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#ONTENTS ,IST OF CONTRIBUTORS VII 0REFACE
IX
-ICHAEL 0 -ANNS AND +ATJA $ETERDING (EPATITIS IN THE CLINICS n 4REATMENT OPTIONS
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE $IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS 4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER #OMPARATIVE PATHOLOGY 3TEPHAN 5RBAN AND 5LRIKE 0ROTZER (EPATITIS " VIRUS ,ESSONS LEARNED FROM THE VIRUS LIFE CYCLE 2ALF "ARTENSCHLAGER 'ANG ,ONG AND $ARIUS -ORADPOUR #HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT -ANFRED ( 7OLFF AND !XEL 3CHMIDT (EPATITIS ! INFECTION !XEL 3CHMIDT AND -ANFRED ( 7OLFF (EPATITIS % INFECTION (ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON "ACTERIAL INFECTIONS OF THE LIVER !CHIM (ARDER AND (EINZ -EHLHORN #OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITES OR THEIR DISTINCT LIFE CYCLE STAGES 3TEFAN ,àTH AND !NSGAR 7 ,OHSE !UTOIMMUNE HEPATITIS IN HUMANS
VI
#ONTENTS
*AN 2OTHUIZEN (EPATITIS IN DOGS !NDY % $URHAM (EPATITIS IN HORSES "UD # 4ENNANT 7ILLIAM % (ORNBUCKLE AND *OHN , 'ERIN 4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION +AI $ALLMEIER AND -ICHAEL .ASSAL (EPADNAVIRUSES HAVE A NARROW HOST RANGE n DO THEY 0ERCY ! +NOLLE AND $IRK 3TABENOW 4HE LIVER AS IMMUNE ESCAPE SITE FOR PATHOGENS /LAF 7EBER $RUG CANDIDATES FOR THE TREATMENT OF VIRAL HEPATITIS )NDEX
,IST OF CONTRIBUTORS $ARRYN , !PPLETON $EPARTMENT FOR )NTERNAL -EDICINE 6IRGINIA #OMMON WEALTH 5NIVERSITY 2ICHMOND 6! 53! E MAIL DAPPLETON MCVH VCUEDU 2ALF "ARTENSCHLAGER $EPARTMENT OF -OLECULAR 6IROLOGY 5NIVERSITY OF (EI DELBERG )M .EUENHEIMER &ELD (EIDELBERG 'ERMANY E MAIL RALF?BARTENSCHLAGER MEDUNI HEIDELBERGDE +AI $ALLMEIER 5NIVERSITY (OSPITAL &REIBURG )NTERNAL -EDICINE )) -OLECU LAR "IOLOGY (UGSTETTER 3TR &REIBURG 'ERMANY E MAIL KAIDALLMEIER WEBDE +ATJA $ETERDING $EPARTMENT OF 'ASTROENTEROLOGY (EPATOLOGY AND %NDO CRINOLOGY (ANNOVER -EDICAL 3CHOOL #ARL .EUBERG 3TR (ANNO VER 'ERMANY E MAIL DETERDINGKATJA MH HANNOVERDE !NDY % $URHAM 4HE ,IPHOOK %QUINE (OSPITAL &OREST -ERE ,IPHOOK (AMPSHIRE '5 *' 5NITED +INGDOM E MAIL ANDY THELEHCOUK 0ETER 2 'ALLE *OHANNES 'UTENBERG 5NIVERSITËT -EDIZINISCHE +LINIK ,ANGENBECKSTRASSE -AINZ 'ERMANY E MAIL GALLE UNI MAINZDE *OHN , 'ERIN $EPARTMENT OF -OLECULAR 6IROLOGY AND )MMUNOLOGY 'EOR GETOWN 5NIVERSITY -EDICAL 3CHOOL 7ASHINGTON $# 53! !CHIM (ARDER "AYER (EALTH#ARE !' !NIMAL (EALTH 2$ 0ARASITICIDES !LFRED .OBEL 3TR -ONHEIM 'ERMANY E MAIL ACHIMHARDER BAYERHEALTHCARECOM 7ILLIAM % (ORNBUCKLE $EPARTMENT OF #LINICAL 3CIENCES .EW 9ORK 3TATE #OLLEGE OF 6ETERINARY -EDICINE #ORNELL 5NIVERSITY )THACA .9 53! 0ERCY ! +NOLLE )NSTITUTE OF -OLECULAR -EDICINE AND %XPERIMENTAL )MMU NOLOGY 5NIVERSITY (OSPITAL "ONN &RIEDRICH 7ILHELM 5NIVERSITY "ONN 3IGMUND &REUD 3TR "ONN 'ERMANY E MAIL PERCYKNOLLE UKBUNI BONNDE !NSGAR 7 ,OHSE ) $EPARTMENT OF -EDICINE 5NIVERSITY -EDICAL #ENTER (AMBURG %PPENDORF -ARTINISTR (AMBURG 'ERMANY E MAIL ALOHSE UKEUNI HAMBURGDE 'ANG ,ONG $EPARTMENT OF -OLECULAR 6IROLOGY 5NIVERSITY OF (EIDELBERG )M .EUENHEIMER &ELD (EIDELBERG 'ERMANY E MAIL GANG?LONG MEDUNI HEIDELBERGDE
VIII
,IST OF CONTRIBUTORS
4HOMAS ,ONGERICH )NSTITUTE OF 0ATHOLOGY 5NIVERSITY OF (EIDELBERG )M .EUENHEIMER &ELD (EIDELBERG 'ERMANY E MAIL THOMASLONGERICH MEDUNI HEIDELBERGDE 3TEFAN ,àTH ) $EPARTMENT OF -EDICINE 5NIVERSITY -EDICAL #ENTER (AM BURG %PPENDORF -ARTINISTR (AMBURG 'ERMANY E MAIL SLUETH UKEDE -ICHAEL 0 -ANNS $EPARTMENT OF 'ASTROENTEROLOGY (EPATOLOGY AND %NDO CRINOLOGY (ANNOVER -EDICAL 3CHOOL #ARL .EUBERG 3TR (ANNO VER 'ERMANY E MAIL MANNSMICHAEL MH HANNOVERDE (EINZ -EHLHORN $EPARTMENT OF 0ARASITOLOGY (EINRICH (EINE 5NIVERSITY $àSSELDORF 'ERMANY E MAIL MEHLHORN UNI DUESSELDORFDE $ARIUS -ORADPOUR $IVISION OF 'ASTROENTEROLOGY AND (EPATOLOGY #ENTRE (OSPITALIER 5NIVERSITAIRE 6AUDOIS 5NIVERSITY OF ,AUSANNE ,AUSANNE 3WITZERLAND E MAIL DARIUSMORADPOUR CHURCH -ICHAEL .ASSAL 5NIVERSITY (OSPITAL &REIBURG )NTERNAL -EDICINE ))-OLECU LAR "IOLOGY (UGSTETTER 3TR &REIBURG 'ERMANY E MAIL NASSAL UKLUNI FREIBURGDE 5LRIKE 0ROTZER )NSTITUTE OF 6IROLOGY 4ECHNICAL 5NIVERSITY -UNICH (ELM HOLTZ #ENTER -UNICH n .ATIONAL 2ESEARCH #ENTER FOR %NVIRONMENTAL (EALTH 4OGERSTR -àNCHEN 'ERMANY E MAIL PROTZER VIROLOGIETUMDE *AN 2OTHUIZEN $EPARTMENT OF #LINICAL 3CIENCES OF #OMPANION !NIMALS &ACULTY OF 6ETERINARY -EDICINE 5NIVERSITY 5TRECHT 9ALELAAN 4$ 5TRECHT 4HE .ETHERLANDS E MAIL JROTHUIZEN VETUUNL 0ETER 3CHIRMACHER )NSTITUTE OF 0ATHOLOGY 5NIVERSITY OF (EIDELBERG )M .EUENHEIMER &ELD (EIDELBERG 'ERMANY E MAIL PETERSCHIRMACHER MEDUNI HEIDELBERGDE !XEL 3CHMIDT 0RIVATE 5NIVERSITY OF 7ITTEN(ERDECKE &ACULTY OF -EDICINE !LFRED (ERRHAUSEN 3TR 7ITTEN 'ERMANY E MAIL AXEL T ONLINEDE -ARTIN & 3PRINZL *OHANNES 'UTENBERG 5NIVERSITËT -EDIZINISCHE +LINIK ,ANGENBECKSTRASSE -AINZ 'ERMANY E MAIL SPRINZL MEDKLINIKUNI MAINZDE $IRK 3TABENOW )NSTITUTE OF -OLECULAR -EDICINE AND %XPERIMENTAL )MMU NOLOGY 5NIVERSITY (OSPITAL "ONN &RIEDRICH 7ILHELM 5NIVERSITY "ONN 3IGMUND &REUD 3TR "ONN 'ERMANY E MAIL DIRKSTABENOW UKBUNI BONNDE "UD # 4ENNANT $EPARTMENT OF #LINICAL 3CIENCES .EW 9ORK 3TATE #OLLEGE OF 6ETERINARY -EDICINE #ORNELL 5NIVERSITY )THACA .9 53! E MAIL BCT CORNELLEDU 3TEPHAN 5RBAN $EPARTMENT OF -OLECULAR 6IROLOGY /TTO -EYERHOF :EN TRUM 5NIVERSITY OF (EIDELBERG )M .EUENHEIMER &ELD (EIDEL BERG 'ERMANY E MAIL STEPHANURBAN MEDUNI HEIDELBERGDE
,IST OF CONTRIBUTORS
IX
/LAF 7EBER "AYER !' ,EVERKUSEN 'ERMANY E MAIL OLAFWEBER BAYER AGDE (ILMAR 7ISPLINGHOFF )NSTITUTE FOR -EDICAL -ICROBIOLOGY )MMUNOLOGY AND (YGIENE 5NIVERSITY OF #OLOGNE 'OLDENFELS 3TR n #OLOGNE 'ERMANY E MAIL HWISPLINGHOFF UNI KOELNDE -ANFRED ( 7OLFF )NSTITUTE OF -ICROBIOLOGY AND 6IROLOGY 0RIVATE 5NIVER SITY OF 7ITTEN(ERDECKE 3TOCKUMER 3TRASSE 7ITTEN 'ERMANY E MAIL MHWOLFF UNI WHDE
0REFACE (EPATITIS IS AN INFLAMMATION OF THE LIVER TISSUE CAUSING HEPATOCELLULAR INJURY WHICH MAY HAVE DIFFERENT AETIOLOGIES )N HUMANS ACUTE AND CHRONIC HEPATITIS AND HEPATITIS RELATED DISEASES SUCH AS LIVER FAILURE LIVER CIRRHOSIS AND HEPA TOCELLULAR CARCINOMA ARE AMONG THE MOST IMPORTANT CAUSES FOR DISABILITIES AND DEATH 7HEREAS THE REACTION OF THE LIVER TISSUE IS RELATIVELY UNIFORM THE CAUSES FOR HEPATOCELLULAR INJURY ARE HETEROGENEOUS AND INCLUDE VIRUSES TOXINS RADIATION INJURY AND DRUGS BUT ALSO BACTERIA PARASITES AND AUTOIM MUNE REACTIONS )N THIS VOLUME OF "IRKHËUSER !DVANCES IN )NFECTIOUS $ISEASES WE REVIEW TODAYS KNOWLEDGE ABOUT HEPATITIS WITH EMPHASIS ON COMPARATIVE ASPECTS BETWEEN HEPATITIS IN HUMANS AND ANIMALS BUT ALSO BETWEEN DIFFERENT ETIO LOGICAL AGENTS 4HIS BOOK IS DEDICATED TO (EINZ 3CHALLER WHO DEDICATED MOST OF HIS LIFE AS A SCIENTIST TO THE UNDERSTANDING OF THE INTERACTION BETWEEN HEPATITIS " VIRUSES AND THEIR HOSTS (EINZ IS A PERSONALITY WHO MANAGED A DIFFICULT THING TO DO HE SUCCESSFUL LY CROSSED BARRIERS (E WORKED AS AN ENTHUSIASTIC SCIENTIST CROSSING CLASSICAL BARRIERS BETWEEN CHEMISTRY BIOLOGY AND MEDICINE (E GUIDED SCIENTISTS AND STUDENTS AND HELPED TO FORM NEW WAYS OF THINKING AND ORGANIZING ACADEMIC RESEARCH IN 'ERMANY ! REMARKABLE NUMBER OF HIS FELLOWS MADE OUTSTAND ING CARRIERS IN DIFFERENT SCIENTIFIC AREAS &URTHERMORE HE HAS IN SIGNIFICANT WAYS ENHANCED OUR UNDERSTANDING OF THE PATHOGENESIS OF HEPATITIS " VIRUS INFECTIONS HAS CONTRIBUTED TO THE DEVEL OPMENT OF THE CURRENT VACCINE HAS IMPROVED THE CARE OF PATIENTS INFECTED WITH THE VIRUS AND HAS TRAINED SOME OF THE MOST DISTINGUISHED MEMBERS OF THE CURRENT GENERATION OF HEPATOLOGISTS AND VIROLOGISTS "UT HE ALSO CROSSED BORDERS BY SEARCHING FOR APPLICATIONS OF HIS RESEARCH (E IS ONE OF THE FEW WHO IN ADDITION TO A SUCCESSFUL ACADEMIC CAREER HAVE SET THE STAGE FOR A COMMERCIAL SUCCESS STORY n (EINZ WAS A CO FOUNDER OF ONE OF THE FIRST COMPANIES DEDICATED TO BIOTECHNOLOGY "IOGEN )DEC 4HANKS TO HIS MAJOR INPUT AND INTERVENTION THE #ENTER FOR -OLECULAR "IOLOGY (EIDELBERG :-"( AS A BIOMEDICAL RESEARCH CENTER WITH WORLD WIDE REPUTATION WAS FOUNDED ,AST NOT LEAST (EINZ HAS USED THIS SUCCESS FOR A SUSTAINED SUPPORT OF BIOMEDICAL RESEARCH IN ACADEMICS WITH THE h#HICA AND (EINZ 3CHALLER 3TIFTUNGv
XII
0REFACE
(EINZS WORK HAS BEEN CATALYTIC FOR OUR UNDERSTANDING OF HEPATITIS " n ONE OF THE MOST PREVALENT FORMS OF CHRONIC HEPATITIS #ROSSING BORDERS n ARE THERE THAT MANY (ERE WE WOULD LIKE TO TAKE THE OPPORTUNITY TO THANK (EINZ FOR HIS DEDI CATION TO SCIENCE AND WISH HIM ALL THE BEST FOR THE YEARS TO COME *ANUARY
/LAF 7EBER 5LRIKE 0ROTZER
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
(EPATITIS IN THE CLINICS n 4REATMENT OPTIONS -ICHAEL 0 -ANNS AND +ATJA $ETERDING $EPARTMENT OF 'ASTROENTEROLOGY (EPATOLOGY AND %NDOCRINOLOGY (ANNOVER -EDICAL 3CHOOL #ARL .EUBERG 3TR (ANNOVER 'ERMANY
!BSTRACT (EPATITIS IS AN INFLAMMATION OF THE LIVER BASED ON DIFFERENT AETIOLOGIES #LINICIANS DIS TINGUISH ACUTE FROM CHRONIC HEPATITIS 0ATHOPHYSIOLOGICAL CHANGES LEAD TO DAMAGE AND HEPATOCELLULAR DEGENERATION 4HE CAUSES FOR HEPATOCELLULAR INJURY ARE HETEROGENEOUS SUCH AS VIRUSES TOXINS DRUGS AUTOIMMUNITY CRYPTOGENIC 4HE LATEST OFFICIAL CLASSIFICATION OF CHRONIC HEPATITIS BY THE )NTERNATIONAL !SSOCIATION THE 3TUDY OF THE ,IVER )!3, ;= IS STILL VALID AND IS BASED ON !ETIOLOGY )NFLAMMATORY ACTIVITY 'RADING &IBROSIS STAGE 3TAGING 4HIS CLASSIFICATION HAS BECOME VERY RELEVANT SINCE WE NOWADAYS NOT ONLY DIAGNOSE THE DIFFERENT LIVER DISEASES ACCORDING TO THEIR AETIOLOGY BUT ALSO HAVE DEVELOPED SPECIFIC TREAT MENTS THAT ARE TARGETING SPECIFIC AETIOLOGIES OF CHRONIC LIVER DISEASE /VERLAP SYNDROMES WITH PRIMARY BILIARY CIRRHOSIS AND PRIMARY SCLEROSING CHOLANGITIS AND GENETIC LIVER DISEASES ADD TO THE CLINICAL SPECTRUM OF THIS SYNDROME )N THIS CHAPTER WE WILL DESCRIBE THE DIFFERENT CAUSES OF HEPATITIS THEIR TREATMENT OPTIONS AND DIFFERENTIAL DIAGNOSIS
)NTRODUCTION (EPATITIS IS AN INFLAMMATION OF THE LIVER DUE TO VARIOUS REASONS 0ATHOPHYSIOLOGICAL CHANGES LEAD TO HEPATOCELLULAR DAMAGE #AUSES OF THIS HEPATOCELLULAR DEGENERATION ARE HETEROGENOUS SUCH AS TOXINS DRUGS VIRUSES AND AUTOIMMUNITY 4HE PATHOLOGIC CHANGES DUE TO DIFFERENT AETIOLOGIES SHARE SIMILARITIES THESE INCLUDE LOBULAR DISARRAY INFLAMMATION INVOLVING PORTAL TRACTS AND LOBULES AND HEPATOCELLULAR DEGENERATION IN THE FORM OF BALLOONING AND APOPTOSIS -ICROORGANISMS SUCH AS BACTERIA VIRUSES FUNGI OR PARASITES INDUCE THE SECRETION OF BIOLOGICALLY ACTIVE MOLECULES BY MAC ROPHAGES AFTER PENETRATING THE EPITHELIAL SURFACES OF THE BODY !CTIVATED MACROPHAGES SECRETE CYTOKINES WHICH ARE DEFINED AS PROTEINS RELEASED
-ICHAEL 0 -ANNS AND +ATJA $ETERDING
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BY CELLS THAT AFFECT THEIR BEHAVIOUR OR OTHER CELLS THAT BEAR RECEPTORS FOR THEM 4HE CYTOKINES AND CHEMOKINES INITIATE THE PROCESS KNOWN AS INFLAM MATION ,ATER INFLAMMATORY RESPONSES ALSO INVOLVE LYMPHOCYTES WHICH IN THE MEANWHILE HAVE BEEN ACTIVATED BY MICROBIAL ANTIGENS )NFECTION WITH MICROORGANISMS PHYSICAL OR CHEMICAL INJURY LEADS TO CELL DISINTEGRATION OR NECROSIS WHICH IS ASSOCIATED WITH THE RELEASE OF PROTEINS AND ENZYMES FROM THE INJURED CELLS 4HESE PATHOPHYSIOLOGIC CHANGES MAY NOT ONLY RESULT IN AN INCREASE OF TRANSAMINASES BUT ALSO IN LIVER DYSFUNCTION EG IMPAIRED BILIRUBIN METABOLISM OR COAGULATION FACTOR SYNTHESIS #HRONIC HEPATITIS IS A PROGRESSIVE DISEASE OF HETEROGENEOUS MULTIFACTORIAL AETIOLOGY DEFINED AS CONTINUOUS INFLAMMATION OF THE LIVER WITHOUT IMPROVEMENT FOR SIX MONTHS OR LONGER ;= 4ABS AND
)NFECTION 4HE MOST COMMON CAUSES FOR ACUTE AND CHRONIC HEPATITIS ARE VIRAL INFECTIONS &IVE VIRUSES HAVE BEEN IDENTIFIED THAT CAN PRIMARILY MANIFEST CLINICALLY AS ACUTE HEPATITIS HEPATITIS ! VIRUS (!6 HEPATITIS " VIRUS ("6 HEPATI TIS # VIRUS (#6 HEPATITIS $ VIRUS ($6 AND HEPATITIS % VIRUS (%6 7HILE (!6 AND (%6 ARE TRANSMITTED BY THE FAECAL ORAL ROUTE AND ARE OFTEN ASSOCIATED WITH ACUTE ICTERIC HEPATITIS THEY DO NOT LEAD TO CHRONIC INFECTION "Y CONTRAST (#6 ("6 AND ($6 ARE TRANSMITTED PARENTERALLY AND SEXU ALLY 4HEY ARE THE MOST COMMON CAUSE OF HUMAN VIRAL INFECTIONS LEADING TO CHRONIC HEPATITIS ;= ("6 (#6 AND ($6 INFECTIONS CAN LEAD TO VIRAL PERSISTENCE THAT MAY LEAD TO CHRONIC HEPATITIS CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (##
(EPATITIS IN THE CLINICS n 4REATMENT OPTIONS
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(EPATITIS VIRUSES
(EPATITIS ! (EPATITIS " (EPATITIS # (EPATITIS $ (EPATITIS %
0RIMARY NON HEPATOTROPIC VIRUS %PSTEIN "ARR VIRUS INFECTIONS #YTOMEGALOVIRUS (ERPES SIMPLEX VIRUS !UTOIMMUNE HEPATITIS $IFFERENTIAL DIAGNOSIS
!LCOHOL INDUCED LIVER DISEASE $RUG INDUCED LIVER DISEASE #HEMICAL INTOXICATION 0RIMARY BILIARY CIRRHOSIS 0RIMARY SCLEROSING CHOLANGITIS -ETABOLIC LIVER DISEASE 'ENETIC LIVER DISEASES
.ON ALCOHOLIC STEATOHEPATITIS .!3( (AEMOCHROMATOSIS !LPHA ANTITRYPSIN DEFICIENCY 7ILSON DISEASE
(EPATITIS ! (EPATITIS ! IS CONSIDERED THE MOST COMMON CAUSE OF ACUTE VIRAL HEPATITIS WITH SEROPREVALENCES FROM LESS THAN IN WESTERN %UROPEAN COUNTRIES AND UP TO IN DEVELOPING COUNTRIES ; = 4HE MAJOR FORM OF TRANSMISSION IS PERSON TO PERSON VIA THE FAECAL ORAL ROUTE 4HE INCUBATION PERIOD IS APPROXI MATELY n DAYS ;= 4HE ONSET OF SYMPTOMS IS ABRUPT WITH PRODROMAL SYMPTOMS SUCH AS FATIGUE WEAKNESS NAUSEA ABDOMINAL PAIN AND VOMITING ;= $IARRHOEA IS NOT TYPICAL FOR ADULTS BUT IS IN THE CASE OF CHILDREN WITH ACUTE HEPATITIS ! ;= ! FULMINANT COURSE OF HEPATITIS ! IS A RARE EVENT IN YOUNG PATIENTS HOWEVER MORTALITY DUE TO A FULMINANT COURSE INCREASES WITH AGE !PPROXIMATELY ONLY OF FULMINANT HEPATITIS CASES ARE DUE TO ACUTE HEPA TITIS ! IN THE 7ESTERN WORLD ;= 3UPPORTIVE MEASURES ARE THE ONLY TREATMENT FOR ACUTE (!6 INFECTION 0REVENTION OF (!6 INFECTION REQUIRES MAINTENANCE OF HIGH HYGIENIC STANDARDS AND STRATEGIES FOR ACTIVE IMMUNISATION #HRONIC HEPATITIS HAS NOT BEEN REPORTED TO DEVELOP AFTER HEPATITIS ! INFECTION
(EPATITIS " !CUTE HEPATITIS " VARIES FROM AN ASYMPTOMATIC INFECTION TO CHOLESTATIC HEPATITIS AND ACUTE LIVER FAILURE 4HERE IS NO ESTABLISHED TREATMENT FOR ACUTE ("6 INFECTION 3EVERE ACUTE HEPATITIS " IS NOW BEING TREATED WITH LAMIVU DINE WITHIN A 'ERMAN NATIONAL MULTICENTRE STUDY '!(!" SPONSORED BY "-"& $&' AND (EP .ET OUR .ATIONAL .ETWORK OF EXCELLENCE ON VIRAL
-ICHAEL 0 -ANNS AND +ATJA $ETERDING
HEPATITIS !CUTE HEPATITIS " RESOLVES IN MOST SYMPTOMATIC PATIENTS 2ARELY HOWEVER THE DISEASE TAKES A FULMINANT COURSE WITH A MORTALITY RATE OF ; = 4HE BEST WAY TO AVOID A ("6 INFECTION IS ACTIVE IMMUNISATION WITH A RECOMBINANT HEPATITIS " VACCINE 5SUALLY THE ACUTE HEPATITIS " IS SELF LIMIT ING BUT IN SOME CASES PARTICULARLY IN PATIENTS WITH AN ASYMPTOMATIC COURSE OF DISEASE HEPATITIS " DEVELOPS A CHRONIC COURSE 4HIS OCCURS IN n OF ADULTS WITH AN INTACT IMMUNE SYSTEM BUT IN MORE THAT OF ADULT PATIENTS WITH IMMUNODEFICIENCY STATES SUCH AS ()6 COINFECTION POST ORGAN TRANS PLANTATION AND FOLLOWING ANTITUMOUR CHEMOTHERAPY AS WELL AS NEONATES WITH A STILL UNDERDEVELOPED IMMUNE SYSTEM 0ATIENTS WITH A CHRONIC ("6 INFECTION AND LIVER CIRRHOSIS SHOULD RECEIVE ANTIVIRAL THERAPY IF THERE IS VIREMIA INDEPENDENT OF THE LEVEL OF VIRAL REP LICATION )N PATIENTS WITHOUT LIVER CIRRHOSIS VIREMIA INFLAMMATION FIBROSIS SCORE AND THE LEVEL OF TRANSAMINASES SHOULD BE TAKEN INTO CONSIDERATION WHEN CONSIDERING TREATMENT 4HE NEW 'ERMAN GUIDELINES FOR THE DIAG NOSIS AND TREATMENT OF HEPATITIS " ;= ARE A JOINED EFFORT OF (EP .ET THE 'ERMAN NATIONAL EXCELLENCE NETWORK ON VIRAL HEPATITIS THE 'ERMAN SOCIET IES FOR 'ASTROENTEROLOGY $'63 0ATHOLOGY $'0 6IROLOGY 'F6 AND 0EDIATRIC 'ASTROENTEROLOGY AND .UTRITION '0'% 4HE TREATMENT GOAL IN HEPATITIS " IS TO DECREASE ("6 REPLICATION IN ORDER TO DECREASE LIVER INFLAM MATION THEREBY PREVENTING THE PROGRESSION OF FIBROSIS AND THE DEVELOPMENT OF CIRRHOSIS AND ITS COMPLICATIONS INCLUDING (## ;= #URRENTLY )NTERFERON ALPHA NUCLEOTIDES AND NUCLEOSIDES ARE AVAILABLE FOR ANTIVIRAL THERAPY OF CHRONIC ("6 PATIENTS )N CONTRAST TO THE ORAL NUCLEOSIDE ANALOGUES INTER FERON HAS DIRECT IMMUNOMODULATORY PROPERTIES AND TREATMENT RESPONSE IS SUSTAINED IN A SIGNIFICANT PROPORTION OF PATIENTS 0EGYLATED INTERFERON ALPHA A HAS BEEN FOUND TO BE MORE EFFECTIVE THAN CONVENTIONAL INTERFERON IN THE TREATMENT OF ("6 INFECTION IN A 0HASE )) STUDY ;= ! NUMBER OF FACTORS ARE PREDICTIVE IN THE RESPONSE TO )NTERFERON ALPHA EG LOW SERUM ("6 $.! LEVELS HIGH SERUM ALANINE AMINOTRANSFERASE !,4 LEVELS AND CERTAIN ("6 GENOTYPES IN PARTICULAR GENOTYPE ! .UCLEOSIDE AND NUCLEOTIDE ANALOGUES HAVE A GOOD SAFETY RECORD AND SHOW LESS ADVERSE EFFECTS THAN INTERFERON (OWEVER THEY OFTEN LEAD TO DRUG RESISTANCE AND VIRAL REBOUND AFTER THE TERMINATION OF TREATMENT IS USUAL 4HEREFORE KNOWLEDGE OF THE PROS AND CONS OF THE VARIOUS TREATMENT OPTIONS NOWADAYS AVAILABLE IS IMPORTANT TO ALLOW THE BEST CHOICE OF TREATMENT FOR THE INDIVIDUAL PATIENT BASED ON AN INDIVIDUAL JUDGEMENT OF THE APPROPRIATE BENEFIT RISK RATIO ;= 4AB
(EPATITIS # 4HE RATE OF CHRONICITY IN PATIENTS WITH ACUTE HEPATITIS # IS n 0ATIENTS WITH ASYMPTOMATIC ACUTE HEPATITIS # ARE MORE LIKELY TO DEVELOP CHRONIC HEPATITIS 4HEREFORE THE MAIN AIM OF OPTIMAL PATIENT MANAGEMENT IN ACUTE
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4HE BIOCHEMICAL RESPONSE WAS VARIABLE DEFINED IN DIFFERENT STUDIES NORMALISATION OF TRANSAMINASES OR !,4 DECREASE %NTECAVIR OR 4ELBIVUDINE UPPER LIMIT OF NORMAL
)N LAMIVUDINE RESISTANT PATIENTS VIROLOGICAL BREAKTHROUGH DEVELOPED IN OF PATIENTS AFTER YEAR IN AFTER YEARS AND AFTER YEARS TREATED WITH %NTECAVIR 4REATMENT WAS STOPPED IN PATIENTS WITH A VIRAL REPLICATION = COPIESML AFTER TREATMENT WEEK ABOUT OF PATIENTS
HEPATITIS # PATIENTS LIES IN AVOIDING CHRONICITY AND SUBSEQUENTLY IN PRE VENTING CIRRHOSIS ASSOCIATED COMPLICATIONS &ULMINANT ACUTE HEPATITIS # IS ALMOST UNKNOWN IN THE 7ESTERN WORLD &ORTUNATELY IT HAS BEEN SHOWN THAT THE INITIATION OF INTERFERON MONOTHERAPY DURING THE ACUTE PHASE OF HEPATITIS # VIRUS INFECTION SIGNIFICANTLY REDUCES THE EVOLUTION OF CHRONIC HEPATITIS # ;= )MMEDIATE TREATMENT OF ACUTE (#6 INFECTION WITHIN n MONTHS AFTER INFECTION LED TO OF SUSTAINED VIROLOGICAL RESPONSE RATES BETWEEN n USING 0%' INTERFERON ALPHA B FOR MONTHS IN SUBSEQUENT TRIALS ;= !T PRESENT A NATIONWIDE (EP .ET STUDY COMPARES IMMEDIATE ANTIVIRAL TREATMENT OF 0%' INTERFERON ALPHA B MONOTHERAPY WITH A DELAYED START OF TREATMENT AFTER WEEKS WITH COMBINATION OF 0%' INTERFERON ALPHA B PLUS WEIGHT BASED DOSING OF RIBAVIRIN #HRONICITY IS ASSOCIATED WITH THE RISK OF DEVELOPING LIVER CIRRHOSIS AND SUBSEQUENTLY TO DEVELOP HEPATIC DECOMPEN SATION AND HEPATOCELLULAR CARCINOMA
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&IGURE $EVELOPMENT OF ANTIVIRAL TREATMENT IN CHRONIC HEPATITIS # IN THE RECENT YEARS -ODIFIED ACCORDING TO -ANNS ET AL ;=
7ORLDWIDE MORE THAN MILLION PEOPLE ARE CONSIDERED TO BE CHRONI CALLY INFECTED WITH THE HEPATITIS # (#6 VIRUS #OMBINATION THERAPY OF CHRONIC HEPATITIS # WITH PEGYLATED INTERFERON ALPHA PLUS RIBAVIRIN IS STILL THE STANDARD OF CARE SINCE ;= (OWEVER THIS TREATMENT IS ONLY SUCCESS FUL IN APPROXIMATELY HALF OF THE PATIENTS CHRONICALLY INFECTED WITH HEPATITIS # GENOTYPE 4HIS THERAPY CAN BE ASSOCIATED WITH SIGNIFICANT SIDE EFFECTS AND COSTS ;= 4HE STANDARD OF CARE FOR THE TREATMENT OF CHRONIC HEPATITIS # PATIENTS 0%' INTERFERON ALPHA PLUS RIBAVIRIN HAS BEEN OPTIMISED OVER THE RECENT YEARS AFTER WHICH LED TO FURTHER IMPROVEMENTS IN RESPONSE WITH SUSTAINED VIROLOGICAL RESPONSE RATES 362 UP TO FOR THE DIFFICULT TO TREAT GENOTYPES AND MORE THAT FOR THE SO CALLED EASY TO TREAT GENOTYPE AND PATIENTS ; n= &IG "OTH INTERFERON AND RIBAVI RIN INDUCE SIDE EFFECTS THAT HAVE TO BE CONSIDERED IN THE MANAGEMENT OF PATIENTS WITH CHRONIC HEPATITIS # 4HE INTERFERON RELATED SIDE EFFECTS CAN BE DIVIDED INTO INTERFERON INDUCED BONE MARROW DEPRESSION FLU LIKE SYMPTOMS NEUROPSYCHIATRIC DISORDERS AND AUTOIMMUNE SYNDROMES 4HE MAIN PROBLEM OF RIBAVIRIN IS HAEMOLYTIC ANAEMIA /VERALL SIDE EFFECTS RESULT IN n PREMATURE WITHDRAWALS FROM THERAPY AND AN ADDITIONAL n OF PATIENTS
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REQUIRE DOSE MODIFICATIONS ;= 4HE BIG UNMET NEED IN THE TREATMENT OF CHRONIC HEPATITIS # IS THE THERAPY OF NON RESPONDERS TO PREVIOUS 0%' INTERFERON AND RIBAVIRIN TREATMENT (ERE ONLY THE NEW SMALL DIRECT ANTIVIRAL DRUGS THE SO CALLED 34!4 # DRUGS WILL LEAD TO FURTHER IMPROVEMENTS ;=
(EPATITIS $ 4HE HEPATITIS DELTA VIRUS ($6 IS AN 2.! VIROID DEPENDENT FOR INFECTION ON OBLIGATORY HELPER FUNCTIONS PROVIDED BY THE ("6 IT THEREFORE CAN ONLY INFECT INDIVIDUALS WITH SIMULTANEOUS ("6 INFECTION !CUTE INFECTION WITH ($6 CAN BE SIMULTANEOUS WITH ACUTE ("6 INFECTION COINFECTION OR CAN OCCUR IN PATIENTS CHRONICALLY INFECTED WITH ("6 AS A SUPER INFECTION 7HILE SUPER INFECTION USUALLY IS ASSOCIATED WITH CHRONICITY AND A HIGHER RATE OF CIRRHOSIS DEVELOPMENT COMPARED TO MONOINFECTED PATIENTS ;n= ACUTE ("6($6 COINFECTION USUALLY LEADS TO SPONTANEOUS CLEARANCE AND CHRONICITY IS LESS THAN ! RECENT STUDY HAS SHOWN THAT 0%' INTERFERON ALPHA A DISPLAYS A SIGNIFICANT ANTIVIRAL EFFICACY IN MORE THAN OF ($6("6 COINFECTED PATIENTS ALONE OR IN COMBINATION WITH ADEFOVIR !DEFOVIR DOES NOT ALTER ($6 REPLICATION BUT MAY BE CONSIDERED FOR PATIENTS WITH HIGH ("6 LEV ELS #OMBINATION THERAPY OF 0%' INTERFERON ALPHA A PLUS ADEFOVIR HAS NO ADVANTAGES FOR ($6 2.! REDUCTION BUT IS SUPERIOR IN REDUCTION OF QUANTI TATIVE (BS!G LEVELS ;= ("S!G LOSS WAS ONLY SEEN IN THE GROUP OF PATIENTS TREATED WITH A COMBINATION OF 0%' INTERFERON ALPHA A PLUS ADEFOVIR
(EPATITIS % (EPATITIS % IS TRANSMITTED BY THE FAECAL ORAL ROUTE 4HE SYMPTOMS ARE UNSPE CIFIC AND SIMILAR TO HEPATITIS ! IE FLU LIKE SYMPTOMS INCLUDING FEVER ABDOM INAL PAIN ANOREXIA NAUSEA DIARRHOEA AND VOMITING ; = ,IKE OTHER FORMS OF ACUTE HEPATITIS THE MAINSTAY OF THERAPY IS IN MONITORING THE COMPLICATIONS AND IN TREATING THE SYMPTOMS 4HE (%6 INFECTION IS USUALLY SELF LIMITED (OWEVER FULMINANT HEPATITIS MAY OCCUR !CUTE HEPATITIS % IS ALMOST ABSENT IN THE DEVELOPED WORLD BUT IS THE MOST PREVALENT CAUSE OF ACUTE HEPATIC IN SOME PARTS OF THE DEVELOPING WORLD LIKE +ASHMIR PARTS OF )NDIA 4ASCHKENT AND AT THE HORN OF !FRICA LIKE PARTS OF %THIOPIA 3O FAR CHRONIC HEPATITIS HAS NOT BEEN REPORTED TO DEVELOP AFTER HEPATITIS % INFECTION
0RIMARY NON HEPATOTROPIC VIRUS INFECTIONS 3EVERAL OTHER VIRAL INFECTIONS MAY DAMAGE THE LIVER BUT ARE NOT PRIMARILY REGARDED AS HEPATOTROPIC 4HESE INFECTIONS INCLUDE %BSTEIN "ARR VIRUS CYTO MEGALOVIRUS AND HERPES SIMPLEX VIRUS 4AB
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!UTOIMMUNITY HEPATITIS !UTOIMMUNE HEPATITIS !)( IS ANOTHER ENTITY OF CHRONIC HEPATITIS !)( IS CHARACTERISED BY A LOSS OF TOLERANCE AGAINST HEPATIC TISSUE WHICH LEADS TO A CHRONIC MAINLY PERIPORTAL HEPATITIS AND DESTRUCTION OF HEPATIC PARENCHYMA !)( MAY ALSO START AS ACUTE HEPATITIS AND MAY EVEN MANIFEST AS FULMINANT HEPATITIS 4HE ESTIMATED PREVALENCE IN .ORTHERN %UROPE IS CASES PER MILLION ;= 4HERE IS NO SINGLE SENSITIVE AND SPECIFIC DIAGNOSTIC MARKER OF !)( $IAGNOSIS IS MADE FROM A COMBINATION OF CLINICAL BIOCHEMICAL SERO LOGICAL AND HISTOLOGICAL FEATURES ;= !)( IS MOST PREVALENT IN FEMALES AND IS OFTEN FOUND CLUSTERED IN FAMILIES 3EROLOGIC DETECTION OF AUTOANTIBODIES IS ONE OF THE DISTINGUISHING FEATURES ;= THAT HAS LEAD TO THE SUB CLASSIFICA TION OF !)( IN THREE GROUPS !)( TYPE IS CHARACTERISED BY THE PRESENCE OF ANTINUCLEAR ANTIBODIES !.! ANDOR ANTI SMOOTH MUSCLE ANTIBODIES 3-! DIRECTED PREDOMINANTLY AGAINST SMOOTH MUSCLE ACTIN !)( TYPE IS CHARACTERISED BY ANTI LIVER KIDNEY MICROSOMAL AUTOANTIBODIES ,+- DIRECTED AGAINST CYTOCHROME 0 #90 $ AND WITH LOWER FREQUENCY AGAINST 5$0 GLUCURONOSYLTRANSFERASES 5'4 ; = !)( TYPE IS CHAR ACTERISED BY AUTOANTIBODIES AGAINST SOLUBLE LIVER ANTIGENS 3,!,0 ; = 3EROPOSITIVITY IN FLUORESCENCE TESTS IS CONSIDERED AT TITRES GREATER THAN ;= 4HE CLINICAL PRESENTATION RANGES FROM A SPECTRUM OF BENIGN ASYMPTOM ATIC DISEASE TO FULMINANT HEPATITIS ; = )N HALF OF THE PATIENTS THE ONSET IS INSIDIOUS AND HALF SHOW FEATURES OF CHRONIC LIVER DISEASE !)( IS THEREFORE CHARACTERISED BY NON SPECIFIC FEATURES SUCH AS RIGHT UPPER ABDOMINAL PAIN FATIGUE ARTHRALGIAS MYALGIA JAUNDICE AND PRURITUS !BOUT OF PATIENTS SHOW AN ACUTE ONSET OF !)( AND RARE CASES OF FULMINANT PROGRESSION OF !)( LEADING TO ACUTE LIVER FAILURE HAVE ALSO BEEN REPORTED ;= .EXT TO THE AUTOANTIBODIES THE DIAGNOSIS OF !)( IS ESTABLISHED BY THE EXCLUSION OF OTHER AETIOLOGIES OF CHRONIC HEPATITIS 4HE LIVER HISTOLOGY IN !)( IS CHARACTERISED BY THE PRESENCE OF INTERFACE HEPATITIS IN WHICH SEVERAL MONONUCLEAR CELLS INFILTRATE THE PORTAL TRACT INVADE THE ADJACENT LIVER PARENCHYMA AND SURROUND DYING HEPATOCYTES ;= 3TUDIES HAVE SHOWN THAT UNTREATED !)( HAD A VERY POOR PROGNOSIS WITH n YEAR SURVIVAL RATES OF AND AND FURTHERMORE DEMONSTRATED THAT IMMUNOSUPPRESSIVE TREATMENT SIGNIFICANTLY IMPROVED SURVIVAL ; = 4HE GOAL OF TREATMENT IS A COMPLETE BIOCHEMICAL AND HISTOLOGICAL RESOLUTION OF INFLAMMATION AS WELL AS CLINICAL REMISSION OF SYMPTOMS 4HE STANDARD TREAT MENT OF !)( IS EITHER PREDNISOLONE MONOTHERAPY OR COMBINATION THERAPY WITH PREDNISOLONE AND AZATHIOPRINE #OMBINATION THERAPY IS PREFERRED ON THE WHOLE BECAUSE IT ALLOWS THE REDUCTION OF PREDNISOLONE AND THEREBY THE REDUCTION OF STEROID ASSOCIATED SIDE EFFECTS /VERLAP SYNDROMES OF !)( AND 0"# AND OF !)( AND 03# BOTH APPEAR TO BE PRESENT IN ABOUT OF !)( PATIENTS ; = /VERLAP SYNDROMES ARE CONDITIONS IN WHICH PATIENTS HAVE CLINICAL HISTOLOGICAL AND ALSO IMMUNOLOGI
(EPATITIS IN THE CLINICS n 4REATMENT OPTIONS
CAL FEATURES OF BOTH DISEASES n !)( AND PRIMARY BILIARY CIRRHOSIS 0"# OR !)( AND PRIMARY SCLEROSING CHOLANGITIS 03#
$IFFERENTIAL DIAGNOSIS !LCOHOL INDUCED LIVER DISEASE !LCOHOL INDUCED LIVER DISEASE MAY BE DISTINGUISHED INTO FATTY LIVER STEATO SIS ALCOHOLIC STEATOHEPATITIS !3( AND ALCOHOL INDUCED LIVER CIRRHOSIS !LCOHOLIC STEATOHEPATITIS WHICH IS MAINLY SEEN IN MIDDLE AGED WOMEN MAY PRESENT CLINICALLY AS A SEVERE SUBACUTE DISEASE WITH AN UNFAVOURABLE PROGNOSIS NO SCIENTIFICALLY PROVEN TREATMENT OPTIONS HIGH MORTALITY AND DISAPPOINTING RESULTS SO FAR AFTER LIVER TRANSPLANTATION )N LIVER CIRRHOSIS WAS THE TH LEADING CAUSE OF DEATH IN THE 53! AND OF THE CASES WERE ALCOHOL RELATED ;= )T IS ASSUMED THAT A CERTAIN THRESHOLD OF THE AMOUNT OF DAILY CONSUMED ALCOHOL AND THE LENGTH OF TIME HAS TO BE EXCEEDED FOR DEVELOPMENT OF ALCOHOLIC LIVER DISEASE 4HIS HAS BEEN PROPOSED AS BEING A DAILY INTAKE OF ALCOHOL OVER n YEARS OF DOSES IN EXCESS OF n GDAY FOR MALES AND n GDAY FOR FEMALES ;= 3TUDIES HAVE BEEN PERFORMED IN ORDER TO EXPLAIN THE BIOCHEMICAL AND HISTOLOGICAL FEATURES OF ACUTE ALCO HOLIC LIVER DISEASE )T HAS BEEN ASSUMED THAT THE METABOLISM OF ALCOHOL MAY RESULT IN THE GENERATION OF FATTY LIVER OXIDATIVE STRESS AND ACETALDEHYDE ALL OF WHICH ARE THOUGHT TO BE IMPORTANT IN DISEASE PATHOGENESIS )N SOME IF NOT THE MAJORITY OF PATIENTS IMMUNE MECHANISMS SEEM TO CONTRIBUTE TO PATHO GENESIS ,IVER FIBROSIS AND ULTIMATELY CIRRHOSIS IS THE FINAL COMMON PATH WAY OF ALCOHOLIC LIVER DISEASE #IRRHOSIS ITSELF IS A PRECANCEROUS CONDITION #HRONIC ALCOHOL ABUSE PRODUCES A WIDE RANGE OF MORPHOLOGICAL CHANGES IN THE LIVER THE MOST FREQUENT BEING FATTY LIVER STEATOSIS ALCOHOLIC HEPATITIS AND CIRRHOSIS ;= 0ATIENTS WITH CIRRHOSIS MAY DEVELOP ASCITES SPLENOMEGALY ICTERUS PRU RITUS HEPATO ENCEPHALOPATHY OR EVEN HEPATORENAL SYNDROME #UTANEOUS MANIFESTATIONS OF ALCOHOL LIVER DISEASE INCLUDE $UPYTRENS CONTRACTURE ALCOHOL CAUSES FLUSHING TELEANGIECTASES AND PALMAR ERYTHEMA !LSO PERIPH ERAL NEUROPATHY AND CEREBELLAR ATAXIA CAN BE ASSOCIATED WITH ALCOHOLIC LIVER DISEASE 0ATIENTS MAY ALSO SHOW SIGNS OF FEMINISATION WITH HYPOGONADISM AND GYNECOMASTIA 4HE OUTCOME OF PATIENTS WITH CIRRHOSIS IS DICTATED BY THE DEVELOPMENT OF COMPLICATIONS OF PORTAL HYPERTENSION SUCH AS VARICEAL BLEEDING AND ASCITES THE ONSET OF HEPATIC ENCEPHALOPATHY AND HEPATOCEL LULAR CARCINOMA 0HARMACOTHERAPY AND TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNTS 4)03 ARE IMPORTANT IN THE PREVENTION OF VARICEAL BLEEDING .ON SELEC TIVE BETA BLOCKERS REDUCE PORTAL PRESSURE THROUGH A REDUCTION IN PORTAL AND COLLATERAL BLOOD FLOW 0ROPANOLOL IS THE MOST COMMON NON SELECTIVE BETA BLOCKER MOST WIDELY USED IN THE PHARMACOLOGICAL TREATMENT OF PORTAL
