13 NIH Consensus Statement on Management of Hepatitis C: 2002. HIH Consens State Sci Statements 2002;19:1–46. 14 Bresci G, Del Corso L, Romanelli AM, et al: The use of recombinant interferon-alfa-2b in elderly patients with anti-HCV-positive chronic active hepatitis. J Am Geriatr Soc 1993;41:857–862. 15 Van Thiel DH, Fridlander L, Caraceni P, et al: Treatment of hepatitis C virus in elderly persons with interferon- . J Gerontol 1995; 50:M330–M333. 16 Horiike N, Masumoto T, Nakanishi K, et al: Interferon therapy for patients more than 60 years of age with chronic hepatitis C. J Gastroenterol Hepatol 1995;10:246–249. 17 Marcus E-L, Tur-Kaspa R: Viral hepatitis in older adults. J Am Geriatr Soc 1997; 45:755– 763. 18 Gao B, Hong F, Radeva S: Host factors and failure of interferon- treatment of hepatitis C virus. Hepatology 2004;39:880–890.

19 Floreani A, Minola E, Carderi I, Ferrara F, Rosa Rizzotto E, Baldo V: Are elderly patients poor candidates for pegylated interferon plus ribavirin in the treatment of chronic hepatitis C? J Am Geriatr Dis 2006; 54:549–550. 20 Bacosi M, Russo F, D’Innocenzo S, Santolamazza M, Migliorasi L, Ursitti A, De Angelis A, Patrizi F, Ricci GL: Amantadine and interferon in the combined treatment of hepatitis C virus in elderly patients. Hepatol Res 2002;22:231–239. 21 Torre F, Campo N, Giusto R, Ansaldi F, Icardi GC, Picciotto A: Antiviral activity of amantadine in elderly patients with chronic hepatitis C. Gerontology 2001;47:330–333. 22 Mirand AL, Welte JW: Alcohol consumption among the elderly in a general population from Erie County, New York. Am J Public Health 1996;86:978–984. 23 Adams WL, Cox NS: Epidemiology of problem drinking among elderly people. Int J Addict 1995;30:1693–1716. 24 Smith JW: Medical manifestations of alcoholism in the elderly. Int J Addict 1995; 30: 1749–1798. 25 Monto A, Patel K, Bostrom A, Pianko S, Pockros P, McHutchison JG, Wright TL: Risks of a range of alcohol intake on hepatitis-C-related fibrosis. Hepatology 2004; 39: 826–834. 26 Fabris P, Floreani A, Carlotto A, Giordani MT, Baldo V, Stecca C, Marchiorio L, Tramarin A, Bertin T, Negro F, deLalla F: Alcohol is an important co-factor for both steatosis and fibrosis in Northern Italian patients with chronic hepatitis C. J Hepatol 41: 644– 651, 2004. 27 Rigler SK: Alcoholism in the elderly. Am Fam Physicians 2000;61:1710–1716.

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28 Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, Arase Y, Fukuda M, Chayama K, Murashima N, Kumada H: Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2,215 patients. J Hepatol 1998;28:930–938. 29 Benvegnù L, Gios M, Alberti A: Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut 2004; 53: 744–749.

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30 Regimbeau JM, Colombat M, Mognol P, Durand F, Abdalla E, Degott C, Degos F, Farges O, Belghiti J: Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl 2004;2(suppl 1):S69–S73. 31 Lui WY, Chau GY, Wu CW, King KL: Surgical resection of hepatocellular carcinoma in elderly cirrhotic patients. Hepatogastroenterology 1999;46:640–645. 32 Randall HR, Cao S, deVera ME: Transplantation in elderly patient. Arch Surg 2003; 138: 1089–1092. 33 Zetterman RK, Belle SH, Hoofnagle JH, Lawlor S, Wei Y, Everhart J, Wiesner RH, Lake JR: Age and liver transplantation: a report on the liver Transplantation Database. Transplantation 1998;66:500–506.

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34 Baccarani U, Adani GL, Toniutto P, Sainz M, Lorenzin D, Viale PL, Ramacciato G, Risaliti A, Bresadola F: Liver transplantation from old donors into HCV and non-HCV recipients. Transpl Proc 2004;36:527–528. 35 Fernandez-Merino FJ, Nuno-Garza J, Lopez-Hervas P, Lopez-Buenadicha A, Quijano-Collazo Y, Vicente-Lopez E: Donor age a risk factor for patient survival in the liver transplant. Transpl Proc 2003; 35: 1795– 1797.

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Dig Dis 2007;25:144–150 DOI: 10.1159/000099479

Intestinal Malabsorption in the Elderly Peter R. Holt Strang Cancer Research Laboratory, Rockefeller University, New York, N.Y., USA

Key Words Small intestine, structural and functional changes Intestinal micronutrient absorption Vitamin B12 malabsorption Small intestinal bacterial overgrowth syndrome Pancreatic disease Investigation of structural changes Celiac disease

Abstract Background: Intestinal malabsorption in the elderly is infrequent, and clinical features are muted so that the diagnosis is often missed. Physiologic changes with aging are restricted to altered absorption of calcium and perhaps zinc and magnesium; however, achlorhydria can lead to impaired absorption of vitamin B12, folic acid, and calcium. Methods and Results: Small bowel bacterial overgrowth occurs more commonly in elderly than in younger patients, accompanying gastric hypochlorhydria, altered intestinal motor activity, or diseases such as Parkinson’s disease. Changes in pancreatic anatomy and secretion occur but are insufficient to produce macronutrient malabsorption. In addition to pancreatic cancer and pancreatic stones, older patients may present with severe pancreatic insufficiency of unknown etiology. Celiac disease is recognized as very common at all ages and may not become evident until late in life. Manifestations of celiac disease in the elderly are occult and the diagnosis often is not considered until serologic tests are performed and confirmed by upper small intestinal biopsy. Associated intestinal lymphoma, esophageal carcinoma, intestinal pseudo-obstruction, and splenic atrophy may be more common

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in the elderly. Treatment of older patients with celiac disease with a gluten-free diet may be difficult, and intensive vitamin and micronutrient replacement is mandatory. A pragmatic approach to the evaluation of malabsorption in elderly patients is discussed. Copyright © 2007 S. Karger AG, Basel

Introduction

Medical students who are introduced to the subject of malabsorption generally visualize an emaciated child whose major symptoms are diarrhea accompanied by the passage of foul-smelling oily stools. In contrast to this clinical picture, the majority of adult patients with malabsorption describe minimal gastrointestinal symptoms of colonic dysfunction, such as excessive bloating, crampy abdominal pain, and the passage of excess gas. Many others do not have overt gastrointestinal symptoms at all, but present with micronutrient depletion or deficiency. This is particularly pertinent in the elderly, who appear to adjust well to malabsorption-induced colonic dysfunction. The micronutrient depletion most often present includes fat-soluble vitamin deficiency, particularly the consequences of vitamin D deficiency, as well as folate and vitamin B12 depletion, and low serum iron or iron deficiency anemia. Trace metal deficiencies may occur in patients with primary disorders of the small bowel epithelium and frequently are not recognized.

Peter R. Holt, MD Strang Cancer Research Laboratory, Rockefeller University 1230 York Avenue, New York, NY 10021 (USA) Tel. +1 212 734 0567/ext. 2070, Fax +1 212 249 0013 E-Mail [email protected]

Structural and Functional Changes in the Small Intestine

In order to distinguish diseases that lead to impaired intestinal absorption from changes that may occur with the aging process, it is necessary to be aware of these agerelated decrements in digestive and absorptive functions. Based upon older studies, there is the misconception that small intestinal villus height and surface area are reduced compared with that in young controls. However, careful evaluation of jejunal biopsy specimens from healthy elderly volunteers shows that the anatomy of epithelial cells and the surface area does not differ from that found in the young [1]. In the rat, although villus cell numbers in the proximal small intestine are similar in the young and old, crypt cell numbers are greater in Fischer 344 rats over age 24 months [2] accompanied by increased epithelial cell proliferation [3] and altered controls of cell production [4]. Similar changes have been described in the human small bowel epithelium [5]. Thus, abnormalities in upper intestinal villus architecture in an elderly person appear to be the result of disease and not the aging process. There is little evidence for reduction in brush border disaccharides enzymes with aging, with the exception of lactase (lactase-phlorizin hydrolase), the activity of which falls dramatically in the majority of the world’s population with age. One careful study of lactose malabsorption and intolerance showed that subjects over age 74 years showed significantly lower lactose absorption based upon breath hydrogen analysis than younger individuals. However, intolerance symptoms amongst patients with malabsorption were less in the elderly [6]. Although there is evidence for a decrease in the small intestinal concentrations of other brush border enzymes in rodents [7], there is little confirmation of this change in humans. There is abundant discordance in studies of changes in the absorption of macronutrients and some micronutrients with advanced age. One reason for this discrepancy is that mucosal weight and the content of epithelial cell transporters and some enzymes is higher per unit length of intestine in older rodents than in the young. Thus when intestinal absorption is studied as a function of protein concentration, it often is found to be reduced in older animals when compared to the young [8]. However, when calculated as a function of intestinal length, absorption usually is found to be unaltered [9, 10]. Lipid absorption overall appears to be little altered by the aging process [11]. Lymphatic fat and apolipoIntestinal Malabsorption in the Elderly

protein A4 transport was shown to be similar in mesenteric lymph-cannulated 8- to 10- and 24- to 26-monthold Wistar rats [12] and fecal fat excretion was maintained in volunteers provided 100 g [13] or 1300 g [14] of fat. However, Thomson’s group [15] recently described some reduction in rat ileal uptake of fatty acids in vitro, accompanied by up to 50% reduction in intestinal fatty acid-binding protein. It is possible that the reserve capacity of the small intestine in humans is large enough so that little malabsorption is observed until functional defects are severe.

Intestinal Micronutrient Absorption

Although there is little evidence for major malabsorption of macronutrients as a physiologic function of age, selected impaired absorption of several micronutrients does occur. Very early studies suggested that atrophy of the colonic mucosa occurs with advancing age [16], associated with alterations in water and electrolyte transport. Renal responses to sodium restriction are impaired in the elderly [17]; however in a recent study, mineralocorticoid-sensitive electrogenic sodium absorption was not lower in biopsies from the colon of human volunteers over the age of seventy [18]. The absorption of metal ions as a function of age has not received much attention; however, a recent report of careful studies in the rat suggests that zinc absorption may be considerably decreased, magnesium absorption decreased only moderately, and copper absorption is unaffected [19]. To the author’s knowledge, detailed examination of small intestinal metal transporters as a function of age in humans or rodents has not been performed. It is well known that calcium absorption falls with advancing age, which contributes to age-associated osteopenia [20]. Reduced calcium absorption appears to result from alteration of vitamin D metabolism or their effects at the intestinal level [21]. Plasma 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) levels are lower in the elderly than in the young [21], and this has been ascribed to impaired formation of this hormone at the level of the kidney [22]. It is now recognized that intestinal epithelial cells can synthesize the active form of vitamin D 1,25(OH)2D3 from circulating 25-hydroxy vitamin D3 [23]. Such local production of 1,25(OH)2D3 may determine vitamin D activity in the intestine. Whether this function is altered in the elderly is unknown.

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Vitamin B12 Malabsorption

Vitamin B12 depletion is very common in the elderly. In an evaluation of the Farmingham study population, up to 15% of people over the age of 65 were described as showing evidence of vitamin B12 deficiency and many of these had serum vitamin B12 levels within the conventionally defined normal range [24]. Vitamin B12 absorption requires hydrolysis of food-bound vitamin B12 in the stomach, binding of the released B12 to a gastric protein – the R binder with the subsequent release of vitamin B12 from R binding by acid and pancreatic enzymes. B12 binding to intrinsic factor and absorption of the B12 intrinsic factor complex is accomplished by specific receptors in the ileum. Pernicious anemia, due to atrophic gastritis, with failure to secrete intrinsic factor into the stomach as well as surgical resection or diseases of the ileum preventing intestinal absorption, represent the cause of vitamin B12 deficiency in only a minority of elderly patients. The most common cause of such deficiency is food-bound vitamin B12 malabsorption, associated with reduced gastric acid secretion and atrophic gastritis. In such patients, although intrinsic factor secretion is maintained, the absence of gastric acid results in failure of vitamin B12 to be released from food [25]. Food-bound B12 malabsorption may be associated with significant neurologic, psychologic, and hematologic abnormalities [26]. Malabsorption of food-bound B12 responds not only to parental vitamin B12 therapy, but the disorder may be treated with oral crystalline vitamin B12 in doses of 250– 1,000 g/day. This regimen eliminates B12 depletion and maintains normal serum vitamin B12 levels, together with reversal of clinical abnormalities in most patients. Folic acid is absorbed mainly in the upper small intestine so that diseases of this area of the bowel frequently lead to reduced circulating folic acid and evidence of megaloblastic anemia. In addition, it should be recognized that folic acid in foods is present as the heptapeptide requiring hydrolysis by pancreatic enzymes with the release of monoglutamate folic acid. Optimal absorption of folate monoglutamate requires a pH !7 [27], thus achlorhydria can result in reduced folic acid absorption and folate depletion [28]. One factor that may modify folate depletion in the presence of achlorhydria is jejunal bacterial overgrowth, since the abundance of bacteria in the upper small intestine may produce folic acid, overcoming folate malabsorption due to the high pH. It should also be remembered that, whereas vitamin B12 stores often are sufficient in the presence of B12 malabsorption to prevent vitamin B12 deficiency for many years, folate 146

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stores are quite limited and folic acid deficiency in the absence of absorption of food folate may occur within weeks or months.

Small Intestinal Bacterial Overgrowth Syndrome

Small intestinal bacterial overgrowth may induce occult malabsorption in the elderly, although the frequency of this disorder has been disputed [29, 30]. Structural causes such as post-gastrectomy states and intestinal strictures may result in bacterial overgrowth as also occurs in younger subjects; upper intestinal diverticulosis is common in advanced age, but rarely induces complications such as malabsorption [31]. Bacterial overgrowth in the absence of structural abnormalities appears to occur in older individuals based on breath H2 analysis after a 50-gram glucose challenge [32] and may lead to nutritional deficiencies [33]. Such small bowel bacterial overgrowth may be associated with gastric achlorhydria [34, 35], but in some subjects appears to result from altered intestinal motor function rather than changes in gastric pH or changes in luminal IgA secretion [36]. Thorough studies of motor activity in the elderly demonstrate some delay in gastric emptying, but little effect in overall small and large bowel transit [37, 38]. The classic observations of Vantrappen’s group [38] showed that changes in interdigestive motor complexes occur in patients with bacterial overgrowth and it has been suggested that this is the mechanism for malabsorption in the absence of structural alterations. However, one study in a small number of elderly subjects showed no evidence of abnormalities in the interdigestive (housekeeping) motor complex [39]. More important, probably, are diseases such as depression, hypothyroidism, and Parkinson’s disease and the use of certain drugs such as antidepressants, analgesics, and calcium channel antagonists that slow gastrointestinal transit [40]. Enteric nervous system neuron dysfunction clearly can occur as a function of age [41], although consistent clinical effects are not universal.

Pancreatic Disease

Cross-sectional studies comparing younger with older individuals suggest that minor decrements in pancreatic enzyme output occur with advancing age. However, functional as well as structural changes do not occur in everyone, nor do they begin at a specific age or progress continuously. It has been suggested that arteriosclerosis may Holt

reduce pancreatic blood flow and that intralobular fibrosis, accompanied by ductal epithelial hyperplasia and pancreatic atrophy, occurs to a modest extent [42]. Irregularity and dilatation of the main pancreatic duct and its secondary duct branches may be seen in abdominal ultrasound examinations [43] and by endoscopic retrograde cholangiopancreatography (ERCP) in elderly patients [44]. Overall, however, such structural changes are not necessarily associated with decrements in pancreatic function. Some studies have suggested a reduction of up to 40% in secretin-pancreozymin-stimulated lipase, trypsinogen and bicarbonate secretions [45]. However, it should be remembered that malabsorption does not occur until 80–90% of pancreatic enzyme secretion is lost. Some studies have suggested that serum levels of pancreatic enzymes may be elevated in elderly patients without evidence of pancreatic disease [46]. Pancreatic insufficiency with enough reduction in function and enzyme secretion to produce malabsorption may become apparent in the elderly without a previous history of pancreatic disorders. The classical description of pancreatic insufficiency of unknown etiology by Amman and Sulser [47] showed that 75% of pancreatic insufficiency of unknown etiology throughout the life span was present in the older age range. Amman’s group suggested that ‘vascular insufficiency’ was responsible for pancreatic insufficiency in the elderly. Patients with pancreatic exocrine insufficiency and pancreatic calcification without the usual associated etiologic factors have been described from France [48] and Japan [49]. It is possible that the diagnosis in some of these patients was the more recently reported disease of immune-mediated lymphocytic chronic pancreatitis [50, 51]. Indeed, the patients described by Laugier and Sarles [48] in France may have had this disorder since they were originally described as having hyperglobulinemia and elevations of IgG4 have now become recognized as occurring frequently in autoimmune idiopathic pancreatitis. Some authors have suggested that pancreatic insufficiency should be sought in older patients who suffer from weight loss of unknown etiology [52] or ‘geriatric cachexia’, but this is probably rarely the cause. Pancreatic insufficiency also, of course, may occur as a result of chronic alcohol consumption, and individuals with chronic pancreatitis secondary to excessive alcohol intake may survive into the geriatric age group. Gallstone pancreatitis, although more frequent in the elderly than in the young, uncommonly results in chronic atrophic pancreatitis. Diabetes mellitus has been associated with pancreatic insufficiency in several studies [53].

Another form of chronic pancreatitis that is important in older patients is obstructive pancreatitis, caused either by an ampullary tumor or by carcinoma at the head of the pancreas. This usually is not associated with pancreatic calcification and protein plugs since it is of relatively acute onset. In this situation the main pancreatic duct often is dilated, which is uncommonly found in patients with alcoholic or idiopathic pancreatitis. Occasionally, stones may obstruct the pancreatic ducts, leading to chronic pancreatitis and malabsorption. Pancreatic duct stones increase in prevalence with advancing age and is seen in as many as 15% of patients older than 90 years [49]. Most patients with severe pancreatic insufficiency present with voluminous oily stools, near-normal serum albumin levels, and a normal xylose tolerance test. Tests of pancreatic insufficiency as the cause of malabsorption may be invasive and specific, noninvasive and indirect, or anatomical. Specific testing for a reduction in pancreatic enzyme output, following stimulation with a meal or cholecystokinin-pancreozymin requires the passage of a duodenal tube and is rarely performed in elderly patients, except in research facilities. Anatomical tests of pancreatic abnormalities include the presence of extensive pancreatic calcification, ultrasound examination, CT scanning, and/or ERCP to demonstrate widening of major and minor ducts. These changes imply but do not prove the presence of atrophy of parenchymal acinar tissue. Indirect functional tests include pancreatic lauryl testing, the p-aminobenzoic acid test and measurement of fecal elastase. All of these tests will be diagnostic if pancreatic insufficiency is severe. Fecal elastase determination has been utilized to evaluate subclinical covert reductions in exocrine pancreatic function in elderly individuals. One study of 914 subjects 50–75 years of age showed some reduction in fecal elastase (!200 per g feces) in 11.5% and severe insufficiency (!100 per g feces) in over 5% [54]. Since other studies have also shown reduction in fecal elastase with advancing age, this test may be optimal to evaluate pancreatic function in older individuals.

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Investigation of Structural Changes

Evaluation of structural diseases of the small intestine classically has required barium studies of the small bowel or endoscopy, such as push enteroscopy and colonoscopy with evaluation of the distal ileum. Recently, capsule endoscopy has been introduced and has greatly expanded our ability to evaluate small bowel disorders 147

using a minimally invasive method that is more suitable for older patients than complex visual endoscopy. How could capsule endoscopy assist in the diagnosis management of disorders resulting from malabsorption? Capsule endoscopy has increasingly been used for the diagnosis of early Crohn’s disease of the distal bowel [55]. Furthermore, it has been used to evaluate patients with suspected celiac diseases or malabsorption of unknown etiology [56, 57]. In celiac disease that is unresponsive to a glutenfree diet, capsule endoscopy can be used to determine whether patients may have ulcerative jejunitis and the presence of small bowel lymphoma. Capsule endoscopy is a painless and relatively noninvasive diagnostic tool but has the rare risk of entrapment of the capsule in strictures or diverticula. Thus, some authors recommend that small bowel X-rays should be performed to exclude these disorders prior to the administration of the capsule [58].

Celiac Disease

Celiac disease now is recognized as a very common genetic disorder that occurs in 1 in 100–150 of the population in many parts of the world [59, 60]. Most patients display no or minimal symptoms so that the diagnosis is often delayed [61] and must be suspected in individuals who are at increased risk, including patients with dermatitis herpetiformis, family members of patients with celiac disease, patients with certain autoimmune disorders, including autoimmune thyroiditis [62] and those with juvenile diabetes. In addition, physicians should suspect the disease in patients with pronounced or early osteoporosis, unexplained low serum iron determinations or iron deficiency anemia, or low serum folic acid measurements [63, 64]. In the absence of symptoms, the diagnosis often is made by tests for the antibody to tissue transglutaminase. Even if symptoms of malabsorption are present, elderly individuals display less severe complaints than younger adult patients with celiac disease, thus, the disease is very covert and often is not diagnosed until serologic tests or small bowel biopsy [65] are performed. Serologic testing for tissue transglutaminase has not been standardized at the present time, so that small bowel biopsy confirmation is important to confirm the diagnosis. In any case, celiac disease is much more common in the elderly than generally is recognized. About one quarter of the newly diagnosed patients with celiac disease are over the age of 60 [66], and many celiacs diagnosed young are reaching ‘old age’. The usual colonic symptoms that are seen in patients with celiac disease that result from 148