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HYPERTENSION 3TUDIES SHOWED THAT WITH THE USE OF ` BLOCKERS THERE WAS A SIGNIFICANT REDUCTION IN THE RISK OF BLEEDING OF ABOUT COMPARED TO UNTREATED CONTROLS OR PATIENTS RECEIVING A PLACEBO ;= 4HERE ARE SEVERAL CONTRAINDICATIONS IN THE USE OF ` BLOCKERS INCLUDING BRADYCARDIA HYPOTEN SION AND SEVERE ASTHMA BRONCHIALE 0ATIENTS WITH HIGH RISK VARICES AND CONTRAINDICATIONS TO ` BLOCKERS MAY BE CONSIDERED FOR OESOPHAGEAL BAND LIGATION /ESOPHAGEAL BAND LIGATION HAS REPLACED SCLEROTHERAPY AS THE PREFERRED FORM OF MANAGEMENT OF OESOPHA GEAL VARICES TODAY 4REATMENT OPTIONS FOR THE MANAGEMENT OF ACUTE BLEEDING OESOPHAGEAL VARICES ARE FOR EXAMPLE OCTREOTIDESOMATOSTATIN VASOPRESSINNITRATES TER LIPRESSIN ENDOSCOPIC THERAPY SCLEROTHERAPYBANDING BALLON TAMPONADE 4)03 AND SURGICAL PROCEDURES LIKE PORTO CAVAL SHUNTING ;= 4HE DEVELOPMENT OF ASCITES IS A MAJOR COMPLICATION OF CIRRHOSIS AND IS ASSOCIATED WITH A DECREASED QUALITY OF LIFE AND AN INCREASED RISK FOR INFEC TIONS AND RENAL FAILURE !MONG PATIENTS WITH COMPENSATED LIVER CIRRHOSIS NEARLY n OF PATIENTS WILL DEVELOP ASCITES IN THE NATURAL COURSE OF THEIR DISEASE ;= 4HERAPIES FOR ASCITES INCLUDE SODIUM RESTRICTION DIURETICS LARGE VOLUME PARACENTESIS THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT 4)03 AND THE PERITONEOVENOUS SHUNT THE LATTER BEING ONLY RARELY APPLIED THESE DAYS 3PONTANEOUS BACTERIAL PERITONITIS IS A COMPLICATION RELATED TO ASCITES WITH A HIGH MORTALITY RATE )MMEDIATE DIAGNOSIS AND EARLY THERAPY WITH ANTIBIOTICS IS ESSENTIAL (EPATIC ENCEPHALOPATHY CAN BE DEFINED AS A SPECTRUM OF NEUROPSYCHIAT RIC ABNORMALITIES OCCURRING IN PATIENTS WITH ADVANCED LIVER DISEASE 0ATIENTS OFTEN PRESENT CHANGES IN BEHAVIOUR INCLUDING SOMNOLENCE AND CONFUSION 4HERAPY OF HEPATIC ENCEPHALOPATHY IS BASED ON PREVENTION OF PRODUCTION AND RESORPTION OF AMMONIA !LL THE DESCRIBED COMPLICATIONS OF LIVER CIRRHOSIS ARE COMMON TO ALL FORMS OF LIVER CIRRHOSIS INDEPENDENT OF AETIOLOGY THEREFORE THEY ARE ALSO CONSEQUENCES OF CHRONIC HEPATITIS VIRUS INFECTIONS &URTHERMORE INCREASED ALCOHOL CONSUMPTION IS OFTEN AN IMPORTANT COFAC TOR OF MORBIDITY IN OTHER CAUSES OF CHRONIC LIVER DISEASE IN PARTICULAR CHRONIC HEPATITIS # AND ITS CONSEQUENCES
$RUG INDUCED LIVER DISEASE (EPATOTOXICITY IS THE MOST FREQUENT CAUSE OF DRUG INDUCED MORTALITY 4OXICITY MAY BE MAINLY DOSE DEPENDENT AND PREDICTABLE -ANY ENVIRONMEN TAL HEPATOTOXINS INCLUDING HALOGENATED MOLECULES AND TOXIC MUSHROOMS CAN LEAD TO LIVER FAILURE %XCEPT IN THE CASE OF ACETAMINOPHEN PARACETAMOL WHICH INDUCES INTRINSIC HEPATOTOXCITY MOST CASES OF DRUG INDUCED LIVER DISEASE ARE ASSOCIATED WITH SUICIDE OR INCORRECT DRUG ADMINISTRATION $RUGS ASSOCIATED WITH HEPATOTOXICITY ARE FOR EXAMPLE ANTICONVULSANTS NEUROLOGIC
(EPATITIS IN THE CLINICS n 4REATMENT OPTIONS
AGENTS ANTIMICROBIAL AGENTS ANTINEOPLASTIC AND IMMUNOSUPPRESSIVE AGENTS 4HE PROGNOSIS IS GENERALLY GOOD IF THE DRUG IS STOPPED AT THE FIRST SYMPTOM OR SIGN OF LIVER DISEASE !S MENTIONED PREVIOUSLY ACETAMINOPHEN INDUCES INTRINSIC HEPATOTOXIC ITY 4HE CLINICAL PRESENTATION OF ACUTE LIVER FAILURE DUE TO ACETAMINOPHEN INCLUDES A HYPERACUTE PROGRESSION FROM JAUNDICE TO HEPATIC ENCEPHALOPATHY ;= (EPATIC TRANSAMINASES RISE WITHIN n H WHERE AS PEAK TRANSAMI NASES AND PROTHROMBIN TIMES USUALLY OBSERVED DAYS AFTER INVESTIGATION (OWEVER PROGNOSIS OF ACETAMINOPHEN INDUCED FULMINANT HEPATIC FAILURE HAS A MORE FAVOURABLE OUTCOME COMPARED TO OTHER CAUSES OF DRUG INDUCED LIVER DISEASE )N CHRONIC LIVER DISEASE OF UNKNOWN AETIOLOGY SO CALLED CRYPTOGENIC LIVER DISEASE DRUG INDUCED LIVER INJURY HAS ALWAYS TO BE CONSIDERED AS A CAUSE $IAGNOSIS OFTEN RELIES ON THE TERMINATION OF DRUG ADMINISTRATION AND SUB SEQUENT FOLLOW UP /NLY AFTER CAREFUL EVALUATION OF THE BENEFIT RISK RATIO A RE EXPOSURE WITH THE SUSPECTED DRUG MAY BE USED TO PROVE OR DISPROVE THE DIAGNOSIS OF A DRUG INDUCED LIVER DISEASE )N A MINORITY OF CASES WITH CHRONIC LIVER DISEASE AND A DRUG INDUCED AETIOLOGY THE DISEASE IS IMMUNE MEDIATED 4HEN SPECIFIC AUTOANTIBODIES MAY BE DETECTABLE AND MAY INDICATE AETIOLOGY AND PATHOGENETIC MECHANISMS
#HEMICAL INTOXICATION )T IS DIFFICULT TO MAKE A DEFINITIVE STATEMENT ABOUT HEPATOTOXICITY OF SPECIFIC CHEMICALS AND ENVIRONMENTAL AGENTS BECAUSE THE EFFECTS MAY BE EXTREMELY DIVERSE (EPATOTOXIC CHEMICALS ARE FOR EXAMPLE HALOGENATED AROMATIC HYDROCARBONS NITROAROMATIC COMPOUNDS CHLORINATED ETHYLENES AND PESTI CIDES !LSO METALS LIKE ARSENIC BERYLLIUM AND COPPER CAN LEAD TO CHRONIC LIVER DISEASE !LTHOUGH CHEMICALS ARE OFTEN ACCUSED OF CAUSING CHRONIC LIVER DISEASE IT IS OFTEN VERY DIFFICULT TO PROVE THE AETIOLOGY IN THE INDIVIDUAL PATIENT
0RIMARY BILIARY CIRRHOSIS 0RIMARY BILIARY CIRRHOSIS 0"# IS A CHRONIC PROGRESSIVE CHOLESTATIC DISEASE CHARACTERISED BY A GRANULOMATOUS DESTRUCTION OF THE INTRAHEPATIC BILE DUCTS WHICH IS ASSOCIATED WITH THE DEVELOPMENT OF PORTAL AND PERIPORTAL INFLAM MATION SUBSEQUENT FIBROSIS AND CAN LEAD TO CIRRHOSIS 0"# IS PRIMARILY A DIS EASE OF MIDDLE AGED WOMEN WITH MOST CASES OCCURRING BETWEEN AGES n YEARS ; = 0REVALENCE ESTIMATES RANGE FROM TO CASES PER MILLION OF THE POPULATION ; = !NTIMITOCHONDRIAL ANTIBODIES !-! ARE PRESENT IN n OF CASES OF 0"# OFTEN BEFORE CLINICAL SIGNS AND SYMPTOMS APPEAR AND ARE THEREFORE IMPORTANT IN THE DIAGNOSIS !MONG PATIENTS WITH POSITIVE
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!-! SOME PATIENTS MAY NOT HAVE CLINICAL SYMPTOMS AND BIOCHEMICAL ABNORMALITIES IN SUCH CASES A LIVER BIOPSY IS RECOMMENDED 3YMPTOMATIC PATIENTS DESCRIBE PAIN IN THE RIGHT UPPER ABDOMINAL QUAD RANT NAUSEA AND ANOREXIA /THER SYMPTOMS ATTRIBUTED TO 0"# INCLUDING FATIGUE PRURITUS AND KERATOCONJUNCTIVITIS XEROSTOMIA *AUNDICE IS USUALLY A LATE SYMPTOM 4HE MOST CHARACTERISTIC BIOCHEMICALLY ABNORMAL MARKER IN 0"# IS AN ELEVATED SERUM ALKALINE PHOSPHATASE WHICH IS USUALLY MEASURED THREE TO FOUR TIMES THE UPPER LIMIT OF NORMAL ;= 3ERUM TOTAL BILIRUBIN LEV ELS OFTEN RISE DURING DISEASE PROGRESSION BUT ARE COMMONLY WITHIN NORMAL LIMITS AT DIAGNOSIS !S THE PATHOGENESIS OF 0"# IS UNCLEAR IT IS DIFFICULT TO TREAT THE DISEASE /NLY URSODEXOXYCHOLIC ACID 5$#! HAS BEEN SHOWN TO BE EFFECTIVE IN PATIENTS WITH 0"# 53 &OOD AND $RUG !DMINISTRATION APPROVAL 4HERE IS SOME EVIDENCE THAT OTHER DRUGS LIKE CYCLOSPORINE AND AZATHIOPRINE ARE EFFECTIVE AND PREDNISOLONE OR BUDESONIDE MAY ALSO HAVE A BENEFICIAL EFFECT 4HERE IS AN INCREASED RISK OF OSTEOPENIA IN PATIENTS WITH 0"# ASSOCI ATED WITH FEMALE GENDER AND CHOLESTASIS THEREFORE CALCIUM AND VITAMIN $ SHOULD BE GIVEN TO ALL PATIENTS WITH 0"# 4HE NATURAL HISTORY OF PATIENTS WITH 0"# IS HETEROGENEOUS (OWEVER LIVER TRANSPLANTATION OFTEN REMAINS THE ONLY EFFECTIVE THERAPY FOR THOSE PATIENTS WITH END STAGE LIVER DISEASE FROM 0"#
0RIMARY SCLEROSING CHOLANGITIS 0RIMARY SCLEROSING CHOLANGITIS 03# ALSO IS A CHRONIC CHOLESTACTIC LIVER DISEASE 03# IS CHARACTERISED BY CONCENTRIC OBLITERATIVE FIBROSIS OF INTRA HEPATIC AND EXTRAHEPATIC BILIARY TREE LEADING TO ITS DESTRUCTION AND TO BILIARY CIRRHOSIS ; = 4HE AETIOLOGY OF 03# IS UNCLEAR ALTHOUGH GROW ING EVIDENCE SUPPORTS THAT SEVERAL IMMUNE AND NONE IMMUNE MEDIATED MECHANISM AS WELL AS GENETIC PREDISPOSITION PLAY A SIGNIFICANT ROLE IN DISEASE AETIOPATHOGENESIS 4HERE IS A STRONG ASSOCIATION BETWEEN 03# AND INFLAMMATORY BOWEL DISEASE WITH BETWEEN n 03# PATIENTS OF NORTH ERN %UROPEAN ORIGIN HAVING UNDERLYING INFLAMMATORY BOWEL DISEASE ; = ESPECIALLY ULCERATIVE COLITIS 4HE TRUE PREVALENCE OF 03# IS UNKNOWN !LMOST HALF OF ALL 03# PATIENTS ARE ASYMPTOMATIC AT THE TIME OF DIAGNOSIS 4HE ASYMPTOMATIC INDIVIDUAL HAS INCIDENTAL DISCOVERY OF MILDLY ABNORMAL LIVER BLOOD TESTS 4HE PRESENCE OF SYMPTOMS DOES NOT CORRELATE WELL WITH DISEASE SEVERITY &ATIGUE AND PRURITUS ARE THE MOST COMMON SYMPTOMS *AUNDICE ABDOMINAL PAIN AND WEIGHT LOSS ARE USUALLY PRESENT IN THE LATER STAGES OF THE DISEASE &EVER AND CHILLS MAY BE MANIFESTATIONS OF ASCENDING BACTERIAL CHOLANGITIS %NDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY REMAINS THE GOLD STANDARD TO DIAGNOSE LARGE DUCT 03# 4HE FINDING OF MULTIFOCAL STRICTURES AND DILATATIONS WITH BEADED APPEARANCE AND OCCASIONAL DIVERTICULAR FORMATION
(EPATITIS IN THE CLINICS n 4REATMENT OPTIONS
INVOLVING THE INTRAHEPATIC ANDOR EXTRAHEPATIC BILIARY TREES CHARACTERISES THE DISEASE ;= 4HE CLASSIC LABORATORY FINDING IN PATIENTS WITH 03# IS AN INCREASED ALKALINE PHOSPHATISE LEVEL -OST PATIENTS ALSO HAVE RAISED AMINO TRANSFERASES 4HE CLINICAL MANAGEMENT OF 03# PATIENTS SHOULD FOCUS ON ALLEVIATING SYMPTOMS AND COMPLICATIONS OF END STAGE LIVER DISEASE 3EVERAL TREATMENT OPTIONS HAVE BEEN STUDIED FOR 03# INCLUDING PHARMACOLOGICAL ENDOSCOPIC AND SURGICAL MODALITIES 3INCE 03# PATIENTS ARE AT A HIGH RISK OF DEVELOPING CHOLANGIOCELLULAR CARCINOMA AND OTHER MALIGNANT TUMOURS MAINLY OF THE ') TRACT THEY SHOULD BE REGULARLY SCREENED )N MOST CASES LIVER TRANSPLANTATION REMAINS THE ONLY THERAPY THAT IMPROVES SURVIVAL IN THESE PATIENTS )N PARTICULAR IN CHILDREN AN OVERLAP SYNDROME BETWEEN 03# AND AUTOIM MUNE HEPATITIS IS COMMON "IOCHEMICAL AND HISTOLOGICAL CHARACTERISTICS OF BOTH DISEASES DETERMINE DIAGNOSIS AND THERAPEUTIC APPROACH
-ETABOLIC LIVER DISEASE .ON ALCOHOLIC STEATOHEPATITIS .!3( .ON ALCOHOLIC STEATOHEPATITIS IS DEFINED AS A CONSTELLATION OF HISTOLOGICAL ABNORMALITIES IDENTIFIED ON LIVER BIOPSIES THAT ARE SIMILAR TO THOSE SEEN IN ALCOHOLIC LIVER DISEASE BUT THESE HISTOLOGICAL ABNORMALITIES ARE FOUND IN PATIENTS WHO CONSUME LITTLE OR EVEN NO ALCOHOL 4HE PREVALENCE OF .!3( HAS INCREASED OVER THE LAST YEARS IN PARALLEL WITH THE INCREASING PREVALENCE OF OBESITY AND TYPE DIABETES 4HE MOST COMMON UNDERLYING FACTOR FOR .!3( IS THE PRESENCE OF INSULIN RESISTANCE ;n= /BESITY AND A SEDENTARY LIFESTYLE ARE THE TWO LARGEST RISK FACTORS FOR INSULIN RESISTANCE ;= .!3( IS MOST COMMONLY ASYMPTOMATIC 3OME PATIENTS HAVE SYMPTOMS LIKE RIGHT UPPER ABDOMINAL PAIN FATIGUE AND MALAISE ,IVER BIOPSY IS THE GOLD STANDARD FOR DIAGNOSIS .!3( IS TYPICALLY CHARACTERISED BY SERUM !,4 THAT EXCEEDS THE !34 BY UP TO TWO OR THREE FOLD ;= 4HERE IS NO STANDARD TREATMENT FOR .!3( 'ENERAL RECOMMENDATIONS INCLUDE IMPROVING METABOLIC RISK FACTORS 4HE GOAL IS WEIGHT LOSS IMPROV ING INSULIN SENSITIVITY AND TREATING HYPERTRIGLYCERIDEMIA !NTIOXIDANTS AND URSODEOXYCHOLIC ACID HAVE ONLY LITTLE BENEFIT 4HE COMPLICATIONS THAT CAN OCCUR IN .!3( ARE LIVER CIRRHOSIS ACUTE LIVER FAILURE AND HEPATOCELLULAR CARCINOMA !T PRESENT METFORMIN AND OTHER ANTIDIABETIC DRUGS ARE BEING EVALUATED
'ENETIC LIVER DISEASES (AEMOCHROMATOSIS (AEMOCHROMATOSIS IS A MULTIORGAN DISEASE OF EXCESSIVE IRON DEPOSITION 4HE PRINCIPLE ORGANS AFFECTED INCLUDE LIVER HEART PANCREAS AND SKIN
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(AEMOCHROMATOSIS IS ONE OF THE MOST COMMON DISORDERS IN NORTHERN %UROPE 4HE HIGHEST FREQUENCY OCCURS IN )RELAND AND IN THE "ASQUE REGION ;= 4HE MAIN BUT NOT THE ONLY GENE ASSOCIATED WITH HAEMOCHROMATOSIS WAS LABELLED (&% ;= 4HE (&% GENE HAS TWO COMMON MUTATIONS #9 AND ($ !BOUT OF TYPICAL HAEMOCHROMATOSIS PATIENTS IN MANY REGIONS OF THE WORLD ARE HOMOZYGOUS FOR THE #9 MUTATION OF THE (&% GENE $ISEASE MANIFESTATION OCCURS THROUGH INCREASED INTESTINAL IRON ABSORPTION 4HERE IS NO MECHANISM FOR THE INTESTINE TO INCREASE IRON EXCRETION THIS LEADS TO A NET INCREASE IN THE IRON BALANCE RESULTING IN PROGRESSIVE ACCUMULATION IN MULTIPLE ORGANS )N THE EARLY STAGES OF THE DISEASE PATIENTS USUALLY SHOW NO SYMPTOMS 7ITH PROGRESS OF IRON ACCUMULATION ORGAN DYSFUNCTIONS MAY RESULT )N THE LATER STAGE OF THE DISEASE MANY SYMPTOMS OF HAEMOCHROMATOSIS ARE SEC ONDARY TO THE UNDERLYING LIVER DYSFUNCTION INCLUDING SPIDER NAEVI PALMAR ERYTHEMA FATIGUE WEIGHT LOSS AND RIGHT UPPER ABDOMINAL PAIN 4HE MOST COMMON NON LIVER RELATED SYMPTOMS OF HAEMOCHROMATOSIS ARE DIABETES CARDIAC DISEASE ARTHROPATHY ENDOCRINE ABNORMALITIES AND PIGMENTATION OF THE SKIN 'LUCOSE INTOLERANCE HAS BEEN FOUND IN OF HAEMOCHROMATOSIS PATIENTS WITH LIVER CIRRHOSIS ;= )RON ACCUMULATION IN THE PANCREAS MAY RESULT IN PANCREATIC ENDOCRINE DYSFUNCTION AND THEREFORE IN ADULT ONSET DIABETES MELLITUS #ARDIAC DISEASE IN HAEMOCHROMATOSIS INCLUDES BOTH CAR DIOMYOPATHY AND ARRHYTHMIAS %CHOCARDIOGRAPHY IS THE PREFERRED INITIAL DIAGNOSTIC TEST AND ABNORMALITIES CAN BE SEEN IN UP TO OF REFERRED CASES ;= 4HE CHARACTERISTIC PIGMENTATION OF HAEMOCHROMATOSIS IS A BRONZE OR GREY COLOUR OF THE SKIN 4HE INITIAL LABORATORY TESTING INCLUDES SERUM IRON TOTAL IRON BINDING CAPACITY AND FERRITIN %LEVATED TRANSFERRING SATURATION ABOVE AND ELE VATED SERUM FERRITIN ARE SUGGESTIVE OF IRON OVERLOAD 'ENETIC TESTING OF THE #9 -UTATION OFTEN LEADS TO THE EXACT DIAGNOSE OF HAEMOCHROMATOSIS (AEMOCHROMATOSIS CAN BE TREATED SUCCESSFULLY WITH PHLEBOTOMY THERA PY 4HE VENESECTION OF n ML IS EQUIVALENT TO APPROXIMATELY n MG IRON -AINTENANCE VENESECTION AFTER IRON DEPLETION OF n VENESECTIONS PER YEAR ARE DONE IN MOST PATIENTS ALTHOUGH THE RATE OF IRON REACCUMULATION IS HIGHLY VARIABLE ;= ! REASONABLE TARGET FOR THE TRANSFERRING SATURATION IS BELOW
!LPHA ANTITRYPSIN DEFICIENCY !LPHA ANTITRYPSIN IS PRODUCED PRIMARILY BY HEPATOCYTES BUT ALSO BY ALVEO LAR MACROPHAGES AND INTESTINAL CELLS ;= 4HE DISEASE IS ASSOCIATED WITH PULMONARY EMPHYSEMA CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA ALTHOUGH ONLY ABOUT OF HOMOZYGOTES DEVELOP A CLINICALLY SIGNIFICANT LIVER DISEASE 4HE PATHOGENESIS OF LIVER DISEASE IN PATIENTS WITH ALPHA ANTI
(EPATITIS IN THE CLINICS n 4REATMENT OPTIONS
TRYPSIN DEFICIENCY IS LESS CLEAR )T HAS BEEN SUGGESTED THAT CONFORMATIONAL CHANGES OF THE UNSTABLE ALPHA ANTITRYPSIN VARIANTS LEAD TO RETENTION OF POLYMERS OF ABNORMALLY FOLDED ALPHA ANTITRYPSIN IN THE HEPATOCYTE ENDO PLASMATIC RETICULUM ; = !LPHA ANTITRYPSIN DEFICIENCY OFTEN PRESENTS IN THE NEONATAL PERIOD WITH JAUNDICE PALE STOOL DARK URINE AND ELEVATED LIVER ENZYMES (OWEVER THE LIVER DISEASE CAN REMAIN CLINICALLY SILENT FOR MANY YEARS ALTHOUGH ABNORMAL BIOCHEMICAL LIVER ENZYMES AND SIGNS OF LIVER CIR RHOSIS MAY APPEAR 4HERE IS NO SPECIFIC THERAPY FOR ALPHA ANTITRYPSIN DEFICIENCY ASSOCIATED LIVER DISEASE 4HE ONLY TREATMENT OPTION FOR PATIENTS WITH PROGRESSIVE LIVER DISEASE IS A LIVER TRANSPLANTATION !DDITIONALLY IT IS RECOMMENDED TO AVOID OTHER RISK FACTORS SUCH AS PASSIVE AND ACTIVE SMOKING AND HEAVY DRINKING 3INCE THERE IS NO SPECIFIC TREATMENT OPTION THE GOAL HERE IS TO GIVE THESE PATIENTS THE STANDARD MEDICAL SUPPORT AND TO MANAGE THE COMPLICATIONS OF CHRONIC LIVER DISEASE
7ILSON DISEASE 7ILSON DISEASE IS AN AUTOSOMAL RECESSIVE DISORDER THAT LEADS TO A COPPER OVERLOAD IN THE LIVER AND OTHER ORGANS 4HE UNDERLYING GENE HAS BEEN IDEN TIFIED AND MORE THAN SINGLE POINT MUTATIONS OF THIS GENE HAVE BEEN IDEN TIFIED ;= 4HEREFORE UNLIKE IN HAEMOCHROMATOSIS A SINGLE GENETIC TEST IS NOT AVAILABLE ON A ROUTINE BASIS FOR 7ILSON DISEASE 7ILSON DISEASE IS FOUND WORLDWIDE BUT MOST COMMONLY IN NORTHERN CENTRAL AND EASTERN %UROPEAN COUNTRIES ; = 4HE CLINICAL PRESENTATION CAN VARY 7ILSON DISEASE MAY PRESENT AS CHRONIC OR FULMINANT LIVER DISEASE AS A PROGRESSIVE NEUROLOGICAL DISORDER WITHOUT EVIDENT HEPATIC DYSFUNCTION OR AS A RATHER NONDESCRIPT PSYCHIATRIC ILLNESS OR ACUTE EPISODES OF HAEMOLYSIS 4HE HALLMARK OF 7ILSON DISEASE IS THE +AYSER &LEISCHER RING WHICH IS PRESENTED IN OF PATIENTS WITH NEUROLOGICAL SYMPTOMS AND SOMEWHAT OVER A HALF WITHOUT +AYSER &LEISCHER RINGS ARE NOT SPECIFIC FOR 7ILSON DISEASE 4HEY MAY BE FOUND IN PATIENTS WITH OTHER TYPES OF CHRONIC LIVER DISEASE -EDICAL TREATMENT FOR 7ILSON DISEASE INVOLVES EITHER CHELATION OR INDUCTION OF METALLOTHIONINS 4HERE ARE TWO GENERALLY ACCEPTED ORAL CHELATING AGENTS PENICILLAMINE AND TRIENTINE :INC INTERFERES WITH COP PER ABSORPTION FIRSTLY BY COMPETING FOR A COMMON CARRIER ABSORPTION AND SECONDLY INDUCING METALLOTHIONIN IN ENTEROCYTES ALLOWING COPPER ABSORBED INTO THEM TO BE EXCRETED BY DESQUAMATION ;= 5NTREATED 7ILSONS DISEASE IS UNIVERSALLY FATAL WITH MOST PATIENTS DYING FROM LIVER DISEASE AND A MINORITY FROM PROGRESSIVE NEUROLOGIC DISEASE (OWEVER IN MOST CASES LIVER TRANSPLANTATION OFTEN REMAINS THE ONLY EFFECTIVE THERAPY FOR PATIENTS WITH END STAGE LIVER DISEASE THE GENETIC DEFECT IS CURED BY LIVER TRANSPLANTATION
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+( "RECHOT # -ANNS -0 )DENTIFICATION OF CYCLIN ! AS A MOLECULAR TAR GET OF ANTINUCLEAR ANTIBODIES !.! IN HEPATIC AND NON HEPATIC AUTOIMMUNE DISEASES * (EPATOL n -ANNS - 'ERKEN ' +YRIATSOULIS ! 3TARITZ - -EYER ZUM "USCHENFELDE +( #HARACTERISATION OF A NEW SUBGROUP OF AUTOIMMUNE CHRONIC ACTIVE HEPA TITIS BY AUTOANTIBODIES AGAINST A SOLUBLE LIVER ANTIGEN ,ANCET n 7IES ) "RUNNER 3 (ENNINGER * (ERKEL * +ANZLER 3 -EYER ZUM "USCHENFELDE +( ,OHSE !7 )DENTIFICATION OF TARGET ANTIGEN FOR 3,!,0 AUTOANTI BODIES IN AUTOIMMUNE HEPATITIS ,ANCET n 6ERGANI $ !LVAREZ & "IANCHI &" #ANCADO %, -ACKAY )2 -ANNS -0 .ISHIOKA - 0ENNER % ,IVER AUTOIMMUNE SEROLOGY A CONSENSUS STATE MENT FROM THE COMMITTEE FOR AUTOIMMUNE SEROLOGY OF THE )NTERNATIONAL !UTOIMMUNE (EPATITIS 'ROUP * (EPATOL n .IKIAS '! "ATTS +0 #ZAJA !* 4HE NATURE AND PROGNOSTIC IMPLICATIONS OF AUTOIMMUNE HEPATITIS WITH AN ACUTE PRESENTATION * (EPATOL n +IRK !0 *AIN 3 0OCOCK 3 4HOMAS (# 3HERLOCK 3 ,ATE RESULTS OF THE 2OYAL &REE (OSPITAL PROSPECTIVE CONTROLLED TRIAL OF PREDNISOLONE THERAPY IN HEPATITIS " SURFACE ANTIGEN NEGATIVE CHRONIC ACTIVE HEPATITIS 'UT n 2EAD !% 3HERLOCK 3 (ARRISON #6 !CTIVE @JUVENILE CIRRHOSIS CONSID ERED AS PART OF A SYSTEMIC DISEASE AND THE EFFECT OF CORTICOSTEROID THERAPY 'UT n #ZAJA !* 4HE VARIANT FORMS OF AUTOIMMUNE HEPATITIS !NN )NTERN -ED n VAN "UUREN (2 VAN (OOGSTRATEN (*% 4ERKIVATAN 4 3CHALM 37 6LEGGAAR &0 (IGH PREVALENCE OF AUTOIMMUNE HEPATITIS AMONG PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS * (EPATOL n 9OON 9 ( 9I (Y 3MOTHERS "A ,IVER CIRRHOSIS MARTALITY IN THE 5NITED STATES n .)!!! 3URVEILLANCE REPORT "ECKER 5 $EIS ! 3ORENSEN 4) 'RONBAEK - "ORCH *OHNSEN + -ULLER #& 3CHNOHR 0 *ENSEN ' 0REDICTION OF RISK OF LIVER DISEASE BY ALCOHOL INTAKE SEX AND AGE A PROSPECTIVE POPULATION STUDY (EPATOLOGY n -AC3WEEN 2. "URT !$ (ISTOLOGIC SPECTRUM OF ALCOHOLIC LIVER DISEASE 3EMIN ,IVER $IS n $!MICO ' 0AGLIARO , "OSCH * 4HE TREATMENT OF PORTAL HYPERTENSION A META ANALYTIC REVIEW (EPATOLOGY n "OYER 4$ 7RIGHT 4, -ANNS -0 :AKIM AND "OYERS HEPATOLOGY n A TEXTBOOK OF LIVER DISEASE TH EDITION 3AUNDERS %LSEVIER 'INES 0 1UINTERO % !RROYO 6 4ERES * "RUGUERA - 2IMOLA ! #ABALLERIA * 2ODES * 2OZMAN # #OMPENSATED CIRRHOSIS NATURAL HISTORY AND PROG NOSTIC FACTORS (EPATOLOGY n /'RADY *' 3CHALM 37 7ILLIAMS 2 !CUTE LIVER FAILURE REDEFINING THE SYNDROMES ,ANCET n -AHL 4# 3HOCKCOR 7 "OYER *, 0RIMARY BILIARY CIRRHOSIS SURVIVAL OF A LARGE COHORT OF SYMPTOMATIC AND ASYMPTOMATIC PATIENTS FOLLOWED FOR YEARS * (EPATOL n 3HERLOCK 3 3CHEUER 0* 4HE PRESENTATION AND DIAGNOSIS OF PATIENTS WITH PRIMARY BILIARY CIRRHOSIS . %NGL * -ED n
(EPATITIS IN THE CLINICS n 4REATMENT OPTIONS
+IM 72 ,INDOR +$ ,OCKE '2 ))) 4HERNEAU 4- (OMBURGER (! "ATTS +0 9AWN "0 0ETZ *, -ELTON ,* ))) $ICKSON %2 %PIDEMIOLOGY AND NATURAL HISTORY OF PRIMARY BILIARY CIRRHOSIS IN A 53 COMMUNITY 'ASTROENTEROLOGY n 3HIBATA - /NOZUKA 9 -ORIZANE 4 +OIZUMI ( +AWAGUCHI . -IYAKAWA ( +AKO - -ITAMURA + 0REVALENCE OF ANTIMITOCHONDRIAL ANTIBODY IN *APANESE CORPORATE WORKERS IN +ANAGAWA PREFECTURE * 'ASTROENTEROL n 4ALWALKAR *! ,INDOR +$ 0RIMARY BILIARY CIRRHOSIS ,ANCET n !NGULO 0 ,INDOR +$ 0RIMARY SCLEROSING CHOLANGITIS (EPATOLOGY n #HAPMAN 27 4HE MANAGEMENT OF PRIMARY SCLEROSING CHOLANGITIS #URR 'ASTROENTEROL 2EP n !ADLAND % 3CHRUMPF % &AUSA / %LGJO + (EILO ! !AKHUS 4 'JONE % 0RIMARY SCLEROSING CHOLANGITIS A LONG TERM FOLLOW UP STUDY 3CAND * 'ASTROENTEROL n 1UIGLEY %- ,A2USSO .& ,UDWIG * -AC3WEEN 2. "IRNIE '' 7ATKINSON ' &AMILIAL OCCURRENCE OF PRIMARY SCLEROSING CHOLANGITIS AND ULCERATIVE COLITIS 'ASTROENTEROLOGY n 7ANLESS )2 ,ENTZ *3 &ATTY LIVER HEPATITIS STEATOHEPATITIS AND OBESITY AN AUTOPSY STUDY WITH ANALYSIS OF RISK FACTORS (EPATOLOGY n $IXON *" "HATHAL 03 /"RIEN 0% .ONALCOHOLIC FATTY LIVER DISEASE PRE DICTORS OF NONALCOHOLIC STEATOHEPATITIS AND LIVER FIBROSIS IN THE SEVERELY OBESE 'ASTROENTEROLOGY n 0AGANO ' 0ACINI ' -USSO ' 'AMBINO 2 -ECCA & $EPETRIS . #ASSADER - $AVID % #AVALLO 0ERIN 0 2IZZETTO - .ONALCOHOLIC STEATOHEPATITIS INSULIN RESISTANCE AND METABOLIC SYNDROME FURTHER EVIDENCE FOR AN ETIOLOGIC ASSOCIATION (EPATOLOGY n 2UHL #% %VERHART *% $ETERMINANTS OF THE ASSOCIATION OF OVERWEIGHT WITH ELEVATED SERUM ALANINE AMINOTRANSFERASE ACTIVITY IN THE 5NITED 3TATES 'ASTROENTEROLOGY n $IEHL !- 'OODMAN : )SHAK +' !LCOHOLLIKE LIVER DISEASE IN NONALCO HOLICS ! CLINICAL AND HISTOLOGIC COMPARISON WITH ALCOHOL INDUCED LIVER INJURY 'ASTROENTEROLOGY n -ERRYWEATHER #LARKE !4 0OINTON ** 3HEARMAN *$ 2OBSON +* 'LOBAL PREVALENCE OF PUTATIVE HAEMOCHROMATOSIS MUTATIONS * -ED 'ENET n &EDER *. 'NIRKE ! 4HOMAS 7 4SUCHIHASHI : 2UDDY $! "ASAVA ! $ORMISHIAN & $OMINGO 2 *R %LLIS -# &ULLAN ! ET AL ! NOVEL -(# CLASS ) LIKE GENE IS MUTATED IN PATIENTS WITH HEREDITARY HAEMOCHROMATOSIS .AT 'ENET n .IEDERAU # &ISCHER 2 0URSCHEL ! 3TREMMEL 7 (AUSSINGER $ 3TROHMEYER ' ,ONG TERM SURVIVAL IN PATIENTS WITH HEREDITARY HEMOCHROMATOSIS 'ASTROENTEROLOGY n !DAMS 0# +ERTESZ !% 6ALBERG ,3 2ATE OF IRON REACCUMULATION FOLLOW ING IRON DEPLETION IN HEREDITARY HEMOCHROMATOSIS )MPLICATIONS FOR VENESECTION THERAPY * #LIN 'ASTROENTEROL n
-ICHAEL 0 -ANNS AND +ATJA $ETERDING
#ARRELL 27 ,OMAS $! !LPHA ANTITRYPSIN DEFICIENCYnA MODEL FOR CON FORMATIONAL DISEASES . %NGL * -ED n 3IFERS 2. &INEGOLD -* 7OO 3, -OLECULAR BIOLOGY AND GENETICS OF ALPHA ANTITRYPSIN DEFICIENCY 3EMIN ,IVER $IS n ,OMAS $! %VANS $, &INCH *4 #ARRELL 27 4HE MECHANISM OF : ALPHA ANTITRYPSIN ACCUMULATION IN THE LIVER .ATURE n -AIER $OBERSBERGER 4 &ERENCI 0 0OLLI # "ALAC 0 $IENES (0 +ASERER + $ATZ # 6OGEL 7 'ANGL ! $ETECTION OF THE (IS'LN MUTATION IN 7ILSON DISEASE BY RAPID POLYMERASE CHAIN REACTION !NN )NTERN -ED n &IRNEISZ ' ,AKATOS 0, 3ZALAY & 0OLLI # 'LANT 44 &ERENCI 0 #OMMON MUTATIONS OF !40" IN 7ILSON DISEASE PATIENTS FROM (UNGARY !M * -ED 'ENET n (OOGENRAAD 45 :INC TREATMENT OF 7ILSONS DISEASE * ,AB #LIN -ED n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS -ARTIN & 3PRINZL AND 0ETER 2 'ALLE *OHANNES 'UTENBERG 5NIVERSITËT -EDIZINISCHE +LINIK ,ANGENBECKSTRASSE -AINZ 'ERMANY
!BSTRACT 4HERE IS A VARIETY OF DIFFERENTIAL DIAGNOSES OF ACUTE AND CHRONIC HUMAN HEPATITIS REGULARLY SEEN IN CLINICAL PRAXIS 2ISK FACTOR ASSESSMENT FOR SPECIFIC ENTITIES PROVIDES IMPORTANT INFORMATION AND SHOULD GUIDE INDIVIDUAL DIAGNOSTIC PROCEDURES ,IVER SCREENING TESTS OFTEN REMAIN THE FIRST INDICATOR FOR HEPATIC PATHOLOGIES AND SHOULD INCLUDE QUANTIFICATION OF LIVER ENZYMES LIVER FUNCTION PARAMETERS AND CHOLESTATIC PARAMETERS .EVERTHELESS VIRUS SEROLOGY SHOULD ALWAYS BE DONE DURING FURTHER LABORATORY EVALUATION 4O ESTIMATE THE PARENCHYMAL LIVER DAMAGE AND TO EXCLUDE BILIARY OBSTRUCTION OR HEPATIC LESIONS AN ABDOMINAL ULTRASOUND SCAN IS ESSENTIAL ! LIVER BIOPSY MAY COMPLETE THE DIAGNOSTIC APPROACH IF EITHER THE UNDERLYING HEPATIC PATHOLOGY REMAINS OBSCURE OR PARENCHYMAL LIVER DAMAGE NEEDS TO BE DEFINED
)NTRODUCTION (UMAN HEPATITIS MAY PRESENT AS ACUTE OR CHRONIC LIVER DISEASE WHICH MAY CAUSE MILD OR SEVERE HEPATIC DAMAGE 4HUS THE RESULTING CLINICAL SPEC TRUM OF HUMAN HEPATITIS RANGES FROM ASYMPTOMATIC COURSES TO MANIFEST DISEASE &URTHER DIAGNOSTIC EVALUATION IS ESSENTIAL AS DIFFERENT HEPATIC AND EXTRAHEPATIC PATHOLOGIES MAY MIMIC HUMAN HEPATITIS "ESIDE ROUTINE LABORATORY TESTS OF LIVER ENZYMES WHICH ARE REGULARLY THE FIRST INDICATOR OF HEPATITIS FURTHER DIAGNOSTIC ASSESSMENT NEEDS TO ORCHESTRATE PATIENT HISTORY CLINICAL FINDINGS AND LABORATORY INVESTIGATIONS ,IVER HISTOLOGY AND DIAGNOSTIC IMAGING ARE IMPORTANT COMPLEMENTARY DIAGNOSTIC TOOLS TO IDENTIFY THE HEPATIC PATHOLOGY 3UBSEQUENTLY THE DIFFERENTIAL DIAGNOSIS GIVES FIRST INSIGHTS INTO THE STAGE PROGNOSIS AND THERAPEUTIC OPTIONS OF NEWLY DIAGNOSED HEPATITIS
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
$IFFERENTIATION OF VIRAL HEPATITIS !NAMNESTIC FINDINGS $URING DIFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS A SPECIAL FOCUS SHOULD BE SET ON HEPATITIS ! " AND # WHICH ARE THE MOST COMMON CAUSES OF VIRAL HEPATITIS WORLDWIDE )N %UROPE AND .ORTHERN !MERICA PATIENTS WITH IDENTI FIED LIVER DISEASE SHOW A PREVALENCE OF HEPATITIS " BETWEEN AND WHEREAS A PREVALENCE BETWEEN AND HAS BEEN REPORTED FOR HEPA TITIS # "ESIDE THIS A RELEVANT PROPORTION OF PATIENTS WITH VIRAL HEPATITIS ALSO PRESENTS WITH HEPATIC CO MORBIDITY WHICH COMPLICATES DIFFERENTIAL DIAGNOSIS ;n= 6IRAL HEPATITIS IS CHARACTERISED BY RISK FACTORS ASSOCIATED WITH VIRAL INFECTION 4HUS PATIENT HISTORY MAY GUIDE TO THE VIRAL PATHOGEN $UE TO THE FAECAL ORAL TRANSMISSION ROUTE OF HEPATITIS ! VIRUS (!6 INDIVIDUALS ACCOM MODATED IN COLLECTIVE HOUSINGS ARE AT HIGHER RISK OF ACQUIRING (!6 INFECTION &URTHER RISK FACTORS HAVE BEEN IDENTIFIED FOR CLINICAL EMPLOYEES AND SEWAGE WORKERS AS WELL AS FOR HOMOSEXUAL MEN AND INDIVIDUALS FROM LOWER SOCIAL BACKGROUND $UE TO GLOBAL MIGRATION AND TOURISM INCREASING NUMBERS OF PATIENTS FROM (!6 ENDEMIC REGIONS HAVE TO BE CONSIDERED ;= /NLY A VERY FEW CASES OF FAECAL ORAL INFECTIONS WITH HEPATITIS % VIRUS (%6 HAVE BEEN REPORTED IN %UROPE AND WERE USUALLY CONNECTED WITH A PREVIOUS STAY IN (%6 ENDEMIC AREAS INCLUDING )NDIA EASTERN !SIA AND !FRICA !N (%6 SERO PREVALENCE OF IN SOME REMOTE AREAS OF THE 5NITED 3TATES ALSO SUGGESTS AUTOCHTHONOUS CASES OF HEPATITIS % IN THE NORTHERN HEMISPHERE ;= (EPATITIS " VIRUS ("6 AND HEPATITIS # VIRUS (#6 SHOW PARENTERAL TRANSMISSION ROUTES AND ARE THE PREDOMINANT PATHOGENS OF VIRAL HEPATITIS 4HEREFORE CLINICAL HISTORY SHOULD IDENTIFY PATIENTS WHO HAVE RECEIVED BLOOD TRANSFUSIONS OR SURGICAL INTERVENTIONS 0ATIENTS SUFFERING FROM HAEMOPHILIA OR RECEIVING CHRONIC HAEMODIALYSIS WERE IDENTIFIED AS RISK GROUPS 4HESE RISK FACTORS ARE OF SPECIAL RELEVANCE IF THEY ORIGINATE FROM THE ERA WITHOUT EFFICIENT HEPATITIS SCREENING ; = 3INCE VIRAL SCREENING OF BLOOD DONORS AND BLOOD PRODUCTS HAS BEEN IMPLEMENTED FOR ("6 AND (#6 THE ESTIMATED RISK FOR TRANSFUSION ASSOCIATED (#6 AND ("6 INFECTION HAS DECLINED TO AND PER TRANSFUSED UNIT IN %UROPE RESPECTIVELY ;= 2EMAINING GROUPS AT RISK FOR ("6 AND (#6 ARE EMPLOYEES IN THE HEALTH CARE SETTING AND INTRAVENOUS DRUG ADDICTS 0ARTICULARLY DRUG ADDICTS DEMON STRATE A VERY HIGH (#6 PREVALENCE OF n ; = 5NSAFE SEXUAL PRACTICES ARE THE MOST IMPORTANT INFECTIOUS ROUTE WHICH IS RESPONSIBLE FOR TO OF NEW ("6 INFECTIONS EXCLUDING OTHER RISK FACTORS ;= 3EXUAL TRANSMISSION RATE FOR (#6 IS MUCH LOWER AND HAS BEEN SUGGESTED TO RANGE FROM TO DURING LONG TERM SEXUAL PARTNERSHIPS IF NO OTHER RISK BEHAVIOUR HAS BEEN DOCUMENTED ;= )N AREAS OF HIGH ("6 PREVALENCE PERINATAL TRANSMISSION FROM ("6 INFECTED MOTHERS TO NEWBORNS CONTRIBUTES TO A LARGE PROPORTION OF INFECTIONS 6ERTICAL ("6 TRANSMISSION
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
4ABLE #LINICAL CHARACTERISTICS OF VIRAL HEPATITIS (EPATITIS !