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the passage of unabsorbed macronutrients and bile acids into the large intestine are muted in the elderly, who may complain only of vague dyspepsia [67] or have manifestations only of micronutrient deficiencies. Celiac disease also may behave different in the elderly than in the young, because lymphoma of the small intestine may be more common [68] and small intestinal and squamous cell esophageal carcinomas occur in excess of expected estimates from age-adjusted cancer registries [69]. Some patients with celiac disease also have weight loss and chronic gastrointestinal blood loss associated with diffuse intestinal ulceration [70]. Splenic atrophy, associated with cavitation of mesenteric lymph nodes [71] or intestinal pseudo-obstruction, also occurs [72]. Studies of younger celiac patients who have been treated with a gluten-free diet for a long period of time have shown that the intestinal architecture is usually distorted and that modest malabsorption may be present [73]. This decrement in intestinal absorptive function may be added to the minor changes that occur as a function of age, and thus be exaggerated in such celiac disease individuals. The recorded prevalence of several malignancies amongst patients with celiac disease ranges from 11 to 14% and appears to increase with the duration of clinical follow-up. When the diagnosis of celiac disease is made, the management of older patients with a gluten-free diet does not differ from that of younger individuals. However, older patients may have difficulty in changing lifestyles, and careful introduction of the diet is crucial. The patient may tend to neglect maintaining such a gluten-free diet, so that intense involvement of trained dietitians usually is needed to effect a satisfactory dietary regimen. Furthermore, secondary vitamin and micronutrient deficiencies must be treated more intensively than in the young, since the effect of the disease is added to changes in vitamin homeostasis that occur in the elderly. Particular care should be taken in the management of calcium and vitamin D homeostasis in older patients with celiac disease who already may have underlying osteopenia before the development of overt disease. In order to lower the frequency of crippling and disabling fractures, repeated measurements of bone densitometry is important to insure adequate treatment of calcium or vitamin D deficiency, often in conjunction with bisphosphonates. A strict gluten-free diet also will increase bone density. Small bowel resection involving significant length of the ileum leads to malabsorption of bile salts with or without steatorrhea and carbohydrate and protein as well as micronutrient malabsorption if the resection involves Holt

primarily the jejunum. Older patients recover small bowel function following intestinal resection at a slower rate than the young. A pragmatic workup of suspected malabsorption in an elderly patient usually avoids complex and invasive testing. Prolonged fecal collections are poorly tolerated, but a simple qualitative test for fat malabsorption will diagnose steatorrhea of 115 g/day. The 25-gram xylose test with 1- and 2-hour xylose determinations has been validated in the elderly. The 1-gram 14C-xylose breath test has high specificity and sensitivity for diagnosing bacterial

overgrowth, but is not available in many centers – often the response to therapeutic testing with antibiotics is the way that such bacterial overgrowth is diagnosed. Upper gastrointestinal endoscopy with biopsy is the only specific test for celiac disease and collection of luminal contents for quantitative bacterial counting can be performed simultaneously. Pancreatic insufficiency can be diagnosed using fecal elastase testing, and imaging of the pancreas can suggest the presence of chronic pancreatitis.

References 1 Corazza GR, Frazzoni M, Gatto MR, Gasbarrini G: Ageing and small-bowel mucosa: a morphometric study. Gerontology 1986; 32:60–65. 2 Holt PR, Pascal RR, Kotler DP: Effect of aging upon small intestinal structure in the Fischer rat. J Gerontol 1984; 39:642–647. 3 Holt PR, Yeh KY: Small intestinal crypt cell proliferation rates are increased in senescent rats. J Gerontol 1989;44:B9–B14. 4 Holt PR, Yeh KY, Kotler DP: Altered controls of proliferation in proximal small intestine of the senescent rat. Proc Natl Acad Sci USA 1988;85:2771–2775. 5 Corazza GR, Ginaldi L, Quaglione G, Ponzielli F, Vecchio L, Biagi F, Quaglino D: Proliferating cell nuclear antigen expression is increased in small bowel epithelium in the elderly. Mech Ageing Dev 1998;104:1–9. 6 Di Stefano M, Veneto G, Malservisi S, Strocchi A, Corazza GR: Lactose malabsorption and intolerance in the elderly. Scand J Gastroenterol 2001;36:1274–1278. 7 Jang I, Jung K, Cho J: Influence of age on duodenal brush border membrane and specific activities of brush border membrane enzymes in Wistar rats. Exp Anim 2000; 49: 281–287. 8 Chen TS, Currier GJ, Wabner CL: Intestinal transport during the life span of the mouse. J Gerontol 1990;45:B129–B133. 9 Ferraris RP, Hsiao J, Hernandez R, Hirayama B: Site density of mouse intestinal glucose transporters declines with age. Am J Physiol 1993;264:G285–G293. 10 Hollander D, Dadufalza VD: Increased intestinal absorption of oleic acid with aging in the rat. Exp Gerontol 1983;18:287–292. 11 Holt PR, Balint JA: Effects of aging on intestinal lipid absorption. Am J Physiol 1993; 264:G1–G6. 12 Hayashi H, Sato Y, Kanai S, Masuda M, Ohta M, Funakoshi A, Nagao K, Imaizumi K, Miyasaka K: Lymphatic lipid transport is not impaired in ageing rat intestine. Mech Ageing Dev 2000;113:219–225.

Intestinal Malabsorption in the Elderly

13 Arora S, Kassarjian Z, Krasinski SD, Croffey B, Kaplan MM, Russell RM: Effect of age on tests of intestinal and hepatic function in healthy humans. Gastroenterology 1989; 96: 1560–1565. 14 Simko V, Michael S: Absorptive capacity for dietary fat in elderly patients with debilitating disorders. Arch Intern Med 1989; 149: 557–560. 15 Woudstra TD, Drozdowski LA, Wild GE, Clandinin MT, Agellon LB, Thomson AB: The age-related decline in intestinal lipid uptake is associated with a reduced abundance of fatty acid-binding protein. Lipids 2004;39: 603–610. 16 Yamagata A: Histopathological studies of the colon in relation to age. Jpn J Gastroenterol 1965;62:229–235. 17 Crane MG: Effects of aging on renin activity and aldosterone activity. J Lab Clin Med 1976;87:947–959. 18 Greig ER, Mathialahan T, Boot-Handford RP, Sandle GI: Molecular and functional studies of electrogenic Na+ transport in the distal colon and rectum of young and elderly subjects. Gut 2003;52:1607–1615. 19 Coudray C, Feillet-Coudray C, Rambeau M, Tressol JC, Gueux E, Mazur A, Rayssiguier Y: The effect of aging on intestinal absorption and status of calcium, magnesium, zinc, and copper in rats: a stable isotope study. J Trace Elem Med Biol 2006; 20:73–81. 20 Bullamore JR, Wilkinson R, Gallagher JC, Nordin BE, Marshall DH: Effect of age on calcium absorption. Lancet 1970;ii:535–537. 21 Gallagher JC, Riggs BL, Eisman J, Hamstra A, Arnaud SB, DeLuca HF: Intestinal calcium absorption and serum vitamin D metabolites in normal subjects and osteoporotic patients: effect of age and dietary calcium. J Clin Invest 1979;64:729–736. 22 Tsai KS, Heath H 3rd, Kumar R, Riggs BL: Impaired vitamin D metabolism with aging in women. Possible role in pathogenesis of senile osteoporosis. J Clin Invest 1984; 73: 1668–1672.

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23 Tangpricha V, Flanagan JN, Whitlatch LW, Tseng CC, Chen TC, Holt PR, Lipkin MS, Holick MF: 25-Hydroxyvitamin-D1-hydroxylase in normal and malignant colon tissue. Lancet 2001;357:1673–1674. 24 Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP, Allen RH: Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr 1994;60:2–11. 25 Carmel R, Sinow RM, Siegel ME, Samloff IM: Food cobalamin malabsorption occurs frequently in patients with unexplained low serum cobalamin levels. Arch Intern Med 1988;148:1715–1719. 26 Andres E, Affenberger S, Vinzio S, Kurtz JE, Noel E, Kaltenbach G, Maloisel F, Schlienger JL, Blickle JF: Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment. Am J Med 2005; 118: 1154–1159. 27 MacKenzie JF, Russell RI: The effect of pH on folic acid absorption in man. Clin Sci Mol Med 1976;51:363–368. 28 Russell RM, Krasinski SD, Samloff IM, Jacob RA, Hartz SC, Brovender SR: Folic acid malabsorption in atrophic gastritis. Possible compensation by bacterial folate synthesis. Gastroenterology 1986;91:1476–1482. 29 Holt PR: Diarrhea and malabsorption in the elderly. Gastroenterol Clin North Am 2001; 30:427–444. 30 Saltzman JR, Kowdley KV, Pedrosa MC, Sepe T, Golner B, Perrone G, Russell RM: Bacterial overgrowth without clinical malabsorption in elderly hypochlorhydric subjects. Gastroenterology 1994; 106:615–623. 31 Akhrass R, Yaffe MB, Fischer C, Ponsky J, Shuck JM: Small-bowel diverticulosis: perceptions and reality. J Am Coll Surg 1997; 184:383–388. 32 Parlesak A, Klein B, Schecher K, Bode JC, Bode C: Prevalence of small bowel bacterial overgrowth and its association with nutrition intake in nonhospitalized older adults. J Am Geriatr Soc 2003;51:768–773.

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33 Roberts SH, James O, Jarvis EH: Bacterial overgrowth syndrome without ‘blind loop’: a cause for malnutrition in the elderly. Lancet 1977;ii:1193–1195. 34 Pereira SP, Gainsborough N, Dowling RH: Drug-induced hypochlorhydria causes high duodenal bacterial counts in the elderly. Aliment Pharmacol Ther 1998;12:99–104. 35 Husebye E, Skar V, Hoverstad T, Melby K: Fasting hypochlorhydria with Gram-positive gastric flora is highly prevalent in healthy old people. Gut 1992;33:1331–1337. 36 Riordan SM, McIver CJ, Wakefield D, Bolin TD, Duncombe VM, Thomas MC: Small intestinal bacterial overgrowth in the symptomatic elderly. Am J Gastroenterol 1997;92: 47–51. 37 Brogna A, Ferrara R, Bucceri AM, Lanteri E, Catalano F: Influence of aging on gastrointestinal transit time. An ultrasonographic and radiologic study. Invest Radiol 1999; 34: 357–359. 38 Vantrappen G, Janssens J, Hellemans J, Ghoos Y: The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J Clin Invest 1977;59:1158–1166. 39 Husebye E, Engedal K: The patterns of motility are maintained in the human small intestine throughout the process of aging. Scand J Gastroenterol 1992;27:397–404. 40 O’Mahony D, O’Leary P, Quigley EM: Aging and intestinal motility: a review of factors that affect intestinal motility in the aged. Drugs Aging 2002;19:515–527. 41 Wade PR: Aging and neural control of the gastrointestinal tract. I. Age-related changes in the enteric nervous system. Am J Physiol 2002;283:G489–G495. 42 Kreel L, Sandin B: Changes in pancreatic morphology associated with aging. Gut 1973;14:962–970. 43 Glaser J, Hogemann B, Krummenerl T, Schneider M, Hultsch E, van Husen N, Gerlach U: Sonographic imaging of the pancreatic duct. New diagnostic possibilities using secretin stimulation. Dig Dis Sci 1987; 32: 1075–1081. 44 Anand BS, Vij JC, Mac HS, Chowdhury V, Kumar A: Effect of aging on the pancreatic ducts: a study based on endoscopic retrograde pancreatography. Gastrointest Endosc 1989;35:210–213. 45 Vellas BJ, Balas D, Lafont C, Senegas-Balas F, Albarede JL, Ribet A: Adaptive response of pancreatic and intestinal function to nutritional intake in the aged. J Am Geriatr Soc 1990;38:254–258. 46 Mohiuddin J, Katrak A, Junglee D, Green MF, Dandona P: Serum pancreatic enzymes in the elderly. Ann Clin Biochem 1984; 21: 102–104.