(EPATITIS "
(EPATITIS #
(EPATITIS $
(EPATITIS %
4RANSMISSION
FAECAL ORAL PERCUTANEOUS PERCUTANEOUS PERCUTANEOUS FAECAL ORAL PERCUTANEOUS SEXUAL SEXUAL SEXUAL PERINATAL PERINATAL PERINATAL
)NCUBATION PHASE DAYS
n
n
n
n
n
#LINICAL ILLNESS n ADULTS n INFANTS
n
HIGHER WITH SUPER INFECTION
n ADULTS
*AUNDICE
ADULTS INFANTS
n
n
UNKNOWN
COMMON
&ULMINANT
RARE
n
UP TO IN PREG NANT WOMEN
#ASE FATALITY RATE
n
n
n
COINFEC TION SUPER INFECTION
n n IN PREGNANT WOMEN
#HRONIC HEPATITIS
NONE
n ADULTS n INFANTS
COINFEC NONE TION SUPER INFECTION
FROM ("E!G POSITIVE MOTHERS TO NEWBORNS OCCURS IN n 4HE RATE OF VERTICAL INFECTION DECLINES TO n IF THE MOTHER IS ("E!G NEGATIVE AND REDUCES FURTHER TO n FOLLOWING ACTIVE AND PASSIVE ("6 IMMUNISATION OF THE NEWBORN ;= ,IKE WITH (!6 INFECTIONS WITH ("6 ANDOR (#6 HAVE TO BE CONSIDERED IN PATIENTS ORIGINATING FROM ENDEMIC AREAS ($6 INFECTIONS ONLY AFFECT ("6 POSITIVE PATIENTS AND MAY CAUSE SEVERE HEPATITIS DURING SUPERINFECTION WHEREAS CO INFECTION WITH ($6 DOES NOT RELEVANTLY ALTER THE ACUTE NATURAL COURSE OF HEPATITIS " 0ARTICULARLY IN AREAS WITH HIGH ("6 PREVALENCE ($6 INFECTIONS HAVE TO BE CONSIDERED .ON HEPATOTROPIC VIRAL INFECTIONS CAN CAUSE ATYPICAL HEPATITIS 4HE PREDOMINANT VIRAL PATHOGENS RESPONSIBLE FOR ATYPICAL HEPATITIS ORIGINATE FROM THE HERPESVIRIDAE FAMILY #YTOMEGALOVIRUS #-6 %PSTEIN "ARR VIRUS %"6 VARICELLA ZOSTER VIRUS 6:6 AND HERPES SIMPLEX VIRUS (36 ARE THE MOST IMPORTANT PATHOGENS 4HE COURSE OF ATYPICAL HEPATITIS DEPENDS ON THE HOST IMMUNE COMPETENCY AND RANGES FROM MILD TO FULMINANT MANI FESTATIONS #HRONIC ACTIVE COURSES COMPARABLE TO HEPATITIS " AND # ARE NOT OBSERVED BUT RECURRENT EXACERBATIONS OF LATENT INFECTIONS ARE POSSIBLE AND COMMON FOR #-6 4HE SEROPREVALENCE OF HERPESVIRIDAE IS HIGH IN THE GENERAL POPULATION AND REACHES ABOUT FOR #-6 FOR %"6 AND FOR (36 RESPECTIVELY ;n= 4HUS DE NOVO INFECTION USUALLY DOES NOT CAUSE HEPATITIS IN THE ADULT POPULATION AND REACTIVATION OF LATENT
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
INFECTIONS IS THE MOST IMPORTANT PATHOMECHANISM 3PECIFICALLY REACTIVATED #-6 INFECTIONS HAVE TO BE CONSIDERED IN PATIENTS WHO ARE IMMUNOSUP PRESSED RECEIVING HIGH DOSE CHEMOTHERAPY OR SUFFERING FROM OTHER CAUSES OF IMMUNODEFICIENCY %XCEPTIONAL DE NOVO INFECTIONS WHICH MAY MANIFEST WITH HEPATITIS ARE CONGENITAL (36 INFECTIONS OR %"6 INFECTIONS IN LATE CHILDHOOD OR EARLY ADOLESCENCE ;= %XOTIC VIRAL HEPATITIS IS PREDOMINANTLY BASED ON INFECTIONS WITH ARBOVIRIDAE 4HUS THE VIRUS IS USUALLY TRANSMITTED BY INSECT VECTORS WHICH ARE ENDEMIC IN TROPICAL OR SUBTROPICAL REGIONS 4HE MOST COM MON VIRAL ENTITIES ARE 9ELLOW FEVER AND $ENGUE FEVER ; = !LSO VIRAL ZOONOSES WHICH ARE ENDEMIC IN TROPICAL AND SUBTROPICAL REGIONS CONTRIBUTE TO HEMORRHAGIC FEVER WITH HEPATIC INVOLVEMENT 0ARTICULARLY PATIENTS WITH A RECENT HISTORY OF FOREIGN TRAVEL ARE AT RISK OF DEVELOPING EXOTIC HEPATITIS AND SHOULD BE IDENTIFIED ; =
#LINICAL FINDINGS !CUTE MANIFESTATIONS 4HE CLINICAL FINDINGS OF ACUTE HUMAN HEPATITIS ORIGINATE FROM HEPATOCYTE DAMAGE AND IMPAIRED LIVER FUNCTION WHICH COULD LEAD TO VEGETATIVE SYMP TOMS JAUNDICE AND ENCEPHALOPATHY #ONCLUSIVELY THE CLINICAL FINDINGS DUR ING HUMAN HEPATITIS ARE USUALLY NON SPECIFIC AND ONLY THE CHRONOLOGICAL SEQUENCE OF SYMPTOMS MIGHT INDICATE THE RESPONSIBLE CAUSE 6IRAL HEPATITIS IS CHARACTERISED BY THREE DIFFERENT PERIODS OF ACUTE INFECTION "EFORE ONSET OF SYMPTOMS PATIENTS UNDERGO AN INCUBATION PERIOD WHICH LASTS FROM WEEKS TO MONTHS 4HE DURATION OF THE INCUBATION PERIOD IS HIGHLY VARIABLE BECAUSE IT DEPENDS ON THE CAUSATIVE VIRAL AGENT AND ON THE IMMUNE COMPETENCY OF THE INFECTED PERSON %LEVATED LIVER ENZYMES ARE OFTEN THE ONLY PATHOLOGICAL FINDING WHICH USUALLY MAKES VIRAL HEPATITIS AN INCIDENTAL DIAGNOSIS DURING ITS INCUBATION PERIOD 4HE PRODROMAL PHASE SUBSEQUENTLY PRESENTS WITH CLINICAL FEATURES OF DROWSINESS FATIGUE FLU LIKE SYMPTOMS AND EPIGASTRIC PAIN 4HESE SYMPTOMS USUALLY PERSIST UNTIL ONSET OF JAUNDICE WHICH MARKS THE BEGIN NING OF THE ICTERIC PHASE *AUNDICE USUALLY RESOLVES WITHOUT RESIDUAL HEPATIC DAMAGE IF THE IMMUNE SYSTEM IS ABLE TO ELIMINATE THE VIRAL PATHOGEN !S JAUNDICE DOES NOT DEVELOP IN A RELEVANT PROPORTION OF PATIENTS MANIFESTA TIONS OF ACUTE VIRAL HEPATITIS ARE OFTEN MISINTERPRETED AS UNSPECIFIC FLU LIKE SYMPTOMS 3OMETIMES PROLONGED JAUNDICE IS OBSERVED WITHOUT DEVELOPING CHRONIC INFECTION 3OME PATIENTS DEVELOP EXTRAHEPATIC MANIFESTATIONS OF VIRAL HEPATITIS WHICH ARE BASED ON IMMUNE MEDIATED MECHANISMS 4HE RATE OF FULMINANT HEPATITIS DEPENDS ON THE NATURAL COURSE OF THE CAUS ATIVE VIRAL PATHOGEN AND IS OBSERVED IN LESS THAN OF HEPATITIS ! IN OF HEPATITIS " AND IN RARE CASES OF ACUTE HEPATITIS # 0ATIENTS AT INCREASED RISK OF DEVELOPING FULMINANT HEPATITIS ARE IMMUNOCOMPROMISED PATIENTS AND PATIENTS WITH UNDERLYING LIVER DISEASE OR LIVER CIRRHOSIS )NCREASED RATES OF FUL
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
MINANT HEPATITIS HAVE ALSO BEEN OBSERVED IN PREGNANT WOMEN WITH HEPATITIS % AND DURING HEPATITIS $ SUPERINFECTIONS 4HE CLINICAL PICTURE OF FULMINANT HEPA TITIS IS CHARACTERISED BY PRONOUNCED JAUNDICE AND MAY LEAD TO LIVER FAILURE AND SUBSEQUENT MULTIORGAN FAILURE (EPATIC ENCEPHALOPATHY SERUM ELECTRO LYTE DERANGEMENT CEREBRAL OEDEMA HEMORRHAGIC COAGULOPATHY AND INSTABLE GLUCOSE HOMEOSTASIS MAY DEVELOP AS SEVERE COMPLICATIONS 4HE RESULTING CASE FATALITY RATE HAS BEEN ESTIMATED TO BE BELOW FOR ACUTE HEPATITIS ! ABOUT FOR ACUTE HEPATITIS # AND FOR ACUTE HEPATITIS " ;=
#HRONIC MANIFESTATIONS OF VIRAL HEPATITIS 3YMPTOMS OF CHRONIC HEPATITIS ARE NON SPECIFIC AND SEEN INFREQUENTLY 4HEY CONSIST OF FATIGUE ABDOMINAL DISCOMFORT AND DEPRESSIVE SYMPTOMS 4HUS THE DIFFERENTIAL DIAGNOSE OF CHRONIC HEPATITIS MAY NOT BE AS RELIANT ON CLINICAL FINDINGS AT INITIAL STAGES ,IVER SPECIFIC SIGNS OF CHRONIC HEPATITIS ARE FINALLY DETERMINED BY PROGRESSION TO END STAGE LIVER DISEASE RESULTING IN IMPAIRED LIVER FUNCTION AND CIRRHOSIS 4HUS PROGRESSIVE IMPAIRMENT OF LIVER FUNCTION MAY GRADUALLY CAUSE COAGULOPATHY JAUNDICE AND ENCEPHALOPATHY ,IVER CIRRHOSIS AND RESULTING PORTAL HYPERTENSION MAY EVENTUALLY PROVOKE ASCITES PERIPHERAL OEDEMA AND GASTROINTESTINAL HAEMORRHAGE !MONG THESE SYMPTOMS ASCITES IS CONSIDERED THE LANDMARK SIGN OF DECOMPENSATED CIR RHOSIS AND OCCURS WITH A FREQUENCY OF n PER YEAR ;= 3IGNS OF CIRRHOSIS ARE OFTEN MISSING UNLESS COMPLICATIONS LIKE SPONTANEOUS BACTERIAL PERITO NITIS PORTAL VEIN THROMBOSIS AND HEPATOCELLULAR CARCINOMA HAVE INDUCED DECOMPENSATION !S A RESULT CIRRHOTIC COMPLICATIONS MAY PRESENT AS ACUTE OR SUBACUTE HEPATIC PATHOLOGY AS LONG AS THE UNDERLYING CIRRHOSIS HAS NOT BEEN RECOGNISED BEFORE 3OMETIMES THE CHRONIC COURSE OF VIRAL HEPATITIS IS COMPLICATED BY ACUTE EXACERBATIONS WHICH MAY LEAD TO ACUTE LIVER FAILURE 0ARTICULARLY CHRONIC HEPATITIS " SHOWS INFLAMMATORY FLARES WITH AN ASSOCI ATED MORTALITY OF ;=
%XTRAHEPATIC MANIFESTATION OF VIRAL HEPATITIS $IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS CAN BE BASED ON EXTRAHEPATIC MANIFESTATIONS WHICH REGULARLY OCCUR DURING ACUTE AND CHRONIC LIVER DAMAGE %XTRAHEPATIC MANIFESTATIONS DEPEND ON THE CAUSATIVE PATHOLOGY AND AFFECT DIFFERENT ORGAN SYSTEMS &REQUENT EXTRAHEPATIC MANIFESTATIONS DURING ACUTE VIRAL HEPATITIS ARE CUTANEOUS RASH ERYTHEMA AND ARTHRALGIA 4HESE EXTRAHE PATIC SYMPTOMS OCCUR IN n DURING ACUTE (!6 INFECTION AND IN DURING ACUTE ("6 INFECTION AND IN A LESS DEFINED RATE OF ACUTE (#6 INFEC TIONS %XTRAHEPATIC MANIFESTATIONS ARE EVEN MORE COMMON DURING CHRONIC VIRAL HEPATITIS AND MAY SPECIFY THE UNDERLYING VIRAL PATHOGEN (EPATITIS " CAUSES IMMUNE COMPLEX MEDIATED VASCULITIS WHICH MAY LEAD TO NEUROPATHY
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
4ABLE $IFFERENTIAL DIAGNOSES OF HUMAN HEPATITIS .ATURAL COURSE
#HARACTERISTICS
$IAGNOSTIC TESTS
-ETABOLIC LIVER DISEASE &ATTY LIVER DISEASE
#HRONIC
)NCIDENCE INCREASING WITH AGE M W "-) KGM INCREASED WAIST CIRCUMFER ENCE
-EDICAL HISTORY DIABETES AND ALCOHOL SCREENING SERUM LIPIDS EXCLUSION OF OTHER LIVER DISEASE
(AEMO CHROMATOSIS
#HRONIC PROGRESSIVE
0TS Y M W HYPER PIGMENTATION DIABETES MELLITUS
&AMILY HISTORY FERRITIN TRANSFERRIN STATURATION (&% SCREENING
_ !NTI TRYPSIN DEFICIENCY
#HRONIC PROGRESSIVE
0ULMONARY EMPHYSEMA
&AMILY HISTORY _ ANTI TRYPSIN SERUM ACTIVITY GENETIC SCREENING
7ILSON DISEASE
#HRONIC PROGRES 0TS Y COOMBS NEGATIVE &AMILY HISTORY SERUM COP SIVE FULMINANT HAEMOLYSIS +AISER &LEISCHER PER COERULOPLASMIN LEVEL HEPATIC DETERIORA RING NEUROLOGICAL SYMPTOMS AND RENAL COPPER EXCRETION TION
#HOLESTATIC LIVER DISEASE -ALIGNANT OBSTRUCTION
3UBACUTE PRO GRESSIVE
0TS Y INCIDENCE INCREAS ING WITH AGE WEIGHT LOSS FEVER AND NIGHT SWEATS
$IAGNOSTIC IMAGING ENDO SCOPIC SCREENING IF APPLICA BLE AND BIOPSY OF IDENTIFIED LESIONS
"ILIARY CONCREMENTS
!CUTE RECURRENT
)NCIDENCE INCREASING WITH AGE M W COLIC RIGHT UPPER QUADRANT PAIN
$IAGNOSTIC IMAGING AND RET ROGRADE ENDOSCOPIC CHOLAN GIOGRAPHY
!UTOIMMUNE LIVER DISEASE !UTOIMMUNE #HRONIC UNDULA 0TS nY nY M W HEPATITIS TION OF REMISSION EXTRAHEPATIC AUTOIMMUNE AND INCREASED DISEASE ACTIVITY
-EDICAL HISTORY EXCLUSION OF OTHER LIVER DISEASE AUTOIMMUNE SEROLOGY PARTICULARLY !.! 3-! ,+- 3,!
0RIMARY SCLEROSING CHOLANGITIS
#HRONIC RECUR 0TS nY M W RECURRENT RENT FLARES OF CHOLANGITIS INFLAMMATORY INCREASED ACTIVITY BOWEL DISEASE COMPLICATING CHOLANGIOCARCINOMA
$IAGNOSTIC IMAGING AND RETROGRADE ENDOSCOPIC CHOLANGIOGRAPHY AUTO IMMUNE SEROLOGY PARTICU LARLY P!.#! AND !.!
0RIMARY BILIARY CIRRHOSIS
#HRONIC SLOWLY PROGRESSIVE
0TS Y M W EXTRAHEPATIC -EDICAL HISTORY HISTOLOGY AUTOIMMUNE DISEASE EXCLUSION OF OTHER LIVER DIS EASE AUTOIMMUNE SEROLOGY PARTICULARLY !-!
4OXIC HEPATITIS !LCOHOL TOXIC
#HRONIC AND )NCIDENCE INCREASING WITH ACUTE DEPENDING AGE M W ALCOHOL INTAKE ON ALCOHOL INTAKE OUTSIDE MEAL TIME AND n GDAY
-EDICAL HISTORY ALCOHOL SCREENING EXCLUSION OF OTHER LIVER DISEASE
/THER TOXIC AGENTS
#HRONIC ACUTE AND FULMINANT DEPENDING ON CAUSATIVE AGENT
$RUG HISTORY DRUG SCREEN ING EXCLUSION OF OTHER LIVER DISEASE
.EW OR CHRONIC MEDICATION INTENTIONAL OR ACCIDENTAL INTOXICATION
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
4ABLE CONTINUED .ATURAL COURSE
#HARACTERISTICS
$IAGNOSTIC TESTS
5NDERLYING DISEASE WITH DETERIORATION OF HEPATIC OR SYSTEMIC CIRCULATION
-EDICAL HISTORY IDENTIFICA TION OF CARDIO VASCULAR PATHOLOGY SEPSIS EXTENSIVE BURNS TRAUMA OR HEPATIC MALPERFUSION
)SCHAEMIC HEPATITIS #HRONIC ACUTE AND FULMINANT DEPENDING ON CAUSATIVE INSULT 0ARASITIC AND BACTERIAL HEPATITIS !CUTE AND 3YSTEMIC MANIFESTATIONS CHRONIC DEPEND DEPENDING ON UNDERLYING ING ON UNDERLYING PATHOGEN INFECTION
4RAVEL ANAMNESIS IMMUNE STATUS AND SPECIFIC MICRO BIAL HISTOLOGICAL AND SERO LOGICAL DIAGNOSTICS
0TS PATIENTS Y YEARS M MALE W FEMALE "-) BODY MASS INDEX !.! ANTI NUCLEAR ANTIBODY !-! ANTI MITOCHONDRIAL ANTIBODY P!.#! ANTI PERINUCLEAR NEUTROPHILE CYTOPLASMATIC ANTI BODY 3-! SMOOTH MUSCLE ANTIBODY ,+- LIVER KIDNEY MICROSOMAL ANTIBODY ,+- SOLUBLE LIVER ANTIGEN ANTIBODY
NEPHROPATHY OR 2AYNAUD 3YNDROME 3PECIFICALLY MEMBRANOUS GLOMERU LONEPHRITIS AND PANARTERITIS NODOSA OFTEN INVOLVING SPLANCHNIC ARTERIES ARE HIGHLY SUGGESTIVE FOR HEPATITIS " )N CONTRAST HEPATITIS # IS CLEARLY LINKED TO MIXED ESSENTIAL CRYOGLOBULINEMIA WHICH MAY ALSO CAUSE 2AYNAUD 3YNDROME RENAL IMPAIRMENT AND ARTHROPATHY 4HE ASSOCIATION OF CHRONIC HEPATITIS # WITH LYMPHOPROLIFERATIVE DISEASES HAS NOT BEEN DEFINED AS WELL BUT SHOULD BE CONSIDERED ;= -OREOVER VIRAL HEPATITIS COULD PROVOKE OTHER MANIFES TATIONS INCLUDING NEURITIS MYELITIS 'UILLAIN "ARRÏ SYNDROME ;= 3JOGRENS SYNDROME ;= CARDIOMYOPATHY ;= AND LICHEN PLANUS ;=
$IFFERENTIATION OF OTHER CAUSES OF LIVER DAMAGE $ESPITE VIRAL HEPATITIS BEING ONE OF THE LEADING CAUSES OF HUMAN HEPATITIS WORLDWIDE OTHER HEPATIC PATHOLOGIES SHOULD BE IDENTIFIED BY CLINICAL HIS TORY $IFFERENTIAL DIAGNOSIS RANGES FROM COMMON TOXIC OR ISCHAEMIC EVENTS HEREDITARY ENTITIES TO AUTOIMMUNE DISEASES WHICH MANIFEST AS ACUTE OR CHRONIC LIVER DISEASE 0RIOR TO ACCURATE DIAGNOSIS OF A SPECIFIC HEPATIC PATHOL OGY OTHER DEFINED DISEASE ENTITIES MUST FIRST BE EXCLUDED
.ON ALCOHOLIC STEATOHEPATITIS 0ARTICULARLY HEPATIC STEATOSIS ANDOR NON ALCOHOLIC STEATOHEPATITIS .!3( HAVE BECOME AN INCREASING MEDICAL BURDEN IN INDUSTRIALISED COUNTRIES
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
REQUIRING DIAGNOSTIC ATTENTION $EPENDING ON THE ANALYSED COHORT BETWEEN AND OF THE GENERAL POPULATION ARE AFFECTED BY HEPATIC STEATOSIS ;= (ENCE POPULATION BASED SURVEYS HAVE ALSO STATED THAT HEPATIC STEATOSIS OR .!3( MIGHT BE RESPONSIBLE FOR n OF PATIENTS WITH ELEVATED LIVER ENZYMES ; = 4HIS GROUP OF PATIENTS IS CHARACTERISED BY RISK FACTORS WHICH COULD BE IDENTIFIED BY CLINICAL HISTORY 3PECIFICALLY OBESE PATIENTS "-) KGM HAVE A HIGH PREVALENCE OF STEATOSIS HEPATITIS COMPARED TO NON OBESE INDIVIDUALS "-) KGM WHO SHOW A PREVALENCE OF ONLY ;= %NLARGED WAIST CIRCUMFERENCE ETHNIC BACKGROUND AND DIABETES MELLITUS ARE FURTHER RISK FACTORS OF HEPATIC STEATOSIS ;= $IFFERENT STUDIES SUGGEST THAT PATIENTS WITH STEATOSIS MAY DEVELOP .!3( IN n OR EVEN END UP WITH CIRRHOSIS IN n OF ALL CASES ;= $IFFERENTIATION FROM VIRAL HEPATITIS IS HAMPERED BY THE FACT THAT CHRONIC VIRAL INFLAMMATION INDUCES HEPATIC STEATOSIS AND THAT STEATOSIS PROMOTES DISEASE PROGRESSION OF CHRONIC VIRAL HEPATITIS
4OXIC HEPATITIS 4OXIC HEPATITIS IS A FURTHER IMPORTANT DIFFERENTIAL DIAGNOSIS WHICH IS OFTEN LINKED TO CHRONIC ALCOHOL CONSUMPTION OR HEPATOTOXIC MEDICATION 4HE OVERALL PREVALENCE OF ALCOHOL RELATED LIVER DISEASE IS HIGHER IN MALE PATIENTS AND INCREASES WITH AGE !LCOHOLIC LIVER DISEASE SHOULD BE STRONGLY SUSPECTED IN PATIENTS WITH AN ALCOHOL CONSUMPTION MORE THAN n GDAY WHICH EQUALS A DAILY INDULGENCE OF ABOUT L BEER L WINE OR ML DISTILLED SPIRITS ;= 3PECIFIC DRINKING HABITS LIKE ALCOHOL CONSUMPTION OUTSIDE MEAL TIMES SHOULD ALSO BE RECOGNISED AS RISK FACTORS FOR ALCOHOLIC LIVER DISEASE ;= #OMPARED TO MEN WHO SHOW A HIGHER PREVALENCE OF ALCOHOLIC LIVER DISEASE FEMALE INDIVIDUALS CONSUMING ALCOHOL ON A REGULAR BASIS ARE AT HIGHER RISK OF DEVELOPING ALCOHOL RELATED LIVER DISEASE ;= #LEAR AETIOLOGI CAL DIFFERENTIATION OF LIVER DAMAGE DURING CHRONIC ALCOHOL CONSUMPTION IS HINDERED BY A RELEVANT PROPORTION OF PATIENTS WITH ADDITIONAL VIRAL HEPATITIS ANDOR OBESITY ;= 4O IDENTIFY OTHER CAUSES OF TOXIC HEPATITIS CLINICAL HIS TORY SHOULD FOCUS ON MEDICATIONS WHICH WERE STARTED WITHIN n MONTHS PRIOR TO ONSET OF LIVER DAMAGE .EW MEDICATIONS ARE OFTEN RESPONSIBLE FOR HEPATOTOXICITY %VEN MEDICATIONS WHICH WERE ADMINISTERED FOR MORE THAN MONTHS HAVE BEEN IDENTIFIED AS CAUSATIVE HEPATOTOXIC AGENTS )N WESTERN COUNTRIES ACETAMINOPHEN IS THE NUMBER ONE CAUSE OF ACUTE LIVER FAILURE LEADING TO LIVER TRANSPLANTATION !S LIFE THREATENING AMOUNTS OF HEPATOTOXIC AGENTS ARE REGULARLY INGESTED DURING SUICIDAL ATTEMPTS ANAMNESIS SHOULD ALSO FOCUS ON LIFE CRISIS AND DEPRESSIVE SYMPTOMS &URTHERMORE DRUGS LIKE AMPHETAMINES AND COCAINE HAVE BEEN ASSOCIATED WITH ACUTE LIVER DAMAGE AND SHOULD BE SCREENED )N %UROPE ACCIDENTAL INGESTION OF FUNGAL TOXIN DEATH CAP MUSHROOM !MANITA PHALLOIDES HAS TO BE CONSIDERED DURING ASSESSMENT OF LIVER FAILURE
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
)SCHAEMIC HEPATITIS ! FURTHER FOCUS SHOULD BE SET ON ISCHAEMIC HEPATITIS CAUSED BY SEVERE HYPOTENSION LIVER CONGESTION AND THROMBO EMBOLIC EVENTS !S ISCHAEMIC HEPATITIS USUALLY AFFECTS CRITICALLY ILL PATIENTS CLINICAL HISTORY SHOULD RECOG NISE CHRONIC HEART FAILURE MYOCARDIAL INFARCTION ARRHYTHMIAS EXTENSIVE TRAUMA AND SEPSIS ;= #HRONIC HEPATIC CONGESTION DUE TO CARDIAC INSUF FICIENCY MIGHT EVEN CAUSE FIBROTIC REMODELLING AND END STAGE LIVER DISEASE ;= &INALLY LIVER SPECIFIC VASCULAR PATHOLOGIES OF THE LIVER LIKE "UDD #HIARI SYNDROME AND VENO OCCLUSIVE DISEASE CONTRIBUTE TO ACUTE AND CHRONIC HEPATIC DAMAGE AS WELL ; = )SCHAEMIC HEPATITIS USUALLY DOES NOT PRESENT WITH PROLONGED SUB CLINICAL PERIODS AND MIMICS THE CLINICAL PICTURE OF ACUTE HEPATITIS 4HE INTERVAL BETWEEN THE INITIAL ISCHAEMIC EVENT AND THE CLINICAL MANIFESTATION OF HEPATIC DAMAGE ONLY TAKES HOURS $EPENDING ON THE EXTENT OF ISCHAEMIC LIVER DAMAGE LIVER FAILURE AND ITS COMPLICATIONS MAY ENSUE 4HE SYMPTOMS OF ACUTE LIVER DAMAGE ARE ESSENTIALLY THE SAME AS FOR VIRAL HEPATITIS STATED BEFORE THOUGH EXTRAHEPATIC MANIFESTATIONS RESEMBLE THE UNDERLYING PATHOLOGY
(EREDITARY LIVER DISEASE (EREDITARY LIVER DISEASES MAY ALSO PRESENT WITH HEPATITIS TYPE LIVER DAMAGE (AEMOCHROMATOSIS IS THE MOST COMMON HEREDITARY DISEASE OF THE CAUCASIAN POPULATION (AEMOCHROMATOSIS SHOULD BE SUSPECTED IF MALE PATIENTS USU ALLY OLDER THAN YEARS PRESENT WITH SIGNS OF LIVER DAMAGE )RON OVERLOAD ALSO AFFECTS THE ENDOCRINE PANCREAS AND DIABETES MELLITUS MIGHT BE ASSOCI ATED WITH HAEMOCHROMATOSIS &URTHER INDICATORS FOR HAEMOCHROMATOSIS ARE ATYPICAL CARDIAC DISEASE UNEXPLAINED ARTHROPATHY OR MALE SEXUAL DYSFUNC TION &OR FIRST DEGREE RELATIVES OF PATIENTS SUFFERING FROM HAEMOCHROMATOSIS FURTHER DIAGNOSTIC WORKUP IS ALSO RECOMMENDED ;= 7ILSONS DISEASE MAY MIMIC DIVERSE HEPATIC ENTITIES RANGING FROM ACUTE HEPATIC FAILURE TO CIRRHO SIS !LTHOUGH IT IS A RARE ENTITY 7ILSONS DISEASE SHOULD THEREFORE BE INCLUDED IN DIFFERENTIAL DIAGNOSIS OF ACUTE AND CHRONIC HEPATITIS 0ARTICULARLY PATIENTS BETWEEN AND YEARS OF AGE SHOULD BE SCREENED FOR 7ILSONS DISEASE 0ATIENTS HIGHLY SUSPICIOUS FOR 7ILSONS DISEASE ARE THOSE WITH NEUROLOGICAL FINDINGS IN ADDITION TO HEPATIC PATHOLOGY 4HE SPECTRUM OF NEUROLOGICAL SIGNS INCLUDES TREMOR ATAXIA AND SEIZURES 0SYCHIATRIC SYMPTOMS INCLUDING DEPRES SION NEUROSIS OR EVEN FRANK PSYCHOSIS HAVE BEEN OBSERVED &INALLY OTHER ORGAN SYSTEMS INCLUDING THE HEART AND KIDNEY MIGHT BE AFFECTED BY 7ILSONS DISEASE ;= !LPHA ANTITRYPSIN !4 DEFICIENCY WHICH AFFECTS ABOUT IN n NEWBORNS SHOULD ALSO BE INCLUDED IN DIFFERENTIAL DIAGNOSIS 4HE CLINICAL PICTURE OF !4 DEFICIENCY IS USUALLY RESTRICTED TO SIGNS OF HEPATIC AND PULMONARY DISEASE (EPATIC MANIFESTATIONS MIGHT RANGE FROM ELEVATED LIVER ENZYMES ANDOR JAUNDICE TO LIVER CIRRHOSIS !S THE LIFETIME RISK OF LIVER
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
CIRRHOSIS IS ABOUT n IN PATIENTS SHOWING !4 DEFICIENCY PATIENTS WITH UNEXPLAINED LIVER DAMAGE SHOULD UNDERGO DIAGNOSTIC SCREENING FOR THIS ENTITY ;=
!UTOIMMUNE DISEASE !UTOIMMUNE HEPATITIS !)( IS THE PREDOMINANT AUTOIMMUNE DISEASE AFFECTING THE LIVER )N %UROPE !)( SHOWS AN INCIDENCE OF IN PER SONS PER YEAR ;= !)( SHOWS A BIPOLAR INCIDENCE DURING LIFETIME WITH A JUVENILE AND AN ADULT PEAK 2ECENT OBSERVATIONS SUGGEST THAT !)( MAY ALSO BE COMMON IN THE ELDERLY POPULATION !)( MAY PRESENT AS ACUTE HEPATIC DETERIORATION OR AS CHRONIC LIVER DAMAGE AND CIRRHOSIS !N INCONSISTENT COURSE WITH HEPATIC FLARE UPS AND PERIODS OF REMISSION IS REGULARLY OBSERVED DURING !)( 4HE DIAGNOSIS OF !)( IS BASED ON A DEFINED CLINICAL AND SERO LOGICAL SCORING SYSTEM THAT REQUIRES THE STRICT EXCLUSION OF OTHER HEPATIC PATHOLOGIES SUCH AS VIRAL TOXIC OR CHOLESTATIC LIVER DISEASE ;= 0ARTICULARLY !)( SHOULD BE EXCLUDED IN EVERY PATIENT WHO ALSO PRESENTS WITH OTHER AUTOIMMUNE DISEASES !S !)( IS ASSOCIATED WITH GENETIC FACTORS LIKE (,! $2 AND $2 A POSITIVE FAMILY HISTORY MIGHT LEAD TO !)( ;= #HRONIC AUTOIMMUNE PATHOLOGIES AFFECTING THE BILE DUCTS LIKE PRIMARY BILIARY CIR RHOSIS 0"# AND PRIMARY SCLEROSING CHOLANGITIS 03# ALSO MIMIC CHRONIC HUMAN HEPATITIS AND REGULARLY LEAD TO LIVER CIRRHOSIS AND END STAGE LIVER DISEASE 7HEREAS 0"# IS CHARACTERISED BY A GRADUAL PROGRESS OF CHOLESTATIC MANIFESTATIONS AND LIVER DAMAGE 03# IS OFTEN COMPLICATED BY RECURRING CHOLESTATIC EPISODES $ETERIORATION OF CHOLESTATIC SYMPTOMS DURING 03# ARE USUALLY CAUSED BY RECURRENT CHOLANGITIS 4HEY MAY FOLLOW BILIARY INTERVEN TIONS OR ARE BASED ON OBSTRUCTION BY DE NOVO CHOLANGIOCARCINOMA 03# USUALLY AFFECTS MALE PATIENTS AND MANIFESTS ITSELF BETWEEN THE TH AND TH DECADE OF LIFE !BOUT OF ALL 03# PATIENTS ALSO SUFFER FROM INFLAMMA TORY BOWEL DISEASE PREDOMINANTLY ULCERATIVE COLITIS ;= 0"# PRIMARILY AFFECTS WOMEN AND USUALLY DOES NOT MANIFEST IN PATIENTS YOUNGER THAN YEARS "EFORE LIVER DAMAGE HAS CAUSED VISUAL SIGN OF JAUNDICE AND CIRRHOSIS PATIENTS OFTEN REPORT ABOUT CHRONIC PRURITUS &URTHERMORE AUTOIMMUNE DISEASE LIKE 3JOGRENS SYNDROME AND 3CLERODERMIA ARE ASSOCIATED WITH 0"# "ESIDE DISTINCT 03# 0"# AND !)( OVERLAP SYNDROMES BETWEEN THESE THREE PATHOLOGIES ARE POSSIBLE ;=
#HOLESTASIS AND PATHOLOGIES OF BILIRUBIN HOMEOSTASIS "ESIDE PARENCHYMAL LIVER DAMAGE CHOLESTATIC DISEASES HAVE TO BE CONSID ERED IN THE DIFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS -ECHANIC BILIARY TRACT OBSTRUCTION BY GALLSTONES AND MALIGNANCIES ARE THE MOST COMMON PATHOLO GIES AFFECTING THE BILIARY TREE "OTH ARE ASSOCIATED WITH TYPICAL PRESENTATION
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
EXAMINATION FINDINGS AND CLINICAL HISTORY MIGHT ALREADY ALLOW FOR DIFFEREN TIATION 4HUS MALIGNANCIES SHOULD BE STRONGLY CONSIDERED IN PATIENTS COM PLAINING ABOUT ANOREXIA LOSS OF APPETITE NIGHT SWEATS AND FEVER )N CONTRAST GALLSTONES USUALLY PRESENT WITH POSTPRANDIAL COLIC PAIN OF THE RIGHT UPPER ABDOMEN 0ARTICULARLY FEMALE FERTILE AND OBESE PATIENTS ARE AT HIGHER RISK TO DEVELOP GALLSTONES )F BILE DUCT OBSTRUCTION HAS BEEN EXCLUDED HAEMOLYSIS SHOULD BE INCLUD ED INTO DIAGNOSTIC WORKUP 3EVERAL HEREDITARY INFECTIOUS AND HAEMATOLOGIC ENTITIES ARE POSSIBLE CAUSES AND LABORATORY TESTING FOR HAEMOLYSIS SHOULD BE INCLUDED AS AN INITIAL STEP TOWARDS DIFFERENTIAL DIAGNOSE -ILD HYPERBILIRUBI NAEMIA RESULTING FROM HEREDITARY DEFICIENCY OF BILIRUBIN METABOLISM SHOULD COMPLETE DIFFERENTIATION OF JAUNDICE
"ACTERIAL AND PARASITIC HEPATITIS 3EVERAL BACTERIAL OR PARASITIC INFECTIONS AFFECT THE LIVER EITHER DUE TO DIRECT HEPATIC INVOLVEMENT OR DUE TO EFFECTS OF SYSTEMIC INFLAMMATION "ACTERIAL LIVER ABSCESS USED TO BE A FREQUENT INFECTIOUS COMPLICATION BUT THE INCIDENCE HAS DECLINED SINCE POTENT ANTIBIOTICS HAVE BEEN AVAILABLE "ACTERIAL LIVER ABSCESSES ARE USUALLY POLYMICROBIAL INCLUDING AEROBIC 'RAM NEGATIVE OR 'RAM POSITIVE SPECIES AS WELL AS ANAEROBIC BACTERIA ;= 4HE BACTERIA REACH THE LIVER EITHER BY THE BILIARY OR THE HAEMATOLOGICAL ROUTE !S A CONSEQUENCE THE BILIARY AND SPLANCHNIC SYSTEM SHOULD BE INTENSIVELY SCREENED FOR BACTE RIAL FOCI !MEBIC ABSCESSES ARE PARTICULARLY OBSERVED IN PATIENTS ORIGINAT ING FROM ENDEMIC AREAS OR WITH POSITIVE TRAVEL ANAMNESIS #LINICAL HISTORY DIFFERENTIATES PRECEDING BLOODY DIARRHOEA WHICH CHARACTERISE AMEBIASIS IN ONLY OF ALL CASES ;= "ESIDE COMMON COMMENSAL BACTERIA MANY OTHER BACTERIAL PATHOGENS INCLUDING TYPHOID FEVER AND BRUCELLOSIS MIGHT CAUSE HEPATIC DETERIORATION ,EPTOSPIROSIS A VERY COMMON ZOONOSIS HAS TO BE CONSIDERED IF ACUTE FLU LIKE SYMPTOMS ARE ACCOMPANIED BY HAEMOLYTIC JAUNDICE AND RENAL IMPAIRMENT !LSO SECONDARY SYPHILIS SHOWS LIVER INVOLVE MENT WITH HEPATITIS IN UP TO OF ALL CASES "ESIDE NON SPECIFIC GENERAL SYMPTOMS LYMPHADENOPATHY AND CHARACTERISTIC MACULOPAPULAR RASH OF THE PALM AND SOLES MAY BE OBSERVED &OR PATIENTS WITH A POSITIVE TRAVEL HISTORY SCHISTOSOMIASIS AND MALARIA ARE IMPORTANT DIFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS 0ARTICULARLY SCHIS TOSOMIASIS CONTRIBUTES TO A LARGE NUMBER OF PATIENTS WITH LIVER FIBROSIS WORLDWIDE AND HAS TO BE CONSIDERED IN PATIENTS ORIGINATING FROM ENDEMIC AREAS IN %ASTERN !SIA AND .ORTHERN !FRICA !S RECURRENT SCHISTOSOMIASIS MAY AGGRAVATE PROGRESSION OF CHRONIC VIRAL HEPATITIS BOTH ENTITIES REQUIRE DIAGNOSTIC ATTENTION AND TREATMENT 0ARTICULARLY IN %GYPT WHERE EFFORTS TO ERADICATE SCHISTOSOMIASIS WITH INTRAVENOUS MEDICATIONS HAVE CONTRIBUTED TO A HIGH (#6 PREVALENCE BY CONTAMINATED SYRINGES CO INFECTIONS WITH BOTH ENTITIES HAVE BECOME A SERIOUS MEDICAL BURDEN ;= -ALARIA TRANSIENTLY
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
AFFECTS THE LIVER THROUGHOUT ITS LIFECYCLE AND CAUSES HAEMOLYTIC JAUNDICE DURING ERYTHROCYTIC STAGES .EVERTHELESS HEPATOCYTE DAMAGE IS OBSERVED PREDOMINANTLY DURING 0LASMODIUM FALCIPARUM INFECTIONS AND PARTICULARLY IN PATIENTS WITH UNDERLYING VIRAL HEPATITIS ACUTE LIVER FAILURE HAS BEEN DOCU MENTED ;=
$IAGNOSTIC TESTS ,IVER ENZYMES )N UP TO OF ALL CASES ACUTE HEPATITIS DOES NOT PRESENT WITH CLINICAL SYMP TOMS SO LABORATORY FINDINGS ARE OFTEN THE ONLY INDICATORS FOR HEPATITIS AND HELP TO DIFFERENTIATE THE CAUSES OF LIVER DAMAGE ! POPULATION BASED SURVEY IN %UROPE FOR EXAMPLE HAS IDENTIFIED ELEVATED LIVER ENZYMES DEFINED AS TIMES THE UPPER REFERENCE LIMIT 52, IN UP TO OF THE GENERAL POPULATION %LEVATION OF ALANINE AMINOTRANSFERASE !,4 ANDOR ASPARTATE AMINO TRANSFERASE !34 TEN TIMES BEYOND THE 52, ARE RELIABLE MARKERS TO DIS CRIMINATE ACUTE HEPATIC DAMAGE FROM UNSPECIFIC OR CHRONIC CAUSES OF !,4 AND !34 ELEVATIONS #UT OFF VALUES TO IDENTIFY ACUTE HEPATIC INJURY ARE 5L FOR !34 SENSITIVITY SPECIFICITY AND 5L FOR !,4 SENSI TIVITY SPECIFICITY ;= ! PROPORTION OF UP TO OF MILD LIVER ENZYME ELEVATIONS X 52, WERE ASSOCIATED WITH VIRAL HEPATITIS IN INDUSTRIALISED COUNTRIES AND THE NUMBERS ARE DECLINING DUE TO VACCINATION AND SCREENING EFFORTS %LEVATED !,4 = 52, OCCURS IN OF (#6 POSITIVE INDIVIDUALS AND IN DURING ("6 INFECTION ;= )N CONTRAST ONLY ABOUT OF PRONOUNCED !34 ELEVATIONS 5L ARE CAUSED BY VIRAL HEPATITIS IN THE PATIENTS ATTENDING CLINIC ;= +INETICS OF !34 AND !,4 ELEVATIONS DURING ACUTE VIRAL HEPATITIS ARE CHARACTERISED BY A GRADUAL SLOPE WHICH REACHES ITS MAXIMUM AFTER A VARIABLE PERIOD OF THREE OR MORE WEEKS FROM ONSET OF FIRST ENZYME ELEVATION $URING FURTHER TIME COURSE THE !34 AND !,4 LEVELS DECLINE GRADUALLY !34 !,4 2ATIO ARE REGULARLY OBSERVED DURING VIRAL HEPATITIS IN ABOUT OF THE INFECTED PATIENTS ;= 4HOUGH VIRAL HEPATITIS IS NOT THE MAIN CAUSE WHICH IS RESPONSIBLE FOR SEVERE LIVER DAMAGE LABORATORY FINDINGS OCCUR IN OTHER SETTINGS )N A SIGNIFICANT PROPORTION OF PATIENTS WITH INCIDENTALLY DIAGNOSED !34 ELEVATIONS 5L IT WAS ATTRIBUTED TO ISCHAEMIC HEPATIC EVENTS 0ARTICULARLY DURING VERY HIGH !34 AND !,4 ELEVATIONS 5L ISCHAEMIC HEPATITIS SHOULD BE CONSIDERED 4HIS LABORATORY FINDINGS FURTHER LIMITS THE SPECTRUM OF POTENTIAL DIFFERENTIAL DIAGNOSIS TO ISCHAEMIC TOXIC OR ACUTE VIRAL HEPATITIS ;= #LINICAL OBSERVATIONS OF ISCHAEMIC HEPATITIS HAVE SHOWN THAT THE MEDIAN PEAK !,4 LEVEL REACHES 5L DURING CONGESTIVE HEART FAILURE AND 5L DURING HYPOXEMIA ;= !T TIME OF CLINICAL ADMISSION PATIENTS
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
4ABLE #HARACTERISTIC LABORATORY PATTERNS OF HUMAN HEPATITIS $ISEASE 6IRAL HEPATITIS
PEAK !,4 =52,
!34!,4 RATIO
PEAK "ILI MGDL
04 SECONDS
n
!LCOHOLIC HEPATITIS
n
n
4OXIC HEPATITIS
EARLY
TRANSIENT
)SCHEMIC HEPATITIS
EARLY
TRANSIENT
=52, TIMES UPPER REFERENCE LIMIT 04 PROTHROMBIN TIME PROLONGATION
&IGURE $IAGNOSTIC ALGORITHM OF VIRAL HEPATITIS
WITH ISCHAEMIC HEPATITIS OFTEN HAVE ALREADY REACHED MAXIMUM PEAK !,4 VALUES SUGGESTING THAT THE ISCHAEMIC EVENT CAUSES A FAST AND STEEP INCLINE OF LIVER ENZYMES PRIOR TO CLINICAL ADMISSION 4HEREFORE THE ISCHAEMIC EVENT ITSELF IS REGULARLY NOT WITNESSED BY THE CLINICIAN $URING FURTHER FOLLOW UP
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
A FAST DECLINE OF LIVER ENZYMES IS TYPICALLY OBSERVED DURING ISCHAEMIC LIVER DAMAGE )SCHAEMIC HEPATITIS IS ALSO CHARACTERISED BY A LACTATE DEHYDROGE NASE ,$( ELEVATION WHICH REACHES MEDIAN PEAK LEVEL 5L ;= 4HE MEAN !,4,$( RATIO IS SIGNIFICANTLY LOWER DURING ISCHAEMIC HEPATITIS COMPARED TO VIRAL HEPATITIS AND A !,4,$( RATIO IS USEFUL TO DIFFEREN TIATE ISCHAEMIC HEPATITIS FROM VIRAL HEPATITIS WITH A SENSITIVITY OF AND A SPECIFICITY OF ;= 4OXIC HEPATITIS SHARES SEVERAL LABORATORY FEATURES OF ISCHAEMIC HEPATITIS "ESIDE FAST KINETICS AND HIGH PEAK LEVELS OF LIVER ENZYME ALTERATIONS THE !,4,$( RATIO USUALLY DOES NOT EXCEED A CUT OFF VALUE OF ;= $ESPITE THE DIFFERENT CHARACTERISTICS OF TOXIC HEPATITIS THE DIAGNOSIS IS OFTEN MISSED 4HE LEADING FACTOR TOWARDS THE RIGHT DIAGNOSIS IS A CAREFUL HISTORY OF TOXIN OR DRUG EXPOSITION 5NCOMPLICATED ALCOHOLIC HEPATITIS IS THE MOST COMMON TOXIC HEPATITIS AND USUALLY PRESENTS WITH MILD LABORATORY ALTERATIONS $URING UNCOMPLICATED ALCOHOLIC HEPATITIS AMINOTRANSFERASES OFTEN DO NOT EXCEED TIMES THE UPPER REFERENCE LIMIT )T HAS BEEN SHOWN THAT !34!,4 RATIO IS REASONABLY SPECIFIC TO IDENTIFY ALCOHOLIC HEPATITIS FROM OTHER CAUSES OF ACUTE LIVER DAMAGE AND THE MAJORITY OF PATIENTS n WITH ALCOHOLIC HEPATITIS SHOW AN !34!,4 RATIO ;= )N THE GENERAL POPULATION PRESENTING WITH !34 ELEVATIONS 5L ALMOST OF ALL CASES WERE CONTRIBUTED TO CHOLESTATIC DISEASE ;= ,IVER ENZYME ELEVATION DURING MECHANICAL BILIARY OBSTRUCTION EXCEEDS 5L IN n #HARACTERISTICALLY THE ELEVATED LIVER ENZYMES RESOLVE WITHIN A WEEK DESPITE PERSISTING CHOLESTASIS ;= 3ERUM ALKALINE PHOSPHATASE !0 DERIVED FROM THE CHOLANGIAL EPITHELIAL IS AN IMPORTANT LABORATORY INDICATOR FOR CHOLESTASIS -ILD !0 ELEVATIONS BELOW THREE TIMES THE REFERENCE LIMIT ARE CONSIDERED NON SPECIFIC AND MAY OCCUR DURING OTHER HEPATIC PATHOLOGIES )N CONTRAST STRIKING !0 ELEVATIONS STRONGLY SUGGEST BILE DUCT OBSTRUCTION IF EXTRAHEPATIC SKELETAL SOURCES OF !0 HAVE BEEN EXCLUDED 'AMMA GLU TAMYL TRANSPEPTIDASE ''4 IS CONSIDERED TO BE MORE SPECIFIC FOR HEPATIC PATHOLOGIES BECAUSE NO RELEVANT QUANTITIES OF ''4 ARE FOUND IN BONE TIS SUE !S ''4 IS MAINLY LOCATED IN THE MICROSOMAL CELLULAR COMPARTMENT IT MAY BE INDUCED BY ALCOHOL AND TOXIC DRUGS )F ''4 INDUCTION IS SUSPECTED THE !0''4 RATIO OFFERS A HELPFUL PARAMETER TO IDENTIFY CHOLESTATIC DISEASE $URING CHRONIC HEPATITIS ELEVATION OF LIVER ENZYMES SHOWS VARI ABLE PROFILES AND IS EVEN MISSING IN A RELEVANT PROPORTION OF PATIENTS 4HEREFORE THE DIAGNOSTIC VALUE TO DIFFERENTIATE THE CAUSES OF CHRONIC LIVER DAMAGE OR CHRONIC HEPATITIS IS RELATIVELY LOW .EVERTHELESS THE !34!,4 RATIO HELPS TO IDENTIFY LIVER CIRRHOSIS IN PATIENTS WITH CHRONIC LIVER DISEASE OF DIFFERENT AETIOLOGY IF ALCOHOLIC LIVER DISEASE HAS BEEN EXCLUDED ;n= !S MENTIONED BEFORE COMBINATIONS OF LABORATORY PARAMETERS LIKE !34 !,4 AND !,4,$( RATIO OR ADDITIONAL TESTING OF CHOLESTATIC PARAM ETERS MIGHT HELP TO INCREASE DISCRIMINATORY POWER OF LIVER TESTS REGARDING CHRONIC ENTITIES
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
0ARAMETERS OF LIVER FUNCTION ,IVER FUNCTION TESTS ARE MAINLY BASED ON ANALYSIS OF SERUM BILIRUBIN PRO THROMBINE TIME AND ALBUMIN 4IME COURSE AND QUANTITY OF IMPAIRED LIVER FUNCTION PROVIDES ADDITIONAL SPECIFICATIONS OF DIFFERENT PATHOLOGIES AND THEIR PROGNOSIS (YPERBILIRUBINAEMIA MAY INDICATE HEPATITIS AND USUALLY SHOWS DELAYED KINETICS COMPARED TO AMINOTRANSFERASE LEVELS 4OTAL SERUM BILIRUBIN CONSISTS OF A MAJOR CONJUGATED DIRECT AND A MINOR UNCONJU GATED INDIRECT FRACTION )F HEPATOCELLULAR MALFUNCTION AND HEPATOBILIARY OBSTRUCTION IS RESPONSIBLE FOR HYPERBILIRUBINAEMIA THE PROPORTION OF DIRECT BILIRUBIN USUALLY DOES NOT FALL BELOW (ENCE LOWER CONCENTRATIONS OF DIRECT BILIRUBIN SUGGEST ANOTHER CAUSE FOR JAUNDICE SUCH AS HAEMOLYSIS ;= $ESPITE THE FACT THAT HYPERBILIRUBINAEMIA IS ASSOCIATED WITH LIVER DAMAGE JAUNDICE IS AN INCONSISTENT FINDING DURING ACUTE VIRAL HEPATITIS 0ARTICULARLY CHILDREN WITH ACUTE VIRAL HEPATITIS OFTEN DO NOT DEVELOP JAUNDICE OR SHOW MILD BILIRUBIN ELEVATIONS ! CLINICAL OBSERVATION DESCRIBED PEAK BILIRUBIN MMOLL MGDL IN ONLY OF CHILDREN WITH ACUTE HEPATITIS ;= )N CONTRAST ADULTS MAY DEVELOP JAUNDICE IN OF CASES OF ACUTE HEPATITIS ! ;= n OF CASES OF ACUTE HEPATITIS " ; = AND ABOUT OF CASES OF ACUTE HEPATITIS # ;= "ILIRUBIN PROTHROMBINE TIME 04 AND SERUM ALBUMIN HELP TO ESTIMATE PROGNOSIS OF ACUTE AND CHRONIC HEPATIC DISEASE AS THE DETERIORATION OF LIVER FUNCTION MIGHT BE ASSOCIATED WITH WORSE OUTCOME &OR ACUTE HEPATIC DAM AGE A 04 CUT OFF SECONDS INTERNATIONAL NORMALISED RATIO A TOTAL SERUM BILIRUBIN GDL MMOLL AND ALBUMIN GL INDICATES SEVERE LIVER DAMAGE OR PREDICTS LIKELIHOOD OF DEATH ;= !SSESSMENT OF CHRONIC HEPATIC DAMAGE RELIES ON SIMILAR VARIABLES BUT OTHER CUT OFF VALUES HAVE BEEN DEFINED TO ESTIMATE THE OUTCOME )N CONCLUSION SOME OF THESE LABORA TORY PARAMETERS HAVE BEEN INCLUDED INTO STANDARDISED ASSESSMENT OF ACUTE AND CHRONIC LIVER FAILURE AND ARE IMPORTANT TO DEFINE THE INDICATION FOR LIVER TRANSPLANTATION FOR DIFFERENT AETIOLOGIES ;n=
3PECIFIC SEROLOGICAL AND MOLECULAR TESTS 3INCE THE INTRODUCTION OF SPECIFIC SEROLOGICAL AND MOLECULAR TESTS FOR DIFFER ENT TYPES OF VIRAL HEPATITIS THEY ARE THE MOST IMPORTANT DIAGNOSTIC TOOL TO CONFIRM OR RULE OUT DIFFERENT ENTITIES OF HEPATITIS )N ADDITION AUTOIMMUNE SEROLOGY IS ABLE TO NARROW THE PANEL OF DIFFERENTIAL DIAGNOSIS OF AUTOIM MUNE MEDIATED LIVER DISEASES )MMUNOGLOBULIN - ANTIBODIES AGAINST (!6 ANTI (!6 )G- ARE TYPI CALLY PRESENT AT ONSET OF SYMPTOMS AND REMAIN DETECTABLE FOR AN AVERAGE OF n MONTHS AFTER INFECTION 3OME SEROLOGICAL STUDIES SUGGEST THAT POSITIVE (!6 )G- FOR MORE THAN MONTHS PRESENT IN ONLY ABOUT OF ALL CASES )N CONTRAST TOTAL ANTI (!6 )G' TITRES ARE VERY DURABLE AND PERSIST FOR LONG
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
PERIODS AFTER INFECTION 4HEREFORE DETECTION OF (!6 )G- IS CONSIDERED AS ROUTINE TEST TO IDENTIFY ACUTE (!6 INFECTION AND (!6 )G' RESEMBLES PAST EXPOSURE AND IMMUNITY AGAINST (!6 ;= %NZYME IMMUNOABSORBENT ASSAYS %)! ARE STANDARD DIAGNOSTIC TESTS TO IDENTIFY ACUTE OR CHRONIC HEPATITIS " VIRUS INFECTION 4HE STANDARD SCREENING TESTS ARE ABLE TO IDENTIFY ("6 INFECTION AS EARLY AS n WEEKS PRIOR TO THE ONSET OF SYMPTOMS OF ACUTE HEPATITIS " 4HE RECOMMENDED STANDARD SCREEN ING TEST FOR ("6 IS BASED ON THE DETECTION OF HEPATITIS " SURFACE ANTIGEN ("S!G AND HEPATITIS " CORE ANTIGEN ("C!G SPECIFIC ANTIBODIES )N A SMALL PROPORTION OF PATIENTS ("S!G TARGETED ASSAYS FAIL TO DETECT ("6 INFECTION 4HESE FALSE NEGATIVE ("S!G TESTS RESULT FROM ("S!G TITRES BELOW THE DETECTION LIMIT DURING CHRONIC ("6 INFECTION AND FROM ("S!G ESCAPE MUTATIONS WHICH ARE NOT DETECTED BY ANTIBODIES EMPLOYED FOR ROUTINE SCREENING 4ESTS AGAINST ("E!G AND ("6 NUCLEIC ACIDS ARE RECOMMENDED COMPLEMENTARY TESTS TO IDENTIFY ACTIVE ("6 REPLICATION )N CONTRAST NEU TRALISING ANTI ("S!G ANTIBODIES )5ML INDICATE AN ELIMINATED ("6 INFECTION OR IMMUNISATION AGAINST ("6 ;= )N PATIENTS WITH POSITIVE ("S!G TITRES AND A HIGH RISK OF ($6 INFECTION ASSAYS OF TOTAL ANTI ($6 ANTIBODIES ARE CONSIDERED AS SUFFICIENT TEST TO IDENTIFY HEPATITIS $ CO OR SUPER INFECTION &IRST GENERATION %)!S TO DETECT ANTI (#6 SPECIFIC IMMUNGLOBULINS HAVE BEEN INTRODUCED BY AS SCREENING FOR (#6 INFECTION ;= .OWADAYS THIRD GENERATION %)!S ARE IMPLEMENTED IN CLINICAL PRACTICE WHICH DETECT A PANEL OF SPECIFIC IMMUNGLOBULINS AGAINST EPITOPES OF DIFFERENT STRUCTURAL AND NON STRUCTURAL (#6 PROTEINS 4HESE THIRD GENERATION %)!S SHOW A SPECIFIC ITY OF ABOUT AND HAVE REDUCED THE DIAGNOSTIC WINDOW AFTER (#6 INFEC TION TO ABOUT WEEKS ;= 0ATIENTS WITH (#6 INFECTION HAVE DETECTABLE ANTIBODIES IN n AT CLINICAL PRESENTATION BUT AFTER THREE MONTHS ABOUT WILL HAVE DEVELOPED DETECTABLE ANTIBODY TITRES ;= )G- ANTIBODIES ARE NO RELIABLE MARKERS TO DISCRIMINATE ACUTE FROM CHRONIC (#6 INFECTION AS n OF CHRONICALLY (#6 INFECTED PATIENTS STILL SHOW POSITIVE ANTI (#6 )G- TITRES ; = 0ATIENTS WITH SIGNS AND SYMPTOMS OF ACUTE HEPATITIS AND NEGATIVE (#6 SEROLOGY SHOULD UNDERGO (#6 NUCLEIC ACID TESTS (#6 0#2 ASSAYS SHOW A HIGH SENSITIVITY AND ARE ABLE TO DETECT A MINIMAL (#6 2.! THRESHOLD OF n )5ML IN THE SERUM 4HE HIGH SENSITIVITY DETECTS ACTIVE (#6 REPLICATION ALREADY n WEEKS AFTER (#6 INFECTION 1UANTITATIVE (#6 2.! TESTS AND (#6 GENOTYPING ARE COMPLEMENTARY TESTS DESIGNED TO IDENTIFY PROGNOSIS OF (#6 INFECTION AND TO MONITOR RESPONSE TO (#6 THERAPY ;= !UTOIMMUNE MEDIATED LIVER DAMAGE IS ASSOCIATED WITH DIFFERENT TYPES OF AUTO ANTIBODIES )NDICATORS OF !)( ARE ELEVATED ANTIBODY TITRES DIRECTED AGAINST LIVERKIDNEY MICROSOMES ,+- SOLUBLE LIVER ANTIGEN 3,! AND LIVER PANCREAS ANTIGENS !N ELEVATION OF TOTAL SERUM GAMMAGLOBULIN IS ALSO INDICATIVE FOR !)( !)( IS ALSO ASSOCIATED WITH HIGH TITRES OF ANTI NUCLEAR ANTIBODY !.! ANDOR ANTI SMOOTH MUSCLE ANTIBODY 3-!