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47 Amman RW, Sulser H: Die senile chronische Pankreatitis: eine neue nosologische Einheit? Schweiz Med Wschr 1976; 106: 429– 437. 48 Laugier R, Sarles H: The pancreas; in James OFW (ed): Clinics in Gastroenterology. Philadelphia, Saunders, 1985, p 749. 49 Nagai H, Ohtsubo K: Pancreatic lithiasis in the aged. Its clinicopathology and pathogenesis. Gastroenterology 1984;86:331–338. 50 Nahon Uzan K, Levy P, O’Toole D, Belmatoug N, Vullierme MP, Couvelard A, Ponsot P, Palazzo L, Abbas A, Hammel P, Ruszniewski P: Is idiopathic chronic pancreatitis an autoimmune disease? Clin Gastroenterol Hepatol 2005;3:903–909. 51 Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Zhang L, Clain JE, Pearson RK, Petersen BT, Vege SS, Farnell MB: Diagnosis of autoimmune pancreatitis: the Mayo clinic experience. Clin Gastroenterol Hepatol 2006;4:1010–1016. 52 Baschetti R: Pancreatic insufficiency and weight loss in older patients. Q J Med 2004; 97:377–380. 53 Hardt PD, Hauenschild A, Nalop J, Marzeion AM, Jaeger C, Teichmann J, Bretzel RG, Hollenhorst M, Kloer HU: High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study screening fecal elastase-1 concentrations in 1,021 diabetic patients. Pancreatology 2003;3:395–402. 54 Rothenbacher D, Low M, Hardt PD, Klor HU, Ziegler H, Brenner H: Prevalence and determinants of exocrine pancreatic insufficiency among older adults: results of a population-based study. Scand J Gastroenterol 2005;40:697–704. 55 Fireman Z, Eliakim R, Adler S, Scapa E: Capsule endoscopy in real life: a four-centre experience of 160 consecutive patients in Israel. Eur J Gastroenterol Hepatol 2004; 16: 927– 931. 56 Teramoto Matsubara O, Zamarripa Dorsey F, Lopez Acosta ME: Capsule endoscopy: The evolution in the diagnosis of small bowel diseases (in Spanish). Rev Gastroenterol Mex 2005;70:138–142. 57 Biagi F, Rondonotti E, Campanella J, Villa F, Bianchi PI, Klersy C, De Franchis R, Corazza GR: Video capsule endoscopy and histology for small-bowel mucosa evaluation: a comparison performed by blinded observers. Clin Gastroenterol Hepatol 2006; 4: 998– 1003. 58 Fireman Z: The light from the beginning to the end of the tunnel. Gastroenterology 2004;126:914–916. 59 Fasano A, Berti I, Gerarduzzi T, Not T, Colletti RB, Drago S, Elitsur Y, Green PH, Guandalini S, Hill ID, Pietzak M, Ventura A, Thorpe M, Kryszak D, Fornaroli F, Wasserman SS, Murray JA, Horvath K: Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003; 163: 286–292.

60 Maki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti M, Karttunen T, Ilonen J, Laurila K, Dahlbom I, Hansson T, Hopfl P, Knip M: Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348: 2517–2524. 61 Gasbarrini G, Ciccocioppo R, De Vitis I, Corazza GR: Coeliac disease in the elderly. A multicentre Italian study. Gerontology 2001; 47:306–310. 62 Ravaglia G, Forti P, Maioli F, Volta U, Arnone G, Pantieri G, Talerico T, Muscari A, Zoli M: Increased prevalence of coeliac disease in autoimmune thyroiditis is restricted to aged patients. Exp Gerontol 2003;38:589– 595. 63 McIntyre AS, Long RG: Prospective survey of investigations in outpatients referred with iron deficiency anaemia. Gut 1993; 34:1102– 1107. 64 Pare P, Douville P, Caron D, Lagace R: Adult celiac sprue: changes in the pattern of clinical recognition. J Clin Gastroenterol 1988; 10:395–400. 65 Gillberg R, Dotevall G, Kastrup W, Lindstedt G, Mobacken H, Swolin B: Conventional malabsorption tests: do they detect the adult patient with villous atrophy? Scand J Clin Lab Invest 1984;44:91–98. 66 Logan RF, Rifkind EA, Busuttil A, Gilmour HM, Ferguson A: Prevalence and ‘incidence’ of celiac disease in Edinburgh and the Lothian region of Scotland. Gastroenterology 1986;90:334–342. 67 Swinson CM, Levi AJ: Is coeliac disease underdiagnosed? BMJ 1980;281:1258–1260. 68 Holmes GK, Stokes PL, Sorahan TM, Prior P, Waterhouse JA, Cooke WT: Coeliac disease, gluten-free diet, and malignancy. Gut 1976; 17:612–619. 69 Swinson CM, Slavin G, Coles EC, Booth CC: Coeliac disease and malignancy. Lancet 1983;1:111–115. 70 Robertson DA, Dixon MF, Scott BB, Simpson FG, Losowsky MS: Small intestinal ulceration: diagnostic difficulties in relation to coeliac disease. Gut 1983;24:565–574. 71 Matuchansky C, Colin R, Hemet J, Touchard G, Babin P, Eugene C, Bergue A, Zeitoun P, Barboteau MA: Cavitation of mesenteric lymph nodes, splenic atrophy, and a flat small intestinal mucosa. Report of six cases. Gastroenterology 1984;87:606–614. 72 Dawson DJ, Sciberras CM, Whitwell H: Coeliac disease presenting with intestinal pseudo-obstruction. Gut 1984; 25: 1003– 1008. 73 Kumar PJ, Walker-Smith J, Milla P, Harris G, Colyer J, Halliday R: The teenage coeliac: follow-up study of 102 patients. Arch Dis Child 1988;63:916–920.

Holt

Dig Dis 2007;25:151–159 DOI: 10.1159/000099480

Diverticular Disease in the Elderly Giuseppe Comparato a Alberto Pilotto b Angelo Franzè c Marilisa Franceschi a, b Francesco Di Mario a a

Chair of Gastroenterology, University of Parma, Parma, b Department of Geriatrics, Casa Sollievo della Sofferenza, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, and c Gastroenterology and Endoscopy Unit, Azienda Ospedaliera, Parma, Italy

Key Words Colonic diverticula, causes Diverticular disease, elderly Diverticulitis Diverticulitis, diagnosis Diverticular colitis, pathogenesis Diverticulosis, definitions and epidemiology

Surgery for acute complications of diverticular disease of the sigmoid colon carries significant rates of morbidity and mortality, the latter of which occurs predominantly in cases of severe comorbidity. Postoperative mortality and morbidity are to a large extent driven by patient-related factors. Copyright © 2007 S. Karger AG, Basel

Abstract There are few diseases whose incidence varies as greatly worldwide as that of diverticulosis. Its prevalence is largely age-dependent: the disease is uncommon in those under the age of 40, the prevalence of which is estimated at approximately 5%; this increases to 65% in those 665 years of age. Of patients with diverticula, 80–85% remain asymptomatic, while, for unknown reasons, only three-fourths of the remaining 15–20% of patients develop symptomatic diverticular disease. Traditional concepts regarding the causes of colonic diverticula include alterations in colonic wall resistance, disordered colonic motility and dietary fiber deficiency. Currently, inflammation has been proposed to play a role in diverticular disease. Goals of therapy in diverticular disease should include improvement of symptoms and prevention of recurrent attacks in symptomatic, uncomplicated diverticular disease, and prevention of the complications of disease such as diverticulitis. Diverticulitis is the most usual clinical complication of diverticular disease, affecting 10– 25% of patients with diverticula. Most patients admitted with acute diverticulitis respond to conservative treatment, but 15–30% require surgery. Predictive factors for severe diverticulitis are sex, obesity, immunodeficiency and old age.

© 2007 S. Karger AG, Basel 0257–2753/07/0252–0151$23.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ddi

Definitions and Epidemiology

Diverticulosis of the colon is an acquired condition that results from herniation of the mucosa through defects in the muscle layer [1]. There are few diseases whose incidence varies as greatly as that of diverticulosis [2]. The true prevalence of diverticulosis is difficult to define since most individuals are asymptomatic [3]. Diverticular disease is found commonly in developed countries. It is now widely accepted that chronic diverticular formation occurs in westernized societies due to a lack of fiber in the diet [4]. The prevalence is largely age-dependent, as it is uncommon in those under the age of 40, in whom the prevalence is estimated at approximately 5%; this increases to 65% in those 665 years of age (fig. 1) [5–7]. Of patients with diverticula, 80–85% remain asymptomatic, while, for unknown reasons, only three-fourths of the remaining 15–20% of patients develop symptomatic diverticular disease. These patients have some symptoms but no signs of inflammation [8]. The remaining one-fourth, or approximately 5% of all patients with diverticula, develops diverticulitis and a small number develop compli-

Prof. Francesco Di Mario Dipartimento di Scienze Cliniche, Sezione di Gastroenterologia Università degli Studi di Parma Via Gramsci 14, IT–43100 Parma (Italy) Tel. +39 0521 702 772, Fax +39 0521 291 582, E-Mail [email protected]

80 Women

Men

70 60 50 40 30 20 10 0

0–10

11–20

21–30

31–40

41–50

51–60

61–70

71–80

Fig. 1. Prevalence of diverticulosis for age according to age.

cations of diverticulitis such as abscess formation, fistulas, obstruction, or hemorrhage [9]. Diverticular disease should be classified as [10]: (1) symptomatic uncomplicated diverticular disease: single episode of non-specific symptoms, such as lower discomfort or abdominal pain, bloating, abdominal tenderness, constipation, diarrhea without any sign of inflammation (fever, neutrophilia, phlogosis of diverticula); (2) recurrent symptomatic uncomplicated diverticular disease: more than one attack per year of non-specific symptoms without signs of inflammation, or (3) complicated diverticular disease: abdominal symptoms associated with signs of inflammation.