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
&IGURE $IFFERENTIATION OF LIVER DISEASE BY !34!,4 RATIO 3ERUM SPECIMENS WERE OBTAINED FROM PATIENTS WITH HISTOLOGICALLY PROVEN LIVER DISEASE 2ATIO WAS CALCULATED FROM THE HIGHEST !34 AND !,4 LEVELS DURING FOLLOW UP ;= 7ITH KIND PERMIS SION FROM 3PRINGER 3CIENCE AND "USINESS -EDIA
4HE DIAGNOSTIC VALUE OF AUTO ANTIBODIES IS LIMITED BY THE FACT THAT THEY ARE MISSING IN A SIGNIFICANT NUMBER OF PATIENTS WITH !)( 4HEREFORE A CLINICAL SCORING SYSTEM INTRODUCED BY AN INTERNATIONAL PANEL DOES NOT REGARD AUTO ANTIBODIES AS AN ABSOLUTE PREREQUISITE FOR DIAGNOSIS OF !)( ;= !NOTHER MARKER OF AUTOIMMUNE DISEASE ANTI MITOCHONDRIAL ANTIBODY !-! IS FOUND IN ALMOST ALL PATIENTS n WITH 0"# ;= 4HE IDENTI FIED !-! DURING 0"# ARE SPECIFICALLY DIRECTED AGAINST THE MITOCHONDRIAL PYRUVATE DEHYDROGENASE COMPLEX - TYPE OF !-! WHICH HELPS TO DIS CRIMINATE OTHER ENTITIES WHICH MAY BE ASSOCIATED WITH POSITIVE !-! TITRES - TYPE OF !-! SHOWS A SPECIFICITY OF AND A SENSITIVITY RATE OF FOR THE DIAGNOSIS OF 0"# ;= /THER AUTO ANTIBODIES FOUND IN PATIENTS WITH 0"# ARE 3-! !.! RHEUMATOID FACTOR AND ANTITHYROID ANTIBODIES !BOUT n OF PATIENTS HAVE FEATURES OF BOTH 0"# AND !)( WHICH IS CONSIDERED AS OVERLAP SYNDROME ;=
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
&INALLY 03# WHICH AFFECTS HEPATIC BILE DUCTS IS ASSOCIATED WITH HIGH TITRES OF PERINUCLEAR ANTI NEUTROPHILE CYTOPLASMATIC ANTIBODIES P!.#! IN OF ALL CASES AND WITH ANTI NUCLEAR ANTIBODIES !.! TITRES IN UP TO OF ALL CASES ;= 0ATIENTS WITH 03# MIGHT SHARE CHARACTERISTICS OF !)( 4HESE CASES ARE NAMED AUTOIMMUNE CHOLANGITIS OR ARE CLASSIFIED AS !)( OVERLAP ;=
$IAGNOSTIC IMAGING $IAGNOSTIC IMAGING IS IMPORTANT TO DIFFERENTIATE ACUTE FROM CHRONIC LIVER DIS EASE AND TO RECOGNISE BILE DUCT OBSTRUCTION OR HEPATIC LESIONS &OR THIS PUR POSE ULTRASOUND IS A VERY IMPORTANT COST EFFECTIVE SCREENING TOOL AND SHOULD BE ROUTINELY INCLUDED IN DIFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS !CUTE LIVER DAMAGE FOR EXAMPLE CORRELATES WITH CHANGES OF HEPATIC MORPHOLOGY LIKE AN ENLARGED LIVER DIAMETER ROUNDED LIVER MARGINS AND A PARENCHYMA OF REDUCED ECHOGENICITY -OREOVER ACUTE HEPATIC DETERIORATION MIGHT BE BASED ON HEPATIC MALPERFUSION )N THIS SETTING DILATED HEPATIC VEINS ARE INDICATORS FOR HEPATIC CONGESTION AND DUPLEX ULTRASOUND MIGHT IDENTIFY THROMBOTIC OCCLUSIONS OR REDUCED BLOOD FLOW OF ARTERIAL PORTAL OR VENOUS VESSELS 4HE SONOGRAPHIC CHARACTERISTICS TO IDENTIFY PRONOUNCED LIVER FIBROSIS OR CIRRHOSIS ARE QUITE WELL DEFINED BUT DETECTION OF MILD HEPATIC FIBROSIS IS STILL CHALLENGING 0REDOMINANTLY AN IRREGULAR LIVER SURFACE AND INTERRUPTED SONOGRAPHIC SIGNALS OF THE HEPATIC CAPSULE ARE ASSOCIATED WITH LIVER FIBROSIS OR CIRRHOSIS 3ONOGRAPHIC ASSESSMENT OF THE LIVER SURFACE REACHES A SENSITIV ITY BETWEEN AND AND A SPECIFICITY BETWEEN AND FOR THE DETECTION OF LIVER FIBROSIS OR CIRRHOSIS ;n= 2ELATIVE HYPERTROPHY OF THE CAUDAL LOBE CHANGES OF THE LIVER DIAMETERS AND IRREGULAR PATTERNS OF THE INTRAHEPATIC VESSELS ARE ADDITIONAL SIGNS OF CHRONIC LIVER DAMAGE ; = &URTHER ASSESSMENT OF THE VENOUS BLOOD FLOW ARTERIAL RESISTANCE AND PORTAL VELOCITY MIGHT INCREASE THE SENSITIVITY FOR THE DETECTION OF LIVER CIRRHOSIS OR PORTAL HYPERTENSION ; = 3PLENOMEGALY IS AN EXTRAHEPATIC INDICATOR FOR PORTAL HYPERTENSION AND COULD IDENTIFY HAEMOLYTIC DISEASE ESPECIALLY IF SONOGRAPHIC SIGNS OF LIVER CIRRHOSIS ARE ABSENT &INALLY ENLARGED LYMPH NODES LOCALISED IN THE LIVER HILUM MAY INDICATE VIRAL HEPATITIS ;= 5NFORTUNATELY DIFFERENTIATION OF HEPATIC FIBROSIS FROM HEPATIC STEATOSIS IS HAMPERED BY THE FACT THAT CHARACTERISTICS OF HEPATIC STEATOSIS LIKE INCREASED PARENCHYMAL ECHOGENICITY AND ULTRASOUND ABSORPTION OFTEN LEAD TO UNDERESTIMATION OF COEXISTING MILD FIBROSIS ; = #HOLESTATIC DISEASE IS A CRUCIAL DIFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS #HOLESTASIS IS ROUTINELY IDENTIFIED BY ULTRASOUND DEPENDING ON THE ANATOMIC SITE OF BILIARY OBSTRUCTION "ESIDE GALLSTONES AND CHOLECYSTITIS WHERE THE SEN SITIVITY REACHES MORE THAN ULTRASOUND IS REASONABLY SENSITIVE ^ FOR DETECTION OF INTRAHEPATIC CHOLESTASIS WHEREAS SENSITIVITY FOR DETECTION OF CHOLEDOCHOLITHIASIS WITHOUT DILATED BILE DUCTS DROPS TO #OMPUTED TOMOGRAPHY REACHES SIMILAR LEVELS OF SENSITIVITY FOR DETECTION FOR BILIARY
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
OBSTRUCTION EG ABOUT ;= &URTHER IMPROVEMENT OF BILIARY IMAGING HAS BEEN PROPOSED BY MAGNETIC RESONANCE CHOLANGIOGRAPHY BUT IS NOT YET AVAILABLE FOR ROUTINE USE 5P TO NOW ENDOSCOPIC RETROGRADE CHOLANGIOSCOPY %2# IS THE MOST SENSITIVE DIAGNOSTIC TOOL TO IDENTIFY BILIARY PATHOLOGIES AND SHOULD BE CONSIDERED IF BILIARY OBSTRUCTION IS SUSPECTED FOR CLINICAL REASONS %2# ALSO DETECTS MINIMAL BILE DUCT IRREGULARITIES AND THEREFORE IS CONSIDERED THE GOLDEN STANDARD FOR DIAGNOSIS OF 03# AND OFFERS TREATMENT OPTIONS FOR DOMINANT STRICTURES OR BILIARY CONCREMENTS ;= "ESIDE ULTRASOUND WHICH IS A VALUABLE TOOL TO SCREEN AND MONITOR FOCAL HEPATIC LESIONS CONTRAST ENHANCED COMPUTED TOMOGRAPHY #4 IS THE STAN DARD PROCEDURE TO CONFIRM HEPATIC METASTASIS OR (## %SPECIALLY IN CONTEXT OF LIVER CIRRHOSIS EARLY ARTERIAL PHASE ENHANCEMENT OF (## NODULES ALLOWS DETECTION OF (## #OMPARED TO ULTRASOUND WHICH REACHES A SENSITIVITY OF ENHANCED #4 SHOWS A SENSITIVITY OF OR MORE FOR THE DETECTION OF (## 4HEREFORE #4 IS STANDARD FOR THE BASELINE ASSESSMENT AND MONITORING OF CIRRHOTIC LIVERS IN CONTEXT OF (## TREATMENT ; = #ONTRAST ENHANCED ULTRASOUND APPEARS TO BE A VERY PROMISING ALTERNATIVE AND MIGHT BE EQUIVA LENT FOR THE DIAGNOSIS OF (## AND OTHER FOCAL HEPATIC LESIONS
(ISTOLOGY (ISTO MORPHOLOGICAL ASSESSMENT OF THE LIVER IS A HALLMARK OF DIFFERENTIAL DIAGNOSIS ,IVER HISTOLOGY DEFINES THE INFLAMMATORY ACTIVITY OF HEPATITIS AND IS ABLE TO QUANTIFY THE EXTENT OF ACUTE AND CHRONIC LIVER DAMAGE CAUSED BY DIFFERENT ENTITIES (ENCE LIVER HISTOLOGY MAY PREDICT THE PROGNOSIS OF THE UNDERLYING LIVER DISEASE 6IRAL HEPATITIS IS CHARACTERISED BY NECRO INFLAMMATORY CHANGES AND CHRONIC FIBROTIC ALTERATIONS OF LIVER HISTOLOGY 4HE HETEROGENIC MANIFESTATION OF HEPATIC NECROSIS DURING VIRAL HEPATITIS MAY SHOW FOCAL LOBULAR NECROSIS RESTRICTED TO HEPATIC LOBULES PIECEMEAL NECROSIS OF THE PERIPORTAL PLATE OR EXTENSIVE BRIDGING NECROSIS WHICH IS NOT RESTRICTED TO THE HEPATIC LOBULE 4HE TYPICAL INFLAMMATORY INFILTRATES DURING VIRAL HEPATITIS CONSIST OF MONO NUCLEAR CELLS ;= !DDITIONAL CYTOPATHIC EFFECTS OF VIRAL HEPATITIS HAVE BEEN SUGGESTED SUCH AS BILE DUCT LESIONS AND HEPATIC STEATOSIS WHICH ARE MORE COMMON FEATURES DURING HEPATITIS # COMPARED TO HEPATITIS " ;n= 4O QUANTIFY THE INFLAMMATORY ACTIVITY GRADING AND THE FIBROTIC DAMAGE STAG ING DURING VIRAL HEPATITIS STANDARDISED SCORES HAVE BEEN INTRODUCED 4HE EXTENT OF CELLULAR INFILTRATES AND HEPATIC NECROSIS ARE INCLUDED IN THE ASSESS MENT OF INFLAMMATORY ACTIVITY (ISTOLOGICAL GRADING QUANTIFIES EXTENT OF PERIPORTAL FIBROSIS THE FORMATION OF SEPTAL FIBROSIS UP TO THE DESTRUCTION OF PORTAL ARCHITECTURE IN CASE OF COMPLETE CIRRHOSIS ; = 4HE HISTOLOGICAL SIGNATURE DURING HEPATITIS MIGHT DISCRIMINATE OTHER ENTITIES FROM VIRAL HEPATITIS !)( OFTEN CAUSES A MORE PRONOUNCED PICTURE OF HEPATIC DAMAGE AT THE TIME OF DIAGNOSIS (ENCE HEPATOCELLULAR NECROSIS
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
MULTINUCLEATED HEPATOCYTES AND BROAD AREAS OF PARENCHYMAL COLLAPSE ARE TYPICALLY OBSERVED IN !)( 7HEREAS BILE DUCT DAMAGE OR LOSS AND HEPATIC STEATOSIS ARE UNCOMMON DURING !)( ;= 0RIMARY BILIARY CIRRHOSIS 0"# IS CHARACTERISED BY A CHRONIC NON SUPPURATIVE DESTRUCTIVE CHOLANGITIS OF THE SMALL BILE DUCTS 'RANULOMA FORMATION PROGRESSIVE LOSS OF BILE DUCTS AND CEL LULAR INFILTRATES WITH AN NON HOMOGENIC DISTRIBUTION THROUGHOUT THE LIVER ARE TYPICAL FINDINGS ;= (ISTOLOGY OF 03# MAY ALSO SHOW BILE DUCT DESTRUCTION SIGNS OF CHOLANGITIS AND CHOLESTASIS .EVERTHELESS A PRECISE CHOLANGIOGRAPHIC ASSESSMENT IS THE MOST IMPORTANT DIAGNOSTIC TOOL AS 03# USUALLY AFFECTS THE MEDIAN AND LARGE BILE DUCTS ; = !LSO GRANULOMATOUS HEPATITIS IS A COM MON HISTOLOGICAL FINDING WHICH IS FOUND IN n OF LIVER SPECIMENS "ESIDE 0"# MENTIONED ABOVE THE CAUSES OF GRANULOMATOUS HEPATITIS INCLUDE AUTO IMMUNOLOGICAL INFECTIOUS AND TOXIC ENTITIES 3ARCOIDOSIS AND TUBERCULOSIS REMAIN THE MOST IMPORTANT DIFFERENTIAL DIAGNOSIS AND ARE RESPONSIBLE FOR n OF ALL CASES WITH GRANULOMATOUS HEPATITIS &URTHERMORE THE DIFFER ENTIAL DIAGNOSIS OF GRANULOMATOUS HEPATITIS SHOULD BE EXTENDED IN PATIENTS WITH ACQUIRED IMMUNODEFICIENCY SYNDROME TO ATYPICAL MYCOBACTERIA HISTO PLASMOSIS AND CRYPTOCOCCOSIS )F NO SPECIFIC PATHOLOGY COULD BE IDENTIFIED TOXIC MEDICATIONS SHOULD BE CONSIDERED AS ALTERNATIVE CAUSE
#ONCLUSIONS $IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS SHOULD ALWAYS CONSIDER THE MOST COMMON CAUSES OF LIVER DAMAGE WHICH INCLUDES STEATOHEPATITIS ALCOHOL CON SUMPTION VIRAL HEPATITIS AND BILIARY OBSTRUCTION 4HE MOST FREQUENT CAUSES OF ACUTE HEPATIC DETERIORATION WITH PARTICULARLY HIGH LIVER ENZYME ELEVATIONS ARE VIRAL HEPATITIS HEPATIC ISCHAEMIA AND TOXIC EVENTS $IFFERENTIAL DIAGNOSIS OF CHRONIC HUMAN HEPATITIS NEEDS TO BE EXTENDED TO HEREDITARY METABOLIC DEFECTS AND AUTOIMMUNE DISEASES IF OTHER COMMON HEPATIC PATHOLOGIES ARE UNLIKELY 0ATIENT GROUPS WITH RISK FACTORS FOR RARE ENTITIES OF HUMAN HEPATITIS REQUIRE A SPECIFIC DIAGNOSTIC APPROACH )N LABORATORY ASSESSMENT ELEVATED LIVER ENZYMES ARE USUALLY THE FIRST INDICATOR FOR HUMAN HEPATITIS !DDITIONAL PARAMETERS OF LIVER FUNCTION ARE ESSENTIAL TO ESTIMATE PROGNOSIS AND EXTENT OF UNDERLYING LIVER DAMAGE 6IRAL SEROLOGY SHOULD ALWAYS BE INCLUDED INTO THE DIAGNOSTIC ALGORITHM AS IT IS HIGHLY RELIABLE TO DETECT OR EXCLUDE VIRAL HEPATITIS &URTHER SPECIAL DIAGNOS TIC TESTS FOR EXAMPLE AUTO IMMUNE SEROLOGY MAY BE APPLIED DEPENDING ON SPECIFIC PATIENT HISTORY AND CLINICAL FINDINGS &INALLY ULTRASOUND OF THE LIVER PARENCHYMA IS A COST EFFECTIVE METHOD TO SCREEN FOR BILIARY OBSTRUCTION HEPATIC MASSES AND PRONOUNCED LIVER FIBROSIS OR CIRRHOSIS IT IS THEREFORE RECOMMENDED DURING DIFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS ,IVER BIOPSY MAY COMPLETE THE DIAGNOSTIC APPROACH IF EITHER THE UNDERLYING HEPATIC PATHOLOGY REMAINS OBSCURE OR A DEFINITE QUAN TIFICATION OF LIVER FIBROSIS AND HEPATIC INFLAMMATION IS MANDATORY
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
2EFERENCES
0ENDINO '- -ARIANO ! 3URACE 0 #ASERTA #! &IORILLO -4 !MANTE ! "RUNO 3 -ANGANO # 0OLITO ) !MATO & ET AL 0REVALENCE AND ETIOLOGY OF ALTERED LIVER TESTS A POPULATION BASED SURVEY IN A -EDITERRANEAN TOWN (EPATOLOGY n #LARK *- "RANCATI &, $IEHL !- 4HE PREVALENCE AND ETIOLOGY OF ELEVATED AMINOTRANSFERASE LEVELS IN THE 5NITED 3TATES !M * 'ASTROENTEROL n "ELLENTANI 3 4IRIBELLI # 4HE SPECTRUM OF LIVER DISEASE IN THE GENERAL POPULATION LESSON FROM THE $IONYSOS STUDY * (EPATOL n 3HAPIRO #. #OLEMAN 0* -C1UILLAN '- !LTER -* -ARGOLIS (3 %PIDEMIOLOGY OF HEPATITIS ! SEROEPIDEMIOLOGY AND RISK GROUPS IN THE 53! 6ACCINE 3UPPL 3n %MERSON 35 0URCELL 2( 2UNNING LIKE WATERnTHE OMNIPRESENCE OF HEPATITIS % . %NGL * -ED n !LTER -* &AVERO -3 -OYER ,! -ILLER *+ "LAND ,! .ATIONAL SURVEIL LANCE OF DIALYSIS ASSOCIATED DISEASES IN THE 5NITED 3TATES !3!)/ 4RANS n -ARGOLIS (3 !LTER -* (ADLER 3# (EPATITIS " EVOLVING EPIDEMIOLOGY AND IMPLICATIONS FOR CONTROL 3EMIN ,IVER $IS n /FFERGELD 2 &AENSEN $ 2ITTER 3 (AMOUDA / (UMAN IMMUNODEFI CIENCY VIRUS HEPATITIS # AND HEPATITIS " INFECTIONS AMONG BLOOD DONORS IN 'ERMANY n RISK OF VIRUS TRANSMISSION AND THE IMPACT OF NUCLEIC ACID AMPLIFICATION TESTING %URO 3URVEILL n 7ASLEY ! !LTER -* %PIDEMIOLOGY OF HEPATITIS # GEOGRAPHIC DIFFERENCES AND TEMPORAL TRENDS 3EMIN ,IVER $IS n !LTER -* (ADLER 3# *UDSON &. -ARES ! !LEXANDER 7* (U 09 -ILLER *+ -OYER ,! &IELDS (! "RADLEY $7 ET AL 2ISK FACTORS FOR ACUTE NON ! NON " HEPATITIS IN THE 5NITED 3TATES AND ASSOCIATION WITH HEPATITIS # VIRUS INFECTION *AMA n !REVALO *! (EPATITIS " IN PREGNANCY 7EST * -ED n 3TARAS 3! $OLLARD 3# 2ADFORD +7 &LANDERS 7$ 0ASS 2& #ANNON -* 3EROPREVALENCE OF CYTOMEGALOVIRUS INFECTION IN THE 5NITED 3TATES n #LIN )NFECT $IS n #RAWFORD $( -ACSWEEN +& (IGGINS #$ 4HOMAS 2 -C!ULAY + 7ILLIAMS ( (ARRISON . 2EID 3 #ONACHER - $OUGLAS * ET AL ! COHORT STUDY AMONG UNIVERSITY STUDENTS IDENTIFICATION OF RISK FACTORS FOR %PSTEIN "ARR VIRUS SEROCON VERSION AND INFECTIOUS MONONUCLEOSIS #LIN )NFECT $IS n 8U & 3TERNBERG -2 +OTTIRI "* -C1UILLAN '- ,EE &+ .AHMIAS !* "ERMAN 3- -ARKOWITZ ,% 4RENDS IN HERPES SIMPLEX VIRUS TYPE AND TYPE SEROPREVALENCE IN THE 5NITED 3TATES *AMA n 'RIFFITHS 0$ %LLIS $3 :UCKERMAN !* /THER COMMON TYPES OF VIRAL HEPATITIS AND EXOTIC INFECTIONS "R -ED "ULL n -ONATH 40 #ETRON -3 0REVENTION OF YELLOW FEVER IN PERSONS TRAVELING TO THE TROPICS #LIN )NFECT $IS n $EEN *, (ARRIS % 7ILLS " "ALMASEDA ! (AMMOND 3. 2OCHA # $UNG .-
-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
(UNG .4 (IEN 44 &ARRAR ** 4HE 7(/ DENGUE CLASSIFICATION AND CASE DEFINITIONS TIME FOR A REASSESSMENT ,ANCET n 'EISBERT 47 *AHRLING 0" %XOTIC EMERGING VIRAL DISEASES PROGRESS AND CHALLENGES .AT -ED 3n "IANCO % 3TROFFOLINI 4 3PADA % 3ZKLO ! -ARZOLINI & 2AGNI 0 'ALLO ' "ALOCCHINI % 0ARLATO ! 3ANGALLI - ET AL #ASE FATALITY RATE OF ACUTE VIRAL HEPATITIS IN )TALY n !N UPDATE $IG ,IVER $IS n $!MICO ' 'ARCIA 4SAO ' 0AGLIARO , .ATURAL HISTORY AND PROGNOSTIC INDICATORS OF SURVIVAL IN CIRRHOSIS A SYSTEMATIC REVIEW OF STUDIES * (EPATOL n 9UEN -& 9UAN (* (UI #+ 7ONG $+ 7ONG 7- #HAN !/ 7ONG "# ,AI #, ! LARGE POPULATION STUDY OF SPONTANEOUS ("E!G SEROCONVERSION AND ACUTE EXACERBATION OF CHRONIC HEPATITIS " INFECTION IMPLICATIONS FOR ANTIVI RAL THERAPY 'UT n (AUSFATER 0 #ACOUB 0 3TERKERS 9 4HIBAULT 6 !MOURA : .GUYEN , 'HILLANI 0 ,EBLOND 6 0IETTE *# (EPATITIS # VIRUS INFECTION AND LYMPHOPROLIFERA TIVE DISEASES PROSPECTIVE STUDY ON PATIENTS IN &RANCE !M * (EMATOL n (ECKMANN *' +AYSER # (EUSS $ -ANGER " "LUM (% .EUNDORFER " .EUROLOGICAL MANIFESTATIONS OF CHRONIC HEPATITIS # * .EUROL n (ADDAD * $ENY 0 -UNZ 'OTHEIL # !MBROSINI *# 4RINCHET *# 0ATERON $ -AL & #ALLARD 0 "EAUGRAND - ,YMPHOCYTIC SIALADENITIS OF 3JOGRENS SYNDROME ASSOCIATED WITH CHRONIC HEPATITIS # VIRUS LIVER DISEASE ,ANCET n 4ERAGAKI - .ISHIGUCHI 3 4AKEUCHI + 9OSHIYAMA - !KIOKA + 9OSHIKAWA * 0REVALENCE OF HEPATITIS # VIRUS INFECTION AMONG PATIENTS WITH HYPERTRO PHIC CARDIOMYOPATHY (EART 6ESSELS n 4ANEI 2 7ATANABE + .ISHIYAMA 3 #LINICAL AND HISTOPATHOLOGIC ANALYSIS OF THE RELATIONSHIP BETWEEN LICHEN PLANUS AND CHRONIC HEPATITIS # * $ERMATOL n #LARK *- 4HE EPIDEMIOLOGY OF NONALCOHOLIC FATTY LIVER DISEASE IN ADULTS * #LIN 'ASTROENTEROL 3n "ROWNING *$ 3ZCZEPANIAK ,3 $OBBINS 2 .UREMBERG 0 (ORTON *$ #OHEN *# 'RUNDY 3- (OBBS (( 0REVALENCE OF HEPATIC STEATOSIS IN AN URBAN POP ULATION IN THE 5NITED 3TATES IMPACT OF ETHNICITY (EPATOLOGY n &ARRELL '# ,ARTER #: .ONALCOHOLIC FATTY LIVER DISEASE FROM STEATOSIS TO CIRRHOSIS (EPATOLOGY 3n3 "ECKER 5 $EIS ! 3ORENSEN 4) 'RONBAEK - "ORCH *OHNSEN + -ULLER #& 3CHNOHR 0 *ENSEN ' 0REDICTION OF RISK OF LIVER DISEASE BY ALCOHOL INTAKE SEX AND AGE A PROSPECTIVE POPULATION STUDY (EPATOLOGY n "ELLENTANI 3 3ACCOCCIO ' #OSTA ' 4IRIBELLI # -ANENTI & 3ODDE - 3AVERIA #ROCE , 3ASSO & 0OZZATO ' #RISTIANINI ' ET AL $RINKING HABITS AS COFAC TORS OF RISK FOR ALCOHOL INDUCED LIVER DAMAGE 4HE $IONYSOS 3TUDY 'ROUP 'UT n 2AWSON *3 !CHORD *, 3HOCK LIVER 3OUTH -ED * n -YERS 20 #ERINI 2 3AYEGH 2 -OREAU 2 $EGOTT # ,EBREC $ ,EE 33
$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
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-ARTIN & 3PRINZL AND 0ETER 2 'ALLE
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$IFFERENTIAL DIAGNOSIS OF HUMAN HEPATITIS
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#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
#OMPARATIVE PATHOLOGY 4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER )NSTITUTE OF 0ATHOLOGY 5NIVERSITY OF (EIDELBERG )M .EUENHEIMER &ELD (EIDELBERG 'ERMANY
!BSTRACT (EPATITIS IS DEFINED AS A NECROINFLAMMATION OF THE LIVER DISPLAYING LIVER CELL DAMAGE INFLAMMATORY CELL INFILTRATES AND REGENERATION TO A VARIABLE EXTENT )N CONTRAST TO ACUTE HEPATITIS WHICH IS CHARACTERISED BY A SELF LIMITING DAMAGE OF THE ACINAR PARENCHYMA CHRONIC HEPATITIS IS PATHOMORPHOLOGICALLY DEFINED BY THE PERSISTENCE OF NECROINFLAMMA TION PORTAL PREDOMINANCE OF MONONUCLEAR INFLAMMATORY INFILTRATES AND THE DEVELOPMENT OF FIBROSIS 7HEREAS (!6 AND (%6 DO NOT CAUSE CHRONIC HEPATITIS IN HUMANS ("6 ALONE OR IN COMBINATION WITH ($6 AND (#6 INFECTION MAY RESULT IN CHRONIC LIVER DISEASE IN HUMANS WHICH MAY PROGRESS TO LIVER CIRRHOSIS AND (## )NITIAL ANIMAL MODELS FOR THE STUDY OF VIRAL HEPATITIS BELONGED TO THE GROUP OF NONHUMAN PRIMATES ESPECIALLY CHIMPANZEES WHICH CAN BE INFECTED BY HUMAN HEPATITIS VIRUSES 4HESE MODELS DEVELOP A MILDER ACUTE HEPATITIS COMPARED TO HUMANS AND ALTHOUGH CHRONIC HEPATITIS MAY ALSO DEVELOP PROGRESSIVE LIVER DISEASE AND LIVER CIRRHOSIS ARE GENERALLY ABSENT )N THE CASE OF ("6 SEVERAL MAMMALIAN AND AVIAN ("6 RELATED VIRUSES ARE KNOWN 4HE MOST INTENSIVE LY CHARACTERISED MODEL IS THE %ASTERN WOODCHUCK INFECTED WITH 7(6 4HIS EXAMPLE IS THE ONLY MODEL IN WHICH CHRONIC LIVER DISEASE AND (## FREQUENTLY DEVELOP 2ECENTLY THE TREE SHREW 4UPAIA BELANGERI HAS BECOME AN INTERESTING MODEL SINCE IT CAN BE INFECTED WITH HUMAN HEPATITIS VIRUSES IT CAN BE HANDLED MORE EASILY COMPARED TO CHIMPANZEES AND IT CAN BE USED IN TRANSPLANTATION MODELS !DDITIONALLY SEVERAL TRANSGENIC MICE AND HUMAN MOUSE CHIMERA HAVE BEEN DEVELOPED WHICH ALLOW FOR THE STUDYING OF VIRAL REPLICATION AND NOVEL THERAPEUTIC APPROACHES IN VIVO
)NTRODUCTION #OMPARATIVE PATHOLOGY OF HEPATITIS MAY ADDRESS SEVERAL TOPICS THE DIF FERENCES BETWEEN ACUTE AND CHRONIC HEPATITIS DIFFERENCES IN HISTOLOGICAL FEATURES DUE TO CAUSATIVE AGENTS AS WELL AS TYPICAL AND ATYPICAL FORMS OF HEPATITIS EG FOLLOWING LIVER TRANSPLANTATION !DDITIONALLY THE FEATURES OF HEPATITIS CAN BE COMPARED BETWEEN DIFFERENT SPECIES EG HUMANS AND RODENTS &INALLY CERTAIN AREAS WITHIN HUMAN HEPATITIS CAN BE STUDIED IN ANI MAL MODELS
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
(EPATITIS REPRESENTS A NECROINFLAMMATION OF THE LIVER WHICH IS HISTOLOGI CALLY CHARACTERISED BY A VARIABLE EXTENT OF LIVER CELL DAMAGE INFLAMMATORY CELL INFILTRATES AND REGENERATION )N CONTRAST TO ACUTE HEPATITIS WHICH IS CHARACTERISED BY A PREDOMINANCE OF DAMAGE IN THE ACINAR PARENCHYMA CHRONIC HEPATITIS IS PATHOMORPHOLOGICALLY DEFINED BY THE PERSISTENCE OF NECROINFLAMMATION THE PREDOMINANCE OF PORTAL MONONUCLEAR INFLAMMATORY INFILTRATES AND VARIABLE NECROINFLAMMATORY ACTIVITY AT THE PORTAL PARENCHY MAL INTERFACE AS WELL AS THE DEVELOPMENT OF FIBROSIS
4HE MORPHOLOGICAL PATTERN OF HEPATITIS !CUTE HEPATITIS 'ENERAL ASPECTS 4HE SEVERITY OF ACUTE HEPATITIS MAY VARY FROM ASYMPTOMATIC TO FULMINANT HEPATIC FAILURE !CCORDINGLY THE HISTOLOGICAL CHANGES SEEN IN ACUTE HEPATITIS MAY VARY -ILD ACUTE HEPATITIS TYPICALLY SHOWS A VARIABLE PICTURE INCLUDING HEPATOCELLULAR SWELLING SINGLE CELL NECROSIS APOPTOSIS ACIDOPHILIC BODIES CHOLESTASIS CANALICULAR AND HEPATOCELLULAR ACINAR INFLAMMATION +UPFFER CELL ACTIVATION PROMINENCE CEROID PHAGOCYTOSIS AND LIVER CELL REGENERA TION 4HE COMBINATION OF HEPATOCELLULAR CELL DEATH @DROP OUT AND SMALL REGENERATING HEPATOCYTES MAY LEAD TO A DISARRAY OF LIVER CELL PLATES WHICH IS AN IMPORTANT DIAGNOSTIC CRITERION OF ACUTE HEPATITIS /F NOTE A MILD PORTAL INFLAMMATION MOSTLY LYMPHOPLASMACYTIC SOMETIMES EVEN INCLUDING SOME MILD BILE DUCT DAMAGE MAY BE A MINOR COMPONENT OF ACUTE HEPATITIS )N CONTRAST TO CHRONIC HEPATITIS PORTAL INFLAMMATION DOES NOT PREDOMINATE AND THE OUTLINE OF THE PORTAL TRACT REMAINS WELL DEFINED TOWARDS THE ACINAR PARENCHYMA )N MORE SEVERE DISEASE THERE MAY BE CONFLUENT NECROSES FRE QUENTLY PRONOUNCED AROUND PERIVENULAR AREAS OR EVEN BRIDGING NECROSES CONNECTING CENTRAL PORTAL OR CENTRAL CENTRAL AREAS #ONSEQUENTLY A COLLAPSE OF THE RETICULIN FIBRE FRAMEWORK MAY BE SEEN IN APPROPRIATE STAINS EG MODIFIED 'OMORIS WHICH MAY BE REPLACED BY FIBROUS SCARRING AFTER THE HEPATITIS HAS RESOLVED )N CASE OF EXTENSIVE CONFLUENT NECROSES A DUCTULAR REACTION WHICH CONSISTS OF DUCTULAR PROLIFERATIONS ASSOCIATED FIBROSIS AND NEUTROPHILIC INFILTRATION OCCURS AT THE PORTAL INTERFACE 4HIS FEATURE MAY MIMIC EXTRA ACINAR CHOLESTASIS EG BILE DUCT OBSTRUCTION AND HAS THUS TO BE DIFFERENTIATED )N CASE OF FULMINANT ACUTE HEPATITIS PANACINAR AND MUL TIACINAR NECROSIS ARE OBSERVED WHICH ARE ASSOCIATED WITH APPROXIMATION OF INDIVIDUAL PORTAL TRACTS LARGE COLLAPTIC AREAS AND EXTENSIVE FUTILE DUCTULAR REACTION !CUTE HEPATITIS MAY BE CAUSED BY VIRAL INFECTION EG HEPATOTROPIC VIRUSES BUT ALSO %PSTEIN "ARR VIRUS %"6 CYTOMEGALOVIRUS #-6 (ERPES SIMPLEX VIRUS (36 6ARICELLA ZOSTER VIRUS 6:6 ADENOVIRUS ENTEROVIRUS
#OMPARATIVE PATHOLOGY
ETC DRUGS TOXINS ALCOHOL EXPOSURE BACTERIAL INFECTION AS WELL AS AUTOIM MUNITY AND 7ILSONS DISEASE 3INCE THERE ARE ONLY A FEW PATHOGNOMONIC FEATURES THAT ALLOW A PRECISE HISTOLOGICALLY BASED DEFINITION OF THE ETIOLOGY IT IS RATHER THE CHALLENGE FOR THE CLINICIAN THAN FOR THE PATHOLOGIST TO DETERMINE THE UNDERLYING ETIOLOGY .EVERTHELESS A SPECIFIC AND SOMETIMES OVERLAPPING PATTERN MAY POINT TO THE UNDERLYING ETIOLOGY
3PECIFIC FEATURES IN ACUTE HEPATITIS 4HE HISTOLOGICAL SPECTRUM BY WHICH THE LIVER MAY REACT TO CERTAIN AGENTS OR DAMAGE IS LIMITED .EVERTHELESS AN EVALUATION OF THE MORPHOLOGICAL INJURY PATTERN INCLUDING THE RECOGNITION OF SUBTLE FEATURES EG ACIDOPHILIC BOD IES EOSINOPHILS MAY ALLOW FOR THE IDENTIFICATION OF THE CAUSATIVE AGENT !DDITIONALLY IMMUNOHISTOLOGICAL AND MOLECULAR PATHOLOGICAL ANALYSES MAY ALLOW DIAGNOSIS IN A SUBSET OF CASES 4HE MOST IMPORTANT DIAGNOSTIC PATTERNS INCLUDE VIRUS TYPE HEPATITIS STEATOHEPATITIS ZONAL RESTRICTED PARENCHYMAL DAMAGE MONONUCLEOSIS LIKE HEPATITIS GRANULOMATOUS HEPATITIS AND FOCAL NECROTISING HEPATITIS 6IRUS TYPE HEPATITIS 4HE TYPICAL LESION IN ACUTE VIRUS HEPATITIS CONSISTS OF SPOTTY CYTOLYTIC NECROSIS RESULTING IN A @DROP OUT OF INDIVIDUAL HEPATOCYTES WITHIN THE HEPATOCELLULAR PLATES AND APOPTOSIS RESULTING IN ACIDOPHILIC BODIES &IG ! 4HE REMNANTS OF THESE CELLS ARE EITHER REMOVED BY BLOOD FLOW OR THEY ARE PHAGOCYTOSED LEADING TO CEROID LADEN MACROPHAGES AND PROMINENCE OF +UPFFER CELLS )N HEPATITIS ! VIRUS (!6 AND HEPATITIS % VIRUS (%6 INFECTION THERE MAY BE TWO COMMON SOMETIMES OVERLAPPING PICTURES POINTING TO THE CAUSATIVE AGENT ONE INCLUDES A PERIPORTAL ACCENTUATED INFLAMMATORY PATTERN RICH IN PLASMA CELLS WITH NO OR LITTLE PERIVENULAR NECROSIS ; = 4HE SECOND FEATURE IS SO CALLED CHOLESTATIC HEPATITIS WITH PROMINENT PERIVENULAR CHOLESTASIS AND ONLY MINIMAL INFLAMMATORY INFILTRATION 2ARELY (!6 MAY PRESENT AS ACUTE HEPATIC FAILURE ;= 3TEATOHEPATITIS 3TEATOHEPATITIS REPRESENTS THE PROGRESSIVE FORM OF FATTY LIVER DISEASE AND IS DEFINED BY THREE HISTOLOGICAL FEATURES STEATOSIS BALLOONING AND NECROIN FLAMMATORY LESIONS ; = 4HE HISTOLOGICAL CHANGES ARE USUALLY PRONOUNCED IN THE PERIVENULAR REGION %VENTUALLY LIPOGRANULOMAS -ALLORY $ENK BODIES AND GLYCOGENATED NUCLEI MAY BE SEEN 3TEATOHEPATITIS IS USUALLY CAUSED BY CHRONIC ALCOHOL ABUSE OR NON ALCOHOLIC CONDITIONS INCLUDING ADIPOSITAS TYPE )) DIABETES MELLITUS METABOLIC SYNDROME AND DRUGS EG AMIODARON NIFE DIPINE STEROIDS
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
&IGURE (EPATITIS PATTERN ! 6IRAL TYPE HEPATITIS PATTERN SHOWING FOCAL CYTOLYTIC LIVER CELL NECROSIS AND ACIDOPHILIC BODIES " :ONAL PATTERN 4HERE IS PERIVENULAR NECROSIS WITH LEUCOCYTIC DEMARCATION AND HAEMORRHAGE IN THIS CASE OF DRUG INDUCED HEPATITIS # (EPATIC SARCOIDOSIS WITH EPITHELIOID CELL GRANULOMA WITH MULTINUCLEATED GIANT CELLS $ %"6 HEPATITIS WITH SINGLE FILE ROWING OF LEUCOCYTES SHOWING SOME NUCLEAR ATYPIA
:ONAL PATTERN 4HE ZONAL PATTERN SHOWS NECROSIS RESTRICTED TO A CERTAIN AREA OF THE LIVER ACINUS IN PARTICULAR OF THE ACINAR ZONE AS SEEN IN ISCHAEMIC LIVER CELL DAM AGE &IG " 4HIS PATTERN MAY SOMETIMES BE OBSERVED IN SEVERE ACUTE VIRAL HEPATITIS BUT PARTICULARLY WHEN ASSOCIATED WITH PROMINENT EOSINOPHILIC OR NEUTROPHILIC INFILTRATION CHOLESTASTIS OR PERIBILIARY BASOPHILIA MAY POINT TO DRUG AND TOXIN INDUCED LIVER DISEASE EG PHENPROCOUMON ;= .OTABLY DRUG OR TOXIN INDUCED HEPATITIS WHICH CAN PRODUCE ALL FORMS OF ACUTE CHRONIC VASCULAR AND NEOPLASTIC LIVER DISEASES HAS TO BE CONSIDERED GENER ALLY IN HEPATITIS OF UNCERTAIN ETIOLOGY ;= -ONONUCLEOSIS LIKE HEPATITIS 4HE MONONUCLEOSIS LIKE PATTERN SHOWS ONLY MILD OR ABSENT LIVER CELL DAM AGE AND PROMINENT LYMPHOCYTES ARE SEEN WITHIN THE HEPATIC SINUSOIDS TYPI CALLY WITH SINGLE FILE LIKE ROWING AND PORTAL TRACTS &IG $ 4HIS PATTERN IS TYPICAL FOR ACUTE LIVER INVOLVEMENT IN %"6 INFECTION )N SOME CASES OF ACUTE HEPATITIS # VIRUS (#6 INFECTION THERE MAY BE A PROMINENT INTRASINUSOI
#OMPARATIVE PATHOLOGY
DAL LYMPHOCYTE AGGREGATION WITHOUT SEVERE LIVER CELL DAMAGE REMINISCENT OF %"6 HEPATITIS ;= !N ADDITIONAL DIFFERENTIAL DIAGNOSIS FOR THIS PATTERN INCLUDES MALIGNANT LYMPHOMA EG HEPATOSPLENIC 4 CELL LYMPHOMA ;= )MMUNOHISTOLOGICAL AND MOLECULAR PATHOLOGICAL ANALYSES DETECTION OF VIRAL NUCLEID ACIDS CLONALITY OF 4 CELL RECEPTOR REARRANGEMENT MAY ALLOW DIFFER ENTIATION IN MOST CASES 'RANULOMATOUS PATTERN (EPATIC GRANULOMAS CONSIST OF HISTIOCYTIC EVEN EPITHELIOID CELLS A VARIED NUMBER OF MONONUCLEAR CELLS AND SOMETIMES MULTINUCLEATED GIANT CELLS (ISTOLOGICALLY CASEATING EG TUBERCULOSIS GRANULOMAS NON CASEATING GRAN ULOMAS LIPOGRANULOMAS AND FIBRIN RING GRANULOMAS CAN BE DIFFERENTIATED )N MOST CASES HEPATIC GRANULOMAS DEVELOP IN RESPONSE TO INFECTIONS ESPECIALLY BACTERIAL OR PARASITIC DRUG HYPERSENSITIVITY EG ACETYLSALICYLIC ACID AMOXI CILLIN OR SYSTEMIC DISEASES EG SARCOIDOSIS &IG # (ISTOCHEMICAL STAINS LIKE 0!3 'RAM 'IEMSA 'ROCKOTT 7ARTHIN 3TARRY OR (ALE MAY BE HELPFUL FOR DETERMINING THE CAUSE OF A GIVEN GRANULOMA #ASEATING GRANULOMAS IN CONTRAST TO NON CASEATING GRANULOMAS SHOW A CENTRAL NECROSIS SURROUNDED BY EPITHELIOID CELLS MULTINUCLEATED GIANT CELLS AND HISTIOCYTES 4HEY ARE TYPICALLY SEEN IN TUBERCULOSIS &IG $ .ON CASE ATING GRANULOMAS IN PORTAL TRACTS NEAR DAMAGED BILE DUCTS ARE ALMOST CER TAINLY DUE TO PRIMARY BILIARY CIRRHOSIS ,IPOGRANULOMAS ARE FREQUENTLY SEEN IN STEATOHEPATITIS AND CONSIST OF A FAT VACUOLE SURROUNDED BY LYMPHOCYTES /CCASIONALLY FIBRIN RING GRANULOMAS COMPOSED OF A FAT VACUOLE SURROUNDED BY A RING OF FIBRIN EPITHELIOID CELLS GIANT CELLS AND NEUTROPHILS MAY BE SEEN 4HEY MAY BE OBSERVED IN INFECTIOUS DISEASES EG 1 FEVER SYSTEMIC DIS EASES (ODGKINS DISEASE SYSTEMIC LUPUS ERYTHEMATODES OR DRUG INDUCED LIVER DAMAGE ALLOPURINOL ;n= &OCAL NECROTISING PATTERN 4HE FOCAL NECROTISING PATTERN OF ACUTE HEPATITIS SHOWS NON ZONAL RESTRICTED GROUP OR BRIDGING NECROSIS WITH HAEMORRHAGE WHICH MAY BE DEMARCATED BY POLYMORPHIC NEUTROPHILS 4HIS TYPE OF ACUTE HEPATITIS IS MAINLY SEEN IN ATYPICAL FORMS OF HEPATITIS INCLUDING (36 &IG ! 6:6 ADENOVIRUS &IG " ENTEROVIRUS ETC AND MOST FREQUENTLY OCCURS IN THE SETTING OF IMMUNOSUPPRESSION !TYPICAL HEPATITIS DIFFERS FROM CLASSICAL HEPATITIS IN THAT IT FREQUENTLY ALLOWS DIAGNOSIS DUE TO ADDITIONAL TYPICAL MORPHOLOGICAL FEATURES !DENOVIRAL INFECTION WHICH RARELY OCCURS IN LIVER ALLOGRAFTS MAY MIMIC #-6 HEPATITIS MICROABSCESS FORMATION &IG # IN ITS INITIAL STAGES BUT MAY PROCEED TO CONFLUENT HAEMORRHAGIC NECROSES RESULTING IN USUALLY FATAL INFECTION ;= "ESIDE HAEMORRHAGIC NECROSES THE PRESENCE OF @SMUDGE CELLS IS A DIAGNOSTIC FEATURE IN ADENOVIRAL HEPATITIS !NOTHER FREQUENTLY FATAL VIRAL INFECTION IS ACUTE NECROTISING (ERPES SIMPLEX OR 6ARIZELLA ZOSTER HEPA TITIS WHICH SHOW CHARACTERISTIC EOSINOPHILIC OR BASOPHILIC NUCLEAR INCLUSIONS #OWDRY BODIES IN VIABLE HEPATOCYTES ADJACENT TO NECROSES ;=
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
&IGURE !TYPICAL HEPATITIS ! &OCAL NECROTISING (ERPES SIMPLEX HEPATITIS .OTE THE EOSI NOPHILIC COWDRY TYPE NUCLEAR INCLUSIONS IN THE VITAL HEPATOCYTES ADJACENT TO THE NECROSIS INSERT (36 IMMUNOHISTOCHEMISTRY " &OCAL NECROTISING ADENOVIRUS HEPATITIS WITH NUMEROUS SMUDGE CELLS INSERT # -ICROABSCESS FORMATION IN #-6 HEPATITIS INSERT #-6 IMMUNOHIS TOCHEMISTRY $ (EPATIC TUBERCULOSIS SHOWING CASEATING NECROSIS SURROUNDED BY EPITHELIOID GRANULOMA WITH LANGHANS TYPE MULTINUCLEATED GIANT CELL
#HRONIC HEPATITIS 'ENERAL ASPECTS )N ADULTS CHRONIC HEPATITIS IS PRIMARILY GROUPED ACCORDING TO THE UNDERLYING ETIOLOGY ;= 4HUS INFECTIONS DRUGSTOXINS AUTOIMMUNITY METABOLIC INHER ITED DISEASES AND NON DEFINED @CRYPTOGENIC MECHANISMS ARE DIFFERENTIATED #LASSICAL INFECTIOUS AGENTS CAUSING CHRONIC HEPATITIS INCLUDE HEPATITIS " VIRUS ("6 INFECTION ALONE OR IN COMBINATION WITH HEPATITIS $ VIRUS ($6 AND (#6 INFECTION )NFREQUENTLY %"6 INFECTION MAY INDUCE CHRONIC HEPATITIS ;= 7HETHER A FEW BACTERIA SUCH AS THE (ELICOBACTER SPE CIES MAY CAUSE CHRONIC HEPATITIS OR ACCELERATE DISEASE PROGRESSION IS RATHER QUESTIONABLE ;= "ESIDE PURE AUTOIMMUNE HEPATITIS SO CALLED AUTOIM MUNE OVERLAP SYNDROMES WITH PRIMARY BILIARY CIRRHOSIS 0"# AND PRIMARY SCLEROSING CHOLANGITIS 03# ARE DIAGNOSED VERY INFREQUENTLY 4HE LIST OF MEDICATIONS WHICH MAY INDUCE CHRONIC HEPATITIS IS STILL GROWING DUE TO THE INCREASING NUMBER OF APPROVED DRUGS #LASSICAL AGENTS INCLUDE ANTIBIOTICS
#OMPARATIVE PATHOLOGY
EG NITROFURANTOINE AND ANTIEPILEPTICS EG PHENYTOIN )MPORTANTLY EVEN HERBS SUCH AS THE #HINESE MEDICINAL HERB *IN "U (UAN HAVE BEEN IDENTI FIED TO INDUCE CHRONIC HEPATITIS -ETABOLIC DISEASES MOSTLY DO NOT BELONG TO THE CLASSICAL ETIOLOGICAL SPECTRUM OF CHRONIC HEPATITIS ALTHOUGH ESPECIALLY 7ILSONS DISEASE MAY SHOW HEPATITIC FEATURES
0ATHOMORPHOLOGY AND SPECIAL FEATURES OF CHRONIC HEPATITIS "Y DEFINITION CHRONIC HEPATITIS SHOWS A PREDOMINANCE OF PORTAL INFLAMMA TION )NTERFACE HEPATITIS IN OLDER TERMINOLOGY PIECEMEAL NECROSIS ACINAR INFLAMMATION AND PORTAL OR SEPTAL FIBROSIS ARE FACULTATIVE FEATURES $ISEASE PROGRESSION IS DRIVEN BY THE EXTENT OF INTERFACE HEPATITIS AND IS MORPHOLOGI CALLY CHARACTERISED BY CYTOPLASMIC DEGENERATION AND APOPTOSIS OF PERIPORTAL HEPATOCYTES IN CLOSE CONTACT WITH INFILTRATING LYMPHOCYTES 4HE FEATURES OF CYTOPLASMIC DEGENERATION INCLUDE HEPATOCELLULAR BALLOONING GRANULAR AGGREGATION OF CELL ORGANELLES AND PARTIAL DISSOLUTION OF NUCLEAR AND CELLULAR MEMBRANES ;= 4HE MORPHOLOGY BASED DEFINITION OF THE UNDERLYING ETIOLOGY IS NOT POSSIBLE IN MOST CASES AND IT REQUIRES THE CLINICAL PATHOLOGICAL CONTEXT TO PREVENT NON ESSENTIAL ADDITIONAL DIAGNOSTIC PROCEDURES 4HUS CLINICAL AND SEROLOGICAL INFORMATION ARE IMPORTANT FOR THE ASSESSMENT OF A LIVER BIOPSY SPECIMEN .EVERTHELESS THERE ARE SEVERAL CHARACTERISTIC FEATURES INDICATING THE CAUSATIVE AGENT )N CASE OF ("6 THESE INCLUDE GROUND GLASS HEPATOCYTES &IG ! OR SO CALLED @SANDED NUCLEI FREQUENTLY IN IMMUNOSUPPRESSED PATIENTS 'ROUND GLASS HEPATOCYTES ARE THE MORPHOLOGICAL CORRELATE OF ("S ANTIGEN OVERLOAD OF THE ENDOPLASMIC RETICULUM @3ANDED NUCLEI ARE CHARACTERISED BY EOSINOPHILIC HOMOGENOUS FINE GRAINED NUCLEAR INCLUSIONS GIVING THE IMPRESSION OF SAND LIKE GRANULATION 4HEY ARE LESS FREQUENTLY SEEN COMPARED TO GROUND GLASS HEPATOCYTES AND ARE CAUSED BY NUCLEAR ("C ANTI GEN OVERLOAD ;= "ESIDE CHRONIC ("6 INFECTION THEY ARE OBSERVED MORE FREQUENTLY IN THE CASE OF AN ("6 ($6 COINFECTION )N THESE CASES THEY ARE IMMUNOHISTOLOGICALLY POSITIVE FOR THE DELTA ANTIGEN ;= 'ENERALLY THE LIVER HISTOLOGY IN ("6 ($6 COINFECTION SHOWS MORE SEVERE INFLAMMATORY ACTIVITY COMPARED TO ("6 MONOINFECTION #YTOPLASMIC OR MEMBRANOUS ("C ANTIGEN STAINING AS WELL AS MEMBRANOUS ("S ANTIGEN STAINING HAVE DIAGNOSTIC IMPORTANCE SINCE THEY MARK VIRAL REPLICATING CELLS ;= -OLECULAR BIOLOGICAL APPROACHES FOR 0#2 BASED DETECTION OF VIRAL NUCLEIC ACIDS HAVE BEEN ESTABLISHED BUT THEY ARE ONLY USED IN SELECTED CASES IN WHICH DIAGNOSIS IS DIFFICULT EG UNCLEAR MORPHOLOGY (#6 INFECTION IS GENERALLY MILDER AND MORE FREQUENTLY SHOWS PERI PORTAL MACROVESICULAR STEATOSIS SINUSOIDAL INFLAMMATORY AGGREGATES WITH PRONOUNCED +UPFFER CELL ACTIVATION AND PORTAL LYMPH FOLLICLE FORMATION &IG " COMPARED TO ("6 ;= %SPECIALLY THE FORMATION OF PORTAL LYMPH FOLLICLES IS CONSIDERED TYPICAL FOR (#6 INFECTION ALTHOUGH IT IS NOT PATHOG
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
&IGURE 3PECIAL FEATURES OF CHRONIC HEPATITIS ! #HRONIC HEPATITIS " WITH NUMEROUS GROUND GLASS HEPATOCYTES " 0ORTAL LYMPHOID FOLLICLE IN (#6 INFECTION # !UTOIMMUNE HEPATITIS WITH MARKED INTERFACE HEPATITIS NUMEROUS PLASMA CELLS AND PSEUDOGLAND FORMATION $ $RUG INDUCED HEPATITIS WITH SPARSE PORTAL MONONUCLEAR INFLAMMATORY INFILTRATES AND INTERMINGLED EOSINOPHILS
NOMONIC IN ANY CASE )MMUNOHISTOLOGICAL DETECTION OF (#6 PROTEINS IS POSSIBLE ON SNAP FROZEN TISSUE BUT RESULTS OBTAINED FROM FORMALIN FIXED PARAFFIN EMBEDDED TISSUE ARE UNRELIABLE IN MOST CASES ; = (ISTOLOGICAL CHARACTERISTICS OF UNTREATED AUTOIMMUNE HEPATITIS &IG # ARE SEVERE INFLAMMATORY ACTIVITY AND ALMOST ALWAYS INCLUDE THE FEATURES OF CHRONICITY AT TIME OF DIAGNOSIS 4HERE IS TYPICALLY SEVERE INTERFACE HEPATITIS ROSETTE FORMATION OF PERIPORTAL HEPATOCYTES PLASMA CELL RICH PORTAL INFLAMMA TORY INFILTRATES AND BY DEFINITION NO OR ONLY MINIMAL BILE DUCT DAMAGE ;=
)NFLAMMATORY ACTIVITY AND FIBROSIS IN CHRONIC VIRAL HEPATITIS 4HE DEGREE OF INFLAMMATION AND HEPATOCELLULAR DAMAGE NECROINFLAMMA TION MAY VARY CONSIDERABLY INTERINDIVIDUALLY AS WELL AS DURING THE COURSE OF A CHRONIC HEPATITIS IN A GIVEN PATIENT 4HUS THE INFLAMMATORY ACTIVITY SEEN IN A LIVER BIOPSY SPECIMEN GRADING ONLY REFLECTS A SNAPSHOT OF THE DISEASE PROCESS ;= .EVERTHELESS INFLAMMATORY ACTIVITY ESPECIALLY THE
#OMPARATIVE PATHOLOGY
&IGURE 'RADING OF CHRONIC HEPATITIS ! -INIMAL CHRONIC HEPATITIS GRADE SHOWING MODER ATE PORTAL INFLAMMATION AND AN INTACT LIMITING PLATE " -ILD CHRONIC HEPATITIS GRADE ADDI TIONALLY SHOWING FOCAL PIECEMEAL NECROSIS AND SOME ACINAR SINGLE CELL NECROSIS # #ONFLUENT INTERFACE HEPATITIS AND NUMEROUS PARENCHYMAL CYTOLYTIC NECROSIS IN THIS CASE OF MODERATE CHRONIC HEPATITIS GRADE $ 3EVERE CHRONIC HEPATITIS GRADE WITH MARKED INTERFACE HEPA TITIS AND HEPATOCELLULAR GROUP NECROSIS TOP
DEGREE OF INTERFACE HEPATITIS HAS A HIGH PREDICTIVE VALUE WITH RESPECT TO DISEASE PROGRESSION ;= $URING THE LAST DECADES SEVERAL ATTEMPTS HAVE BEEN MADE TO ASSESS INFLAMMATORY ACTIVITY MORE OBJECTIVELY BY INTRODUCING GRADING SYSTEMS THAT SCORE THE VARIOUS PARAMETERS OF INFLAMMATORY ACTIVITY 3EVERAL SCORING SYSTEMS HAVE BEEN BROADLY ACCEPTED BUT UNTIL NOW NO SINGLE WORLDWIDE CONSENSUS FOR THE USE OF A CERTAIN SYSTEM HAS BEEN ACHIEVED 3YSTEMS PROPOSED INCLUDE THE SCORES ACCORDING TO $ESMET ET AL ;= "ATTS AND ,UDWIG ;= )SHAKS MODIFIED HISTOLOGICAL ACTIVITY INDEX M(!) ;= ORIGINATING FROM +NODELLS SCORE ;= AND THE -%4!6)2 SCORE FOR ASSESS MENT OF CHRONIC (#6 INFECTION ;= $ESMETS SCORE 4AB IS DESCRIPTIVE IN TERMS OF INFLAMMATORY ACTIVITY AND DISTINGUISHES FOUR GRADES MINIMAL MILD MODERATE SEVERE GRADE TO &IG !n$ 4HIS GRADING SYSTEM HAS SEVERAL ADVANTAGES COMPARED TO OTHER SCORES IT HAS A GOOD INTER AND INTRAOBSERVER REPRODUCIBILITY ; = IT ALSO HAS A BROAD APPLICABILITY AND IMPORTANTLY IT HAS A GOOD CORRELATION TO THE MORE COMPLEX M(!) SCORE 4AB 4HE DEGREE OF FIBROSIS AND TISSUE REMODELLING ARCHITECTURAL DISTOR TION STAGING IS THE MOST IMPORTANT INTEGRATIVE MEASURE FOR PROGRESSION
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
4ABLE 'RADING OF CHRONIC VIRAL HEPATITIS ACCORDING TO $ESMET 3CHEUER ;= GRADE
VERBAL
M(!) 3CORE HISTOLOGICAL FEATURES
MINIMAL
n
MILD PORTAL INFLAMMATION NONE OR MINIMAL ACINAR INFLAMMATION FEW SINGLE CELL NECROSIS NO INTERFACE HEPATITIS
MILD
n
MILD TO MODERATE PORTAL INFLAMMATION FOCAL INTERFACE HEPATITIS SOME SINGLE CELL NECROSIS NO CONFLUENT NECROSIS
MODERATE
n
MODERATE TO SEVERE PORTAL INFLAMMATION CONFLUENT INTERFACE HEPATITIS MULTIPLE SINGLE CELL NECROSIS SOME CONFLUENT NECROSIS NO BRIDGING OR PANACINAR NECROSIS
SEVERE
n
SEVERE PORTAL INFLAMMATION AND INTERFACE HEPATITIS SEVERE ACINAR INFLAMMATION INCLUDING CONFLUENT BRIDGING AND PANACINAR NECROSIS
4ABLE )SHAKS MODIFIED HISTOLOGICAL ACTIVITY INDEX M(!) ;=
INTERFACE HEPATITIS
NONE FOCAL FEW PORTAL TRACTS FOCAL MAJORITY OF PORTAL TRACTS CONTINUOUS OF PORTAL TRACTS CONTINUOUS OF PORTAL TRACTS
CONFLUENT NECROSES
NONE FOCAL FEW ZONE NECROSIS MULTIPLE ZONE NECROSIS ZONE AND FEW PORTOCENTRAL BRIDGING NECROSIS ZONE AND MULTIPLE PORTOCENTRAL BRIDGING NECROSIS PANACINARMULTIACINAR NECROSIS
SINGLE CELL NECROSES
NONE FOCUS-0& OBJECTIVE = TO FOCI-0& TO FOCI-0& FOCI-0&
PORTAL INFLAMMATION
NONE MILD FEW OR ALL PORTAL TRACTS MODERATE FEW OR ALL PORTAL TRACTS MODERATE ALL PORTAL TRACTS SEVERE ALL PORTAL TRACTS
REVERSIBILITY AND FUNCTIONAL HEPATIC RESERVE IN CHRONIC LIVER DISEASE 4HUS THE STAGING OF CHRONIC HEPATITIS IS AN IMPORTANT HISTOLOGICAL CRITERION TO EVALUATE PROGNOSIS AND THERAPEUTIC OPTIONSINDICATION WHICH INCLUDE BOTH INITIAL AND TIME COURSE BIOPSIES $URING THE LAST YEARS SEVERAL NON INVASIVE TESTS HAVE BEEN INTRODUCED TO ASSESS LIVER FIBROSIS ;= BUT SO FAR ALL HAVE
#OMPARATIVE PATHOLOGY
&IGURE 3TAGING OF CHRONIC HEPATITIS ! &IBROUS EXTENSION OF THE PORTAL TRACTS STAGE " 0ORTAL AND SEPTAL FIBROSIS STAGE # 0ORTAL AND SEPTAL FIBROSIS WITH FORMATION OF INCOM PLETE PSEUDOLOBULI AND ARCHITECTURAL DISTORTION STAGE $ #OMPLETE CIRRHOTIC REMODELLING STAGE
FAILED IN IDENTIFYING CLINICALLY RELEVANT STAGES OF EARLY PROGRESSION IN THE EVALUATION OF ARCHITECTURAL DISTORTION AND IN THE MEASURING OF FIBROSIS IN FATTY LIVER DISEASE ADEQUATELY 3INCE THOSE PATIENTS HAVE A HIGH NEED FOR TREATMENT LIVER BIOPSY REMAINS THE GOLD STANDARD IN ROUTINE DIAGNOSTICS ;= !NALOGOUS TO THE GRADING SYSTEMS SEVERAL SCORING SYSTEMS HAVE BEEN PROPOSED FOR THE STAGING OF CHRONIC HEPATITIS ; = 4HE SCORE ACCORD ING TO $ESMET ET AL 4AB WHICH WAS DEVELOPED FROM 3CHEUERS SCORE ;= DESCRIPTIVELY SEPARATES FIVE STAGES NONE MILD MODERATE SEVERE FIBRO SIS AND CIRRHOSIS &IG !n$ 4HE ADVANTAGES OF THIS SYSTEM INCLUDE SIMPLE APPLICABILITY CLEAR DEFINITION AND COMPARABLY SMALL INTER AND INTEROB SERVER VARIABILITY ;= /F NOTE $ESMETS SCORE DOES NOT DIFFERENTIATE THE EXTENT OF CIRRHOSIS THE FINAL STAGE OF FIBROSIS WHICH IS A LIMITATION OF ALL QUALITATIVE SCORING SYSTEMS INTRODUCED SO FAR 3INCE IT IS NOW WELL KNOWN THAT EFFECTIVE ANTIVIRAL THERAPY MAY LEAD TO THE REGRESSION OF LIVER FIBROSIS ;= IN THERAPEUTIC STUDIES THE USE OF THE SEMIQUANTITATIVE FIBROSIS SCORES SUCH AS THE ONE ESTABLISHED BY #HEVALIER ET AL 4AB IS RECOMMENDED ;=
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
4ABLE 3TAGING OF CHRONIC VIRAL HEPATITIS ACCORDING TO $ESMET 3CHEURER ;= SCORE
VERBAL
HISTOLOGICAL FEATURES
NO FIBROSIS
NO PORTAL FIBROSIS
MILD FIBROSIS
ENLARGED PORTAL TRACTS WITHOUT SEPTA
MODERATE FIBROSIS INCOMPLETE PORTOPORTAL SEPTA PRESERVED ARCHITECTURE
SEVERE FIBROSIS
PORTAL FIBROSIS WITH SEPTA AND ARCHITECTURAL DISTORTION DIFFER ENCES IN CENTRAL VEIN n PORTAL TRACT DISTANCES NO EVIDENCE OF COMPLETE CIRRHOTIC REMODELLING
CIRRHOSIS
PROBABLE OR DEFINITE CIRRHOTIC REMODELLING
4ABLE 3EMIQUANTITATIVE 3EVERITY 3CORE ;= CRITERIUM
SCORE
VERBAL
NORMAL OR ABSENCE OF VEIN CIRRHOSIS MODERATELY THICKENED STELLATE ASPECT OF VEIN WALL -ARKEDLY THICKENED WALL ANNULAR ASPECT OF VEIN WALL WITH NUMEROUS FIBROUS EXTENSIONS BETWEEN HEPATOCYTES
PERISINUSOIDAL FIBROSIS
NORMAL LOCALISED FIBROSIS DIFFUSE FIBROSIS
PORTAL TRACT
NORMAL ENLARGED WITHOUT SEPTA ENLARGED WITH SEPTA CIRRHOSIS
NUMBER OF SEPTA
NONE ) SEPTAMM SEPTAMM NODULAR ORGANISATION
WIDTH OF SEPTA
THIN ANDOR INCOMPLETE THICK AND LOOSE CONNECTIVE MATRIX VERY THICK AND DENSE CONNECTIVE MATRIX BIOPSY AREA
CENTRAL VEIN
$ETERMINING FACTORS OF HEPATITIS CAUSED BY HEPATOTROPIC VIRUS 4HE GENERAL MECHANISMS OF VIRAL HEPATITIS INCLUDE HEPATOCELLULAR DAMAGE INFLAMMATORY CELL INFILTRATES AND REGENERATION 4HEY ARE COMMON TO ALL HEPATITIS VIRUS INFECTIONS 4HE DEVELOPMENT OF CHRONIC VIRAL HEPATITIS IS A RESULT OF THE INSUFFICIENCY OF THE HOST IMMUNE SYSTEM TO CLEAR THE AGENT 3EVERAL VIRUSES HAVE DEVELOPED MECHANISMS THAT FACILITATE THEIR ESCAPE FROM THE HOST DEFENSIVE MECHANISMS 4HUS CHRONICITY AND ITS COURSE REPRESENTS A COMPLEX INTERPLAY BETWEEN VIRAL AND HOST FACTORS DETERMINING THE MORPHOL OGY AND FINAL OUTCOME OF A HEPATITIS VIRUS INFECTION
#OMPARATIVE PATHOLOGY
#AUSATIVE AGENT )N CONTRAST TO ("6 INFECTION (#6 INFECTION BECOMES CHRONIC IN MOST CASES WHICH IS THE RESULT OF SEVERAL FACTORS 4HE DEGREE OF VIRAL REPLICATION IN ACUTE (#6 INFECTION IS COMPARABLY HIGH USUALLY SURPASSING THE CAPACITY OF THE IMMUNE SYSTEM !LTHOUGH A TYPE ) INTERFERON RESPONSE IS INITIATED BY THE INNATE IMMUNE SYSTEM IT OFTEN FAILS TO INDUCE VIRAL CLEARANCE IN VIVO DUE TO INTERACTIONS OF (#6 PROTEINS WITH MEDIATORS OF THE INTERFERON RESPONSE SYSTEM ;= 3OME (#6 PROTEINS HAVE BEEN SHOWN TO INHIBIT THE ACTIVITY ON .+ AND DENDRITIC CELLS ; = $URING (#6 INFECTION NUMEROUS QUASISPE CIES ARE PRODUCED DUE TO THE POOR PROOFREADING POTENTIAL OF THE VIRAL $.! POLYMERASE OVERWHELMING THE CAPACITY OF THE ADAPTIVE IMMUNE SYSTEM ;= $ESPITE THESE VIRAL MECHANISMS ABOUT OF (#6 INFECTIONS ARE CLEARED DURING THE ACUTE PHASE )MPORTANTLY THE ADDITION OF ANTIVIRAL THERAPY LEADS TO AN ALMOST CURE OF ACUTE (#6 INFECTION )N CONTRAST CHRONIC ("6 INFECTION PERSISTS EVEN FOLLOWING SEROCONVERSION WHICH MAY BE DUE TO ("E!G SECRETION PRODUCING 4 CELL TOLERANCE AND DOWNREGULATION OF ("6 REPLICATION ;= 4HUS THERE IS A BALANCE BETWEEN MINIMISED VIRAL REPLICATION AND CONTROL OF THE INFECTION BY THE CELLULAR AND HUMORAL IMMUNE SYSTEM RESULTING IN LIFE LONG PROTECTIVE IMMUNITY
(OST FACTORS 7HETHER AN ACUTE HEPATITIS RESOLVES OR BECOMES CHRONIC IS ULTIMATELY DETER MINED BY THE HOSTS DEFENSE MECHANISMS IN CLEARING THE INFECTION 4HE 4 CELL RESPONSE SEEMS TO PLAY A MAJOR ROLE IN THE RESOLUTION OF A HEPATOTROPIC VIRAL INFECTION AND PATIENTS SUFFERING FROM CHRONIC INFECTION ONLY SHOW A NARROWED AND TRANSIENT 4 CELL RESPONSE COMPARED TO THOSE WHO CLEARED THE VIRUS ; = /NE OF THE BEST EXAMPLES IN THIS REGARD IS THE COMMON CHRONICITY RATE IN INFANTS VERTICALLY INFECTED BY ("6 IN CONTRAST TO INFECTED ADULTS WHICH IS MAINLY DUE TO THE IMMATURITY OF THE IMMUNE SYSTEM !DDITIONALLY REAC TIVATION OF AN ("6 INFECTION MAY OCCUR FOLLOWING IMMUNOSUPPRESSION DUE TO ORGAN TRANSPLANTATION ; = )MPORTANTLY ("6 AS WELL AS (#6 INFEC TION MAY SHOW AN ATYPICAL RE INFECTION PATTERN AFTER LIVER TRANSPLANTATION KNOWN AS FIBROSING CHOLESTATIC HEPATITIS &#( WHICH TYPICALLY DEVELOPS WITHIN THE FIRST MONTH AFTER TRANSPLANTATION AND RAPIDLY LEADS TO GRAFT FAILURE (ISTOLOGICALLY &#( IS CHARACTERISED BY HEPATOCELLULAR BALLOONING CHOLESTA SIS WITH PROMINENT DUCTULAR PROLIFERATION AND INTENSE PERISINUSOIDAL FIBROSIS BUT THERE IS A LACK OF SIGNIFICANT INFLAMMATORY CELL INFILTRATION )N THE CASE OF ("6 BALLOONED HEPATOCYTES SHOW INTENSE CYTOPLASMIC AND NUCLEAR STAINING FOR ("C!G SUGGESTING MAXIMAL VIRAL REPLICATION ; = 4HE PRESENCE OF CONCURRENT LIVER DISEASES MAY NEGATIVELY INFLUENCE THE PROGRESSION OF CHRONIC VIRAL HEPATITIS #ONSIDERING RECENT EPIDEMIOLOGIC DATA FATTY CHANGE EITHER IN ALCOHOLIC OR NON ALCHOLIC FATTY LIVER DISEASE EG
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
OBESITY INSULIN RESISTANCE METABOLIC SYNDROME PROBABLY REPRESENTS THE MOST IMPORTANT ISSUES IN THIS CONTEXT SINCE IT HAS BEEN SHOWN THAT FATTY CHANGE CAUSES SINGLE CELL NECROSIS AND APOPTOSIS ACCELERATING FIBROSIS PRO GRESSION ; = 7HEREAS PERIPORTAL OR MIDZONAL MACROVESICULAR STEATOSIS MAY BELONG TO THE SPECTRUM OF (#6 INFECTION ESPECIALLY GENOTYPE ;= PERIVENULAR ACCENTUATION IS HIGHLY INDICATIVE OF AN ADDITIONAL ALCOHOLIC OR NON ALCOHOLIC LIVER CELL DAMAGE ESPECIALLY WHEN SEEN IN COMBINATION OF NON NECROSIS ASSOCIATED PERISINUSOIDAL FIBROSIS ANDOR -ALLORY $ENK BODIES !LTHOUGH ENDOTHELIAL IRON DEPOSITS HAVE BEEN OBSERVED IN CHRONIC VIRAL HEPATITIS HEPATOCELLULAR SIDEROSIS SHOULD RAISE THE QUESTION OF CONCURRENT GENETIC HAEMOCHROMATOSIS EG (&% MUTATION #ONCURRENT LIVER DISEASE MAY BE OBSERVED IN UP TO OF BIOPSIES OBTAINED FROM (#6 INFECTED INDIVIDUALS
!NIMAL MODELS !NIMAL MODELS AND NATURAL OCCURRING VARIANTS OF HUMAN HEPATITIS VIRUSES (EPATITIS ! VIRUS 3EVERAL NONHUMAN PRIMATE ANIMAL MODELS HAVE BEEN USED FOR STUDY OF (!6 INFECTION BUT MOST OF THE DATA COME FROM INOCULATION EXPERIMENTS IN TWO ANIMAL SPECIES CHIMPANZEES AND TAMARINS 3AGUINUS MYSTAX !DDITIONALLY SOME INFORMATION IS DERIVED FROM THE INFECTION OF OWL MONKEYS ;n= (ISTOLOGICAL CHANGES IN THE LIVER OF THESE ANIMALS CLOSELY RESEMBLE (!6 INFECTION IN MAN INCLUDING FOCAL NECROSIS BALLOONING DEGENERATION APOPTO SIS CHOLESTASIS AND +UPFFER CELL PROLIFERATION 4HE INFLAMMATORY INFILTRATE IS MAINLY COMPOSED OF LYMPHOCYTES BUT NEUTROPHILS EOSINOPHILS AND PLASMA CELLS ARE ALSO OBSERVED 4HE SEVERITY OF HEPATITIS RANGES FROM MILD WITH FOCAL NECROSIS TO MODERATE WITH BRIDGING NECROSIS AND ALL ANIMALS RECOVER COM PLETELY )N CONTRAST TO HUMANS ANIMALS ARE ALMOST NEVER SYMPTOMATIC DURING EXPERIMENTAL (!6 INFECTION ;=
(EPATITIS % VIRUS -ACAQUE SPECIES CHIMPANZEES AND OWL MONKEYS ARE THE MOST FREQUENT ANIMAL MODELS USED FOR STUDY OF (%6 BUT ADDITIONALLY PIGS AND RATS MAY BE USEFUL FOR SOME STUDIES (ISTOLOGICAL CHANGES IN THE LIVER OF NONHUMAN PRIMATES AND HUMANS ARE SIMILAR 4HERE IS FOCAL CYTOLYTIC NECROSIS WITH MINIMAL INFLAMMATORY INFILTRATION IN BOTH SPECIES )NFLAMMATORY INFILTRATES IF PRESENT CONSIST MAINLY OF NEUTROPHILS #HOLESTATIC HEPATITIS BALLOONING HEPATOCELLULAR CHOLESTASIS IS COMMON AND PSEUDOGLAND FORMATION HAS
#OMPARATIVE PATHOLOGY
BEEN REPORTED ; = 4HE MORTALITY OF HEPATITIS % IN THE THIRD TRIMESTER OF PREGNANCY IN HUMANS IS REPORTED TO BE APPROXIMATELY WHICH IS MUCH HIGHER THAN IN PREGNANT RHESUS MONKEYS ; = !DDITIONALLY IN CONTRAST TO HUMANS IN WHOM IMMUNITY DEVELOPS RECURRENT HEPATITIS % HAS BEEN REPORTED IN TAMARINS ;=
(EPATITIS " VIRUS .ATURAL ANIMAL MODEL SYSTEMS FOR THE STUDYING OF ("6 INFECTION CAN BE DIFFERENTIATED IN THOSE BEING PERMISSIVE FOR HUMAN ("6 AND THOSE INFECTED BY ("6 RELATED VIRUSES #HIMPANZEES CAN BE INFECTED WITH ("6 AND THIS MODEL CONTRIBUTED MUCH TO OUR CURRENT UNDERSTANDING OF THE MOLECULAR VIROLOGY OF CHRONIC HEPATITIS " 4HE ADVANTAGES OF THIS MODEL INCLUDE THE FACT THAT IT IS THE ONLY MODEL FOR IMMUNOLOGICAL STUDIES OF THE NATURAL COURSE OF THE INFECTION THE POSSIBILITY TO USE DEFINED INOCULA AND STUDY THE EARLY PHASES OF INFEC TION 4HE DISADVANTAGES OF THIS MODEL ARE ETHICAL CONSIDERATIONS LIMITING BIOMEDICAL RESEARCH ON PRIMATES COMPARABLY HIGH COSTS AND LIMITED AVAIL ABILITY OF CHIMPANZEES LISTED AS AN ENDANGERED SPECIES SINCE 4HE CLINICAL COURSE OF THE INFECTION IS ONLY VERY MILD AND THE HUMORAL IMMUNE RESPONSE IS WEAK AND MORE RESTRICTED COMPARED TO HUMANS !DDITIONALLY VERTICAL TRANSMISSION OCCURS ONLY RARELY IN CONTRAST TO ("6 IN HUMANS )N CHIMPANZEES THERE ARE TWO HISTOLOGICALLY DISTINCTIVE TYPES OF INFECTION THE FIRST TYPE IS A SELF LIMITING ACUTE HEPATITIS 4HE SECOND TYPE RESULTS IN CHRONIC HEPATITIS WITH PORTAL LYMPHOCYTIC INFILTRATION FORMATION OF LYM PHOID FOLLICLES USUALLY NOT SEEN IN HUMANS AND VARIABLE USUALLY MILD LIVER CELL NECROSIS )NTERFACE HEPATITIS IS GENERALLY NOT SEEN IN ("6 INFECTED CHIM PANZEES 4HEREFORE CHIMPANZEES DO NOT DEVELOP PROGRESSIVE FIBROSIS AND LIVER CIRRHOSIS ; = )T HAS BEEN SHOWN THAT INFECTION WITH ("6 RELATED VIRUSES NATURALLY MAY TAKE PLACE IN CHIMPANZEES GIBBONS ORANG UTANS AND RHESUS MONKEYS BUT THESE ANIMALS DO NOT SEEM TO DEVELOP MORPHOLOGICAL EQUIVALENTS OF HEPATITIS ;n= !NOTHER TRANSIENTLY ("6 INFECTIBLE ANIMAL MODEL REPRESENTS THE TREE SHREW SPECIES 4UPAIA BELANGERI ;= WHICH DEVEL OPS SHORT TERM REPLICATION FOLLOWED BY SEROCONVERSION BUT DOES NOT SHOW HISTOLOGICAL CHANGES OF HEPATITIS ("6 RELATED VIRUSES CAN BE GROSSLY DIVIDED IN MAMMALIAN HEPATITIS VIRUSES ORTHOHEPADNAVIRUSES AND AVIAN HEPATITIS VIRUSES AVIHEPADNAVI RUSES 4HE FIRST ("6 RELATED VIRUS DESCRIBED WAS THE WOODCHUCK HEPATITIS VIRUS 7(6 WHICH CAUSES CHRONIC HEPATITIS WITH SOME INTERFACE ACTIVITY COMPARABLE TO THAT IN HUMANS WITH CHRONIC ("6 INFECTION ALTHOUGH INFLAM MATORY ACTIVITY IS GENERALLY MILDER !DDITIONALLY 7(6 INFECTED WOOD CHUCKS DEVELOP HEPATOCELLULAR CARCINOMA (## WITH HIGHER FREQUENCY BUT IN CONTRAST TO HUMANS THEY DO NOT DEVELOP LIVER CIRRHOSIS ; = /THER MAMMALIAN ("6 RELATED VIRUSES INCLUDE THE GROUND SQUIRREL HEPATITIS VIRUS
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
'3(6 ; = THE ARCTIC SQUIRREL HEPATITIS VIRUS !3(6 AND THE WOOLLY MONKEY HEPATITIS " VIRUS 7-(6 )N GENERAL ALL OF THESE ANIMALS SHOW ONLY MILD HISTOLOGICAL LIVER ABNORMALITIES DESPITE SOMETIMES HIGH SERUM TITRES AND (## DEVELOPMENT IS SEEN INFREQUENTLY ; = 7OOLLY MONKEY HEPATITIS " VIRUS 7-("6 USUALLY CAUSES CHRONIC HEPATITIS WITH NO OR MINOR SYMPTOMS BUT FULMINANT 7-("6 HEPATITIS MAY OCCUR 4HE DEVELOP MENT OF LIVER CIRRHOSIS HAS NOT BEEN REPORTED ;= !BOUT ONE THIRD OF AGED ARCTIC SQUIRRELS DEVELOP FOCAL LIVER LESIONS WHICH INCLUDE LIVER CELL ADENOMAS (##S AND LARGE NODULES SHOWING MICROVESICULAR STEATOSIS ;= )MPORTANTLY THESE LESIONS ARE ALSO OBSERVED IN ANIMALS NOT INFECTED WITH THE ARCTIC SQUIR REL HEPATITIS VIRUS !3(6 4HUS THIS MODEL DIFFERS SIGNIFICANTLY FROM 7(6 INFECTION IN WHICH MOST INFECTIONS RESULT IN (## DEVELOPMENT WITHIN n YEARS ;= 4HE GROUP OF AVIHEPADNAVIRUSES INCLUDE THE PROTOTYPIC DUCK HEPATITIS " VIRUS $("6 AND SEVERAL RELATED FAMILY MEMBERS HERON HEPATITIS " VIRUS (("6 SNOW GOOSE HEPATITIS VIRUS 3'(6 ROSS GOOSE HEPATITIS " VIRUS 2'("6 WHITE STORK HEPATITIS " VIRUS 73("6 AND CRANE HEPATITIS " VIRUS ;n= $("6 INFECTION CAUSES AN ACUTE HEPATITIS AND ITS SEVERITY COR RELATES WITH THE DEGREE OF VIREMIA BUT IN CONTRAST TO MAMMALIAN HEPATITIS VIRUSES ONLY VERY MILD OR EVEN NO HISTOLOGICAL CHANGES OCCUR DURING $("6 PERSISTENCE (## DEVELOPMENT HAS BEEN OBSERVED IN $("6 INFECTED 0EKIN DUCKS BUT ONLY IN A FEW CASES SUCH THAT ITS RELATION TO $("6 IS QUESTIONABLE ; n=
(EPATITIS $ VIRUS 3INCE ($6 REPRESENTS AN INCOMPLETE VIRUS WHICH HAS AN ABSOLUTE REQUIRE MENT FOR ("6 FOR REPLICATION AND TRANSMISSION ANIMAL MODELS ARE RESTRICTED TO THOSE PERMISSIVE FOR ("6 INFECTION ;= "OTH IN HUMANS AND IN ANIMAL MODELS THE REPLICATION OF ("6 IS DIMINISHED DURING ACUTE ($6 REPLICATION ($6 INFECTION MAY EITHER OCCUR AS A CO INFECTION WITH ("6 OR AS A SUPERIN FECTION IN ("6 CARRIERS )N THE CHIMPANZEE MODEL CO INFECTION RESULTS IN A MODERATELY ACTIVE HEPATITIS WHICH MAY SHOW TWO DIFFERENT COURSES 7HEREAS IN THE UNIMODAL COURSE OF DISEASE THERE IS PARALLEL EXPRESSION OF ("C AND DELTA ANTIGEN IN THE NUCLEI OF INFECTED HEPATOCYTES THE BIMODAL INFECTION IS CHARACTERISED BY THE EXPRESSION OF ONE OR THE OTHER ANTIGEN DURING THE SECOND PHASE ;= )N CONTRAST A SUPERINFECTION OF ($6 RESULTS IN A MORE SEVERE HEPATITIS WHICH IN MORE THAN OF CASES RESULTS IN VIRAL PERSISTENCE ;= !DDITIONALLY THE ($6 GENOTYPE SEEMS TO INFLUENCE THE SEVERITY OF LIVER DISEASE ;= !LTHOUGH ($6 INFECTION RESULTS IN A MORE SEVERE HEPATITIS IN CHIMPANZEES COMPARED TO OTHER HEPATITIS VIRUSES THEY DO NOT DEVELOP A PROGRESSIVE DISEASE COMPARED TO THE ONE SEEN IN HUMANS !LTHOUGH THERE IS NO INDICATION THAT ($6 INFECTION MAY TAKE PLACE NATURALLY IN 7(6 INFECTION IT HAS BEEN SHOWN THAT ($6 CAN BE TRANSMITTED
#OMPARATIVE PATHOLOGY
TO 7(6 CARRYING %ASTERN WOODCHUCKS WHICH RESULTS IN ACUTE AND CHRONIC HEPATITIS IN A HIGH PROPORTION OF ANIMALS ;=
(EPATITIS # VIRUS 4HE SITUATION WITH (#6 IS EVEN MORE COMPLEX SINCE THE ONLY TRUE INFECTION MODEL IS THE CHIMPANZEE )N CONTRAST OTHER MAMMALS HAVE NOT BEEN INFECT ED SUCCESSFULLY WITH (#6 ; = !CUTE INFECTION OF CHIMPANZEES USUALLY SHOWS A VARIABLE BUT MILD DEGREE OF FOCAL INFLAMMATION AND HEPATOCELLULAR APOPTOSIS WHEREAS PORTAL INFLAMMATORY INFILTRATION IS NOT PROMINENT )N CONTRAST CHRONICALLY (#6 INFECTED CHIMPANZEES SHOW A VARIABLE DEGREE OF PORTAL INFLAMMATORY INFILTRATES AND FORMATION OF LYMPHOID AGGREGATES 3OMETIMES MILD INTERFACE HEPATITIS MAY BE SEEN WHICH IS NOT ASSOCIATED WITH SIGNIFICANT FIBROSIS EVEN AFTER MORE THAN TEN YEARS OF CHRONIC INFECTION !CINAR INFLAMMATION INCLUDES SINUSOIDAL LYMPHOCYTIC INFILTRATION PAREN CHYMAL INFLAMMATORY FOCI AND APOPTOSIS ;= !LTHOUGH (#6 INFECTION IN CHIMPANZEES RESULTS IN ACUTE HEPATITIS ABOUT OF CHIMPANZEES CONVALESCE WHEREAS ABOUT WILL BECOME PERSISTENTLY VIREMIC A RATE WHICH IS MUCH LOWER COMPARED TO HUMANS ;= 2ECENTLY TRANSIENT ACUTE (#6 INFECTION HAS BEEN REPORTED IN TREE SHREWS 4UPAIA BELANGERI CHINENSIS RESULTING IN ANTI (#6 ANTIBODY PRODUC TION ALTHOUGH THE EFFICIENCY APPROXIMATELY IS MUCH LOWER COMPARED TO ("6 INFECTION ;= 3INCE THE ANIMALS USED IN THIS STUDY HAD BEEN CAUGHT IN THE WILD IT IS NOT CLEAR WHETHER THE MINIMAL HISTOLOGICAL ALTERATIONS OBSERVED IN THIS STUDY HAD BEEN REALLY DUE TO (#6 INFECTION
'" VIRUSES '" VIRUSES ! AND " '"6 ! AND '"6 " ARE MEMBERS OF THE &LAVIVIRIDAE FAMILY AND WERE ISOLATED FROM TAMARINS INFECTED WITH SERUM FROM A HUMAN HEPATITIS PATIENT ; = ! THIRD MEMBER OF THIS GROUP REPRESENTS A RELATED HUMAN VIRUS '" VIRUS # OR ALTERNATIVELY HEPATITIS ' VIRUS '"6 #('6 ; = '"6 ! HAS BEEN SHOWN TO BE A COMMON .EW 7ORLD PRIMATE VIRUS CAUS ING CHRONIC INFECTION WITHOUT APPARENT LIVER DISEASE ;= '"6 " WHICH IS PHYLOGENETICALLY RELATED TO HUMAN (#6 ;= IS CAPABLE OF CAUSING ACUTE HEPATITIS IN TAMARINS ;= 3INCE INDIGENOUS ISOLATES OF '"6 " HAVE NOT BEEN ISOLATED FROM WILD TAMARINS IT SEEMS QUESTIONABLE WHETHER TAMARINS ARE THE NATURAL HOST '"6 #('6 SEEMS TO BE A LYMPHOTROPIC VIRUS RATHER THAN A HEPATOTROPIC VIRUS 0HYLOGENETICALLY IT IS MORE RELATED TO '"6 ! THAN '"6 " '"6 " A PLEIOTROPIC VIRUS HAS BEEN PROPOSED AS A POTENTIAL MODEL FOR THE STUDY OF HUMAN (#6 INFECTION SINCE IT IS PHYLOGENETICALLY MOST CLOSELY
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
RELATED TO (#6 AND CAUSES AN ACUTE SELF RESOLVING HEPATITIS IN TAMARINS RESULTING IN AN INCREASE IN ALANINE AMINOTRANSFERASE AND MILD HEPATITIC CHANGES IN LIVER HISTOLOGY )MPORTANTLY '"6 " DOES NOT CAUSE CHRONIC HEPATITIS IN TAMARINS WHICH IS DIFFERENT FROM (#6 IN HUMANS !DDITIONALLY '"6 " INFECTION CAUSES PROTECTIVE IMMUNITY AFTER RESOLUTION OF THE INFEC TION WHICH IS NOT THE CASE IN RESOLVED HUMAN HEPATITIS # ;=
4RANSGENIC MOUSE MODELS !LTHOUGH TRANSGENIC AND OTHER MOUSE MODELS HAVE ELUCIDATED SOME IMPORTANT ASPECTS OF THE PATHOGENESIS OF VIRAL HEPATITIS THEY HAVE SEVERAL LIMITATIONS MURINE HEPATOCYTES ARE NOT PERMISSIVE FOR HUMAN HEPATITIS VIRUS INFECTIONS 4HEREFORE STUDIES OF THE COMPLETE NATURAL LIFE CYCLE OF HEPATITIS VIRUSES ARE NOT POSSIBLE USING THESE SYSTEMS 4HEREFORE MOST OF THESE MICE DO NOT EXHIBIT A LIVER SPECIFIC PHENOTYPE AND STUDIES ON VIRUS RELATED IMMUNE MEDIATED MECHANISMS OF LIVER INJURY ARE RESTRICTED )NDUCIBLE SYSTEMS EG T4! #RELOX0 MAY OVERCOME THIS PROBLEM IN THE NEAR FUTURE 4HE DESCRIPTION OF THE ENTIRE SPECTRUM OF TRANSGENIC MODELS OF VIRAL HEPATITIS IS BEYOND THE SCOPE OF THIS CHAPTER 4HEREFORE ONLY GENERAL REMARKS ARE GIVEN AND SOME INTERESTING FACTS DERIVING FROM THESE MODELS ARE PRESENTED 3EVERAL TRANSGENIC MOUSE STRAINS EXPRESSING PARTIAL OR COMPLETE COPIES OF THE ("6 GENOME HAVE BEEN DEVELOPED ;n= ("6 TRANSGENIC MICE INOCULATED WITH ($6 DEVELOP VIRAL REPLICATION AND ASSEMBLE NEW ($6 PARTICLES ;= 2ECENTLY A TRANSGENIC MOUSE MODEL FOR CHRONIC HEPATITIS WAS DEVELOPED ;= )N THIS MODEL CHRONIC LIVER DISEASE RESULTED FROM THE ADOP TIVE TRANSFER OF UNPRIMED SYNGENEIC SPLENOCYTES IN ("6 TRANSGENIC IMMU NODEFICIENT 3#)$ MICE !S A RESULT THE ("S ANTIGEN AND VIRAL $.! WERE CLEARED WITHIN A FEW WEEKS WHICH WERE OFTEN ACCOMPANIED BY ("S ANTI BODY SEROCONVERSION BUT IT DID NOT RESULT IN COMPLETE VIRAL ELIMINATION AS INDICATED BY THE REAPPEARANCE OF ("6 $.! AT A LATER TIME (ISTOLOGICALLY THE LIVERS OF THESE MICE SHOWED PORTAL INFLAMMATION ACINAR INFLAMMATION HEPATOCELLULAR DEGENERATION AND REGENERATION AS SEEN IN HUMAN CHRONIC VIRAL HEPATITIS
#HIMERIC MOUSE MODELS 4HERE ARE BASICALLY TWO DIFFERENT CHIMERIC MOUSE MODELS THE FIRST REPRE SENTS THE 4RIMERA MOUSE MODEL WHICH IS DEVELOPED VIA PRECONDITIONING OF NORMAL MICE BY LETHAL BODY IRRADIATION AND RADIOPROTECTION BY 3#)$ MOUSE BONE MARROW TRANSPLANTATION 3UBSEQUENTLY EX VIVO INFECTED HUMAN LIVER TISSUE FRAGMENTS ARE IMPLANTED UNDER THE KIDNEY CAPSULE OR IN THE EAR PINNA OF 4RIMERA MICE ;= ! MODIFICATION OF THIS MODEL IS THE NON OBESE
#OMPARATIVE PATHOLOGY
DIABETICSEVERE COMBINED IMMUNODEFICIENCY ./$3#)$ MOUSE TRANS PLANTED WITH HUMAN LIVER TISSUE ;= 4HE SECOND MOUSE MODEL OF WHICH SEVERAL MODIFICATIONS EXIST IS BASED ON THE ALBUMIN UROKINASETYPE PLASMINOGEN ACTIVATOR U0! TRANSGENIC MOUSE 4HIS MOUSE DEVELOPS A LIVER AUTO TOXIC PHENOTYPE WITH PROGRESSIVE DEPLETION OF TRANSGENE BEARING HEPATOCYTES AND RECONSTITUTION OF THE LIVER PARENCHYMA BY TRANSGENE DEFICIENT HEPATOCYTES VIA TRANSGENE REARRANGE MENT BY MONTHS OF AGE ;= 7HEN THESE MICE ARE CROSS BRED WITH 2!' DEFICIENT MICE LACKING MATURE 4 AND " LYMPHOCYTES ;= HEPATOCYTES MAY XENOGRAFT THE LIVERS OF THE COMPOUND TRANSGENICS EG WOODCHUCK HUMAN TREE SHREW ;n= 2ECENTLY A DERIVATIVE MODEL THE U0!3#)$ MOUSE WAS CHARACTERISED WHICH SHOWS OCCUPATION OF UP TO NEARLY OF THE LIVER PARENCHYMA BY EXPANDED ENGRAFTED HUMAN HEPATOCYTES ; = 4HE ADVANTAGE OF THESE CHIMERIC SYSTEMS IS THE ABILITY TO STUDY VIRAL REPLICATION AND VIRAL SPREAD IN VIVO IN AN ANIMAL SYSTEM WHICH ALLOWS FOR THERAPEUTIC AND VACCINATION STUDIES IN A SMALL ANIMAL SYSTEM .EVERTHELESS CHRONIC VIRAL HEPATITIS CANNOT BE EVALUATED IN THIS MODEL DUE TO THE IMMU NODEFICIENCY BACKGROUND OF 2!' RESPECTIVELY 3#)$ MICE
#LINICALLY RELEVANT HEPATITIS IN DOMESTIC ANIMALS #HRONIC LIVER DISEASE IN DOGS IS SIMILAR TO CHRONIC HEPATITIS IN HUMANS IN THAT THERE ARE MANY DIFFERENT ETIOPATHOLOGICAL FACTORS SUCH AS THE CANINE ADENO VIRUS TYPE ,EPTOSPIROA INTERROGANS VAR GRIPPOTYPHOSA CANINE ACIDOPHIL CELL HEPATITIS VIRUS COPPER ACCUMULATION _ ANTITRYPSIN DEFICIENCY DRUG TOXICITY AND AUTOIMMUNITY ALTHOUGH IN MANY CASES THE ETIOLOGICAL CAUSE REMAINS OBSCURE ;n= (ISTOLOGICALLY CANINE CHRONIC HEPATITIS IS COM PARABLE TO HUMAN HEPATITIS AND SHOWS PORTAL INFLAMMATION WITH INTERFACE HEPATITIS AS WELL AS AN ACINAR INFLAMMATORY COMPONENT AND PROGRESSION TO LIVER CIRRHOSIS ; = !TYPICAL FREQUENTLY FATAL HEPATITIS HAS BEEN REPORTED IN LAMBS BY OVINE ADENOVIRUS TYPE ;= 3IMIAN 6ARICELLA 6IRUS MAY CAUSE FULMINANT HEPATI TIS IN /LD 7ORLD MONKEYS WHICH HISTOLOGICALLY SHOWS SIMILARITIES TO 6ARICELLA ZOSTER VIRUS HEPATITIS IN HUMANS NUCLEAR INCLUSIONS ;=