Causes and Pathogenesis

Colonic diverticula typically form in parallel rows between the taeniae coli because of weakness of the muscle wall at sites of penetration of the vasa recta supplying the mucosa. In European and US populations, diverticula arise mainly in the distal colon, with 90% of patients having sigmoid colon involvement and only 15% having right-sided diverticula [7, 11–13]. Traditional concepts regarding the causes of colonic diverticula include alterations in colonic wall resistance, disordered colonic motility, and dietary deficiencies, especially of fibers [14, 15]. Presently, inflammation has been proposed to play a role in diverticular disease [16]. 152

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Pathological evidence shows that patients with symptomatic diverticular disease often exhibit microscopic inflammation of the mucosa close to diverticula [16]. Experienced colonoscopists sometimes encounter endoscopic findings of diverticular inflammation in patients without clinical evidence of acute diverticulitis. Endoscopic findings included erythema and edema of a diverticular opening, pus emanating from a diverticular orifice, and a polypoid mass of granulation tissue in a diverticular orifice [17]. Whether this inflammation is the actual focus of the diverticular disease remains unclear. In some cases, there may even be extensive inflammation, which is defined as diverticular colitis [18]. Most of these patients are over age 60 and present on endoscopic examination a segment of active inflammation in the sigmoid colon in an area of multiple diverticula causing hematochezia, altered bowel function, and abdominal pain. Endoscopy reveals areas of patchy mucosal hemorrhage granularity and exudate without gross ulceration adjacent to multiple diverticular orifices. Endoscopic biopsies confirm focal chronic active colitis without granulomas [19]. To date, the pathogenesis of diverticular colitis is unknown and its relation to the diverticula is unclear. Postulates include mucosal prolapse, relative ischemia, bacterial overgrowth, increased exposure to intraluminal toxins and antigens secondary to fecal stasis [19, 20]. Some of these factors are similar to those implicated in the pathogenesis of inflammatory bowel disease (IBD) Comparato /Pilotto /Franzè /Franceschi / Di Mario

and this colitis may be considered a ‘bridge’ disease between classic IBD and diverticulitis [21]. There is also evidence that diverticular disease may be based on a disorder of the enteral nervous system, which may, in turn, be caused by an inflammatory process.

Diagnosis

For years, barium enema was the standard investigation in diverticulosis patients, and although it provides information on the number and location of colonic diverticula, it cannot discern their clinical relevance. Inaccurate findings have been reported in nearly a third of patients with diverticulosis [22]. This disorder has, in the past, been regarded as a contraindication to colonoscopy for fear of causing a perforation [23, 24]. Further data and extensive clinical experience have shown that colonoscopy is safe in this population, although the diverticular colon can be difficult to examine because of spasm, luminal narrowing, and fixation.

Therapy

Goals of therapy in diverticular disease should be improvement of symptoms and prevention of recurrent attacks in symptomatic uncomplicated diverticular disease, and prevention of the complications of disease such as diverticulitis [16]. Up until now several therapies have been proposed, including: high-fiber diet and/or fiber supplementation; spasmolytics; probiotics; antibiotics, and mesalazine (5ASA). A significant inverse association has been reported between dietary fiber intake and risk of development of clinically evident diverticular disease. Insoluble fiber from fruits and vegetables was noted to be more protective than cereal fibers [25]. These results provide support for a recommendation that patients with asymptomatic diverticular disease might benefit from increasing their fruit and vegetable fiber intake. Several uncontrolled studies suggest that fiber supplementation benefits patients with symptomatic diverticular disease [25], but no large placebo-controlled trials have been performed. Nevertheless, a high-fiber diet, fiber supplementation, or both are generally recommended and are likely to do no harm. Similarly, no evidence supports the use of antispasmodic agents, despite the cramping and bloating often Diverticular Disease in the Elderly

associated with symptomatic diverticular disease [9]. The role of probiotics in the treatment of diverticular disease remains unclear. To date there is only one study that reports an improvement in symptoms in patients with non-complicated diverticular disease after treatment with Escherichia coli Nissle [26]. Rifaximin, a broad-spectrum, poorly absorbed antibiotic, and more recently, mesalazine, appear to be of some advantage in obtaining symptom relief in uncomplicated diverticular disease, and in reducing the incidence of the primary complications of this disease [27, 28]. The rationale for antibiotic therapy in these patients involves the role of intestinal microflora in determining symptoms by fiber degradation and gas production [29]. Mesalazine is widely and effectively used for the treatment of IBD. Inflammation seems to play an important pathogenic role in diverticulitis, diverticular disease-associated chronic colitis and symptomatic uncomplicated diverticular disease [18, 20, 30]. Inflammation in such diseases seems to be generated by a heightened production of proinflammatory cytokines, reduction in anti-inflammatory cytokines, and enhanced intramucosal synthesis of nitric oxide. The use of mesalazine in the treatment of such diseases is advisable based on its anti-inflammatory properties, as it can reduce mucosal hyperemia, edema, erosion and other inflammatory signs observed near and often well away from the diverticular orifices themselves [18– 20, 30]. Several studies showed promising results of mesalazine in the prevention and treatment of symptoms in symptomatic uncomplicated disease [31–34].

Complications

Diverticulitis Diverticulitis is the most usual clinical complication of diverticular disease, affecting 10–25% of patients with diverticula [7]. Diverticulitis is the result of a micro- or macroperforation of a diverticulum, due to erosion of the luminal wall by increased intraluminal pressure or thickened fecal material in the neck of diverticulum. Microperforations can be contained by pericolic fat and mesentery causing small pericolic abscesses. Macroperforations can result in an extensive abscess, which can continue around the bowel wall and form a large inflammatory mass or extend to other organs. Free perforation into the peritoneum causes peritonitis [8]. Diverticulitis is characterized by acute, constant or intermittent abdominal pain most often occurring in the Dig Dis 2007;25:151–159

153

Table 1. Diverticulitis and differential diagnosis

Differential diagnosis

Scenarios and diagnostic considerations

Acute appendicitis

Suspect if RLQ symptoms or non-resolution with medical therapy

Crohn’s disease

Suspect if aphthous ulcers, perianal involvement, or chronic diarrhea

Colonic carcinoma

Suspect if weight loss, bleeding. Diagnose with colonic evaluation after acute inflammation resolved

Ischemic colitis

Suspect if high-risk patient, bloody diarrhea, or thumbprinting. Diagnose with limited flexible sigmoidoscopy

Pseudomembranous colitis

Suspect with antibiotic use. Diagnose with stool toxin or limited flexible sigmoidoscopy

Complicated ulcer disease

Suspect if pneumoperitoneum or peritonitis, or with clinical history, NSAID use, or dyspepsia

Ovarian cyst, abscess, torsion

Suspect in female patient with unilateral pain. Diagnose with pelvic or transvaginal ultrasound

Ectopic pregnancy

Suspect in female patient of childbearing age. Diagnose with pregnancy test and ultrasound

left lower quadrant and is sometimes associated with a change in bowel habits. Hematochezia is rare, although anorexia, nausea and vomiting can arise. Fever and leukocytosis are generally present. Some patients may complain of dysuria and frequency that are induced by bladder irritation from the adjacent inflamed colon [8]. On physical examination, localized tenderness is generally found in the left lower quadrant and may be associated with guarding and rebound tenderness; bowel sounds are often decreased but may be normal early in the condition or increased in the presence of obstruction [15]. Several conditions should be excluded in its differential diagnosis (table 1). Elderly people with diverticulosis are also at risk for ischemic colitis. Features helpful in its differential diagnosis include the presence of thumbprinting on abdominal radiographs and hematochezia, both suggestive of ischemia. Clinical signs and symptoms are often sufficient to justify a clinical diagnosis; laboratory studies (the white blood cell count is usually elevated with predominance of polymorphonuclear cells) and imaging can be used to confirm diagnosis. Table 2 shows the imaging examinations commonly used to confirm diagnosis. CT with intravenous and oral contrast is the test of choice to confirm a suspected diagnosis of diverticulitis [35–38]. Criteria suggestive of diverticulitis include pericolic infiltration of fatty tissue, colonic wall thickening and abscess formation. 154

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Need for admission is the initial decision to be made in uncomplicated diverticulitis. The following parameters should be considered in making this decision [8, 15]: patient’s presentation; ability to tolerate oral intake; comorbidity, and adequate outpatient support. Based on these criteria, elderly patients have a high probability of needing hospital admission for adequate treatment. Figure 2a, b illustrates a decision-making flow chart for appropriate treatment. In patients with uncomplicated diverticulitis who are clinically stable and able to tolerate fluids, outpatient treatment with broad-spectrum antibiotics covering anaerobes and Gram-negative rods for 7–10 days (table 3) and a clear liquid diet is adequate. Patients should improve within 48–72 h, at which time solid foods may be introduced very cautiously [8, 15]. Close follow-up is considered very important: if the patient experiences increasing pain, fever or an inability to tolerate fluid intake, hospitalization is appropriate. Hospitalization is recommended if patients show signs of significant inflammation, are unable to take oral fluid, are 175 years of age, or have significant comorbidity: these characteristics are in fact present in most elderly. These patients need intravenous antibiotics (table 3) and should have clear liquids or nothing by mouth and intravenous liquid. Improvement of symptoms should be expected within 2–4 days, at which point a solid diet can be Comparato /Pilotto /Franzè /Franceschi / Di Mario

- No severe symptoms - Ability to tolerate oral intake - Adequate outpatient support - No significant comorbidity

Outpatients

Clear liquid diet Broad-spectrum oral antibiotics Close follow-up

a

Clinical improvement within 2–4 days

No clinical improvement within 2–4 days or increasing of fever, pain or no ability to tolerate oral intake

Diet can be slowly advanced and oral antibiotic therapy can be completed for 7–10 days

Hospital admission

- Severe symptoms - No ability to tolerate oral intake - No adequate outpatient support - Important comorbidity

Inpatients

Intravenous liquid Intravenous antibiotics Monitoring electrolytic balance

b

Clinical improvement within 2–4 days

No clinical improvement within 2–4 days

Diet can be slowly advanced and oral antibiotic therapy can be completed for 7–10 days

Surgical visit differential diagnosis and complications should be excluded

Fig. 2. Treatment of diverticulitis in outpatients (a)and inpatients (b).

slowly and carefully introduced. If improvement continues, patients may be discharged to complete a 7- to 10-day oral antibiotics course [8, 15]. Most patients admitted with acute diverticulitis respond to conservative treatment, but 15–30% require surgery [11, 39, 40]. For most patients who respond well to conservative treatment, an important clinical question

subsequently involves the likelihood of recurrence and the role of prophylactic surgical resection. The risk of recurrent symptoms after an attack of acute diverticulitis has been reported to be between 7 and 45%; a third of the patients is a reasonable approximation [11, 39, 40]. Recurrent attacks are less likely to respond to medical treatment and have a high mortality rate [39, 40], thus, most

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155

Table 2. Diagnostic modalities in diverticulitis

Table 3. Antibiotic treatment for patients with diverticulitis

CT

Outpatients Amoxicillin-clavulanate (Augmentin) Trimethoprim-sulfamethoxazole (Bactrim, Septra) and metronidazole (Flagyl) Fluoroquinolone and metronidazole

CT scanning has an increasing role in diagnosis, and should be regarded as the diagnostic procedure of choice. Abdominal and pelvic scanning is done with intravenous, oral, and rectal contrast. Criteria suggestive of diverticulitis include pericolic infiltration of fatty tissue, colonic wall thickening, and abscess formation. In many trials comparing CT with barium enema in suspected diverticulitis, sensitivities for CT of 93–98% and specificities of 75–100% have been consistently reported: results significantly more accurate than contrast enemas

Barium enema

Contrast enemas – once the diagnostic standard – are limited by the fact that diverticulitis is mainly an extraluminal process. If they are to be undertaken, water-soluble contrast material should be used and a low-pressure single-contrast study done. Findings deemed highly suggestive of diverticulitis include extravasated contrast material outlining an abscess cavity, intramural sinus tract, or fistula (fig. 2) [9, 46]. Absence of any diverticula should provoke reconsideration of the diagnosis. In retrospective analyses, contrast enema has been shown to have a sensitivity of 62–94%, with false-negative results in 2–15% [47, 48]