#ONCLUDING REMARKS !LTHOUGH LIVER BIOPSY MAY BE A VALUABLE TOOL IN EVALUATING ACUTE HEPATITIS IN HUMANS ESPECIALLY IN TRANSPLANTS IN WHICH SPECIFIC HISTOLOGICAL FEATURES MAY FACILITATE EXPEDITIOUS DIAGNOSIS AND ADEQUATE TREATMENT LIVER BIOPSY REPRESENTS THE GOLD STANDARD IN THE ASSESSMENT OF CHRONIC HEPATITIS SINCE IT PROVIDES CLUES FOR THE DIAGNOSIS PROGNOSIS GRADING STAGING AND THERA PEUTIC OPTIONS -ANY SMALL AND LARGE ANIMAL MODELS INCLUDING TRANSGENICS
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
HAVE BEEN DEVELOPED FOR STUDIES ON CHRONIC VIRAL HEPATITIS WHICH HAVE ELUCI DATED IMPORTANT ASPECTS OF THE MOLECULAR BIOLOGY AND PATHOGENESIS OF VIRAL HEPATITIS .EVERTHELESS THE HISTOLOGICAL DISEASE COURSE IN ANIMALS DIFFERS FROM THAT IN HUMANS IN THAT THE DEGREE OF INFLAMMATORY ACTIVITY IS GENER ALLY MILDER AND THE DEVELOPMENT OF LIVER FIBROSIS OR CIRRHOSIS IS RARELY SEEN &UTURE DEVELOPMENTS EG INDUCIBLE TRANSGENIC MODELS MAY ALLOW CLOSER SIMULATION OF THE HUMAN SITUATION AND HELP TO IMPROVE OUR UNDERSTANDING OF THE PATHOGENESIS AND PROGNOSIS OF CHRONIC HEPATITIS
2EFERENCES
!BE ( "ENINGER 02 )KEJIRI . 3ETOYAMA ( 3ATA - 4ANIKAWA + ,IGHT MICROSCOPIC FINDINGS OF LIVER BIOPSY SPECIMENS FROM PATIENTS WITH HEPATITIS TYPE ! AND COMPARISON WITH TYPE " 'ASTROENTEROLOGY n $IENES (0 (UTTEROTH 4 "IANCHI , 'RUN - 4HOENES 7 (EPATITIS ! LIKE NON ! NON " HEPATITIS LIGHT AND ELECTRON MICROSCOPIC OBSERVATIONS OF THREE CASES 6IRCHOWS !RCH ! 0ATHOL !NAT (ISTOPATHOL n %ISENBACH # ,ONGERICH 4 &ICKENSCHER ( 3CHALASTA ' 3TREMMEL 7 %NCKE * 2ECURRENCE OF CLINICALLY SIGNIFICANT HEPATITIS ! FOLLOWING LIVER TRANSPLAN TATION FOR FULMINANT HEPATITIS ! * #LIN 6IROL n "RUNT %- *ANNEY #' $I "ISCEGLIE !- .EUSCHWANDER 4ETRI "! "ACON "2 .ONALCOHOLIC STEATOHEPATITIS A PROPOSAL FOR GRADING AND STAGING THE HISTOLOGICAL LESIONS !M * 'ASTROENTEROL n +LEINER $% "RUNT %- 6AN .ATTA - "EHLING # #ONTOS -* #UMMINGS /7 &ERRELL ,$ ,IU 9# 4ORBENSON -3 5NALP !RIDA ! ET AL $ESIGN AND VALIDATION OF A HISTOLOGICAL SCORING SYSTEM FOR NONALCOHOLIC FATTY LIVER DISEASE (EPATOLOGY n +ASPER (5 $REBBER 5 (IRSCH ) $IENES (0 -ORPHOLOGISCHE 6ERËNDERUNGEN DER MEDIKAMENTENINDUZIERTEN ,EBERSCHËDIGUNG 0ATHOLOGE n )SHAK +' :IMMERMAN (* -ORPHOLOGIC SPECTRUM OF DRUG INDUCED HEPATIC DISEASE 'ASTROENTEROL #LIN .ORTH !M n "AMBER - -URRAY ! !RBORGH "! 3CHEUER 0* +ERNOFF 0" 4HOMAS (# 3HERLOCK 3 3HORT INCUBATION NON ! NON " HEPATITIS TRANSMITTED BY FAC TOR 6))) CONCENTRATES IN PATIENTS WITH CONGENITAL COAGULATION DISORDERS 'UT n ,ONGERICH 4 3CHIRMACHER 0 $IENES (0 3TEIN ( ,ODDENKEMPER # ;-ALIGNANT LYMPHOMAS OF THE LIVER NEW DIAGNOSTIC ALGORITHMS= 0ATHOLOGE n 0ELLEGRIN - $ELSOL ' !UVERGNAT *# &AMILIADES * &AURE ( 'UIU - 6OIGT ** 'RANULOMATOUS HEPATITIS IN 1 FEVER (UM 0ATHOL n -URPHY % 'RIFFITHS -2 (UNTER *! "URT !$ &IBRIN RING GRANULOMAS A NON SPECIFIC REACTION TO LIVER INJURY (ISTOPATHOLOGY n -ORENO ! -ARAZUELA - 9EBRA - (ERNANDEZ -* (ELLIN 4 -ONTALBAN # 6ARGAS *! (EPATIC FIBRIN RING GRANULOMAS IN VISCERAL LEISHMANIASIS 'ASTROENTEROLOGY n
#OMPARATIVE PATHOLOGY
6ANDERSTIGEL - :AFRANI %3 ,EJONC *, 3CHAEFFER ! 0ORTOS *, !LLOPURINOL HYPERSENSITIVITY SYNDROME AS A CAUSE OF HEPATIC FIBRIN RING GRANU LOMAS 'ASTROENTEROLOGY n ,ONGERICH 4 (AFERKAMP + 4OX 5 3CHIRMACHER 0 !CUTE LIVER FAILURE IN A RENAL TRANSPLANT PATIENT CAUSED BY ADENOVIRAL HEPATITIS SUPERIMPOSED ON A FIBROSING CHOLESTATIC HEPATITIS " (UM 0ATHOL n ,ONGERICH 4 %ISENBACH # 0ENZEL 2 +REMER 4 &LECHTENMACHER # (ELMKE " %NCKE * +RAUS 4 3CHIRMACHER 0 2ECURRENT HERPES SIMPLEX VIRUS HEPA TITIS AFTER LIVER RETRANSPLANTATION DESPITE ACYCLOVIR THERAPY ,IVER 4RANSPL n $ESMET 6* 'ERBER - (OOFNAGLE *( -ANNS - 3CHEUER 0* #LASSIFICATION OF CHRONIC HEPATITIS DIAGNOSIS GRADING AND STAGING (EPATOLOGY n $REBBER 5 /DENTHAL - $RIES 6 3CHRIMACHER 0 $IENNES (0 ;$IAGNOSIS OF SERONEGATIVE CHRONIC HEPATITIS IN TISSUE= 0ATHOLOGE n 2OCHA - !VENAUD 0 -ENARD ! ,E "AIL " "ALABAUD # "IOULAC 3AGE 0 DE -AGALHAES 1UEIROZ $- -EGRAUD & !SSOCIATION OF (ELICOBACTER SPE CIES WITH HEPATITIS # CIRRHOSIS WITH OR WITHOUT HEPATOCELLULAR CARCINOMA 'UT n )SHAK +' 0ATHOLOGIC FEATURES OF CHRONIC HEPATITIS ! REVIEW AND UPDATE !M * #LIN 0ATHOL n "IANCHI , 'UDAT & 3ANDED NUCLEI IN HEPATITIS " EOSINOPHILIC INCLUSIONS IN LIVER CELL NUCLEI DUE TO EXCESS IN HEPATITIS " CORE ANTIGEN FORMATION ,AB )NVEST n -ORENO ! 2AMON Y #AJAL 3 -ARAZUELA - #ARRENO 6 -ILICUA *- #EREZO % #UESTA # /LIVA ( 3ANDED NUCLEI IN DELTA PATIENTS ,IVER n #HU #- ,IAW 9& )NTRAHEPATIC DISTRIBUTION OF HEPATITIS " SURFACE AND CORE ANTIGENS IN CHRONIC HEPATITIS " VIRUS INFECTION (EPATOCYTE WITH CYTOPLAS MICMEMBRANOUS HEPATITIS " CORE ANTIGEN AS A POSSIBLE TARGET FOR IMMUNE HEPATOCYTOLYSIS 'ASTROENTEROLOGY n "IANCHI , $ESMET 6* 0OPPER ( 3CHEUER 0* !LEDORT ,- "ERK 0$ (ISTOLOGIC PATTERNS OF LIVER DISEASE IN HEMOPHILIACS WITH SPECIAL REFERENCE TO MORPHOLOGIC CHARACTERISTICS OF NON ! NON " HEPATITIS 3EMIN ,IVER $IS n "RODY 2) %NG 3 -ELAMED * -IZRACHI ( 3CHNEIDER 2* 4OBIAS ( 4EPERMAN ,7 4HEISE .$ )MMUNOHISTOCHEMICAL DETECTION OF HEPATITIS # ANTIGEN BY MONOCLONAL ANTIBODY 4/2$*) COMPARED WITH 0#2 VIRAL DETECTION !M * #LIN 0ATHOL n $OUGHTY !, 0AINTER $- -C#AUGHAN '7 .ONSPECIFICITY OF MONOCLO NAL ANTIBODY 4ORDJI FOR THE DETECTION OF HEPATITIS # VIRUS IN LIVER TRANSPLANT RECIPIENTS WITH CHOLESTATIC HEPATITIS ,IVER 4RANSPL 3URG n $IENES (0 %RBERICH ( $RIES 6 3CHIRMACHER 0 ,OHSE ! !UTOIMMUNE HEPATITIS AND OVERLAP SYNDROMES #LIN ,IVER $IS n 3IDDIQUE ) %L .AGA (! -ADDA *0 -EMON ! (ASAN & 3AMPLING VARI ABILITY ON PERCUTANEOUS LIVER BIOPSY IN PATIENTS WITH CHRONIC HEPATITIS # VIRUS INFECTION 3CAND * 'ASTROENTEROL n 'HANY -' +LEINER $% !LTER ( $OO % +HOKAR & 0ROMRAT + (ERION $ 0ARK 9 ,IANG 4* (OOFNAGLE *( 0ROGRESSION OF FIBROSIS IN CHRONIC HEPATITIS # 'ASTROENTEROLOGY n
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
"ATTS +0 ,UDWIG * #HRONIC HEPATITIS !N UPDATE ON TERMINOLOGY AND REPORTING !M * 3URG 0ATHOL n )SHAK + "APTISTA ! "IANCHI , #ALLEA & $E 'ROOTE * 'UDAT & $ENK ( $ESMET 6 +ORB ' -AC3WEEN 2. ET AL (ISTOLOGICAL GRADING AND STAGING OF CHRONIC HEPATITIS * (EPATOL n +NODELL 2' )SHAK +' "LACK 7# #HEN 43 #RAIG 2 +APLOWITZ . +IERNAN 47 7OLLMAN * &ORMULATION AND APPLICATION OF A NUMERICAL SCORING SYS TEM FOR ASSESSING HISTOLOGICAL ACTIVITY IN ASYMPTOMATIC CHRONIC ACTIVE HEPATITIS (EPATOLOGY n "EDOSSA 0 0OYNARD 4 !N ALGORITHM FOR THE GRADING OF ACTIVITY IN CHRONIC HEPATITIS # 4HE -%4!6)2 #OOPERATIVE 3TUDY 'ROUP (EPATOLOGY n 3CHIRMACHER 0 &LEIG 7% 4ANNAPFEL ! ,ANGNER # $RIES 6 4ERRACCIANO , $ENK ( $IENES (0 ;"IOPTIC DIAGNOSIS OF CHRONIC HEPATITIS 2ESULTS OF AN EVIDENCE BASED CONSENSUS CONFERENCE OF THE 'ERMAN 3OCIETY OF 0ATHOLOGY OF THE 'ERMAN 3OCIETY FOR $IGESTIVE AND -ETABOLIC $ISEASES AND OF #OMPENSATED (EPATITIS (EP.ET = 0ATHOLOGE n 'OLDIN 2$ 'OLDIN *' "URT !$ $HILLON 0! (UBSCHER 3 7YATT * 0ATEL . )NTRA OBSERVER AND INTER OBSERVER VARIATION IN THE HISTOPATHOLOGICAL ASSESSMENT OF CHRONIC VIRAL HEPATITIS * (EPATOL n #ASTERA , 6ERGNIOL * &OUCHER * ,E "AIL " #HANTELOUP % (AASER - $ARRIET - #OUZIGOU 0 $E ,EDINGHEN 6 0ROSPECTIVE COMPARISON OF TRANSIENT ELASTOGRAPHY &IBROTEST !02) AND LIVER BIOPSY FOR THE ASSESSMENT OF FIBROSIS IN CHRONIC HEPATITIS # 'ASTROENTEROLOGY n $IENSTAG *, 4HE ROLE OF LIVER BIOPSY IN CHRONIC HEPATITIS # (EPATOLOGY 3n 3CHEUER 0* #LASSIFICATION OF CHRONIC VIRAL HEPATITIS A NEED FOR REASSESS MENT * (EPATOL n !RIMA - 4ERAO ( +ASHIMA + !RITA 4 .ASU - .ISHIZONO ! 2EGRESSION OF LIVER FIBROSIS IN CASES OF CHRONIC LIVER DISEASE TYPE # QUANTITATIVE EVALUATION BY USING COMPUTED IMAGE ANALYSIS )NTERN -ED n #HEVALLIER - 'UERRET 3 #HOSSEGROS 0 'ERARD & 'RIMAUD *! ! HIS TOLOGICAL SEMIQUANTITATIVE SCORING SYSTEM FOR EVALUATION OF HEPATIC FIBROSIS IN NEEDLE LIVER BIOPSY SPECIMENS COMPARISON WITH MORPHOMETRIC STUDIES (EPATOLOGY n 4HIMME 2 "UKH * 3PANGENBERG (# 7IELAND 3 0EMBERTON * 3TEIGER # 'OVINDARAJAN 3 0URCELL 2( #HISARI &6 6IRAL AND IMMUNOLOGICAL DETER MINANTS OF HEPATITIS # VIRUS CLEARANCE PERSISTENCE AND DISEASE 0ROC .ATL !CAD 3CI 53! n %PUB .OV +HAKOO 3) 4HIO #, -ARTIN -0 "ROOKS #2 'AO 8 !STEMBORSKI * #HENG * 'OEDERT ** 6LAHOV $ (ILGARTNER - ET AL (,! AND .+ CELL INHIBITORY RECEPTOR GENES IN RESOLVING HEPATITIS # VIRUS INFECTION 3CIENCE n *INUSHI - 4AKEHARA 4 4ATSUMI 4 +ANTO 4 -IYAGI 4 3UZUKI 4 +ANAZAWA 9 (IRAMATSU . (AYASHI . .EGATIVE REGULATION OF .+ CELL ACTIVITIES BY INHIBITORY RECEPTOR #$.+'! LEADS TO ALTERED .+ CELL INDUCED MODULA TION OF DENDRITIC CELL FUNCTIONS IN CHRONIC HEPATITIS # VIRUS INFECTION * )MMUNOL n
#OMPARATIVE PATHOLOGY
2EHERMANN " .ASCIMBENI - )MMUNOLOGY OF HEPATITIS " VIRUS AND HEPATITIS # VIRUS INFECTION .AT 2EV )MMUNOL n #HAZOUILLERES / -AMISH $ +IM - #AREY + &ERRELL , 2OBERTS *0 !SCHER ., 7RIGHT 4, h/CCULTv HEPATITIS " VIRUS AS SOURCE OF INFECTION IN LIVER TRANSPLANT RECIPIENTS ,ANCET n +AWATANI 4 3UOU 4 4AJIMA & )SHIGA + /MURA ( %NDO ! /HMURA ( )KUTA 9 )DOBE 9 +AWASAKI ( )NCIDENCE OF HEPATITIS VIRUS INFECTION AND SEVERE LIVER DYSFUNCTION IN PATIENTS RECEIVING CHEMOTHERAPY FOR HEMATOLOGIC MALIG NANCIES %UR * (AEMATOL n $AVIES 3% 0ORTMANN "# /'RADY *' !LDIS 0- #HAGGAR + !LEXANDER '* 7ILLIAMS 2 (EPATIC HISTOLOGICAL FINDINGS AFTER TRANSPLANTATION FOR CHRON IC HEPATITIS " VIRUS INFECTION INCLUDING A UNIQUE PATTERN OF FIBROSING CHOLESTATIC HEPATITIS (EPATOLOGY n &ERRELL ,$ 7RIGHT 4, 2OBERTS * !SCHER . ,AKE * (EPATITIS # VIRAL INFECTION IN LIVER TRANSPLANT RECIPIENTS (EPATOLOGY n 7ILLIAMS 2 'LOBAL CHALLENGES IN LIVER DISEASE (EPATOLOGY n 7ALSH -* 6ANAGS $- #LOUSTON !$ 2ICHARDSON -- 0URDIE $- *ONSSON *2 0OWELL %% 3TEATOSIS AND LIVER CELL APOPTOSIS IN CHRONIC HEPATITIS # A MECHANISM FOR INCREASED LIVER INJURY (EPATOLOGY n 'ORDON ! -C,EAN #! 0EDERSEN *3 "AILEY -* 2OBERTS 3+ (EPATIC STEATOSIS IN CHRONIC HEPATITIS " AND # 0REDICTORS DISTRIBUTION AND EFFECT ON FIBROSIS * (EPATOL n #OHEN *) &EINSTONE 3 0URCELL 2( (EPATITIS ! VIRUS INFECTION IN A CHIM PANZEE DURATION OF VIREMIA AND DETECTION OF VIRUS IN SALIVA AND THROAT SWABS * )NFECT $IS n -ATHIESEN ,2 -OLLER !- 0URCELL 2( ,ONDON 74 &EINSTONE 3- (EPATITIS ! VIRUS IN THE LIVER AND INTESTINE OF MARMOSETS AFTER ORAL INOCULATION )NFECT )MMUN n !SHER ,6 "INN ,. -ENSING 4, -ARCHWICKI 2( 6ASSELL 2! 9OUNG '$ 0ATHOGENESIS OF HEPATITIS ! IN ORALLY INOCULATED OWL MONKEYS !OTUS TRIVIRGATUS * -ED 6IROL n 0URCELL 2( %MERSON 35 !NIMAL MODELS OF HEPATITIS ! AND % ),!2 * n 2AMALINGASWAMI 6 0URCELL 2( 7ATERBORNE NON ! NON " HEPATITIS ,ANCET n !RANKALLE 6! #HADHA -3 "ANERJEE + 3RINIVASAN -! #HOBE ,0 (EPATITIS % VIRUS INFECTION IN PREGNANT RHESUS MONKEYS )NDIAN * -ED 2ES n 4SAREV 3! 4SAREVA 43 %MERSON 35 2IPPY -+ :ACK 0 3HAPIRO - 0URCELL 2( %XPERIMENTAL HEPATITIS % IN PREGNANT RHESUS MONKEYS FAILURE TO TRANSMIT HEPATITIS % VIRUS (%6 TO OFFSPRING AND EVIDENCE OF NATURALLY ACQUIRED ANTIBODIES TO (%6 * )NFECT $IS n 3HIKATA 4 +ARASAWA 4 !BE + 4WO DISTINCT TYPES OF HEPATITIS IN EXPERI MENTAL HEPATITIS " VIRUS INFECTION !M * 0ATHOL n 3HOUVAL $ #HAKRABORTY 02 2UIZ /PAZO . "AUM 3 3PIGLAND ) -UCHMORE % 'ERBER -! 4HUNG 3. 0OPPER ( 3HAFRITZ $! #HRONIC HEPATITIS IN CHIMPANZEE CARRIERS OF HEPATITIS " VIRUS MORPHOLOGIC IMMUNOLOGIC AND VIRAL $.! STUDIES 0ROC .ATL !CAD 3CI 53! n
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
(U 8 -ARGOLIS (3 0URCELL 2( %BERT * 2OBERTSON "( )DENTIFICATION OF HEPATITIS " VIRUS INDIGENOUS TO CHIMPANZEES 0ROC .ATL !CAD 3CI 53! n 7ARREN +3 (EENEY *, 3WAN 2! (ERIYANTO 6ERSCHOOR %* ! NEW GROUP OF HEPADNAVIRUSES NATURALLY INFECTING ORANGUTANS 0ONGO PYGMAEUS * 6IROL n ,ANFORD 2% #HAVEZ $ 2ICO (ESSE 2 -OOTNICK ! (EPADNAVIRUS INFEC TION IN CAPTIVE GIBBONS * 6IROL n 4AKAHASHI + "ROTMAN " 5SUDA 3 -ISHIRO 3 0RINCE !- &ULL GENOME SEQUENCE ANALYSES OF HEPATITIS " VIRUS ("6 STRAINS RECOVERED FROM CHIM PANZEES INFECTED IN THE WILD IMPLICATIONS FOR AN ORIGIN OF ("6 6IROLOGY n 7ALTER % +EIST 2 .IEDEROST " 0ULT ) "LUM (% (EPATITIS " VIRUS INFEC TION OF TUPAIA HEPATOCYTES IN VITRO AND IN VIVO (EPATOLOGY n 3UMMERS * 3MOLEC *- 3NYDER 2 ! VIRUS SIMILAR TO HUMAN HEPATITIS " VIRUS ASSOCIATED WITH HEPATITIS AND HEPATOMA IN WOODCHUCKS 0ROC .ATL !CAD 3CI 53! n 0OPPER ( 3HIH *7 'ERIN *, 7ONG $# (OYER "( ,ONDON 74 3LY $, 0URCELL 2( 7OODCHUCK HEPATITIS AND HEPATOCELLULAR CARCINOMA CORRELA TION OF HISTOLOGIC WITH VIROLOGIC OBSERVATIONS (EPATOLOGY n -ARION 0, /SHIRO ,3 2EGNERY $# 3CULLARD '( 2OBINSON 73 ! VIRUS IN "EECHEY GROUND SQUIRRELS THAT IS RELATED TO HEPATITIS " VIRUS OF HUMANS 0ROC .ATL !CAD 3CI 53! n 'ANEM $ 7EISER " "ARCHUK ! "ROWN 2* 6ARMUS (% "IOLOGICAL CHAR ACTERIZATION OF ACUTE INFECTION WITH GROUND SQUIRREL HEPATITIS VIRUS * 6IROL n -ARION 0, 6AN $AVELAAR -* +NIGHT 33 3ALAZAR &( 'ARCIA ' 0OPPER ( 2OBINSON 73 (EPATOCELLULAR CARCINOMA IN GROUND SQUIRRELS PERSIS TENTLY INFECTED WITH GROUND SQUIRREL HEPATITIS VIRUS 0ROC .ATL !CAD 3CI 53! n &EITELSON -! -ILLMAN ) (ALBHERR 4 3IMMONS ( "LUMBERG "3 ! NEWLY IDENTIFIED HEPATITIS " TYPE VIRUS IN TREE SQUIRRELS 0ROC .ATL !CAD 3CI 53! n ,ANFORD 2% #HAVEZ $ "RASKY +- "URNS 2" RD 2ICO (ESSE 2 )SOLATION OF A HEPADNAVIRUS FROM THE WOOLLY MONKEY A .EW 7ORLD PRIMATE 0ROC .ATL !CAD 3CI 53! n 4ESTUT 0 2ENARD #! 4ERRADILLOS / 6ITVITSKI 4REPO , 4EKAIA & $EGOTT # "LAKE * "OYER " "UENDIA -! ! NEW HEPADNAVIRUS ENDEMIC IN ARCTIC GROUND SQUIRRELS IN !LASKA * 6IROL n 0OPPER ( 2OTH , 0URCELL 2( 4ENNANT "# 'ERIN *, (EPATOCARCINOGENICITY OF THE WOODCHUCK HEPATITIS VIRUS 0ROC .ATL !CAD 3CI 53! n -ARION 0, +NIGHT 33 (O "+ 'UO 99 2OBINSON 73 0OPPER ( ,IVER DISEASE ASSOCIATED WITH DUCK HEPATITIS " VIRUS INFECTION OF DOMESTIC DUCKS 0ROC .ATL !CAD 3CI 53! n 3PRENGEL 2 +ALETA %& 7ILL ( )SOLATION AND CHARACTERIZATION OF A HEPA TITIS " VIRUS ENDEMIC IN HERONS * 6IROL n #HANG 3& .ETTER (* "RUNS - 3CHNEIDER 2 &ROLICH + 7ILL ( ! NEW
#OMPARATIVE PATHOLOGY
AVIAN HEPADNAVIRUS INFECTING SNOW GEESE !NSER CAERULESCENS PRODUCES A SIGNIFICANT FRACTION OF VIRIONS CONTAINING SINGLE STRANDED $.! 6IROLOGY n 0ULT ) .ETTER (* "RUNS - 0RASSOLOV ! 3IRMA ( (OHENBERG ( #HANG 3& &ROLICH + +RONE / +ALETA %& ET AL )DENTIFICATION AND ANALYSIS OF A NEW HEPADNAVIRUS IN WHITE STORKS 6IROLOGY n 0RASSOLOV ! (OHENBERG ( +ALININA 4 3CHNEIDER # #OVA , +RONE / &ROLICH + 7ILL ( 3IRMA ( .EW HEPATITIS " VIRUS OF CRANES THAT HAS AN UNEX PECTED BROAD HOST RANGE * 6IROL n #ULLEN *- -ARION 0, .EWBOLD *% ! SEQUENTIAL HISTOLOGIC AND IMMU NOHISTOCHEMICAL STUDY OF DUCK HEPATITIS " VIRUS INFECTION IN 0EKIN DUCKS 6ET 0ATHOL n 2IZZETTO - #ANESE -' 'ERIN *, ,ONDON 74 3LY $, 0URCELL 2( 4RANSMISSION OF THE HEPATITIS " VIRUS ASSOCIATED DELTA ANTIGEN TO CHIMPANZEES * )NFECT $IS n 'ERIN *, !NIMAL MODELS OF HEPATITIS DELTA VIRUS INFECTION AND DISEASE ),!2 * n .EGRO & "ERGMANN +& "AROUDY "- 3ATTERFIELD 7# 0OPPER ( 0URCELL 2( 'ERIN *, #HRONIC HEPATITIS $ VIRUS ($6 INFECTION IN HEPATITIS " VIRUS CARRIER CHIMPANZEES EXPERIMENTALLY SUPERINFECTED WITH ($6 * )NFECT $IS n #ASEY *, 'ERIN *, 'ENOTYPE SPECIFIC COMPLEMENTATION OF HEPATITIS DELTA VIRUS 2.! REPLICATION BY HEPATITIS DELTA ANTIGEN * 6IROL n 0ONZETTO ! #OTE 0* 0OPPER ( (OYER "( ,ONDON 74 &ORD %# "ONINO & 0URCELL 2( 'ERIN *, 4RANSMISSION OF THE HEPATITIS " VIRUS ASSOCIATED DELTA AGENT TO THE EASTERN WOODCHUCK 0ROC .ATL !CAD 3CI 53! n !BE + +URATA 4 4ERAMOTO 9 3HIGA * 3HIKATA 4 ,ACK OF SUSCEPTIBILITY OF VARIOUS PRIMATES AND WOODCHUCKS TO HEPATITIS # VIRUS * -ED 0RIMATOL n 'ARSON *! 7HITBY + 7ATKINS 0 -ORGAN !* ,ACK OF SUSCEPTIBILITY OF THE COTTONTOP TAMARIN TO HEPATITIS # INFECTION * -ED 6IROL n $E 6OS 2 6ERSLYPE # $EPLA % &EVERY * 6AN $AMME " $ESMET 6 2OSKAMS 4 5LTRASTRUCTURAL VISUALIZATION OF HEPATITIS # VIRUS COMPONENTS IN HUMAN AND PRIMATE LIVER BIOPSIES * (EPATOL n "ASSETT 3% "RASKY +- ,ANFORD 2% !NALYSIS OF HEPATITIS # VIRUS INOCU LATED CHIMPANZEES REVEALS UNEXPECTED CLINICAL PROFILES * 6IROL n 8IE :# 2IEZU "OJ *) ,ASARTE ** 'UILLEN * 3U *( #IVEIRA -0 0RIETO * 4RANSMISSION OF HEPATITIS # VIRUS INFECTION TO TREE SHREWS 6IROLOGY n $EINHARDT & 0ETERSON $ #ROSS ' 7OLFE , (OLMES !7 (EPATITIS IN MARMOSETS !M * -ED 3CI n 3IMONS *. 0ILOT -ATIAS 4* ,EARY 40 $AWSON '* $ESAI 3- 3CHLAUDER '' -UERHOFF !3 %RKER *# "UIJK 3, #HALMERS -, ET AL )DENTIFICATION OF TWO FLAVIVIRUS LIKE GENOMES IN THE '" HEPATITIS AGENT 0ROC .ATL !CAD 3CI 53! n 3IMONS *. ,EARY 40 $AWSON '* 0ILOT -ATIAS 4* -UERHOFF !3 3CHLAUDER ''
4HOMAS ,ONGERICH AND 0ETER 3CHIRMACHER
$ESAI 3- -USHAHWAR )+ )SOLATION OF NOVEL VIRUS LIKE SEQUENCES ASSOCI ATED WITH HUMAN HEPATITIS .AT -ED n ,INNEN * 7AGES * *R :HANG +ECK :9 &RY +% +RAWCZYNSKI +: !LTER ( +OONIN % 'ALLAGHER - !LTER - (ADZIYANNIS 3 ET AL -OLECULAR CLONING AND DISEASE ASSOCIATION OF HEPATITIS ' VIRUS A TRANSFUSION TRANSMISSIBLE AGENT 3CIENCE n "UKH * !PGAR #, &IVE NEW OR RECENTLY DISCOVERED '"6 ! VIRUS SPECIES ARE INDIGENOUS TO .EW 7ORLD MONKEYS AND MAY CONSTITUTE A SEPARATE GENUS OF THE &LAVIVIRIDAE 6IROLOGY n /HBA + -IZOKAMI - ,AU *9 /RITO % )KEO + 'OJOBORI 4 %VOLUTIONARY RELATIONSHIP OF HEPATITIS # PESTI FLAVI PLANTVIRUSES AND NEWLY DISCOVERED '" HEPATITIS AGENTS &%"3 ,ETT n 3CHLAUDER '' $AWSON '* 3IMONS *. 0ILOT -ATIAS 4* 'UTIERREZ 2! (EYNEN #! +NIGGE -& +URPIEWSKI '3 "UIJK 3, ,EARY 40 ET AL -OLECULAR AND SEROLOGIC ANALYSIS IN THE TRANSMISSION OF THE '" HEPATITIS AGENTS * -ED 6IROL n #HISARI &6 0INKERT #! -ILICH $2 &ILIPPI 0 -C,ACHLAN ! 0ALMITER 2$ "RINSTER 2, ! TRANSGENIC MOUSE MODEL OF THE CHRONIC HEPATITIS " SUR FACE ANTIGEN CARRIER STATE 3CIENCE n +IM #- +OIKE + 3AITO ) -IYAMURA 4 *AY ' ("X GENE OF HEPATITIS " VIRUS INDUCES LIVER CANCER IN TRANSGENIC MICE .ATURE n 'UICHELAAR -- "ENSON *4 -ALINCHOC - +ROM 2! 7IESNER 2( #HARLTON -2 2ISK FACTORS FOR AND CLINICAL COURSE OF NON ANASTOMOTIC BILIARY STRIC TURES AFTER LIVER TRANSPLANTATION !M * 4RANSPLANT n "ORDIER "" /HKANDA * ,IU 0 ,EE 39 3ALAZAR &( -ARION 0, /HASHI + -EUSE , +AY -! #ASEY *, ET AL )N VIVO ANTIVIRAL EFFICACY OF PRENYL ATION INHIBITORS AGAINST HEPATITIS DELTA VIRUS * #LIN )NVEST n ,ARKIN * #LAYTON - 3UN " 0ERCHONOCK #% -ORGAN *, 3IRACUSA ,$ -ICHAELS &( &EITELSON -! (EPATITIS " VIRUS TRANSGENIC MOUSE MODEL OF CHRONIC LIVER DISEASE .AT -ED n )LAN % "URAKOVA 4 $AGAN 3 .USSBAUM / ,UBIN ) %REN 2 "EN -OSHE / !RAZI * "ERR 3 .EVILLE , ET AL 4HE HEPATITIS " VIRUS TRIMERA MOUSE A MODEL FOR HUMAN ("6 INFECTION AND EVALUATION OF ANTI ("6 THERAPEUTIC AGENTS (EPATOLOGY n -AEDA . 7ATANABE - /KAMOTO 3 +ANAI 4 9AMADA 4 (ATA * (OZUMI . +ATSUME ! .URIYA ( 3ANDHU * ET AL (EPATITIS # VIRUS INFECTION IN HUMAN LIVER TISSUE ENGRAFTED IN MICE WITH AN INFECTIOUS MOLECULAR CLONE ,IVER )NT n 3ANDGREN %0 0ALMITER 2$ (ECKEL *, $AUGHERTY ## "RINSTER 2, $EGEN *, #OMPLETE HEPATIC REGENERATION AFTER SOMATIC DELETION OF AN ALBUMIN PLASMINOGEN ACTIVATOR TRANSGENE #ELL n 3HINKAI 9 2ATHBUN ' ,AM +0 /LTZ %- 3TEWART 6 -ENDELSOHN - #HARRON * $ATTA - 9OUNG & 3TALL !- ET AL 2!' DEFICIENT MICE LACK MATURE LYMPHOCYTES OWING TO INABILITY TO INITIATE 6$ * REARRANGEMENT #ELL n 0ETERSEN * $ANDRI - 'UPTA 3 2OGLER #% ,IVER REPOPULATION WITH XENOGENIC HEPATOCYTES IN " AND 4 CELL DEFICIENT MICE LEADS TO CHRONIC HEPADNA
#OMPARATIVE PATHOLOGY
VIRUS INFECTION AND CLONAL GROWTH OF HEPATOCELLULAR CARCINOMA 0ROC .ATL !CAD 3CI 53! n $ANDRI - "URDA -2 4OROK % 0OLLOK *- )WANSKA ! 3OMMER ' 2OGIERS 8 2OGLER #% 'UPTA 3 7ILL ( ET AL 2EPOPULATION OF MOUSE LIVER WITH HUMAN HEPATOCYTES AND IN VIVO INFECTION WITH HEPATITIS " VIRUS (EPATOLOGY n $ANDRI - "URDA -2 :UCKERMAN $- 7URSTHORN + -ATSCHL 5 0OLLOK *- 2OGIERS 8 'OCHT ! +OCK * "LUM (% ET AL #HRONIC INFECTION WITH HEPA TITIS " VIRUSES AND ANTIVIRAL DRUG EVALUATION IN U0! MICE AFTER LIVER REPOPULA TION WITH TUPAIA HEPATOCYTES * (EPATOL n -ERCER $& 3CHILLER $% %LLIOTT *& $OUGLAS $. (AO # 2INFRET ! !DDISON 72 &ISCHER +0 #HURCHILL 4! ,AKEY *2 ET AL (EPATITIS # VIRUS REPLICA TION IN MICE WITH CHIMERIC HUMAN LIVERS .AT -ED n -EULEMAN 0 ,IBBRECHT , $E 6OS 2 DE (EMPTINNE " 'EVAERT + 6ANDEKERCKHOVE * 2OSKAMS 4 ,EROUX 2OELS ' -ORPHOLOGICAL AND BIOCHEMICAL CHARACTERIZATION OF A HUMAN LIVER IN A U0! 3#)$ MOUSE CHIMERA (EPATOLOGY n "ISHOP , 3TRANDBERG *$ !DAMS 2* "ROWNSTEIN $' 0ATTERSON 2 #HRONIC ACTIVE HEPATITIS IN DOGS ASSOCIATED WITH LEPTOSPIRES !M * 6ET 2ES n #RAWFORD -! 3CHALL 7$ *ENSEN 2+ 4ASKER *" #HRONIC ACTIVE HEPATI TIS IN $OBERMAN PINSCHERS * !M 6ET -ED !SSOC n 'OCKE $* -ORRIS 41 "RADLEY 3% #HRONIC HEPATITIS IN THE DOG THE ROLE OF IMMUNE FACTORS * !M 6ET -ED !SSOC n *ARRETT 7& /.EIL "7 ! NEW TRANSMISSIBLE AGENT CAUSING ACUTE HEPATI TIS CHRONIC HEPATITIS AND CIRRHOSIS IN DOGS 6ET 2EC n 4HORNBURG ,0 3HAW $ $OLAN - 2AISBECK - #RAWFORD 3 $ENNIS ', /LWIN $" (EREDITARY COPPER TOXICOSIS IN 7EST (IGHLAND WHITE TERRIERS 6ET 0ATHOL n 0OFFENBARGER %- (ARDY 2- (EPATIC CIRRHOSIS ASSOCIATED WITH LONG TERM PRIMIDONE THERAPY IN A DOG * !M 6ET -ED !SSOC n #HOUINARD , -ARTINEAU $ &ORGET # 'IRARD # 5SE OF POLYMERASE CHAIN REACTION AND IMMUNOHISTOCHEMISTRY FOR DETECTION OF CANINE ADENOVIRUS TYPE IN FORMALIN FIXED PARAFFIN EMBEDDED LIVER OF DOGS WITH CHRONIC HEPATITIS OR CIRRHOSIS * 6ET $IAGN )NVEST n 3EVELIUS % !NDERSSON - *ONSSON , (EPATIC ACCUMULATION OF ALPHA ANTITRYPSIN IN CHRONIC LIVER DISEASE IN THE DOG * #OMP 0ATHOL n 3EVELIUS % $IAGNOSIS AND PROGNOSIS OF CHRONIC HEPATITIS AND CIRRHOSIS IN DOGS * 3MALL !NIM 0RACT n "OISCLAIR * $ORE - "EAUCHAMP ' #HOUINARD , 'IRARD # #HARACTERIZATION OF THE INFLAMMATORY INFILTRATE IN CANINE CHRONIC HEPATITIS 6ET 0ATHOL n $E"EY "- ,EHMKUHL ($ #HARD "ERGSTROM # (OBBS ,! /VINE ADENOVIRUS SEROTYPE ASSOCIATED MORTALITY IN LAMBS IN THE 5NITED 3TATES 6ET 0ATHOL n 'RAY 7, 0ATHOGENESIS OF SIMIAN VARICELLA VIRUS * -ED 6IROL 3n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
(EPATITIS " VIRUS ,ESSONS LEARNED FROM THE VIRUS LIFE CYCLE 3TEPHAN 5RBAN AND 5LRIKE 0ROTZER $EPARTMENT OF -OLECULAR 6IROLOGY /TTO -EYERHOF :ENTRUM 5NIVERSITY OF (EIDELBERG )M
.EUENHEIMER &ELD (EIDELBERG 'ERMANY )NSTITUTE OF 6IROLOGY 4ECHNICAL 5NIVERSITY -UNICH (ELMHOLTZ #ENTER -UNICH n .ATIONAL
2ESEARCH #ENTER FOR %NVIRONMENTAL (EALTH 4OGERSTR -àNCHEN 'ERMANY
!BSTRACT 4HE HUMAN HEPATITIS " VIRUS ("6 IS THE PROTOTYPE MEMBER OF THE FAMILY OF HEPAD NAVIRIDAE SMALL ENVELOPED VIRUSES WHICH REPLICATE THEIR COMPACT AND HIGHLY ORGANIZED $.! GENOME VIA REVERSE TRANSCRIPTION )N HUMANS ("6 MAY CAUSE INFLAMMATORY LIVER DISEASE HEPATITIS " 7ITH MORE THAN MILLION CHRONICALLY INFECTED PEOPLE AT HIGH RISK TO DEVELOP LIVER CIRRHOSIS OR HEPATOCELLULAR CARCINOMA ("6 IS ONE OF THE MOST IMPORTANT HUMAN PATHOGENS )N RECENT YEARS THE VIRAL LIFE CYCLE HAS BEEN CHARACTERISED IN CONSIDER ABLE DETAIL OUR UNDERSTANDING OF IMMUNOLOGY AND PATHOGENESIS OF HEPATITIS " HAS LARGELY IMPROVED AND NUCLEOST IDE ANALOGUES HAVE BEEN ESTABLISHED AS ANTIVIRALS (OWEVER CURRENT TREATMENT OPTIONS ARE STILL LIMITED BECAUSE THEY ONLY RARELY ELIMINATE THE VIRUS AND THUS LONG TERM TREATMENT IS REQUIRED &OLLOWING A GENERAL INTRODUCTION WE THEREFORE DISCUSS WHICH STEPS IN THE VIRAL LIFE CYCLE MAY SERVE AS TARGETS FOR NOVEL THERAPEUTIC STRATE GIES
4HE HUMAN HEPATITIS " VIRUS 4HE HUMAN HEPATITIS " VIRUS ("6 IS THE PROTOTYPE MEMBER OF A FAMILY OF SMALL ENVELOPED $.! VIRUSES !LL MEMBERS OF THIS FAMILY ARE CHARACTERISED BY A PRONOUNCED LIVER TROPISM AND THEY ARE THEREFORE SUBSUMEDLY NAMED HEPADNAVIRUSES FOR HEPATOTROPIC $.! VIRUSES ("6 IS A NON CYTOPATHIC VIRUS SINCE ITS ASSEMBLY IN HEPATOCYTES PROCEEDS WITHOUT CELL DISRUPTION 4HUS ("6 PRODUCING CELLS CONTINUOUSLY RELEASE PROGENY VIRAL PARTICLES 4HIS HAS BEEN DEMONSTRATED IN STABLY TRANSFECTED HEPATOMA CELL LINES ;= AS WELL AS IN ("6 TRANSGENIC MICE ;= AND EXPLAINS WHY ("6 INFECTION PER SE DOES NOT CAUSE LIVER DAMAGE )T ALSO EXPLAINS WHY ("6 ELICITS LITTLE OR NO INNATE IMMUNE RESPONSES ;= 7HEN THE ADAPTIVE IMMUNE SYSTEM BECOMES ACTIVATED HOWEVER INFLAMMATORY LIVER DISEASE CALLED HEPATITIS " BECOMES EVIDENT AND THE INFECTION MAY BE CLEARED 4HIS USUALLY HAPPENS IF ADULTS BECOME INFECTED BUT OFTEN IS MISSING DURING NEONATAL INFECTION
3TEPHAN 5RBAN AND 5LRIKE 0ROTZER
4HE VIRAL GENOME KB CONSISTING OF A PARTIALLY DOUBLE STRANDED RELAXED CIRCULAR RC $.! SHOWS AN EXTREMELY COMPACT ORGANISATION WITH OVERLAPPING OPEN READING FRAMES OF THE VIRAL POLYMERASE AND STRUCTURAL PRO TEINS ENCODING THE VIRAL CAPSID AND THE THREE ENVELOPE PROTEINS )N ADDITION REGULATORY ELEMENTS LIKE PROMOTERS ENHANCERS AND THE POLYADENYLATION SIGNAL OVERLAP WITH CODING SEQUENCES ;= ,IKE THE ANIMAL HEPADNAVIRUSES EG DUCK HEPATITIS " VIRUS $("6 WOODCHUCK HEPATITIS " VIRUS 7(6 ("6 MULTIPLIES ITS GENOME BY REVERSE TRANSCRIPTION OF AN 2.! PREGENOME &IG ;= &OLLOWING FUSION OF THE VIRAL AND THE CELLULAR MEMBRANE THE NUCLEOCAPSID IS TRANSPORTED TO THE NUCLEAR PORE COMPLEX WHERE THE RC $.! GENOME IS RELEASED INTO THE HEPATOCYTE NUCLEUS )NSIDE THE NUCLEUS THE RC$.! IS CONVERTED TO A COVALENTLY CLOSED CIRCULAR $.! CCC $.! BY CEL LULAR ENZYMES CCC$.! ENCODES FOUR UNIDIRECTIONAL OVERLAPPING OPEN READ ING FRAMES AND CONSTITUTES THE TRANSCRIPTION TEMPLATE FOR THE PREGENOMIC AND THE SUBGENOMIC 2.!S 4HE PREGENOMIC 2.! SERVES AS M2.! FOR THE VIRAL CORE AND POLY MERASE PROTEINS )N ADDITION IT CONTAINS A HAIRPIN LOOP AT THE END WHICH TRIGGERS ITS ENCAPSIDATION TOGETHER WITH THE VIRAL POLYMERASE INTO AN ICOSA HEDRAL NUCLEOCAPSID 4HE NUCLEOCAPSID IN THE VIRION CONSISTS OF SUBUNITS OF THE ("6 CORE PROTEIN WHICH ORGANISE TO SOME EXTENT THE SURROUNDING ENVELOPE PROTEINS ;= 4HE VIRAL ENVELOPE IS BUILT OF A LIPID BILAYER AND IS DENSELY PACKED WITH THE LARGE , MIDDLE - AND n PREDOMINANTLY n SMALL 3 SURFACE PROTEINS 4HESE PROTEINS ARE TRANSLATED FROM THREE SUBGENOMIC M2.!S )N ADDITION ("6 AND OTHER MAMMALIAN HEPADNAVIRUSES ENCODE A REGULATORY PROTEIN CALLED 8 WHICH IS REQUIRED TO ESTABLISH INFECTION IN VIVO IN WOODCHUCKS ; = AND DISPLAYS PLEIOTROPIC EFFECTS WHEN STUDIED IN CELL CULTURE BASED ASSAYS )NFECTED CELLS SECRETE n IN HIGH EXCESS TO COMPLETE VIRIONS n SUBVIRAL PARTICLES WHICH ARE EMPTY ENVELOPES OF SPHERICAL NM PARTICLES AND FILAMENTOUS SHAPE 3PHERES CONTAIN MOSTLY THE 3 PROTEIN AND CAN BE DETECTED IN THE SERUM OF INFECTED INDIVIDUALS AS HEPATITIS " SURFACE ANTIGEN ("S!G 4HE ("6 PRECORE PROTEIN WHOSE CODING SEQUENCE ENCOMPASSES THAT OF THE CORE PROTEIN IS NOT REQUIRED FOR ("6 REPLICATION OR INFECTION BUT IT IS PROCESSED AND SECRETED FROM INFECTED CELLS AS ("E!G ; =
(EPATITIS " VIRUS INFECTION AND RELATED DISEASE ("6 INFECTS LIVERS OF HUMANS HUMANOID PRIMATES LIKE CHIMPANZEES ;= AND GORILLAS AND SURPRISINGLY 4UPAIA BELANGERI A SMALL MAMMAL BELONGING TO THE ORDER SCANDENTIA ; = $EPENDING ON THE HOST IMMUNE RESPONSE THE VIRUS ESTABLISHES EITHER TRANSIENT OR PERSISTENT INFECTION ("6 IS TRANS MITTED BY PERINATAL PERCUTANEOUS AND SEXUAL TRANSMISSION ROUTES AS WELL AS BY CLOSE INTERINDIVIDUAL CONTACT DURING EARLY INFANCY 4HE LATTER OCCURS PRESUMABLY BY OPEN CUTS OR SORES ;= 6ERTICAL TRANSMISSION FROM MOTHERS TO
(EPATITIS " VIRUS ,ESSONS LEARNED FROM THE VIRUS LIFE CYCLE
&IGURE ("6 ATTACHES VIA THE PRE3 DOMAIN OF THE , PROTEIN TO HEPARANSULFATE PROTEOGLY CANS OF THE HEPATOCYTE SURFACE !FTER ENDOCYTOSIS BY AN UNKNOWN MECHANISM FUSION OF THE VIRAL AND THE VESICULAR MEMBRANES OCCURS AND THE $.! CONTAINING NUCLEOCAPSID IS RELEASED !FTER TRANSPORT TO THE NUCLEUS PROBABLY ALONG THE CYTOSKELETON OF THE HEPATOCYTE AND RELEASE OF THE CAPSID INTO THE NUCLEAR PORE COMPLEX THE PARTIALLY DOUBLE STRANDED $.! ENTERS THE NUCLEUS AND IS CONVERTED TO THE COVALENTLY CLOSED CIRCULAR CCC $.! BY CELLULAR ENZYMES !FTER 0OL )) MEDIATED TRANSCRIPTION AND EXPORT OF THE PREGENOMIC 2.! PG2.! INTO THE CYTOPLASM TRANSLATION OF CORE PROTEIN AND THE ("6 POLYMERASE OCCURS !FTER SELF ASSEMBLY OF THE COMPLEX OF PG2.! POLYMERASE AND CORE PROTEIN INTO AN 2.! CON TAINING NUCLEOCAPSID REVERSE TRANSCRIPTION OF THE PG2.! TO A MATURE GENOME TAKES PLACE 4HIS $.! CONTAINING NUCLEOCAPSID CAN EITHER BE RE IMPORTED INTO THE NUCLEUS OR ENVELOPED BY THE ("6 SURFACE PROTEINS AT THE %2 MEMBRANE 4HESE SURFACE PROTEINS HAVE BEEN SYNTHESISED FROM INDEPENDENTLY TRANSCRIBED AND EXPORTED SUBGENOMIC 2.!S %XOCYTOSIS OF AUTONOMOUSLY ASSEMBLED SUBVIRAL PARTICLES AND PROGENY VIRIONS PROCEEDS VIA THE SECRETORY PATHWAY BY A STILL ILL UNDERSTOOD ROUTE
THEIR NEONATES OR INFECTION DURING THE FIRST YEAR OF LIFE RESULTS IN IN PERSISTENT OFTEN LIFE LONG INFECTION )N CONTRAST INFECTION DURING ADULTHOOD IS CLEARED IN OF CASES AND RESULTS IN LIFE LONG PROTECTIVE IMMUNITY ;= )N HUMANS ("6 INFECTION MAY CAUSE INFLAMMATORY LIVER DISEASE n HEPA TITIS " 7ORLDWIDE MORE THAN MILLION PERSONS ARE PERSISTENTLY INFECTED #HRONIC ("6 INFECTION MAY BE SYMPTOMATIC OR ASYMPTOMATIC 0ERSISTENTLY
3TEPHAN 5RBAN AND 5LRIKE 0ROTZER
INFECTED INDIVIDUALS WITHOUT SIGNIFICANT ONGOING NECROINFLAMMATORY DISEASE ARE TERMED ("S!G CARRIERS .ECROINFLAMMATORY DISEASE IS DEFINED BY THE PRESENCE OF INFLAMMATORY ACTIVITY ANDOR FIBROSIS IN LIVER TISSUE BIOPSIES AND OFTEN DETECTED BY AN ELEVATED SERUM TRANSAMINASE ACTIVITY )NDIVIDUALS IN WHOM THE VIRUS PERSISTS FOR MORE THAN SIX MONTHS AND IN WHOM ("6 CAUSES CHRONIC NECROINFLAMMATORY DISEASE ARE CLASSIFIED AS HAVING CHRONIC HEPATITIS " 4HE ONGOING INFLAMMATION IN CHRONIC HEPATITIS " RESULTS IN LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA IN MORE THAN OF PATIENTS ;= /F CHRONIC HEPATITIS " PATIENTS n WILL DEVELOP SERIOUS SEQUELAE DURING THEIR LIFE TIME ACCOUNTING FOR TO MILLION DEATHS PER YEAR WORLDWIDE ;=