Colonscopy

Because of risk of perforation from either the device or air insufflation, endoscopy is generally avoided in initial assessment of the patient with acute diverticulitis. Its use should be restricted to situations in which diagnosis of diverticulitis is unclear. In such cases, limited sigmoidoscopy with minimum insufflation can be helpful to exclude other diagnoses, such as inflammatory, infectious, or ischemic colitis

Abdominal and chest radiographs

Chest and abdominal radiographs should generally be done in patients with clinically significant abdominal pain. A chest radiograph taken while the patient is upright can aid detection of pneumoperitoneum and help to assess cardiopulmonary status. Abdominal radiographs can show abnormal findings in 30–50% of patients which include small or large bowel dilation

authorities agree that elective resection is indicated after two attacks of uncomplicated diverticulitis [41–43]. The risk-benefit analysis of such an approach must be tailored with consideration of severity and responsiveness of the episode, general health of the patient, and risk of subsequent occurrence. Risk of resection is an evolving factor, with reports of increasingly favorable experiences with laparoscopic resections for diverticular disease [44–49]. This approach might reduce the threshold for resection 156

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Inpatients Metronidazole or clindamycin (Cleocin) plus Aminoglycoside (gentamicin [Garamycin] or tobramycin [Tobrex]) or Monobactam (aztreonam [Azactam]) or Third-generation cephalosporin (ceftriaxone [Rocephin], ceftazidime [Fortaz], cefotaxime [Claforan]) alternatively Second-generation cephalosporin (cefoxitin [Mefoxin], cefotetan [Cefotan]) ␤-Lactamase inhibitor combinations (ampicillin-sulbactam [Unasyn], ticarcillin-clavulanate [Timentin])

in some patients by lowering operative morbidity. However, some patients will still have symptoms after surgical resection. Surgery for acute complications of diverticular disease of the sigmoid colon carries a high morbidity rate and a substantial mortality rate. The majority of deceased patients have severe comorbidity. Postoperative mortality and morbidity are to a large extent driven by patientrelated factors [50]. Predictive factors of severity in diverticulitis are sex, obesity, immunodeficiency and age. Disease seems to be more virulent in people younger than 40 years old versus elderly patients: 66–88% of these necessitate urgent surgery during their initial attack with a high risk of recurrences of complications [11, 51–53]. For these reasons, and because of the low risk of an elective procedure in otherwise healthy young patients, resection generally is indicated after one well-documented episode of uncomplicated diverticulitis [39, 41]. Some authors do not agree with this strategy [54, 55]. Complications of diverticulitis include abscess, fistula, bowel obstruction and free perforation. These complications all require surgical consultation. Abscesses occur when the pericolic tissues fail to control the spread of the inflammatory process. Abscess formation should be suspected when fever, leukocytosis, or both persist despite an adequate trial of appropriate antibiotics. A tender mass may be palpable on physical examination. Right upComparato /Pilotto /Franzè /Franceschi / Di Mario

per quadrant pain or elevated transaminase levels may be evidence for a pyogenic liver abscess. CT-guided percutaneous drainage may be appropriate for small abscesses or while patients with sepsis are being stabilized for surgery [29, 54]. Peridiverticular abscesses can progress to form fistulas between the colon and surrounding structures in up to 10% of patients. Colovesical fistulas are the most common variety and require surgery for treatment. Fistulas involving the bladder are more common in men; in women, the uterus is interposed between the colon and the bladder. Intestinal obstruction is uncommon in diverticulitis, occurring in approximately 2% of patients. The small bowel is affected most often, and obstruction usually is caused by adhesions. The colon can become obstructed because of luminal narrowing caused by inflammation or compression by an abscess. Multiple attacks can lead to progressive fibrosis and stricture of the colonic wall. Obstruction is generally self-limiting and responds to conservative therapy. If persistent, obstruction of the colon can be treated by a variety of endoscopic and surgical techniques. Free perforation with peritonitis is rare, but it carries a mortality rate as high as 35% and requires urgent surgical consultation. If generalized peritonitis develops, the mortality rate is even higher. Perforation has been linked to non-steroidal anti-inflammatory drug (NSAID) use in case-control studies [56]. Glucocorticoids may increase this risk. Steroids also may mask symptoms and delay appropriate therapy. Because of this, NSAIDs and glucocorticoids should be used with caution in patients who have known diverticular disease. Mitchell and Shaheen [57] recently concluded that there is a protective association between calcium channel blockers and perforated colonic diverticular disease. Therefore, elderly patients with hypertension and diverticulosis should be preferably prescribed calcium channel blockers for antihypertensive therapy. Hemorrhage Significant lower gastrointestinal bleeding can be caused by diverticula, vascular ectasias, colitis, or neoplasms [58–60]. Diverticular sources have been reported to be the most typically identified cause, accounting for 1 40% of lower gastrointestinal bleeding episodes [61, 62]. Severe hemorrhage can arise in 3–5% of patients with diverticulosis [63, 64]. Despite the fact that most diverticula are in the left colon in subjects from developed Western countries, the site of bleeding may more often be located Diverticular Disease in the Elderly

in the proximal colon [63, 65–68]. Microangiography on resected specimens from patients with bleeding diverticula shows intimal thickening and medial thinning of the vasa recta as it courses over the dome of the diverticulum [65]. These changes arise asymmetrically towards the lumen and lead to segmental weakening of the artery, predisposing to rupture. Factors that initiate this arterial change are unknown, although inflammation does not seem to be a contributing factor. This finding confirms the clinical impression that bleeding rarely complicates diverticulitis. A recent study demonstrated that diverticular hemorrhage is associated with atherosclerosis and ageing: this might explain why diverticulosis is a frequent cause of bleeding in elderly vasculopathic patients. The association of use of NSAIDs with ulcer disease and upper gastrointestinal bleeding is well documented, but data have also implicated these drugs in diverticular bleeding. In a large prospective series of patients with lower gastrointestinal bleeding (of whom 50% were diverticular), a bleeding risk with NSAIDs was reported that was equal to that of duodenal ulcer [69]. In the Health Professionals Follow-Up Study [70], regular NSAID use was associated with an increased risk of diverticular bleeding. Whether patients with diverticulosis should be advised to avoid NSAIDs, as is done for ulcer patients, or use COX2-selective agents, is still not clear. Clinical presentation of diverticular hemorrhage is usually one of an abrupt painless onset. The patient can have mild lower abdominal cramps or the urge to defecate, followed by passage of voluminous red or maroon blood or clots. While melena can sometimes occur with a slowly bleeding right colon lesion, the arterial nature of diverticular bleeding makes this presentation uncommon. Presence of colonic diverticula should not be judged an adequate explanation for a positive fecal occult blood test or as a cause of iron deficiency anemia. Hemorrhage ceases spontaneously in 70–80% of patients, and rebleeding rates range from 22 to 38% [63, 64, 67]. The chance of a third bleeding episode can be as high as 50%, leading many doctors to recommend surgical resection after a second bleeding episode, similar to recommendations made for recurrent diverticulitis [41, 63]. The diagnosis and treatment of lower gastrointestinal bleeds require a coordinated approach. After fluid resuscitation, angiography, nuclear bleeding scans and colonoscopy may be useful in patients with ongoing bleeding. Surgery may be required for patients whose medical management is unsuccessful.

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20 Sheperd NA: Diverticular disease and chronic idiopathic inflammatory bowel disease: associations and masquerades. Gut 1996; 38: 801–802. 21 Tursi A: Mesalazine for diverticular disease of the colon – a new role for an old drug. Expert Opin Pharmacother 2005;6:69–74. 22 Boulos PB, Karamanolis DG, Salmon PR, Clark CG: Is colonoscopy necessary in diverticular disease? Lancet 1984;i:95–96. 23 Wolff W, Shinya H: Colonoscopy. N Engl J Med 1973;288:974–975. 24 Williams CB, Lane RH, Sakai Y: Colonoscopy: an air-pressure hazard. Lancet 1973;ii: 729. 25 Aldoori WH, Giovannucci EL, Rockett HR, Sampson L, Rimm EB, Willett WC: A prospective study of dietary fiber types and symptomatic diverticular disease in men. J Nutr 1998;128:714–719. 26 Fric P, Zavoral M: The effect of non-pathogenic Escherichia coli in symptomatic uncomplicated diverticular disease of the colon. Eur J Gastroenterol Hepatol 2003; 15: 313–315. 27 Papi C, Ciaco A, Koch M, et al: Efficacy of rifaximine in the treatment of symptomatic diverticular disease of the colon. A multicentre double-blind placebo-controlled trial. Aliment Pharmacol Ther 1995;9:33–39. 28 Latella G, Pimpo MT, Sottili S, et al: Rifaximin improves symptoms of acquired uncomplicated diverticular disease of the colon. Int J Colorectal Dis 2003; 18:55–62. 29 Stollmann NH, Raskin JB: Diagnosis and management of diverticular disease of the colon. Am J Gastroenterol 1999; 94: 3110– 3121. 30 Gore S, Sheperd NA, Wilkinson SP: Endoscopic crescentic fold disease of the sigmoid colon: the clinical and histopathological spectrum of a distinctive endoscopic appearance. Int J Colorect Dis 1992;7:76–81. 31 Trespi E, Colla C, Panizza P, Polino MG, Venturini A, Bottani G, De Vecchi P, Matti C: Ruolo terapeutico e profilattico della mesalazina (5-ASA) nella malattia diverticolare sintomatica del crasso. Minerva Gastroenterol Dietol 1999; 45:245–252. 32 Tursi A, Brandimarte G, Daffinà R: Longterm treatment with mesalazine and rifaximin vs. rifaximin alone for patients with recurrent attacks of acute diverticulitis of colon. Dig Liver Dis 2002;34:510–515. 33 Brandimarte G, Tursi A: Rifaximin plus mesalazine followed by mesalazine alone is highly effective in obtaining remission of symptomatic uncomplicated diverticular disease. Med Sci Monit 2004;10:P170–P173. 34 Di Mario F, Aragona G, Leandro G: Efficacy of mesalazine in the treatment of symptomatic diverticular disease. Dig Dis Sci 2005;50: 581–586.

35 Doringer E: Computerized tomography of colonic diverticulitis. Crit Rev Diagn Imaging 1992;33:421–435. 36 Hulnick DH, Megibow AJ, Balthazar EJ, Naidich DP, Bosniak MA: Computed tomography in the evaluation of diverticulitis. Radiology 1984;152:491–495. 37 Cho KC, Morehouse HT, Alterman DD, Thornhill BA: Sigmoid diverticulitis: diagnostic role of CT – comparison with barium enema studies. Radiology 1990; 176: 111– 115. 38 Ambrosetti P, Jenny A, Becker C, Terrier TF, Morel P: Acute left colonic diverticulitis: compared performance of computed tomography and water-soluble contrast enema: prospective evaluation of 420 patients. Dis Colon Rectum 2000;43:1363–1367. 39 Standards Task Force of the American Society of Colon and Rectal Surgeons: Practice parameters for sigmoid diverticulitis: supporting documentation. Dis Colon Rectum 1995;38:126–132. 40 Parks TG: Natural history of diverticular disease of the colon: a review of 521 cases. BMJ 1969;iv:639–642. 41 Stollman NH, Raskin JB: Diagnosis and management of diverticular disease of the colon in adults: ad hoc practice parameters committee of the American College of Gastroenterology. Am J Gastroenterol 1999; 94: 3110–3121. 42 Kohler L, Sauerland S, Neugebauer E: Diagnosis and treatment of diverticular disease: results of a consensus development conference. Surg Endosc 1999;13:430–436. 43 Wong WD, Wexner SD, Lowry A, et al: Practice parameters for the treatment of sigmoid diverticulitis: supporting documentation. Dis Colon Rectum 2000;43:290–297. 44 Franklin ME Jr, Dorman JP, Jacobs M, Plasencia G: Is laparoscopic surgery applicable to complicated colonic diverticular disease? Surg Endosc 1997; 11:1021–1025. 45 Smadja C, Sbai Idrissi M, Tahrat M, et al: Elective laparoscopic sigmoid colectomy for diverticulitis: results of a prospective study. Surg Endosc 1999;13:645–648. 46 Kockerling F, Schneider C, Reymond MA, et al: Laparoscopic resection of sigmoid diverticulitis: results of a multicenter study. Surg Endosc 1999;13:567–571. 47 Berthou JC, Charbonneau P: Elective laparoscopic management of sigmoid diverticulitis: results in a series of 110 patients. Surg Endosc 1999;13:457–460. 48 Stevenson A, Stitz R, Lumley J, Fielding G: Laparoscopically assisted anterior resection for diverticular disease: follow-up of 100 consecutive patients. Ann Surg 1998; 227: 335–342. 49 Lauro A, Alonso Poza A, Cirocchi R, et al: Laparoscopic surgery for colon diverticulitis. Minerva Chir 2002;57:1–5.

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50 Oomen JLT, Engel AF, et al: Mortality after acute surgery for complications of diverticular disease of the sigmoid colon is almost exclusively due to patient-related factors. Colorectal Dis 2006;8:112–119. 51 Konvolinka CW: Acute diverticulitis under age forty. Am J Surg 1994;167:562–565. 52 Freischlag J, Bennion RS, Thompson JE Jr: Complications of diverticular disease of the colon in young people. Dis Colon Rectum 1986;29:639–643. 53 Chautems RC, Ambrosetti P, Ludwig A, Mermillod B, Morel P, Soravia C: Long-term follow-up after first acute episode of sigmoid diverticulitis: is surgery mandatory? A prospective study of 118 patients. Dis Colon Rectum 2002;45:962–966. 54 Reisman Y, Ziv Y, Kravrovitc D, Negri M, Wolloch Y, Halevy A: Diverticulitis: the effect of age and location on the course of disease. Int J Colorectal Dis 1999;14:250–254. 55 Spivak H, Weinrauch S, Harvey JC, Surick B, Ferstenberg H, Friedman I: Acute colonic diverticulitis in the young. Dis Colon Rectum 1997;40:570–574. 56 Goh H, Bourne R: Non-steroidal anti-inflammatory drugs and perforated diverticular disease: a case-control study. Ann R Coll Surg Engl 2002;84:93–96.

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57 Mitchell KL, Shaheen NJ: Preventive therapy in perforated colonic diverticular disease? Calcium channel blockers may hold the key. Gastroenterology 2004;127:680–682. 58 Potter GD, Sellin JH: Lower gastrointestinal bleeding. Gastroenterol Clin North Am 1988;17:341–356. 59 Boley SJ, DiBiase A, Brandt LJ, Sammartano RJ: Lower intestinal bleeding in the elderly. Am J Surg 1979;137:57–64. 60 Gostout CJ, Wang KK, Ahlquist DA, et al: Acute gastrointestinal bleeding: experience of a specialized management team. J Clin Gastroenterol 1992;14:260–267. 61 Peura DA, Lanza FL, Gostout CJ, Foutch PG: The American College of Gastroenterology Bleeding Registry: preliminary findings. Am J Gastroenterol 1997;92:924–928. 62 Longstreth GF: Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage: a populationbased study. Am J Gastroenterol 1997; 92: 419–424. 63 McGuire HH Jr, Haynes BW Jr: Massive hemorrhage for diverticulosis of the colon: guidelines for therapy based on bleeding patterns observed in fifty cases. Ann Surg 1972; 175:847–855.

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64 Zuckerman GR, Prakash C: Acute lower intestinal bleeding. II. Etiology, therapy, and outcomes. Gastrointest Endosc 1999; 49: 228–238. 65 Meyers MA, Alonso DR, Gray GF, Baer JW: Pathogenesis of bleeding colonic diverticulosis. Gastroenterology 1976; 71:577–583. 66 Casarella WJ, Kanter IE, Seaman WB: Rightsided colonic diverticula as a cause of acute rectal hemorrhage. N Engl J Med 1972; 286: 450–453. 67 McGuire HH Jr: Bleeding colonic diverticula: a reappraisal of natural history and management. Ann Surg 1994;220:653–656. 68 Wong SK, Ho YH, Leong AP, Seow-Choen F: Clinical behavior of complicated right-sided and left-sided diverticulosis. Dis Colon Rectum 1997;40:344–348. 69 Wilcox CM, Alexander LN, Cotsonis GA, Clark WS: Non-steroidal anti-inflammatory drugs are associated with both upper and lower gastrointestinal bleeding. Dig Dis Sci 1997;42:990–997. 70 Aldoori WH, Giovannucci EL, Rimm EB, Wing AL, Willett WC: Use of acetaminophen and non-steroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men. Arch Fam Med 1998;7:255–260.

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Dig Dis 2007;25:160–165 DOI: 10.1159/000099481

Bowel Care in the Elderly G.C. Spinzi Department of Gastroenterology, Ospedale Valduce, Como, Italy

Key Words Constipation Fecal impaction Fecaloma Fecal incontinence Elderly, bowel care

Abstract Background: Intestinal complaints are a frequent health concern for elderly people and their care providers. Aims: To explore the distinction between constipation and the subjective complaints in elderly people and to review the diagnosis, causes and treatment of constipation, fecal impaction, and fecal incontinence. Methods: Review of studies that give information on prevalence, causes, symptoms, and treatment of bowel problems in the elderly, excluding uncontrolled clinical observations. Results: Self-reported constipation and laxative use increase with age and are more common among women, blacks and people of low socioeconomic level. The patient’s pharmacological history is fundamental, because medications are the cause of up to 40% of chronic constipation, and are often used inappropriately. The results of most laxative trials require cautious interpretation, but fiber and laxatives are more effective than placebo against constipation. Much additional research is needed to determine the most cost-effective method of treating intestinal complaints in the elderly. Conclusions: Bowel problems in older people have a considerable impact on the quality of life and have many contributory causes that are often amenable to treatment and management. Results of therapy can be good, leading to alleviation of suffering and the ability to lead a fuller life. Copyright © 2007 S. Karger AG, Basel

© 2007 S. Karger AG, Basel 0257–2753/07/0252–0160$23.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ddi

Elderly people frequently suffer from intestinal complaints, which can have a considerable impact on their quality of life [1]. Constipation is common, with a prevalence ranging from 2 to 28% in the elderly population [2]. The incidence rises to more than 80% among residents in homes for the old. Constipation is more common among women, blacks and people of a low socio-economic level. Intestinal disorders are not only frequent but involve significant morbidity, with a high cost; they are therefore a painful problem calling for prompt care and appropriate therapy [3].

Constipation

Patients and doctors tend to define constipation differently. A consensus definition, the Rome II criteria, is set out in table 1. Old patients complain mainly of difficulty in defecating, hard feces, and a feeling of incomplete evacuation [4]. Treatment should therefore aim to relieve these symptoms, not necessarily raising the frequency of bowel movements (BM) per week. We must first of all distinguish between acute and chronic constipation in the elderly patient. If the onset is recent, there may be some abdominal emergency, calling for thorough investigation to reach the correct diagnosis (detailed history, physical examination, rectal exploration, radiology, etc.). Chronic constipation may be primary or secondary. Some causes of secondary constipation are listed in table 2.

Giancarlo Spinzi Department of Gastroenterology, Ospedale Valduce Via Dante 11, IT–22100 Como (Italy) Tel. +39 031 324 363, Fax +39 031 308 047 E-Mail [email protected]

Table 1. Rome II criteria for defining chronic functional constipation in adults [data from 29]

Table 2. Causes of secondary constipation

Two or more of the following for at least 12 weeks in the preceding 12 months: • Straining in more than 25% of defecations • Lumpy or hard stools in more than 25% of defecations • Sensation of incomplete evacuation in more than 25% of defecations • Sensation of anorectal obstruction or blockade in more than 25% of defecations • Manual maneuvers to facilitate more than 25% of defecations • Fewer than 3 defecations per week

Endocrine and metabolic diseases Diabetes mellitus Hypercalcemia Hyperparathyroidism Hypothyroidism Uremia

The patient’s pharmacological history is fundamental, because medications are the cause of up to 40% of cases of chronic constipation, and are often used inappropriately [5]. Table 3 lists the main drugs that can cause constipation. Primary constipation can be classified under three headings: normal transit constipation, the most common form; slow-transit constipation, and anorectal dysfunction. Patients with slow-transit forms often complain of abdominal bloating and infrequent BM [6]; anorectal dysfunction can cause a sensation of incomplete evacuation, or of obstruction, or a need for digital manipulation [7]. The symptoms alone, however, are not enough to distinguish the different subtypes.

Diagnostic Evaluation

A detailed history and thorough physical examination are the basis for initial evaluation of a patient complaining of constipation. Rectal exploration is essential and should aim to assess the anal tone, presence of any masses, skin condition, rectal prolapse, state of the pelvic floor, and sacral dimple, which may suggest neurological problems. The AGA consensus guideline recommends: full blood counts, blood glucose, TSH, calcemia, creatininemia, sigmoidoscopy or colonoscopy in patients older than 50 with rectal bleeding or significant weight loss [8]. The utility of abdominal X-rays in the fasted patient is questioned. Radiopaque markers are the most widely used tool for measuring intestinal transit time, and are inexpensive and reproducible [9]. In patients with defecation disorders the markers localize in the rectal ampulla; in transBowel Care

[data from 12]

Myopathic conditions Amyloidosis Myotonic dystrophy Scleroderma Neurologic diseases Autonomic neuropathy Cerebrovascular disease Hirschsprung’s disease Multiple sclerosis Parkinson’s disease Multiple sclerosis Spinal cord injury, tumor disease Psychological conditions Anxiety Depression Somatization Structural abnormalities Anal fissures, strictures, hemorrhoids Colonic strictures Inflammatory bowel disease Obstructive colonic mass lesions Rectal prolapse or rectocele Other Irritable bowel syndrome Pregnancy Drugs

Table 3. Medications commonly associated

with secondary constipation [data from 30] Antacids containing aluminum or calcium Anticholinergics Antidepressants Antihistamines Calcium channel blockers Clonidine Diuretics Iron Levodopa Narcotics Non-steroidal anti-inflammatory drugs Opioids Psychotropics Sympathomimetics

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port disorders the number and distribution of the markers quantify the extent of the process. Diagnostic investigations should not be overdone in the elderly; sophisticated anorectal function tests are rarely necessary, and most patients respond to conservative therapy. There is no evidence-based data supporting routine use of blood chemistry tests, X-rays or endoscopy in the normal workup for patients with no alarming signs. Transit time, anorectal manometry and a balloon expulsion test show up physiological alterations in selected constipation cases, but no single test gives a full pathophysiological profile [10]. The question of the best diagnostic approach is further complicated by the poor standardization of some tests, and the fact that some patients are not collaborative; most of them will anyway enjoy some relief of symptoms with at least 6 months of medical therapy [8]. Once surgical and medical causes of constipation have been excluded, the focus must be on drugs, which cannot always be stopped. Chronic opioids, for instance, are sometimes unavoidable, so in such cases prophylactic laxatives are preferable. One study found fentanyl caused less constipation than oral morphine [11].