)MMUNE RESPONSE TO ("6 6IRAL CLEARANCE DURING SELF LIMITED ("6 INFECTION IS CHARACTERISED BY A VIG OROUS POLYCLONAL AND MULTISPECIFIC #$ AND #$ 4 CELL RESPONSE TO VIRAL PROTEINS ; = )N CONTRAST A WEAK AND OLIGOCLONAL 4 CELL RESPONSE WAS DESCRIBED IN PERSISTENTLY INFECTED INDIVIDUALS ; = 4HUS IN PATIENTS WHO DEVELOP CHRONIC INFECTION EITHER NO SUFFICIENT 4 CELL RESPONSE IS INDUCED OR AN INITIALLY VIGOROUS 4 CELL RESPONSE IS DIMINISHED )N SELF LIMITED EXPERIMENTAL ("6 INFECTIONS IN CHIMPANZEES A TWO PHASIC 4 CELL RESPONSE HAS BEEN OBSERVED )N THE INITIAL PHASE 4 CELLS CONTROL VIRAL REPLICATION AND ANTIGEN EXPRESSION IN A NON CYTOTOXIC FASHION BY THE SECRE TION OF CYTOKINES WITH INTERFERON )&. a BEING THE MAIN PLAYER (EREBY THE NUMBER OF ANTIGEN POSITIVE HEPATOCYTES AS A POTENTIAL TARGET OF 4 CELL KILLING IS REDUCED )N A SECOND PHASE THE CYTOTOXIC ACTIVITY OF 4 CELLS IS PREDOMINANT AND REMAINING INFECTED CELLS ARE ELIMINATED ; = 4RANSLATION OF VIRAL PROTEINS DURING REPLICATION RESULTS IN THE PROCESS ING OF VIRUS DERIVED PEPTIDES 4HESE PEPTIDES ARE PRESENTED BY MAJOR HISTOCOMPATIBILITY ANTIGENS CLASS ) -(# ) MOLECULES ON THE SURFACE OF INFECTED HEPATOCYTES #YTOTOXIC 4 CELLS WHICH RECOGNISE THESE ANTIGENS IN THE CONTEXT OF THE RESPECTIVE -(# ) MOLECULE MAY BE ACTIVATED TO KILL THE INFECTED CELL EITHER BY SECRETION OF PERFORIN AND GRANZYME OR BY INDUCTION OF APOPTOSIS 3INCE ("6 INFECTED CELLS CONTINUOUSLY EXPRESS VIRAL PROTEINS THEY ARE POTENTIAL TARGETS OF 4 CELL KILLING IF ACTIVATED 4 CELLS GAIN ACCESS TO THE INFECTED CELLS 4HE FAILURE TO INDUCE OR MAINTAIN A VIGOROUS 4 CELL RESPONSE IS ASTON ISHING SINCE HUGE AMOUNTS OF ("S!G AND ("E!G CIRCULATE IN THE BLOOD OF INFECTED PATIENTS 4HE MAJORITY OF 4 CELL EPITOPES ARE SHARED AMONG ALL VIRAL ENVELOPE PROTEINS 4HUS ("S!G DERIVED PEPTIDE ANTIGENS SHOULD BE SUFFICIENT TO ELICIT CELLULAR AS WELL AS HUMORAL IMMUNE RESPONSES TARGETING THE VIRAL ENVELOPE ("E!G IS SMALL ENOUGH TO CROSS THE PLACENTA AND IS DISCUSSED TO INDUCE NEONATAL TOLERANCE ; = 3INCE ("E!G SHARES MOST OF ITS CODING SEQUENCE WITH ("6 CORE PROTEINS BOTH PROTEINS SHARE THE 4
(EPATITIS " VIRUS ,ESSONS LEARNED FROM THE VIRUS LIFE CYCLE
CELL EPITOPES )N ADULT 4 CELL RECEPTOR TRANSGENIC MICE ("E!G SUPPRESSED THE 4 CELL RESPONSE TO ("6 CORE PROTEIN EXPRESSING CELLS INDICATING THAT ("E!GCORE CROSS REACTIVE 4 CELLS EITHER ARE DELETED OR BECOME ANERGISED ;= 3EVERAL POSSIBLE REASONS FOR A DIMINISHED 4 CELL RESPONSE DURING CHRONIC VIRAL HEPATITIS ARE DISCUSSED 4 CELL MODULATION DUE TO OR LOCAL INDUCTION OF TOLERANCE IN THE LIVER ; = SYSTEMIC IMMUNOMODULATION BY THE INDUCTION OF REGULATORY 4 CELLS ANDOR THE EXHAUSTION OF 4 CELLS DUE TO ANTIGEN OVER LOAD ; = 4AKEN TOGETHER INDUCTION AND MAINTENANCE OF A STRONG AND VIGOROUS 4 CELL RESPONSE SEEMS TO BE CRUCIAL TO ACHIEVE VIRUS ELIMINATION (OWEVER IT IS IMPORTANT TO NOTICE THAT A CYTOTOXIC 4 CELL RESPONSE IS THOUGHT TO BE RESPONSIBLE FOR BOTH VIRAL CLEARANCE AND LIVER INJURY DURING ("6 INFECTION ; =
!NTIVIRALLY ACTIVE CYOKINES #YTOKINES ARE RELEASED BY CELLS OF THE IMMUNE SYSTEM BUT ALSO BY PARENCHY MAL CELLS 4HEIR MAIN ROLE IS TO MEDIATE IMMUNE RESPONSES BUT SOME HAVE BEEN PROVEN TO AFFECT ("6 REPLICATION IN HEPATOCYTES TYPE ) AND )) )&. TUMOUR NECROSIS FACTOR 4.& _ AND ), 7HEREAS SECRETION OF )&. _` 4.& _ AND ), MAY BE INDUCED BY RECOGNITION OF MOLECULAR PATTERNS BY MEMBRANE BOUND OR VIRAL NUCLEIC ACIDS BY ENDOSOMAL OR CYTOPLASMIC PAT TERN RECOGNITION RECEPTORS IN A BROAD VARIETY OF CELL TYPES )&. a IS RELEASED BY IMMUNE CELLS EG 4 CELLS .+ CELLS OR MACROPHAGES )&. _ IS LONG KNOWN TO ELICIT ANTIVIRAL ACTIVITY IN ("6 INFECTION AND HAS BEEN THE FIRST APPROVED ANTIVIRAL TREATMENT FOR HEPATITIS " !FTER BINDING TO SPECIFIC RECEPTORS ON THE SURFACE OF INFECTED CELLS )&. _` HAVE THE POTENTIAL TO TRIGGER THE ACTIVATION OF MULTIPLE NONCYTOLYTIC INTRACELLULAR ANTIVIRAL PATH WAYS THAT FOR EXAMPLE INTERFERE WITH TRANSLATION OF VIRAL 2.!S OR INDUCE THEIR DEGRADATION !DOPTIVELY TRANSFERRED VIRUS SPECIFIC 4 CELLS CAN ABOLISH ("6 GENE EXPRESSION AND REPLICATION IN THE LIVER WITHOUT KILLING THE HEPATOCYTES 4HIS ANTIVIRAL FUNCTION WAS MEDIATED BY )&. a AND 4.& _ SECRETED BY THE TRANS FERRED 4 CELLS OR BY ANTIGEN NONSPECIFIC MACROPHAGES OR .+ CELLS ACTIVATED FOLLOWING THE 4 CELL TRANSFER ;= 4HIS SHOWED THAT )&. a AND 4.& _ ARE CENTRAL PLAYERS IN THE NON CYTOPATHIC CONTROL OF ("6 INFECTION )N A SIMILAR MANNER APPLICATION OF ), TO ("6 TRANSGENIC MICE EITHER PREVENTED THE ASSEMBLY OR TRIGGERED THE DEGRADATION OF THE NUCLEOCAPSID PARTICLES WITHIN WHICH ("6 REPLICATION OCCURS ;= ), INFLUENCES ("6 GENE EXPRESSION ;= !NTIVIRAL CYTOKINES MAY THUS ACTI VATE INDEPENDENT VIROCIDAL PATHWAYS INFLUENCING VIRAL GENE EXPRESSION OR ELIMINATING ("6 NUCLEOCAPSID PARTICLES AND THEIR CARGO OF REPLICATING VIRAL GENOMES
3TEPHAN 5RBAN AND 5LRIKE 0ROTZER
#URRENT THERAPEUTIC OPTIONS #URRENTLY APPROVED TREATMENT OPTIONS FOR CHRONIC HEPATITIS " ARE RELATED TO THE DIRECT OR IMMUNMODULATORY ACTION OF INTERFERON _ AND THE INHIBITION OF THE ("6 REVERSE TRANSCRIPTASE ACTIVITY BY NUCLEOSIDE ANALOGUES 0RESENTLY THERE ARE SIX APPROVED MEDICATIONS )&. _ 0%' )&. _ ,AMIVUDINE 4# !DEFOVIR 4ELBIVUDINE AND %NTECAVIR !LTHOUGH THESE DRUGS TO A DIFFERENT LEVEL REDUCE VIRAL LOADS DOWN TO SEVERAL LOGS ELIMINATION OF THE VIRUS IS HARD LY ACHIEVED ;n= )N ADDITION THE SELECTION OF RESISTANT MUTANTS DURING THERAPY ARISES .EVERTHELESS IT HAS CLEARLY BEEN DEMONSTRATED THAT HIGH VIRE MIA IS AN IMPORTANT RISK FACTOR ASSOCIATED WITH PROGRESSION OF ("6 RELATED LIVER DISEASE AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA ;= 4HEREFORE CURRENT THERAPEUTIC GOALS ARE SUSTAINED SUPPRESSION OF ("6 REPLICATION AND REMISSION OF LIVER DISEASE ; = )&. _ HAS DIRECT ANTIVIRAL EFFECTS AND IS IMMUNOMODULATORY AND THUS SHALL STIMULATE THE HOST IMMUNE RESPONSE TO ELIMINATE THE VIRUS 0EGYLATED VERSIONS IMPROVE ITS BIOAVAILABILITY AND THUS ITS THERAPEUTIC EFFICACY ;= (OWEVER ITS SIDE EFFECTS EG INDUCTION OF HEPATITIS FLARES FEVER MYALGIAS THROMBOCYTOPENIA AND DEPRESSION MAKE IT A DIFFICULT TREATMENT FOR MANY APPLICATIONS AND EXCLUDE THERAPY OF ADVANCED OR DECOMPENSATED LIVER DISEASE )N ADDITION THERAPEUTIC EFFECTS ARE LIMITED ONLY ABOUT n ("E!G POSITIVE PATIENTS PROFIT FROM )&. _ TREATMENT SEROCONVERT TO ANTI ("E AND LOSE SERUM ("6 $.! ,OSS OF ("S!G INDICATING VIRUS CLEAR ANCE IS ACHIEVED IN OF PATIENTS !LTHOUGH ("E!G NEGATIVE PATIENTS HAVE A BETTER RESPONSE RATE RESPONSE IS NOT DURABLE IN MOST CASES ;= .UCLEOST IDE ANALOGUES INHIBIT THE VIRAL REVERSE TRANSCRIPTASE AND ARE USUALLY WELL TOLERATED .UCLEOST IDE ANALOGUES CONTROL ("6 REPLICATION BUT RARELY ELIMINATE THE VIRUS n OF TREATED ("E!G POSITIVE PATIENTS SEROCONVERT AFTER LONG TERM TREATMENT TO AN ANTI ("E!G STATE AND CONTROL ("6 REPLICATION SUMMARY IN ;= (OWEVER THIS IS CLOSE TO THE NUMBERS THAT SPONTANEOUSLY SEROCONVERT AND ("E!G SEROCONVERSION ALONE DOES NOT PROTECT FROM THE DEVELOPMENT OF COMPLICATIONS ;= ("6 CCC$.! PERSISTS IN THE HOST CELL NUCLEUS CONTINUES TO PRODUCE ("S!G AND MAY CAUSE A VIRAL REBOUND AND RECURRENT DISEASE IF THE TREATMENT IS STOPPED #ONTINUOUS TREAT MENT IS THEREFORE REQUIRED WHICH OFTEN SELECTS RESISTANT VIRAL VARIANTS WHICH ARE CHARACTERISED BY SPECIFIC AMINO ACID EXCHANGES IN THE ("6 POLYMERASE ;= %MERGENCE OF ANTIVIRAL RESISTANT MUTATIONS CAN LEAD TO NEGATION OF THE INITIAL RESPONSE AND IN SOME CASES HEPATITIS FLARES AND HEPATIC DECOMPEN SATION ;= "ECAUSE OF THE OVERLAPPING READING FRAMES OF THE POLYMERASE WITH ("6 ENVELOPE PROTEINS MUTATIONS WHICH MEDIATE RESISTANCE MAY ALTER THE LATTER OR LEAD TO PREMATURE TRANSLATIONAL TERMINATION ;n= 4HIS MAY AFFECT VIRION SECRETION OR RESULT IN THE GENERATION OF SURFACE PROTEINS WITH A HIGHER ONCOGENIC POTENTIAL ;= 4AKEN TOGETHER TRUE CURE OF INFECTION LOSS OF ("S!G AND SUSTAINED DIS APPEARANCE OF VIREMIA AS MEASURED BY STRINGENT 0#2 ASSAYS IS ACHIEVED
(EPATITIS " VIRUS ,ESSONS LEARNED FROM THE VIRUS LIFE CYCLE
ONLY INFREQUENTLY WITH THE CURRENT REGIMENS ;= 7ITHOUT AN EFFICIENT IMMUNE RESPONSE LONG TIME TREATMENT IS REQUIRED WHICH RAISES CONCERNS ABOUT DRUG EFFICACY AND SAFETY BUT ALSO HIGH TREATMENT COSTS ;= !N INCREASING NUMBER OF ANTIVIRAL DRUGS TARGETING REVERSE TRANSCRIPTION BUT ALSO OTHER STEPS IN THE VIRAL LIFE CYCLE ARE CURRENTLY DEVELOPED WHICH MIGHT IMPROVE TREATMENT OUTCOME IN THE FUTURE ;=
.OVEL AND ESTABLISHED THERAPEUTIC APPROACHES TARGETING THE ("6 LIFE CYCLE 2ECEPTOR BINDING AND ENTRY $UE TO THE LACK OF AN INFECTABLE CELL LINE AND THE DEPENDENCE ON PRIMARY HUMAN HEPATOCYTES THE MECHANISM OF ("6 ENTRY WAS FOR A LONG TIME NOT UNDERSTOOD 4HE RECENT DEVELOPMENT OF A CELL CULTURE BASED ("6 INFECTION SYSTEM ;= AND THE POSSIBILITY TO PRODUCE SUFFICIENT AMOUNTS OF RECOMBI NANT ("6 ; = OR ($6 ; = PARTICLES WITH MUTATIONS IN ENVELOPE PROTEINS FACILITATED THE MAPPING OF IMPORTANT DETERMINANTS OF ("6 ENTRY (AVING THESE TOOLS NOW AT HAND IT AGAIN BECAME A TOPIC OF INTENSIVE RESEARCH WHICH CELLULAR PROTEINS ARE FUNCTIONALLY INVOLVED IN ENTRY AND AT WHICH SPECIFIC STAGES OF ENTRY THE SUBSEQUENTLY DESCRIBED VIRAL DETERMINANTS PLAY SPECIFIC ROLES /NE GENERAL THEME OF HEPADNAVIRAL INFECTIVITY IS THE REQUIREMENT OF . TERMINAL MYRISTOYLATION OF THE RESPECTIVE , PROTEINS FOR INFECTION +NOCKING OUT ;n= OR DISPLACEMENT OF THE MYRISTOYLATION SITE OF THE , PROTEIN TO THE . TERMINUS OF THE - OR 3 PROTEIN ;= RESULTS IN A LOSS OF VIRAL INFECTIVITY 4HROUGH DELETION ANALYSIS IT BECAME FURTHERMORE CLEAR THAT THE . TERMINAL AMINO ACIDS OF THE PRE3 DOMAIN OF THE , PROTEIN ARE ESSENTIAL FOR INFECTION ; = AND DO NOT INTERFERE WITH ASSEMBLY )N CONTRAST THE PRE3 DOMAIN IS DISPENSABLE ;n= ALTHOUGH THE PRESENCE OF AN AMPHIPATHIC MOTIF WHICH SUPPORTS CELL PERMEATION OF FOREIGN PROTEINS ;= INITIALLY SUG GESTED ;= A CRITICAL ROLE )N ADDITION TO THE . TERMINAL OF THE PRE3 DOMAIN OF THE , PROTEIN THE ("6 3 DOMAIN PLAYS A CRUCIAL ROLES FOR THE INFECTIVITY OF THE VIRUS )NTRODUCTION OF MUTATIONS INTO THE CYTOSOLIC LOOP ;= AS WELL AS REPLACEMENT OF #YS RESIDUES IN THE ANTIGENIC LOOP ; = RENDERS HEPATITIS DELTA VIRUS WHICH CARRIES AN ("6 ENVELOPE NON INFECTIOUS 3INCE ACCUMULATING EVIDENCE SUGGESTS THAT ($6 AND ("6 USE IDENTICAL ENTRY PATHWAYS ("6 MOST LIKELY ALSO REQUIRES THE 3 DOMAIN FOR INFECTION ;= 4HE OBSERVATION THAT BOTH MYRISTOYLATION OF THE ("6 , PROTEIN AS WELL AS THE INTEGRITY OF THE . TERMINAL PRE3 AMINO ACIDS ARE ESSENTIAL FOR THE INFECTIVITY OF ("6 INITIATED INVESTIGATIONS ON THE POTENTIAL OF SYNTHETIC AND RECOMBINANT MYRISTOYLATED OR OTHERWISE ACYLATED ("6 PRE3 DERIVED PEPTIDES AND FUSION PROTEINS TO INHIBIT ("6 AND ($6 INFECTION IN VITRO ; n= AND IN VIVO ;= 4HE OUTCOME OF THESE EXPERIMENTS REVEALED
3TEPHAN 5RBAN AND 5LRIKE 0ROTZER
THAT ("6 PRE3 DERIVED LIPOPEPTIDES ARE VERY POTENT ENTRY INHIBITORS OF ("6 AND ($6 INFECTION WITH IN VITRO )# IN THE LOW NONOMOLAR OR EVEN PICOMOLAR RANGE ;= 4HEIR ACTIVITY ESSENTIALLY DEPENDS ON A HIGHLY CON SERVED SEQUENCE MOTIF .0,'&& WHICH IS SUBSTANTIALLY INCREASED BY THE SUBSEQUENT AMINO ACIDS 4HE ACTIVITY ALSO INCREASES WITH THE LENGTH OF THE . TERMINAL ACYL MOIETY EG )# OF # ("6PRE3 CA «- )# OF # ("6PRE3 CA P- ;= 4HE OBSERVATION THAT FIVE SUBCUTANE OUS ADMINISTRATIONS OF LESS THAN MGKG OF A MYRISTOYLATED ("6PRE3 LIPOPEPTIDE COMPLETELY PREVENTED ("6 INFECTION IN THE LIVER OF TRANSPLANTED U0!2!' MICE MAKES THIS NOVEL CLASS OF ("6 ENTRY INHIBITORS INTERESTING FOR FURTHER CLINICAL APPLICATIONS ESPECIALLY TO TREAT CHRONIC ("6 AND ($6 INFECTIONS POSSIBLY IN COMBINATION WITH OTHER THERAPIES
5NCOATING AND NUCLEAR IMPORT !LTHOUGH ALL VIRUSES NEED TO UNCOAT THEIR GENOMES AND MANY OF THEM NEED TO IMPORT IT INTO THE NUCLEUS THEY USUALLY ABUSE CELLULAR PATHWAYS FOR THIS 4HEREFORE TARGETING THESE STEPS IN THE VIRAL LIFE HAS NOT SUCCEEDED YET /NCE THE ("6 CAPSID HAS REACHED THE CYTOPLASM WE HAVE PRESENTLY NO TOOL IN HAND TO PREVENT THE VIRUS ESTABLISHING ITS GENOME IN THE NUCLEUS
6IRAL GENE EXPRESSION AND 2.! EXPORT .ATURAL HELIOXANTHIN COMPOUNDS HAVE BEEN DESCRIBED TO ELICIT ANTIVIRAL ACTIVITY AGAINST A VARIETY OF VIRUSES AND POTENTLY INHIBIT ("6 REPLICATION (ELIOXANTHIN ANALOGUE HAS BEEN CHARACTERISED TO INHIBIT ("6 PROMOTER ACTIVITY BY REDUCING THE ACTIVITY OF THE ESSENTIAL TRANSCRIPTION FACTOR ;= !NTIVIRAL CYTOKINES MAY AFFECT ("6 REPLICATION BY ALTERING GENE EXPRES SION AT TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL STEPS 3IMILAR TO ), AFFECTS THE ACTIVITY OF PROMOTERS IN THE ("6 GENOME DIRECTLY BY AFFECTING TRANSCRIPTION FACTORS )T IS HOWEVER DISCUSSED CONTROVERSIALLY WHETHER IT THEREBY ACTIVATES ;= OR INHIBITS (ÚSEL ET AL UNPUBLISHED RESULTS ("6 REPLICATION )&. _` REDUCED ("6 2.! SPECIFICALLY POSSIBLY BY AFFECTING THE BAL ANCE OF TRANSCRIPTION FACTORS ;= )N ADDITION INTERFERON INDUCED 2.! BINDING PROTEINS HAVE BEEN DESCRIBED WHICH MAY STABILIZE ANDOR DESTABILISE THE PREGENOMIC ("6 2.! BY BINDING AN 2.!SE SENSITIVE STEM LOOP STRUC TURE ;= (OWEVER THE MAIN ACTIVITY OF TYPE ) )&. IS ON CYTOPLASMIC ("6 CAPSIDS SEE BELOW 4HE POSSIBILITY TO USE 2.! INTERFERENCE TO SELECTIVELY PREVENT TRANSLA TION AND INDUCE DEGRADATION OF M2.!S PROMOTED INVESTIGATION ABOUT ITS ANTIVIRAL POTENCY "ECAUSE OF THE LARGELY OVERLAPPING OPEN READING FRAMES IN THE ("6 GENOME AND DUE TO THE FACT THAT ALL ("6 2.!S USE THE SAME
(EPATITIS " VIRUS ,ESSONS LEARNED FROM THE VIRUS LIFE CYCLE
POLYADENYLATION SITE ("6 IS A VERY INTERESTING TARGET FOR 2.! INTERFER ENCE 4HEREFORE SEVERAL STUDIES USED TRANSFECTION OF SMALL INTERFERING 2.!S SI2.! OR EXPRESSION OF SHORT HAIRPIN 2.!S SH2.!S TO ADDRESS THE QUESTION WHETHER ("6 SPECIFIC SH2.!S MAY ABROGATE ("6 GENE EXPRES SION IN CELL CULTURE AND IN VIVO IN ("6 REPLICATING TRANSGENIC MICE ;n= 3INCE THESE MOLECULES ARE EASIER TO HANDLE AND SHOW A HIGHER EFFICACY THEY REPLACED THE USE OF ANTISENSE OLIGONUCLEOTIDES OR RIBOZYMES !DENOVIRAL TRANSDUCTION OF HEPATOCYTES FROM ("6 TRANSGENIC MICE WITH SH2.! TARGETING GENOMIC AND SUBGENOMIC 2.!S RESULTED IN A DRAS TIC DECREASE OF ("6 SECRETION AND A SIGNIFICANT REDUCTION OF ("6 CORE EXPRESSION ;= !DENOVIRAL VECTORS EFFICIENTLY TARGET THE LIVER BUT A HIGH DOSE APPLICATION WHICH WOULD BE NEEDED TO TARGET ALL ("6 INFECTED HEPA TOCYTES MAY RESULT IN UNWANTED SIDE EFFECTS 4HEREFORE EXTENSIVE EFFORTS ARE UNDERTAKEN TO ALLOW A DIRECT ADMINISTRATION OF SI2.!S AS THERAPEUTICS AND SELECTIVELY TARGET THEM TO THE LIVER -AJOR PROBLEMS ARE THE SERUM STABILITY AND A POSSIBLE ACTIVATION OF PATTERN RECOGNITION RECEPTORS BY SINGLE OR DOU BLE STRANDED 2.! MOLECULES WHICH MAY CAUSE SIDE EFFECTS ;= 4HE LATTER HOWEVER MAY ALSO BE USED AS AN ANTIVIRAL STRATEGY 0ROTZER AND (ARTMANN UNPUBLISHED RESULTS BUT REQUIRES A LIVER SPECIFIC RECOGNITION TO MINIMISE SIDE EFFECTS 4HROUGH LIPID ENCAPSIDATION OF CHEMICALLY MODIFIED AND THEREBY STABI LISED SI2.!S -ORRISSEY ET AL ;= DEMONSTRATED A MORE THAN LOG REDUC TION OF ("6 SERUM $.! LEVELS IN TREATED ("6 TRANSGENIC ANIMALS 4HIS PROVES THAT SI2.!S HAVE A THERAPEUTIC POTENTIAL FOR THE TREATMENT OF ("6 INFECTION (OWEVER HUGE EFFORTS ARE NECESSARY TO OPTIMISE THE APPLICATION FORM AND SPECIFICITY AND EFFICACY OF LIVER TARGETING OF SI2.! BASED THERAPIES IN THE FUTURE
%NCAPSIDATION OF PREGENOMIC 2.! AND CAPSID ASSEMBLY !NOTHER PROMISING NEW THERAPEUTIC STRATEGY TO SPECIFICALLY INTERFERE WITH A YET UNADDRESSED STEP IN THE ("6 LIFE CYCLE IS THE PREVENTION OF NUCLEOCAPSID ASSEMBLY FOLLOWED BY AN ACCELERATED DEGRADATION OF THE PARTIALLY ASSEMBLED CAPSID PROTEIN OLIGOMER 4HIS THERAPEUTIC OPTION IS BASED UPON THE OBSER VATION THAT A GROUP OF SYNTHETIC SUBSTANCES CALLED DIHYDROARYLPYRIMIDINES ARE ABLE TO PREVENT SECRETION OF ("6 PARTICLES IN THE CONSTITUTIVELY ("6 EXPRESSING CELL LINE (EP' ;= 4WO PROTOTYPE MEMBERS OF DIHY DROARYLPYRIMIDINES "AY AND "AY HAVE BEEN CHARACTERISED IN SOME DETAIL WITH REGARD TO THEIR ACTIVITY AND THEIR MECHANISM OF ACTION 4HEY DISPLAY AN )# OF N- AND N- RESPECTIVELY AND DIFFER IN THEIR POTENTIAL TO BIND AND MISDIRECT CAPSID ASSEMBLY )NTERESTINGLY "AY NOT ONLY PREVENTED NUCLEOCAPSID FORMATION BUT ALSO INDUCED CORE PROTEIN DEGRADATION VIA A PROTEASOME DEPENDEND PATHWAY )TS ACTIVITY IN ("6 TRANSGENIC MICE AFTER ORAL APPLICATION ;= INDICATED THAT THIS SUBSTANCE
3TEPHAN 5RBAN AND 5LRIKE 0ROTZER
TARGETED THE LIVER WAS TAKEN UP INTO HEPATOCYTES AND INDUCED A REDUCTION OF ("6 SECRETION IN VIVO -ORE RECENT STUDIES AIMED AT DECIPHERING THE MECHANISM OF ACTION OF DIHYDROARYLPYRIMIDINES 4HEY INDICATE THAT "AY ACTS IN A CONCENTRA TION DEPENDENT MANNER IN A DUAL MODE BY ACCELERATING AND MISDIRECTING CAPSID ASSEMBLY ; = 2ECENTLY A WHOLE SET OF DIHYDROARYLPYRIMIDINE DERIVATIVES WITH INCREASED ACTIVITIES HAVE BEEN DEVELOPED AND ARE PRESENTLY CHARACTERISED WITH REGARD TO THEIR BIOAVAILABILITY GENOTYPE SPECIFICITY OF ACTION TOXICITY AND IN VIVO ACTIVITY 5RBAN UNPUBLISHED RESULTS 0RESENTLY WE LACK DETAILED STRUCTURAL INFORMATION ON THE EXACT BINDING SITES OF "AY OR ITS DERIVATIVES TO THE ("6 CORE PROTEIN 3TRUCTURAL INFORMATION WOULD ALLOW ESTIMATION OF THE PROBABILITY OF VIRAL ESCAPE MUTANTS WHICH MAY EVOLVE UNDER SELECTION PRESSURE &URTHERMORE IN VIVO APPLICATION REQUIRES INDUCTION OF CORE PROTEIN DEGRADATION IN ORDER TO PREVENT ITS INTRACELLULAR ACCUMULATION )RRESPECTIVE OF THIS LACK OF KNOWLEDGE DIHYDROARYLPYRIMI DINES REPRESENT A HIGHLY INTERESTING GROUP OF NEW MOLECULES FOR FURTHER CLINICAL DEVELOPMENTS )NTERESTINGLY THE ANTIVIRAL ACTIVITY OF HEME OXYGENASE (/ TARGETS THE SAME STEP IN THE VIRAL CYCLE n CAPSID ASSEMBLY (/ IS A METABOLIC ENZYME CATALYSING THE INITIAL AND RATE LIMITING STEP IN THE OXIDATIVE DEGRADA TION OF HEME )N ADDITION (/ HAS IMMUNOMODULATORY PROPERTIES AND EG PREVENTS APOPTOTIC LIVER DAMAGE IN IMMUNE MEDIATED HEPATITIS IN MICE ;= )T HAS RECENTLY BEEN SHOWN TO AMELIORATE ("6 ASSOCIATED LIVER DAMAGE IN MOUSE MODELS OF ACUTE AND CHRONIC HEPATITIS " ;= &URTHERMORE IT SHOWED A PROFOUND ANTIVIRAL ACTIVITY REPRESSING ("6 REPLICATION AT A POSTTRANSCRIP TIONAL STEP )NTERESTINGLY INDUCTION OF (/ IN HEPATOCYTES REDUCED THE STA BILITY OF THE ("6 CORE PROTEIN LEADING TO A REDUCTION OF CAPSIDS CONTAINING VIRAL REPLICATIVE INTERMEDIATES AND n AS A CONSEQUENCE n BLOCKED THE REFILL OF NUCLEAR CCC$.! ;= 4HUS INDUCTION OF (/ MIGHT BE AN INTERESTING NOVEL THERAPEUTIC OPTION FOR INFLAMMATORY FLARES OF HEPATITIS "
#YTOPLASMIC ("6 CAPSIDS AS TARGET OF INTRACELLULAR DEFENCE PATHWAYS )&. _` AS WELL AS )&. a UPON BINDING TO THEIR RECEPTORS ON HEPATOCYTES TRIGGER INTRACELLULAR EVENTS THAT EITHER INHIBIT THE ASSEMBLY OF PG2.! CON TAINING CAPSIDS OR ACCELERATE THE DEGRADATION OF CAPSID SUBUNITS OR COMPLETE CAPSIDS ; = 7HEREAS )&. _ MAY ALSO DOWNREGULATE ("6 2.! AT THE TRANSCRIPTIONAL LEVEL ; = THE ACTIVITY OF )&. a REMAINS POSTTRANSCRIP TIONALLY ; = 7IELAND ET AL ;= PROPOSED THAT )&.S ACTIVATE HEPATOCELLU LAR MECHANISMS PREVENTING THE FORMATION OF REPLICATION COMPETENT ("6 CAPSIDS AND THEREBY INHIBIT ("6 REPLICATION 4.& _ DESTABILISES ("6 CAPSIDS INDEPENDENT OF )&. SIGNALING PATHWAYS VIA ACTIVATION OF .& g" ; = 4HUS CYTOPLASMIC ("6 2.! CONTAINING CAPSIDS SEEM TO BE A COMMON
(EPATITIS " VIRUS ,ESSONS LEARNED FROM THE VIRUS LIFE CYCLE
TARGET OF INTRACELLULAR DEFENSE MECHANISMS ACTIVATED BY CYTOKINES WHICH ARE ANTIVIRALLY ACTIVE AGAINST ("6
2EVERSE TRANSCRIPTION 4HE FACT THAT ("6 ALTHOUGH CARRYING A $.! GENOME IN THE VIRION REPLI CATES VIA REVERSE TRANSCRIPTION 24 OF AN 2.! INTERMEDIATE PG2.! AND THUS ENCODES A POLYMERASE WITH 24 AND 2.!SE( ACTIVITIES CONSTITUTES THE BASIS FOR BLOCKING THIS 24 STEP 3ELECTIVELY ACTIVE NUCLEOST IDE ANALOGUES EFFICIENTLY BLOCK 24 IN PRESENTLY USED THERAPEUTIC REGIMENS (OWEVER 24 INHIBITORS ALONE DO NOT ELIMINATE THE VIRUS SINCE THEY ACT AT A LATE STEP IN THE VIRAL LIFE CYCLE AND DO NOT DIRECTLY AFFECT ESTABLISHED CCC$.! IN THE NUCLEUS ,AMIVUDINE ,-6 :EFFIX A CYTIDINE ANALOGUE 4# WAS INITIALLY DEVELOPED FOR THE THERAPY OF ()6 PATIENTS AND WAS APPROVED FOR CHRONIC HEPATITIS " IN ;n= (OWEVER ,-6 MONOTHERAPY RESULTS IN A FAST DEVELOPMENT OF RESISTANT ("6 MUTANTS RESISTANCE WITHIN YEARS OF THERAPY MOST FREQUENTLY IN AN -6) EXCHANGE WITHIN THE 9-$$ MOTIF OF THE POLYMERASE ;= 4HIS MUTATION IS OFTEN FOLLOWED BY COMPENSATORY MUTATIONS THAT INCREASE THE REPLICATION DEFECT CAUSED BY THE 9-$$ MUTA TION ; = 2ESISTANCE RESULTS FROM GENETIC ADAPTATION OF THE VIRUS TO THE SELEC TION PRESSURE CAUSED BY DRUG TREATMENT 4HE DEVELOPMENT OF RESISTANCE IS PROMOTED BY I THE HIGH ERROR RATE OF THE VIRAL POLYMERASE NO PROOF READ ING ACTIVITY II THE STRENGTH OF THE SELECTION PRESSURE OF THE DRUG III THE NUMBER OF MUTATIONS NEEDED TO GAIN RESISTANCE COMBINED WITH @FITNESS OF THE RESISTANT ("6 VARIANT IV THE REPLICATION SPACE IN THE LIVER AND V THE VIRUS TITRE IN THE PATIENT 4HE FAST DEVELOPMENT OF ,-6 RESISTANCE MIGHT BE CAUSED BY AN ONLY PARTIAL REPRESSION OF REPLICATION DURING THERAPY VIRUS TITRES IN PATIENTS ARE REDUCED BY @ONLY LOGS IN PATIENTS TREATED WITH MG ,-6 DAILY -OREOVER THE FACT THAT A SINGLE POINT MUTATION CAN ALREADY MEDIATE RESISTANCE AND THE OBSERVATION THAT COMPENSATORY MUTANTS CAN REVERSE THE INITIAL DROP OF REPLICATION COMPETENCE ALSO ABET THERAPY FAILURE DURING LONG TREATMENT PERIODS 4HREE OTHER ORAL NUCLEOST IDE ANALOGUES ARE CURRENTLY MARKETED AND APPROVED AS A FIRST LINE OF THERAPY FOR THE TREATMENT OF CHRONIC HEPATI TIS " ADEFOVIR DIPIVOXIL !$6 (EPSERA AN !-0 ANALOGUE ENTECAVIR "ARACUDE A GUANOSINE ANALOGUE AND TELBIVUDINE 3EBIVO A THYMIDINE ANALOGUE )N ADDITION TENOFOVIR WHICH IS APPROVED FOR ()6 TREATMENT PROVED MORE ACTIVE THAN ADEFOVIR IN ()6("6 COINFECTED PATIENTS ;= AND IS CURRENTLY TESTED IN ("6 MONOINFECTION !LL THERAPIES LOWER THE VIRAL LOAD REDUCE SERUM TRANSAMINASE ACTIVITY AND IMPROVE LIVER HISTOLOGY 3EVERAL STUDIES HAVE SHOWN THAT DEVELOPMENT OF RESISTANCE IN ADEFOVIR TREATED PATIENTS IS LESS FREQUENT THAN IN ,-6 TREATED PATIENTS AFTER
3TEPHAN 5RBAN AND 5LRIKE 0ROTZER
YEARS OF THERAPY ;= )N ADDITION TO THIS SLOWER RATE OF RESISTANCE DEVELOP MENT !DEFOVIR IS EFFECTIVE AGAINST LAMIVUDINE RESISTANT MUTANTS ;n= AND CAN THEREFORE BE USED IN @ADD ON THERAPIES IN PATIENTS WITH VIRAL BREAK THROUGH UNDER ,-6 TREATMENT &OR %NTECAVIR A MUCH LOWER DOSE IS NEEDED FOR AN EFFICIENT REDUCTION OF VIRAL LOADS IN THE SERUM OF CHRONICALLY INFECTED PATIENTS n MGPATIENT DAY !S EXPECTED MONOTHERAPY WITH %NTECAVIR RESULTS IN A DRASTICALLY REDUCED RATE OF ARISING RESISTANT MUTANTS ;= (OWEVER ,-6 RESISTANT MUTANTS ARE TO A LARGE EXTENT CROSS RESISTANT TO ENTECAVIR AND THUS NEED ALTERNATIVE REGIMENS 4ELBIVUDINE ALSO PROVED MORE EFFECTIVE AS A FIRST LINE THERAPY AND SELECTED FEWER DRUG RESISTANT VIRAL VARIANTS THAN ,-6 ; = 3INCE THE MAIN HURDLE OF 24 INHIBITOR THERAPY IS THE SELECTION OF DRUG RESISTANT MUTANTS COMBINATION THERAPY IS OFTEN DISCUSSED BUT HAS NOT PROVEN TO BE SUPERIOR OVER MONOTHERAPY SO FAR
.UCLEAR REIMPORT OF VIRAL GENOMES AND ACCUMULATION OF A CCC$.! POOL #URRENTLY NO MEANS ARE AVAILABLE TO PREVENT IMPORT OF VIRAL GENOMES INTO THE NUCLEUS nWHETHER THIS IS THE INCOMING VIRAL GENOME SEE ABOVE OR THESE ARE NEWLY SYNTHESISED VIRAL GENOMES )N THE NUCLEUS THE INCOMPLETE $.! GENOMES ARE COMPLETED BY HOST ENZYMES TO CCC$.! MOLECULES SERVING AS THE VIRAL TRANSCRIPTION TEMPLATE AND AS THE VIRAL PERSISTENCE FORM .EWLY FORMED CAPSIDS MAY BE TARGETED FROM THE CYTOPLASM TO THE NUCLEUS AND THUS MAY INCREASE THE NUMBER OF NUCLEAR VIRAL REPLICATION TEMPLATES IE CCC$.! MOLECULES 7HEN REVERSE TRANSCRIPTION OF THE ("6 GENOME OR MATURA TION OF VIRAL CAPSIDS IS EFFICIENTLY BLOCKED ACCUMULATION OF A POOL OF ("6 CCC$.! IN THE NUCLEUS OF INFECTED CELLS IS HINDERED AND ("6 CCC$.! MAY BE LOST BY CELL DIVISION (OWEVER DIRECT TARGETING OF THE NUCLEAR CCC$.! IS HARD AND MAY ONLY BE ACHIEVED BY TARGETED NUCLEASES
%NVELOPMENT AND RELEASE OF PROGENY VIRIONS 3O FAR NO DIRECT INHIBITORS OF THE ENVELOPMENT OF ("6 CAPSIDS AND MATU RATION OR RELEASE OF VIRIONS ARE AVAILABLE (OWEVER SINCE AT LEAST TRACE AMOUNTS OF ("6 ENVELOPE PROTEINS ARE DISPLAYED ON THE PLASMA MEMBRANE OF INFECTED HEPATOCYTES THESE MAY SERVE AS A TARGET FOR 4 CELL BASED TREAT MENT STRATEGIES 4 CELLS REDIRECTED AGAINST ("6 SURFACE PROTEINS BY ARTIFICIAL 4 CELL RECEPTORS WHICH RECOGNISE NATIVE 3 OR , PROTEIN ON THE CELL SURFACE USING A SINGLE CHAIN ANTIBODY FRAGMENT AS AN ANTIGEN BINDING DOMAIN SELEC TIVELY KILL INFECTED HEPATOCYTES IN CELL CULTURE ;= (OWEVER EFFICACY AND SAFETY OF SUCH AN APPROACH REMAINS TO BE SHOWN IN IN VIVO MODELS
(EPATITIS " VIRUS ,ESSONS LEARNED FROM THE VIRUS LIFE CYCLE
!CKNOWLEDGMENT 7E THANK (EINZ 3CHALLER FOR LAYING THE FUNDAMENT OF OUR SCIENTIFIC WORK AND FOR TEACHING US IMPORTANT INSIGHT INTO THE MOLECULAR BIOLOGY OF ("6 AS WELL AS ITS VIRUS HOST AND VIRUS CELL INTERACTION 7E WILL REMEMBER MANY FRUITFUL BUT SOMETIMES CHALLENGING DISCUSSIONS WHICH HELPED TO SHARPEN OUR VIEW (EINZ 3CHALLER ALWAYS ENCOURAGED US TO THINK AND WORK INDEPENDENTLY FOLLOWING HIGH SCIENTIFIC STANDARDS 3TEPHEN 5RBAN IS PARTICULARLY INDEBTED TO THE (EINZ AND #HICA 3CHALLER FOUNDATION FOR SUPPORTING HIM WITH A SHORT TERM FELLOWSHIP 7ITHOUT THIS HELP ADMINISTRATIVE REGULATIONS WOULD HAVE PREVAILED THE FURTHER PROGRESS OF HIS SCIENTIFIC WORK 7E ARE ALSO GRATEFUL TO #AROLINE 'ËHLER FOR THE ILLUSTRATION
2EFERENCES
3ELLS -! #HEN -, !CS ' 0RODUCTION OF HEPATITIS " VIRUS PARTICLES IN (EP ' CELLS TRANSFECTED WITH CLONED HEPATITIS " VIRUS $.! 0ROC .ATL !CAD 3CI 53! n 'UIDOTTI ,' -ATZKE " 3CHALLER ( #HISARI &6 (IGH LEVEL HEPATITIS " VIRUS REPLICATION IN TRANSGENIC MICE * 6IROL n 7IELAND 3& 3PANGENBERG (# 4HIMME 2 0URCELL 2( #HISARI &6 %XPANSION AND CONTRACTION OF THE HEPATITIS " VIRUS TRANSCRIPTIONAL TEMPLATE IN INFECTED CHIMPANZEES 0ROC .ATL !CAD 3CI 53! n 3EEGER # -ASON 73 (EPATITIS " VIRUS BIOLOGY -ICROBIOL -OL "IOL 2EV n 3UMMERS * -ASON 73 2EPLICATION OF THE GENOME OF A HEPATITIS "nLIKE VIRUS BY REVERSE TRANSCRIPTION OF AN 2.! INTERMEDIATE #ELL n 3EITZ 3 5RBAN 3 !NTONI # "OTTCHER " #RYO ELECTRON MICROSCOPY OF HEPATITIS " VIRIONS REVEALS VARIABILITY IN ENVELOPE CAPSID INTERACTIONS %-"/ * n #HEN (3 +ANEKO 3 'IRONES 2 !NDERSON 27 (ORNBUCKLE 7% 4ENNANT "# #OTE 0* 'ERIN *, 0URCELL 2( -ILLER 2( 4HE WOODCHUCK HEPATITIS VIRUS 8 GENE IS IMPORTANT FOR ESTABLISHMENT OF VIRUS INFECTION IN WOODCHUCKS * 6IROL n :OULIM & 3APUTELLI * 3EEGER # 7OODCHUCK HEPATITIS VIRUS 8 PROTEIN IS REQUIRED FOR VIRAL INFECTION IN VIVO * 6IROL n 'ANEM $ 0RINCE !- (EPATITIS " VIRUS INFECTIONnNATURAL HISTORY AND CLINICAL CONSEQUENCES . %NGL * -ED n 7ILL ( #ATTANEO 2 +OCH (' $ARAI ' 3CHALLER ( 3CHELLEKENS ( 6AN %ERD 0-#! $EINHARDT & #LONED ("6 $.! CAUSES HEPATITIS IN CHIMPAN ZEES .ATURE n +OCK * .ASSAL - -AC.ELLY 3 "AUMERT 4& "LUM (% VON 7EIZSËCKER & %FFICIENT INFECTION OF PRIMARY TUPAIA HEPATOCYTES WITH PURIFIED HUMAN AND WOOLLY MONKEY HEPATITIS " VIRUS * 6IROL n 9AN 21 3U ** (UANG $2 'AN 9# 9ANG # (UANG ' (UMAN HEPATITIS
3TEPHAN 5RBAN AND 5LRIKE 0ROTZER
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(EPATITIS " VIRUS ,ESSONS LEARNED FROM THE VIRUS LIFE CYCLE
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3TEPHAN 5RBAN AND 5LRIKE 0ROTZER
7U '9 #HEN (3 .OVEL APPROACHES TOWARDS CONQUERING HEPATITIS " VIRUS INFECTION 7ORLD * 'ASTROENTEROL n 'RIPON 0 2UMIN 3 5RBAN 3 ,E * 'LAISE $ #ANNIE ) 'UYOMARD # ,UCAS * 4REPO # 'UGUEN 'UILLOUZO # )NFECTION OF A HUMAN HEPATOMA CELL LINE BY HEPATITIS " VIRUS 0ROC .ATL !CAD 3CI 53! n %NGELKE - -ILLS + 3EITZ 3 3IMON 0 'RIPON 0 3CHNOLZER - 5RBAN 3 #HARACTERIZATION OF A HEPATITIS " AND HEPATITIS DELTA VIRUS RECEPTOR BINDING SITE (EPATOLOGY n ,E 3* #HOUTEAU 0 #ANNIE ) 'UGUEN 'UILLOUZO # 'RIPON 0 )NFECTION PROCESS OF THE HEPATITIS " VIRUS DEPENDS ON THE PRESENCE OF A DEFINED SEQUENCE IN THE PRE 3 DOMAIN * 6IROL n "LANCHET - 3UREAU # )NFECTIVITY DETERMINANTS OF THE HEPATITIS " VIRUS PRE 3 DOMAIN ARE CONFINED TO THE . TERMINAL AMINO ACID RESIDUES * 6IROL n *AOUDE ' 3UREAU # 2OLE OF THE ANTIGENIC LOOP OF THE HEPATITIS " VIRUS ENVELOPE PROTEINS IN INFECTIVITY OF HEPATITIS DELTA VIRUS * 6IROL n "RUSS 6 (AGELSTEIN * 'ERHARDT % 'ALLE 02 -YRISTYLATION OF THE LARGE SURFACE PROTEIN IS REQUIRED FOR HEPATITIS " VIRUS IN VITRO INFECTIVITY 6IROLOGY n 'RIPON 0 ,E 3* 2UMIN 3 'UGUEN 'UILLOUZO # -YRISTYLATION OF THE HEPATITIS " VIRUS LARGE SURFACE PROTEIN IS ESSENTIAL FOR VIRAL INFECTIVITY 6IROLOGY n -ACRAE $2 "RUSS 6 'ANEM $ -YRISTYLATION OF A DUCK HEPATITIS " VIRUS ENVELOPE PROTEIN IS ESSENTIAL FOR INFECTIVITY BUT NOT FOR VIRUS ASSEMBLY 6IROLOGY n *AOUDE ' -OLINA 3 -AUREL 0 3UREAU # -YRISTOYLATION SIGNAL TRANSFER FROM THE LARGE TO THE MIDDLE OR THE SMALL ("6 ENVELOPE PROTEIN LEADS TO A LOSS OF ($6 PARTICLES INFECTIVITY 6IROLOGY n "LANCHET - 3UREAU # )NFECTIVITY DETERMINANTS OF THE HEPATITIS " VIRUS PRE 3 DOMAIN ARE CONFINED TO THE . TERMINAL AMINO ACID RESIDUES * 6IROL n 'UDIMA 3 -EIER ! $UNBRACK 2 4AYLOR * "RUSS 6 4WO POTENTIALLY IMPORTANT ELEMENTS OF THE HEPATITIS " VIRUS LARGE ENVELOPE PROTEIN ARE DISPENS ABLE FOR THE INFECTIVITY OF HEPATITIS DELTA VIRUS * 6IROL n ,EPERE # 2EGEARD - ,E 3* 'RIPON 0 4HE TRANSLOCATION MOTIF OF HEPATITIS " VIRUS ENVELOPE PROTEINS IS DISPENSABLE FOR INFECTIVITY * 6IROL n ,E 3* #HOUTEAU 0 #ANNIE ) 'UGUEN 'UILLOUZO # 'RIPON 0 2OLE OF THE PRE 3 DOMAIN OF THE LARGE ENVELOPE PROTEIN IN HEPATITIS " VIRUS ASSEMBLY AND INFECTIVITY * 6IROL n /ESS 3 (ILDT % .OVEL CELL PERMEABLE MOTIF DERIVED FROM THE 0RE3 DOMAIN OF HEPATITIS " VIRUS SURFACE ANTIGENS 'ENE 4HER n 3TOECKL , &UNK ! +OPITZKI ! "RANDENBURG " /ESS 3 7ILL ( 3IRMA ( (ILDT % )DENTIFICATION OF A STRUCTURAL MOTIF CRUCIAL FOR INFECTIVITY OF HEPATITIS " VIRUSES 0ROC .ATL !CAD 3CI 53! n "LANCHET - 3UREAU # !NALYSIS OF THE CYTOSOLIC DOMAINS OF THE HEPATITIS