Non-Pharmacological Therapy

It may be useful for the patient to keep a diary, recording the frequency and consistency of their BM, and straining. Many patients are convinced they should have daily BM and often small changes in habits can improve their perception of bowel regularity [12].

take gradually – by about 5 g/week – so as to avoid gas and bloating, which can sometimes make this approach unacceptable [14]. More gas is produced with insoluble fibers, so soluble fibers like psyllium, ispaghula, or glucomannan are tolerated – and accepted – better.

Fluid Intake

It is usually believed that adequate fluid intake is important in avoiding constipation, though studies to date have not suggested that drinking more improves the frequency, consistency or facility of BM [15]. There is therefore no real evidence that constipation can be successfully treated by giving the patient more liquids, except in cases of overt dehydration.

Physical Exercise

Physical activity affects colonic motor function, the change being probably proportional to the intensity of the exercise. Population studies confirm that the incidence of constipation is lower among people with heavier physical activity, but it is not clear whether there is actually a causal relation. Prolonged inactivity, especially in the elderly, may slow colonic transit [16]. Modest physical activity is probably helpful in patients with mild constipation. Other factors, such as cognitive function, medications and diet are all equally important in the elderly.

Pharmacological Treatment Bowel Training

Defecation is to some extent a conditioned reflex. Patients should be encouraged to try and empty their bowels in the morning, when intestinal motor activity is strongest, or half an hour after meals, to take advantage of the gastrocolic reflex [13].

Fiber

Dietary fiber increases the bulk of the feces and the frequency of BM, besides shortening mean transit time. In Western countries, fiber intake may range from 5 to 10 g/day, compared with a recommended daily intake of 20–35 g. Patients should be told to increase their fiber in162

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Tramonte et al. [17], in a systematic review of the literature, found that fiber and laxatives were more effective than placebo against constipation. However, it is still not clear whether any particular group of laxatives is preferable to the others, because controlled randomized trials are still scarce, with limited numbers of patients in each single study, and frequent methodological flaws. Laxatives can be classified under several headings: bulk laxatives, stool softener or emollient laxatives, osmotics, and stimulants. Bulk laxatives include soluble products such as psyllium, pectin, and guar, and insoluble ones such as cellulose. They are hydrophilic, absorbing water from the intestinal lumen, thus increasing the mass of the feces and making them softer. Stool softeners include liquid paraffin and the docusates. The docusates lower surface tension so water enSpinzi

ters the bowel more easily. They are well tolerated, but less effective than fiber. They may be useful in patients with anal fissures or hemorrhoids that make defecation painful [12]. Mineral oils such as paraffin are not recommended on account of the risk of aspiration, which could lead to a foreign body reaction in the bronchial tract, and because they bind liposoluble vitamins (A, D, E, K) in the intestinal lumen, reducing their absorption.

Osmotic Laxatives

These hyperosmolar agents draw water into the intestinal lumen by osmosis. The most widely used are magnesium hydroxide or citrate, or sodium biphosphate. They are regarded as safe because they have no systemic effects, but can cause electrolyte imbalance, leading to hypokalemia, salt/water retention, and diarrhea. They must be employed with care in patients with cardiovascular failure or chronic renal insufficiency. The osmotic laxative heading also includes sorbitol, lactulose and polyethylene glycol (PEG). Lactulose is split into short-chain fatty acids by the intestinal flora, but may cause flatulence, worsening the patient’s symptoms. PEG is not metabolized by the intestinal flora, so it does not cause bloating, and its high molecular weight means it is poorly absorbed, does not interact with other medications, and does not give rise to tolerance [18]. The combination of PEG with electrolytes can therefore be a useful long-term solution, for instance for constipation in patients with Parkinson’s disease, multiple sclerosis, or taking drugs that cause constipation. Stimulant laxatives – senna or bisacodyl – increase intestinal motility and water secretion into the lumen, boosting peristalsis, but they may cause cramps. Contrary to widespread belief, these laxatives do not harm the colonic autonomic nervous system; they have no carcinogenic effect, do not give rise to tolerance or physical dependence, and are inexpensive.

Drug Administration (FDA). Tegaserod has been used in cases of irritable bowel with constipation. A recent systematic review [19] found that it raised the number of BM but without significantly relieving abdominal pain and discomfort. Further studies are needed in the elderly population. Lubiprostone is a bicyclic fat that activates chlorine channels, increasing fluid secretion; it has been approved by the FDA. It reduces straining and softens stool, while also increasing the number of BM. It is well tolerated, with no noteworthy side effects, but further investigations are still needed in the elderly. Suppositories and enemas (glycerin, bisacodyl, phosphate) still play a major role, especially for patients with difficulty in evacuation.

Toileting and Toilets

The elderly prefer using the toilet rather than a commode, but want the facilities to be clean, and expect a prompt response when they ask staff for help, so personnel must be motivated and trained to provide the necessary care [20]. We must therefore: (a) ensure dignity and privacy as far as possible; (b) control noise and odors, and (c) provide for assistance if requested. Toilets must be designed with several points in mind: (a) they must provide support for the upper body, with as little risk as possible of falls; (b) the seats should be padded to prevent decubitus ulcers; (c) they must be stable; (d) there must be enough space for cleansing the perineal area, and (e) they must be easy to maneuver.

Fecal Impaction

Metoclopramide is not useful and cisapride, which was widely used in the past though with questionable results, was withdrawn from the USA market in July 2000 on account of reports of cardiac arrhythmias. Colchicine and misprostol, which both speed up intestinal transit, have been approved for this indication by the Food and

Fecalomas are a frequent complication of constipation in the elderly. More than 40% of elderly patients in homes in Great Britain suffered from this problem, which paradoxically often manifests with diarrhea. The presence of hard feces, usually in the distal colon, causes pain, abdominal distension, obstruction, mental confusion, urinary incontinence, and stercoraceous ulcers. About 4% of operations for colonic perforation are for these ulcers, which are often only diagnosed post-mortem, because their clinical presentation is frequently insidious; mortality may even reach 50% [21]. Hard feces may sometimes build up in the proximal rectum, in which case rectal exploration finds no masses and abdominal X-ray may be useful.

Bowel Care

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Physiological tests in patients with fecalomas have not found anorectal dyssynergy, inappropriate contraction of the external anal sphincter or puborectal muscle [14]. These patients have increased rectal compliance and an abnormal sense of fullness in the rectum, which has to be more dilated for them to feel the need to defecate. The first step is to remove the fecaloma manually. Repeated enemas may be needed if the fecaloma is high in the rectum. Once it has been removed, measures must be taken to prevent it recurring. Glycerin suppositories may be useful, 30 min after meals, or PEG with electrolytes every 2–3 days [22].

Fecal Incontinence

This refers to accidental, unintentional loss of liquid or solid stool. The term anal incontinence also covers loss of gas. The prevalence is estimated at 2–7% in the elderly population, and more than 45% among those in institutions [23]. These are probably underestimates because so many people are unwilling to report the symptom, which obviously has devastating effects on a person’s relations with others, self-esteem and quality of life in general, besides the far-reaching economic repercussions. Questioning must bear this possibility in mind, therefore, in elderly people who only report diarrhea. Extreme urgency differs from incontinence, in that the patient senses the presence of feces in the rectum, but cannot contain them. Urgency is more typical of ulcerative proctitis or colitis and serious diarrheic diseases. Fecal continence relies on various factors: rectal compliance, anorectal sensation, sphincter function, normal muscle and nerve function in the pelvic floor. Equally important is the consistency and volume of the stool and the patient’s mental state, which is essential to convey the need to defecate. Changes in any of these factors can contribute to fecal incontinence [14]. There are numerous causes of incontinence. In the elderly the most likely are diabetic neuropathy, neurological diseases (dementia, stroke, etc.), abnormal rectal compliance because of ischemia, pelvic floor dysfunction, sphincter problems, fecalomas, or proctitis due to anal fissures, with rectal fibrosis. The diagnostic workup should start with a thorough history, detailed investigation of what medications the patient is taking, and careful rectal exploration. Neurological tests may be useful in many patients to assess their mental state, sacral reflexes and perineal sensation. Sig164

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moidoscopy or colonoscopy serve to check for inflammation. Further investigations such as anorectal manometry, defecography, electromyography, pudendal nerve function, or rectal ultrasound, should be restricted to the minority of elderly people in good physical and mental condition; history and careful objective examination are usually enough to form the diagnosis in 85% of cases [24]. Diarrhea and constipation are independent risk factors for fecal incontinence. Medical management is based on eliminating food or drugs that cause constipation or diarrhea, and prescribing antidiarrheic medication if no clear cause can be found [25]. Chassagne et al. [26] suggest that eliminating fecalomas is fundamental to improve continence in constipated institutionalized elderly people.

Antidiarrheic Drugs

The main aim is to correct the consistency because it is easier to control formed stool than liquid feces. Loperamide. This synthetic opioid has an excellent safety profile; it inhibits peristalsis, lengthens transit time, improves sphincter tone and resting pressure, and reduces urgency, stool volume and the frequency of BM. By increasing the contact time with the mucosa it permits greater absorption of water and electrolytes [27]. The drug does not pass the blood-brain barrier and does not cause dependence. A dose of 2–4 mg loperamide in the morning, and sometimes before meals, reduces the risk of incontinence. The main side effect is, of course, constipation which, however, is tolerated better than incontinence. Loperamide is more effective than diphenoxylate and salicylate of bismuth. It should not be used in patients with diarrhea associated with Clostridium difficile on account of the risk of toxic megacolon. Diphenoxylate. This opiate also inhibits intestinal motility. It can cross the blood-brain barrier and cause mild euphoria. Excessive use leads to constipation and in cases with intestinal inflammation there is the risk of toxic megacolon. Amitriptyline. This tricyclic antidepressant, with anticholinergic, serotoninergic and antimuscarinic properties, is employed in patients with idiopathic fecal incontinence. Further study is still needed, especially in the elderly, to confirm whether low-dose amitriptyline lowers anorectal pressure, as suggested by a fairly recent open-label trial [28].

Spinzi

Biofeedback

Regardless of the causes of incontinence, this approach may be useful in motivated patients [14] who can sense the rectal distension caused by a balloon, and voluntarily contract the external anal sphincter. Biofeedback is reportedly useful in 50–70% of cooperative patients, but to date there are few studies in the elderly.

Bowel care is an indicator of quality of care for elderly people who frequently suffer from intestinal complaints. Much current information is not evidence-based, and comes from observations or studies not conducted with the necessary rigor. The clinical implications of intestinal disorders are so far-reaching that we urgently need more information, in order to provide better treatment.

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