(EPATITIS " VIRUS ,ESSONS LEARNED FROM THE VIRUS LIFE CYCLE
" VIRUS ENVELOPE PROTEINS FOR THEIR FUNCTION IN VIRAL PARTICLE ASSEMBLY AND INFEC TIVITY * 6IROL n *AOUDE '! 3UREAU # 2OLE OF THE ANTIGENIC LOOP OF THE HEPATITIS " VIRUS ENVELOPE PROTEINS IN INFECTIVITY OF HEPATITIS DELTA VIRUS * 6IROL n *AOUDE ' 3UREAU # %NTRY OF HEPATITIS DELTA VIRUS REQUIRES THE CONSERVED CYSTEINE RESIDUES OF THE HEPATITIS " VIRUS ENVELOPE PROTEIN ANTIGENIC LOOP AND IS BLOCKED BY INHIBITORS OF THIOL DISULFIDE EXCHANGE * 6IROL n 'LEBE $ 5RBAN 3 6IRAL AND CELLULAR DETERMINANTS INVOLVED IN HEPADNA VIRAL ENTRY 7ORLD * 'ASTROENTEROL n "ARRERA ! 'UERRA " .OTVALL , ,ANFORD 2% -APPING OF THE HEPATITIS " VIRUS PRE 3 DOMAIN INVOLVED IN RECEPTOR RECOGNITION * 6IROL n 'LEBE $ 5RBAN 3 +NOOP %6 #AP . +RASS 0 'RUN 3 "ULAVAITE ! 3ASNAUSKAS + 'ERLICH 7( -APPING OF THE HEPATITIS " VIRUS ATTACHMENT SITE BY USE OF INFECTION INHIBITING PRE3 LIPOPEPTIDES AND TUPAIA HEPATOCYTES 'ASTROENTEROLOGY n 'RIPON 0 #ANNIE ) 5RBAN 3 %FFICIENT INHIBITION OF HEPATITIS " VIRUS INFECTION BY ACYLATED PEPTIDES DERIVED FROM THE LARGE VIRAL SURFACE PROTEIN * 6IROL n 0ETERSEN * $ANDRI - -IER 7 ,àTGEHETMANN - 6OLZ 4 VON 7EIZSËCKER & (ABERKORN 5 &ISCHER , 0OLLOK *- %RBES " ET AL 0REVENTION OF HEPATITIS " VIRUS INFECTION IN VIVO BY ENTRY INHIBITORS DERIVED FROM THE LARGE ENVELOPE PROTEIN .AT "IOTECHNOL n 9ING # ,I 9 ,EUNG #( 2OBEK -$ #HENG 9# 5NIQUE ANTIVIRAL MECHANISM DISCOVERED IN ANTI HEPATITIS " VIRUS RESEARCH WITH A NATURAL PRODUCT ANALOGUE 0ROC .ATL !CAD 3CI 53! n 5PRICHARD 3, 7IELAND 3& !LTHAGE ! #HISARI &6 4RANSCRIPTIONAL AND POSTTRANSCRIPTIONAL CONTROL OF HEPATITIS " VIRUS GENE EXPRESSION 0ROC .ATL !CAD 3CI 53! n (EISE 4 'UIDOTTI ,' #HISARI &6 ,A AUTOANTIGEN SPECIFICALLY RECOGNIZES A PREDICTED STEM LOOP IN HEPATITIS " VIRUS 2.! * 6IROL n 3HLOMAI ! 3HAUL 9 )NHIBITION OF HEPATITIS " VIRUS EXPRESSION AND REPLI CATION BY 2.! INTERFERENCE (EPATOLOGY n +LEIN # "OCK #4 7EDEMEYER ( 7USTEFELD 4 ,OCARNINI 3 $IENES (0 +UBICKA 3 -ANN -0 4RAUTWEIN # )NHIBITION OF HEPATITIS " VIRUS REPLICATION IN VIVO BY NUCLEOSIDE ANALOGUES AND SI2.! 'ASTROENTEROLOGY n +ONISHI - 7U #( 7U '9 )NHIBITION OF ("6 REPLICATION BY SI2.! IN A STABLE ("6 PRODUCING CELL LINE (EPATOLOGY n 5PRICHARD 3, "OYD " !LTHAGE ! #HISARI &6 #LEARANCE OF HEPATITIS " VIRUS FROM THE LIVER OF TRANSGENIC MICE BY SHORT HAIRPIN 2.!S 0ROC .ATL !CAD 3CI 53! n (ORNUNG 6 'UENTHNER "ILLER - "OURQUIN # !BLASSER ! 3CHLEE - 5EMATSU 3 .ORONHA ! -ANOHARAN - !KIRA 3 DE &OUGEROLLES ! ET AL 3EQUENCE SPECIFIC POTENT INDUCTION OF )&. ALPHA BY SHORT INTERFERING 2.! IN PLASMACY TOID DENDRITIC CELLS THROUGH 4,2 .AT -ED n -ORRISSEY $6 ,OCKRIDGE *! 3HAW , "LANCHARD + *ENSEN + "REEN 7 (ARTSOUGH + -ACHEMER , 2ADKA 3 *ADHAV 6 ET AL 0OTENT AND PERSIS
3TEPHAN 5RBAN AND 5LRIKE 0ROTZER
TENT IN VIVO ANTI ("6 ACTIVITY OF CHEMICALLY MODIFIED SI2.!S .AT "IOTECHNOL n $ERES + 3CHRODER #( 0AESSENS ! 'OLDMANN 3 (ACKER (* 7EBER / +RAMER 4 .IEWOHNER 5 0LEISS 5 3TOLTEFUSS * ET AL )NHIBITION OF HEPATITIS " VIRUS REPLICATION BY DRUG INDUCED DEPLETION OF NUCLEOCAPSIDS 3CIENCE n 7EBER / 3CHLEMMER +( (ARTMANN % (AGELSCHUER ) 0AESSENS ! 'RAEF % $ERES + 'OLDMANN 3 .IEWOEHNER 5 3TOLTEFUSS * ET AL )NHIBITION OF HUMAN HEPATITIS " VIRUS ("6 BY A NOVEL NON NUCLEOSIDIC COMPOUND IN A TRANSGENIC MOUSE MODEL !NTIVIRAL 2ES n 3TRAY 3* "OURNE #2 0UNNA 3 ,EWIS 7' &INN -' :LOTNICK ! ! HET EROARYLDIHYDROPYRIMIDINE ACTIVATES AND CAN MISDIRECT HEPATITIS " VIRUS CAPSID ASSEMBLY 0ROC .ATL !CAD 3CI 53! n 3TRAY 3* :LOTNICK ! "!9 HAS MULTIPLE EFFECTS ON (EPATITIS " VIRUS CAPSID ASSEMBLY * -OL 2ECOGNIT n 3ASS ' 3OARES -# 9AMASHITA + 3EYFRIED 3 :IMMERMANN 7( %SCHENHAGEN 4 +ACZMAREK % 2ITTER 4 6OLK ($ 4IEGS ' (EME OXYGENASE AND ITS REACTION PRODUCT CARBON MONOXIDE PREVENT INFLAMMATION RELATED APOPTOTIC LIVER DAMAGE IN MICE (EPATOLOGY n 0ROTZER 5 3EYFRIED 3 1UASDORFF - 3ASS ' 3VORCOVA - 7EBB $ "OHNE & (OSEL - 3CHIRMACHER 0 4IEGS ' !NTIVIRAL ACTIVITY AND HEPATOPROTEC TION BY HEME OXYGENASE IN HEPATITIS " VIRUS INFECTION 'ASTROENTEROLOGY n 3CHULTZ 5 3UMMERS * 3TAEHELI 0 #HISARI &6 %LIMINATION OF DUCK HEPA TITIS " VIRUS 2.! CONTAINING CAPSIDS IN DUCK INTERFERON ALPHA TREATED HEPATO CYTES * 6IROL n 7IELAND 3& 'UIDOTTI ,' #HISARI &6 )NTRAHEPATIC INDUCTION OF ALPHA BETA INTERFERON ELIMINATES VIRAL 2.! CONTAINING CAPSIDS IN HEPATITIS " VIRUS TRANSGENIC MICE * 6IROL n 2ANG ! 'UNTHER 3 7ILL ( %FFECT OF INTERFERON ALPHA ON HEPATITIS " VIRUS REPLICATION AND GENE EXPRESSION IN TRANSIENTLY TRANSFECTED HUMAN HEPA TOMA CELLS * (EPATOL n $UMORTIER * 3CHONIG + /BERWINKLER ( ,OW 2 'IESE 4 "UJARD ( 3CHIRMACHER 0 0ROTZER 5 ,IVER SPECIFIC EXPRESSION OF INTERFERON GAMMA FOLLOWING ADENOVIRAL GENE TRANSFER CONTROLS HEPATITIS " VIRUS REPLICATION IN MICE 'ENE 4HER n "IERMER - 0URO 2 3CHNEIDER 2* 4UMOR NECROSIS FACTOR ALPHA INHIBI TION OF HEPATITIS " VIRUS REPLICATION INVOLVES DISRUPTION OF CAPSID )NTEGRITY THROUGH ACTIVATION OF .& KAPPA" * 6IROL n 0URO 2 3CHNEIDER 2* 4UMOR NECROSIS FACTOR ACTIVATES A CONSERVED INNATE ANTIVIRAL RESPONSE TO HEPATITIS " VIRUS THAT DESTABILIZES NUCLEOCAPSIDS AND REDUCES NUCLEAR VIRAL $.! * 6IROL n *ARVIS " &AULDS $ ,AMIVUDINE ! REVIEW OF ITS THERAPEUTIC POTENTIAL IN CHRONIC HEPATITIS " $RUGS n $IENSTAG *, 0ERRILLO 20 3CHIFF %2 "ARTHOLOMEW - 6ICARY # 2UBIN - ! PRELIMINARY TRIAL OF LAMIVUDINE FOR CHRONIC HEPATITIS " INFECTION . %NGL * -ED n
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"OHNE & #HMIELEWSKI - %BERT ' 7IEGMANN + +àRSCHNER 4 3CHULZE ! 5RBAN 3 +RÚNKE - !BKEN ( 0ROTZER 5 4 CELLS REDIRECTED AGAINST HEP ATITIS " VIRUS SURFACE PROTEINS ELIMINATE INFECTED HEPATOCYTES 'ASTROENTEROLOGY n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT 2ALF "ARTENSCHLAGER 'ANG ,ONG AND $ARIUS -ORADPOUR $EPARTMENT OF -OLECULAR 6IROLOGY 5NIVERSITY OF (EIDELBERG )M .EUENHEIMER &ELD
(EIDELBERG 'ERMANY $IVISION OF 'ASTROENTEROLOGY AND (EPATOLOGY #ENTRE (OSPITALIER 5NIVERSITAIRE 6AUDOIS
5NIVERSITY OF ,AUSANNE ,AUSANNE 3WITZERLAND
!BSTRACT #HRONIC LIVER DISEASE CAUSED BY INFECTION WITH THE HEPATITIS # VIRUS (#6 IS AN IMPORTANT MEDICAL PROBLEM !LTHOUGH PRIMARY INFECTION USUALLY IS MILD AND OFTEN ASYMPTOMATIC IN THE VAST MAJORITY OF CASES (#6 ESTABLISHES PERSISTENCE THAT IN THE COURSE OF ONE OR SEVERAL DECADES MAY RESULT IN CHRONIC LIVER DISEASES INCLUDING LIVER CIR RHOSIS AND HEPATOCELLULAR CARCINOMA 4HERAPEUTIC OPTIONS ARE LIMITED AND A VACCINE TO PREVENT (#6 INFECTION IS NOT IN SIGHT $IAGNOSTIC TESTS TO DETECT (#6 CONTAINING BLOOD PRODUCTS HAVE BECOME AVAILABLE AFTER THE FIRST MOLECULAR CLONING OF THE VIRAL GENOME 4HIS ACHIEVEMENT ALSO OPENED THE FIELD FOR STUDIES OF THE VIRAL REPLICATION CYCLE AS WELL AS THE DEVELOPMENT OF SELECTIVE ANTIVIRAL DRUGS (#6 IS A HEPATOTROPIC FLAVIVIRUS WHICH HAS SEVERAL REMARKABLE PROPERTIES !MONG THESE ARE THE POTENT INHIBITION OF THE INDUC TION PHASE OF THE INNATE ANTIVIRAL RESPONSE THE HIGH GENOMIC PLASTICITY AND THE UNUSUAL STRATEGY OF VIRUS PARTICLE ASSEMBLY THAT OCCURS IN CLOSE ASSOCIATION WITH LIPID DROPLETS AND THE VERY LOW DENSITY LIPOPROTEIN PRODUCTION PATHWAY 4HIS CHAPTER WILL BRIEFLY SUM MARISE SOME OLD AND NEW ASPECTS OF CHRONIC HEPATITIS # AND OF THE PATHOGEN RESPONSIBLE FOR THIS DISEASE
)NTRODUCTION (EPATITIS # VIRUS (#6 IS A MAJOR CAUSE OF CHRONIC HEPATITIS LIVER CIR RHOSIS AND HEPATOCELLULAR CARCINOMA (## WORLDWIDE %ND STAGE LIVER DISEASE DUE TO CHRONIC HEPATITIS # IS NOW THE LEADING INDICATION FOR LIVER TRANSPLANTATION ! PROTECTIVE VACCINE IS NOT AVAILABLE YET AND THERAPEUTIC OPTIONS ARE STILL LIMITED !S A CONSEQUENCE THE NUMBER OF PATIENTS PRE SENTING WITH LONG TERM SEQUELAE OF CHRONIC HEPATITIS # INCLUDING (## IS EXPECTED TO FURTHER INCREASE FOR THE NEXT TWO DECADES EVEN IF THE INCIDENCE OF NEW CASES HAS DIMINISHED SINCE THE INTRODUCTION OF ANTI (#6 SCREENING OF BLOOD AND BLOOD PRODUCTS ; = 'IVEN THIS SCENARIO THERE IS AN URGENT NEED TO DEVELOP MORE EFFECTIVE AND BETTER TOLERATED THERAPIES FOR CHRONIC HEPATITIS #
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%PIDEMIOLOGY )T IS ESTIMATED THAT n MILLION PEOPLE WORLDWIDE ARE INFECTED WITH (#6 ;= 4HE VIRUS IS PARENTERALLY TRANSMITTED 7ITH THE INTRODUCTION OF ANTI (#6 SCREENING OF BLOOD AND BLOOD PRODUCTS IN NEW CASES OF POSTTRANSFUSION HEPATITIS # HAVE VIRTUALLY DISAPPEARED )NDEED OVER THE LAST YEARS THE RISK OF POSTTRANSFUSION HEPATITIS # COULD BE REDUCED FROM ABOUT PER BLOOD UNITS TRANSFUSED TO PER n ;= 5NFORTUNATELY THE LACK OF SYSTEMATIC SCREENING OF BLOOD DONORS CONTINUES TO RESULT IN (#6 TRANSMISSION IN COUNTRIES WITH DEVELOPING OR TRANSITIONAL ECONOMIES )N THESE COUNTRIES LARGE SCALE IMMUNISATION AND PARENTERAL THERAPY PROGRAMS EG FOR THE TREATMENT OF SCHISTOSOMIASIS IN %GYPT OR LEISHMANIASIS IN )NDIA AS WELL AS SURGICAL AND DENTAL PROCEDURES WITH INADEQUATELY STERILISED EQUIP MENT HAVE ALSO BEEN IMPORTANT ROUTES OF TRANSMISSION ; = )N THE 7ESTERN WORLD INTRAVENOUS DRUG USE IS NOW THE MAJOR IDENTIFIABLE MODE OF (#6 TRANSMISSION ;= )N ADDITION (#6 TRANSMISSION HAS BEEN DESCRIBED IN THE NOSOCOMIAL SETTING ;n= /CCUPATIONAL NEEDLESTICK INJURIES FROM ANTI (#6 POSITIVE SOURCES RESULT IN SEROCONVERSION IN ON AVERAGE OF RECIPIENTS )NTRANASAL COCAINE USE HAS BEEN IDENTIFIED AS A POSSIBLE MODE OF TRANSMIS SION @STRAW SHARING ;= 3EXUAL TRANSMISSION IS RARE AND CORRELATES WITH HIGH RISK SEXUAL PRACTICES 4HE RISK OF PERINATAL TRANSMISSION IS PROBABLY LESS THAN UNLESS THE MOTHER IS CO INFECTED WITH ()6 ;= )NTRIGUINGLY IN CLINICAL PRACTICE NO EPIDEMIOLOGIC RISK FACTOR CAN BE IDENTIFIED IN UP TO ONE THIRD OF PATIENTS WITH HEPATITIS # @SPORADIC HEPATITIS #
.ATURAL HISTORY !FTER AN INCUBATION PERIOD OF n WEEKS (#6 INFECTION IS USUALLY FOLLOWED BY A CLINICALLY INAPPARENT HEPATITIS ;= /NLY ABOUT OF PATIENTS ARE SYMPTOMATIC &ULMINANT HEPATITIS # IS VERY UNCOMMON /NE OF THE MOST IMPORTANT CLINICAL FEATURES OF HEPATITIS # IS ITS PROGRESSION TO CHRONICITY IN n &IG 4YPICALLY PATIENTS WITH CHRONIC HEPATITIS # HAVE FEW IF ANY SYMPTOMS AND THESE ARE USUALLY NONSPECIFIC INTERMITTENT AND MILD 4HE MOST COMMON SYMPTOM IS FATIGUE 4HE NATURAL HISTORY OF CHRONIC HEPATITIS # HAS BEEN ANALYSED IN SEVERAL RETRO AND PROSPECTIVE STUDIES ; = 7HILE NO INCREASED MORTALITY WAS FOUND IN THE RETROSPECTIVE 6ETERANS !DMINISTRATION STUDY ;= OTHER STUD IES INDICATED THAT CHRONIC HEPATITIS # FREQUENTLY PROGRESSES TO CIRRHOSIS AND (## ;= 3TUDIES WITH A FOLLOW UP OF UP TO YEARS PERFORMED IN COHORTS OF WOMEN INFECTED AT A YOUNG AGE VIA CONTAMINATED ANTI $ IMMUNOGLOBULIN HAVE SHOWN A BENIGN COURSE ; = "Y CONTRAST A RECENT REPORT DESCRIB ING A COHORT OF MALE PLASMA DONORS INFECTED IN THE S REVEALED A POOR OUTCOME WITH ONE THIRD OF PATIENTS HAVING ADVANCED LIVER DISEASE AND HAVING DEVELOPED (## OR END STAGE LIVER DISEASE AFTER A FOLLOW UP OF MORE
Chronic hepatitis C: Portrait of a silent epidemic and the etiologic agent
97
Figure 1. Natural history and management of hepatitis C. Comprehensive management of hepatitis C involves not only antiviral therapy but also preventive measures, liver transplantation (LT) for patients with end-stage liver disease, surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis, and the control of cofactors of disease progression, including, among others, alcohol, hepatitis B virus (HBV) or other coinfections, and overweight.
than 30 years [19]. Factors associated with more frequent and rapid progression to cirrhosis are higher age at the time of infection, male sex, alcohol consumption, coinfections with HBV or HIV, nonalcoholic fatty liver disease (NAFLD), hepatic iron overload, smoking and immunosuppression. Comprehensive management of chronic hepatitis C takes these factors into consideration and aims at improving the ones that can be modified. Once cirrhosis is established, the rate of HCC development is 1–6% per year. HCV infection is responsible for a substantial proportion of the increase in HCC incidence and mortality recently observed in most Western countries [20]. Although experimental evidence raises the possibility that HCV might operate through direct pathways in promoting malignant transformation of hepatocytes, it is generally believed that HCC associated with chronic hepatitis C develops through a general pathway of increased liver cell turnover, induced by chronic liver injury and regeneration, facilitating the development and manifestation of multiple and stepwise genetic alterations [21].
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(#6 GENOME ORGANISATION AND POLYPROTEIN PROCESSING (#6 HAS BEEN CLASSIFIED AS A MEMBER OF THE GENUS (EPACIVIRUS THAT TOGETH ER WITH THE GENERA 0ESTIVIRUS AND &LAVIVIRUS AND THE AS OF YET UNASSIGNED SPECIES '" VIRUS ! '" VIRUS " AND '" VIRUS #HEPATITIS ' VIRUS BELONGS TO THE FAMILY &LAVIVIRIDAE ;= (#6 GENOMES CAN BE GROUPED INTO AT LEAST SIX GENOTYPES THAT DIFFER IN THEIR NUCLEOTIDE SEQUENCE BY n ;n= &URTHERMORE WITHIN AN (#6 GENOTYPE SEVERAL SUBTYPES CAN BE DEFINED THAT DIFFER IN THEIR NUCLEOTIDE SEQUENCES BY n 4HE VARIABILITY OF (#6 GENOMES IS DUE TO THE HIGH ERROR RATE OF THE VIRAL 2.! DEPENDENT 2.! POLYMERASE 2D2P WHICH HAS BEEN CALCULATED TO BE IN THE RANGE OF ABOUT n ;= 4HE GENOME OF (#6 IS A SINGLE STRANDED 2.! OF POSITIVE POLARITY THAT HAS A LENGTH OF APPROXIMATELY KB &IG ! 4HE GENOME ENCODES A LARGE POLYPROTEIN OF ABOUT AMINO ACIDS THAT IS EXPRESSED VIA AN INTERNAL RIBOSOME ENTRY SITE )2%3 FORMED BY DOMAINS )) TO )6 IN THE NON TRANSLATED REGION .42 &IG " 4HE .42 HAS A TRIPARTITE STRUCTURE COMPOSED OF AN ABOUT NT LONG VARIABLE REGION DOWNSTREAM OF THE (#6 CODING REGION A POLY 55# TRACT OF HETEROGENEOUS LENGTH AND A HIGHLY CONSERVED NT SEQUENCE NAMED 8 TAIL &IG " "OTH DOMAINS ) AND )) IN THE .42 AS WELL AS THE 8 TAIL IN THE .42 ARE ESSENTIAL FOR 2.! REPLICATION !N EXTRA CIS ACTING 2.! ELEMENT #2% HAS BEEN IDENTIFIED IN THE TERMINAL CODING REGION OF .3" ;= &IG " 4HIS #2% DESIGNATED "3, IS REQUIRED FOR 2.! REPLICATION THROUGH A 2.!n2.! INTERACTION WITH A SUB REGION DESIGNATED AS 3, IN THE 8 TAIL ;= !S FOR THE OTHER MEMBERS OF THE FLAVIVIRUS FAMILY THE LARGE POLYPROTEIN ENCODED BY THE (#6 GENOME IS PROCESSED BY CELLULAR AND VIRAL PROTEASES TO GENERATE AT LEAST VIRAL PROTEINS ;n= &IG # THAT WILL BE DESCRIBED IN BRIEF 4HE CORE PROTEIN RESIDES AT THE VERY . TERMINUS OF THE POLYPROTEIN AND IS RELEASED FROM THE PRECURSOR BY TWO CLEAVAGES 4HE FIRST ONE SEPARATES CORE FROM % BY SIGNAL PEPTIDASE AND THE SECOND REMOVES THE % SIGNAL PEPTIDE BY SIGNAL PEPTIDE PEPTIDASE RELEASING MATURE CORE WITH AN APPARENT MOLECULAR WEIGHT OF ABOUT K$A ; = 4HE CORE PROTEIN IS THE MAJOR CONSTITUENT OF THE NUCLEOCAPSID THAT MAY FORM BY SELF ASSEMBLY ASSUMED TO BE TRIGGERED BY INTERACTION WITH STRUCTURED 2.! ; = )NTERESTINGLY IN TRANSFECTED AND INFECTED CELLS CORE LOCALISES TO LIPID DROPLETS AND RECENT DATA SUGGEST THAT THESE DROPLETS PLAY A VERY IMPORTANT ROLE IN VIRUS PARTICLE ASSEMBLY ; = % AND % ARE HEAVILY GLYCOSYLATED TYPE ) TRANSMEMBRANE PROTEINS ;= WITH AN . TERMINAL ECTODOMAIN AND SHORT # TERMINAL HYDROPHOBIC TRANS MEMBRANE DOMAINS 4HE (#6 ENVELOPE GLYCOPROTEINS ASSEMBLE AS NON COVALENT HETERODIMERS ;= WITH THE GLYCANS PLAYING AN IMPORTANT ROLE FOR VIRUS INFECTIVITY ;= 4WO HYPERVARIABLE REGIONS (62S HAVE BEEN IDENTI FIED IN % WITH (62 RESIDING IN THE . TERMINAL AMINO ACID RESIDUES
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
&IGURE /RGANISATION OF THE (#6 GENOME ESSENTIAL CIS ACTING 2.! ELEMENTS AND FUNCTIONS OF VIRAL PROTEINS ! 3TRUCTURE OF THE (#6 GENOME #LEAVAGE SITES AND INVOLVED PROTEASES ARE INDICATED BY ARROWS " 2.! ELEMENTS IN THE VIRAL GENOME 4HE .42 WITH ITS DOMAINS IS SHOWN IN THE LEFT BOX THE #2% IN THE .3" CODING REGION IN THE MIDDLE BOX AND THE .42 THAT IS COMPOSED OF THE VARIABLE REGION V R THE POLY 55# TRACT AND THE TERMINAL 8 TAIL IS SHOWN IN THE RIGHT BOX # 0OLYPROTEIN CLEAVAGE PRODUCTS AND THEIR FUNCTIONS IN THE VIRAL REPLICATION CYCLE .O FUNCTIONS COULD BE ASCRIBED TO THE & PROTEIN
;= !LTHOUGH THE SEQUENCE VARIABILITY OF (62 IS HIGH THE CHEMICO PHYSI CAL PROPERTIES OF THE AMINO ACID RESIDUES AT EACH POSITION AND THE CONFOR MATION OF (62 ITSELF ARE HIGHLY CONSERVED AMONG THE DIFFERENT GENOTYPES INDICATING AN IMPORTANT ROLE OF (62 DURING VIRUS ADSORPTION AND ENTRY ; = "ASED ON RECENT COMPARISON OF INTER AND INTRA HOST % SEQUENCES DERIVED FROM SUBJECTS INFECTED WITH (#6 A NEW (62 WAS IDENTIFIED TERMED (62 ;= 4HE SMALL POLYPEPTIDE P IS COMPOSED OF TWO TRANSMEMBRANE REGIONS CONNECTED BY A SHORT CYTOPLASMIC LOOP ; = 7HEN EXPRESSED IN A HET EROLOGOUS SYSTEM P LOCALISED TO THE %2 AND MITOCHONDRIAL MEMBRANES ;n= 0 APPEARS TO FORM AN ION CHANNEL ;= PRESUMABLY ESSENTIAL FOR INFECTIVITY IN VIVO ;= BUT DISPENSABLE FOR 2.! REPLICATION ; = 6ERY RECENTLY IT WAS SHOWN THAT P IS ESSENTIAL FOR EFFICIENT ASSEMBLY AND RELEASE OF INFECTIOUS VIRIONS AND P PROMOTES VIRUS PARTICLE PRODUCTION IN A GENO TYPE SPECIFIC MANNER ;= 6IRUS INFECTIVITY HOWEVER IS LARGELY INDEPENDENT OF P ;=
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4HE INTEGRAL MEMBRANE PROTEIN .3 IS DISPENSABLE FOR 2.! REPLICATION ; = BUT IT IS ESSENTIAL FOR VIRUS PRODUCTION IN CELL CULTURE AND INFECTIVITY IN VIVO ; = .3 CONTAINS AN . TERMINAL TRANSMEMBRANE DOMAIN AND A # TERMINAL CYSTEINE PROTEASE DOMAIN WITH (IS 'LU AND #YS FORMING THE ACTIVE SITE ;n= %NZYMATICALLY ACTIVE .3 IS A DIMER WITH COMPOSITE ACTIVE SITES ;= .3 IS A MULTIFUNCTIONAL PROTEIN CONTAINING A SERINE PROTEASE LOCATED IN THE . TERMINAL ONE THIRD AND AN 2.! HELICASE.40ASE LOCATED IN THE # TERMINAL TWO THIRDS OF THE PROTEIN 4HESE ENZYMATIC ACTIVITIES HAVE BEEN WELL CHARACTERISED AND HIGH RESOLUTION STRUCTURES HAVE BEEN SOLVED ;n= &ULL .3 PROTEASE ACTIVITY REQUIRES ACTIVATION BY .3! THAT INTERCALATES INTO THE .3 . TERMINAL PROTEASE DOMAIN )N ADDITION AN . TERMINAL TRANSMEMBRANE SEGMENT IN .3! TETHERS THE .3 ! ENZYME COMPLEX TO INTRACELLULAR MEMBRANES ;= 4HE .3 ! SERINE PROTEASE IS RESPONSIBLE FOR POLYPROTEIN CLEAVAGE IN THE REGION # TERMINAL OF .3 AND THIS ACTIVITY IS ESSENTIAL FOR THE GENERATION OF THE VIRAL REPLICATION COMPLEX 4HESE PROPER TIES MAKE .3 AN IDEAL TARGET FOR ANTIVIRAL THERAPY 4HE .3 HELICASE IS A MEMBER OF THE SUPERFAMILY $%X($ BOX HELICASES ;= WHICH ARE CAPABLE OF UNWINDING DOUBLE STRANDED 2.! OR OF SINGLE STRANDED 2.! REGIONS WITH EXTENSIVE SECONDARY STRUCTURE IN AN !40 DEPENDENT MANNER 4HE HELICASE ACTIVITY MAY BE INVOLVED IN INITIATION OF 2.! REPLICATION CONTRIBUTE TO THE PROCESSIVITY OF THE REPLICASE COMPLEX AND MAY BE INVOLVED IN THE DISSOCIATION OF THE REPLICATIVE FORM INTO POSITIVE AND NEGATIVE STRAND (#6 2.! .3" IS A HIGHLY HYDROPHOBIC NONSTRUCTURAL PROTEIN INDUCING MEMBRA NOUS VESICLES THAT SERVE AS A SCAFFOLD FOR THE ASSEMBLY OF THE (#6 REPLICA TION COMPLEX ;n= .3" APPEARS TO BE PALMITOYLATED AT TWO # TERMINAL CYSTEINE RESIDUES -OREOVER .3" CAN OLIGOMERISE WHICH MAY CONTRIBUTE TO THE INDUCTION OF MEMBRANE CURVATURE ;= .3! IS AN 2.! BINDING PROTEIN REQUIRED BOTH FOR 2.! REPLICATION AND FOR VIRUS PARTICLE ASSEMBLY )T IS COMPOSED OF AN . TERMINAL AMPHIPA THIC ALPHA HELIX SERVING AS A MEMBRANE ANCHOR ; = AND THREE DISTINCT DOMAINS THAT ARE SEPARATED BY TWO TRYPSIN SENSITIVE LOW COMPLEXITY SEQUENCES $OMAIN ) APPEARS TO BE INVOLVED IN 2.! BINDING DOMAIN )) CONTRIBUTES TO 2.! REPLICATION AND PARTICLE ASSEMBLY DOMAIN ))) IS LARGELY DISPENSABLE FOR 2.! REPLICATION AND IS PRIMARILY REQUIRED FOR ASSEMBLY ; = .3! IS EXPRESSED AS A BASALLY PHOSPHORYLATED AND A HYPERPHOSPHORY LATED FORM P AND P RESPECTIVELY 0HOSPHORYLATION IS MEDIATED AT LEAST IN PART BY CASEIN KINASE ) ALPHA ; = )NTERESTINGLY PARTIAL INHIBITION OF .3! HYPERPHOSPHORYLATION ENHANCES 2.! REPLICATION ARGUING THAT REPLI CASE ACTIVITY MAY BE REGULATED BY THE PHOSPHORYLATION STATUS OF .3! ;= 4HE KEY ENZYME RESPONSIBLE FOR 2.! AMPLIFICATION IS THE .3" 2D2P ;= 4HIS VIRAL ENZYME HAS BEEN EXTENSIVELY STUDIED AND SEVERAL HIGH RESO LUTION 8 RAY CRYSTAL STRUCTURES HAVE BEEN DESCRIBED ; = .3" HAS THE CLASSICAL FINGER PALM AND THUMB SUBDOMAINS WITH THE SPECIAL FEATURE THAT
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
THE FINGER AND THUMB SUBDOMAINS HAVE EXTENSIVE INTERACTIONS RESULTING IN A COMPLETELY ENCLOSED ACTIVE SITE 2D2P ACTIVITY SEEMS TO BE MODULATED BY INTERACTION WITH OTHER VIRAL PROTEINS .3 AND .3! AS WELL AS BY CELLULAR FACTORS ESPECIALLY CYCLOPHILINS ;= )T IS ASSUMED THAT THE ANTIVIRAL ACTIVITY OF CYCLOSPORINE IS DUE TO A SEQUESTRATION OF CYCLOPHILIN ;= )N ADDITION TO THE POLYPROTEIN (#6 APPEARS TO ENCODE A SMALL PROTEIN DESIGNATED !2&0 ALTERNATIVE READING FRAME PROTEIN OR & FRAME SHIFT OR CORE THAT IS PRODUCED BY INTERNAL INITIATION OF TRANSLATION OF AN ALTERNATIVE READING FRAME OR BY RIBOSOMAL FRAME SHIFTING WITHIN THE CORE GENE ;= 4HIS PROTEIN IS DISPENSABLE FOR 2.! REPLICATION IN CELL CULTURE AND IN VIVO AND ITS ROLE IN THE VIRAL REPLICATION CYCLE IF ANY IS LARGELY UNKNOWN ; =
!NATOMY OF THE (#6 PARTICLE 4HE BASIC BIOPHYSICAL PROPERTIES OF THE (#6 PARTICLE WERE INITIALLY DEDUCED FROM INFECTIVITY STUDIES IN CHIMPANZEES 4HE RESULTS INDICATED THAT (#6 FORMS ENVELOPED PARTICLES WITH AN AVERAGE DIAMETER OF ABOUT n NM ; = 4HESE PROPERTIES ARE SIMILAR TO THE ONES OBSERVED WITH (#6 PARTICLES PRODUCED IN CELL CULTURE ;= 6ERY RECENTLY A $ RECONSTRUCTION MODEL OF (#6 LIKE PARTICLES PRODUCED IN INSECT CELLS WAS PROPOSED "Y ANALOGY TO THE HIGH RESOLUTION STRUCTURES OF $ENGUE VIRUS AND TICK BORNE ENCEPHALITIS VIRUS ENVELOPE GLYCOPROTEINS (#6 % AND % HETERODIMERS MAY FORM DIMERS THAT ARE ORIENTED PARALLEL TO THE SURFACE OF THE VIRUS PARTICLE ;= (#6 PARTICLES HAVE THE PROPENSITY TO BIND TO DIFFERENT SERUM COMPO NENTS SUCH AS LIPOPROTEINS ;= AND IMMUNOGLOBULINS ;= EXPLAINING THE HETEROGENEITY OF THE PARTICLES IN TERMS OF SIZE DENSITY AND SEDIMENTATION COEFFICIENTS !SSOCIATION OF (#6 PARTICLES WITH IMMUNOGLOBULINS HAS BEEN REPORTED AND THESE COMPLEXES EXHIBIT AN INTERMEDIATE DENSITY OF APPROXI MATELY n GML )N CONTRAST MOST (#6 PARTICLES PRESENT WITHIN SERUM FROM AN IMMUNOGLOBULIN DEFICIENT PATIENT BANDED AT A DENSITY OF LESS THAN GML ;= 4HIS VIRUS COULD BE IMMUNOPRECIPITATED WITH ANTIBOD IES AGAINST APOLIPOPROTEIN " APO" AND APOLIPOPROTEIN % APO% WHICH ARE COMPONENTS OF LOW DENSITY LIPOPROTEIN ,$, AND VERY LOW DENSITY LIPOPROTEIN 6,$, !DDITIONALLY IT HAS BEEN FOUND THAT BLOCKING 6,$, ASSEMBLY REDUCES (#6 PRODUCTION IN CULTURED HEPATOCYTES ;= &INALLY IN PATIENTS (#6 PARTICLES HAVE BEEN DETECTED AS PART OF VERY LARGE LIPOPROTEIN COMPLEXES DESIGNATED LIPO VIROPARTICLES ;= !LL THESE FINDINGS ARE IN LINE WITH THE ASSUMPTION OF A CLOSE ASSOCIATION OF CIRCULATING (#6 PARTICLES WITH ,$,6,$, 4HE ASSUMPTION IS CORROBORATED BY THE DEPENDENCE OF (#6 INFECTION ON ,$, RECEPTOR AND 32 ") WHICH ARE THE RECEPTORS FOR ,$, AND ($, RESPECTIVELY ;n= 4HUS FAR WE DO NOT KNOW HOW AND WHEN VIRUS PARTICLES ASSOCIATE WITH LIPOPROTEIN COMPONENTS (OWEVER SINCE (#6 ASSEMBLY TAKES PLACE IN CLOSE PROXIMITY OF LIPID DROPLETS ; = WHICH SERVE AS A LIPID SOURCE FOR THE
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ASSEMBLY OF 6,$, PARTICLES WE HYPOTHESISE THAT ASSOCIATION OF STRUCTURAL PROTEINS WITH ONE OR SEVERAL COMPONENTS OF THE 6,$, PATHWAY TAKES PLACE DURING ASSEMBLY -OREOVER (#6 MAY EXPLOIT THE 6,$, PATHWAY TO ASSURE PARTICLE SECRETION
(EPATITIS # VIRUS REPLICATION CYCLE 4HE REPLICATION CYCLE STARTS WITH VIRUS BINDING VIA THE ENVELOPE GLYCOPROTEIN %% COMPLEX TO ITS COGNATE RECEPTORS PRESUMABLY IN A CONSECUTIVE MANNER REVIEWED IN ; = &IG 6IRUS PARTICLES MAY BE TRAPPED BY INTERAC TION WITH HEPARAN SULPHATE AND ,$, RECEPTOR FOLLOWED BY BINDING TO 32 ") #URRENT EVIDENCE SUGGESTS THAT THESE INTERACTIONS PRECEDE ENGAGEMENT WITH #$ FOLLOWED BY INTERACTION WITH CLAUDIN ; = (#6 ENTERS BY RECEPTOR MEDIATED ENDOCYTOSIS WHICH REQUIRES PASSAGE THROUGH A LOW P( COMPARTMENT ;= .EVERTHELESS VIRUS PARTICLES ARE RESISTANT TO LOW P( TREATMENT ARGUING THAT DURING INTERACTION WITH ONE OR SEVERAL ENTRY MOL ECULES THE VIRAL GLYCOPROTEINS ACQUIRE A P( SENSITIVE CONFORMATION ;= 5PON LIBERATION OF THE 2.! GENOME INTO THE CYTOPLASM TRANSLATION TAKES PLACE AT THE ROUGH ENDOPLASMIC RETICULUM R%2 WHERE POLYPROTEIN PRO CESSING OCCURS &IG !FTER OR DURING PROTEOLYTIC CLEAVAGE A MEMBRANE ASSOCIATED REPLICATION COMPLEX FORMS DESIGNATED THE MEMBRANOUS WEB WHICH IS THE SITE OF VIRAL 2.! AMPLIFICATION ; = .EWLY SYNTHESISED POSITIVE STRAND 2.!S ARE COPIED FROM NEGATIVE STRAND 2.! INTERMEDIATES AND POSITIVE STRAND 2.! IS EITHER RE USED FOR 2.! TRANSLATION OR SERVES AS TEMPLATE FOR NEGATIVE STRAND 2.! SYNTHESIS OR IS PACKAGED INTO NUCLEOCAP SIDS !SSEMBLY OCCURS IN CLOSE PROXIMITY TO LIPID DROPLETS WHERE CORE PROTEIN ACCUMULATES ; = 4HE VIRAL REPLICASE APPEARS TO BE RECRUITED PRESUM ABLY VIA CORE TO LIPID DROPLETS WHERE THE VIRAL 2.! GENOME MAY BE TRANS FERRED FROM THE REPLICASE TO THE CORE PROTEIN 3INCE LIPID DROPLETS ARE CLOSELY SURROUNDED BY %2 MEMBRANES THAT MAY CONTAIN THE (#6 GLYCOPROTEINS NUCLEOCAPSIDS FORMING IN CLOSE PROXIMITY TO LIPID DROPLETS MAY ACQUIRE THEIR ENVELOPE VIA BUDDING INTO THE %2 LUMEN 4HIS PROCESS MAY BE CONNECTED TO 6,$, ASSEMBLY ;= AND (#6 PARTICLES MAY BE RELEASED EVENTUALLY ASSOCI ATED WITH COMPONENTS OF 6,$,S VIA THE CONSTITUTIVE SECRETORY PATHWAY
%XPERIMENTAL SYSTEMS 4HE PROPAGATION OF (#6 IN CULTURED CELLS AS WELL AS THE DEVELOPMENT OF EFFICIENT ANIMAL MODELS HAS BEEN A CHALLENGING TASK THAT HAS BEEN OVERCOME IN THE PAST FEW YEARS BY THE ESTABLISHMENT OF PRODUCTIVE CELL BASED REPLICA TION SYSTEMS AS WELL AS SMALL ANIMAL SYSTEMS )N THE FOLLOWING WE WILL PROVIDE ONLY A VERY SHORT OVERVIEW ABOUT THE AVAILABLE MODELS THE INTERESTED READER IS REFERRED TO A RECENT REVIEW ;=
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
&IGURE 3CHEMATIC REPRESENTATION OF THE (#6 REPLICATION CYCLE !FTER BINDING TO A PERMISSIVE HOST CELL (#6 ENTERS MOST LIKELY BY RECEPTOR MEDIATED ENDOCYTOSIS 4HE VIRAL 2.! IS LIBERATED INTO THE CYTOPLASM AND TRANSLATION OCCURS AT THE %2 MEMBRANE 4HE POLYPROTEIN IS PROCESSED AND A MEMBRANOUS REPLICATION COMPLEX DESIGNATED THE MEMBRANOUS WEB -7 IS INDUCED WHERE VIRAL 2.! IS AMPLIFIED 0OSITIVE STRAND 2.! PROGENY IS ENCAPSIDATED AND VIRUS PARTICLES MAY BE RELEASED FROM THE CELL BY THE CONSTITUTIVE SECRETORY PATHWAY
!NIMAL MODELS 4HUS FAR THE ONLY ANIMAL THAT CAN BE INFECTED RELIABLY WITH (#6 IS THE CHIMPANZEE 0AN TROGLODYTES ;= )N SPITE OF ETHICAL CONCERNS AND HIGH COSTS CHIMPANZEE EXPERIMENTS HAVE PROVIDED INVALUABLE INFORMATION SUCH AS THE FIRST SUCCESSFUL TRANSMISSION OF THE NON ! NON " HEPATITIS AGENT FROM HUMAN SERUM TO CHIMPANZEES ;n= THE ESTABLISHMENT OF A HIGH TITRED SERUM POOL FROM WHICH THE FIRST (#6 GENOME WAS CLONED ;= OR THE DEM ONSTRATION OF INFECTIVITY OF MOLECULAR (#6 CLONES ; = "ECAUSE THE CLINICAL COURSE OF DISEASE IN CHIMPANZEES AND HUMANS IS SIMILAR STUDIES OF EXPERIMENTALLY INFECTED ANIMALS HAVE ALSO SHED LIGHT ONTO THE ROLE OF THE IMMUNE RESPONSE IN CONTROLLING VIRUS INFECTION ;= #OMPARABLE TO THE HUMAN SITUATION A SIGNIFICANT PROPORTION OF INFECTED ANIMALS IS UNABLE TO CLEAR THE VIRUS AND CONTRACTS A PERSISTENT INFECTION WITH FLUCTUATING VIRUS TITRES AND EVENTUAL SPORADIC OCCURRENCE OF LIVER INFLAMMA TION !LTHOUGH IT IS NOT YET CLEAR HOW THE VIRUS ESCAPES THE IMMUNE RESPONSE AN INCREASING BODY OF EVIDENCE SHOWS THAT A VIGOROUS IMMUNE REACTION CORRELATES POSITIVELY WITH VIRUS ELIMINATION AS WELL AS LIVER CELL DAMAGE 4HE LATTER OBSERVATION IS IN KEEPING WITH THE NOTION THAT CHRONIC HEPATITIS # IS MAINLY SUSTAINED BY THE IMMUNE REACTION
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!TTEMPTS TO ESTABLISH A ROBUST SMALL ANIMAL MODEL THUS FAR ARE OF LIM ITED SUCCESS ; = (OWEVER SOME PROGRESS HAS BEEN MADE OF WHICH THE MOST PROMISING IS BASED ON THE XENOTRANSPLANTATION OF PRIMARY HUMAN HEPATOCYTES INTO IMMUNODEFICIENT 3#)$ TRANSGENIC MICE OVEREXPRESSING THE MURINE UROKINASE TYPE PLASMINOGEN ACTIVATOR U0! IN THE LIVER ;= 5PON ENGRAFTMENT OF HUMAN HEPATOCYTES EARLY AFTER BIRTH THE ANIMALS DEVELOP CHIMERIC LIVERS COMPOSED OF MURINE AND HUMAN HEPATOCYTES 4HESE MICE CAN BE PRODUCTIVELY INFECTED WITH (#6 WITH VIRUS REPLICATION BEING CONFINED TO THE HUMAN HEPATOCYTES
#ELL CULTURE SYSTEMS )N SPITE OF THE AVAILABILITY OF INFECTIOUS MOLECULAR CLONES OF (#6 GENOMES THEY COULD NOT BE PROPAGATED IN CULTURED CELLS ! MAJOR BREAKTHROUGH IN THE DEVELOPMENT OF A ROBUST AND RELIABLE CELL CULTURE SYSTEM HAS THEREFORE BEEN THE REPLICON SYSTEM ;= &IG ! )N THIS SYSTEM THE REGION ENCODING CORE TO .3 WAS REPLACED BY A SELECTABLE MARKER NEOMYCIN RESISTANCE EXPRESSED VIA THE (#6 )2%3 WHEREAS THE (#6 NONSTRUCTURAL GENES WERE EXPRESSED VIA A HETEROLOGOUS )2%3 5PON TRANSFECTION OF THE HUMAN HEPATOMA CELL LINE (UH A LOW NUMBER OF NEOMYCIN RESISTANT COLONIES WAS OBTAINED THAT CARRIED HIGH AMOUNTS OF AUTONOMOUSLY REPLICATING (#6 2.! (IGH LEVEL REPLICATION WAS DUE TO THE SELECTION FOR BOTH MORE PERMISSIVE (UH CELLS AND REPLICATION ENHANCING MUTATIONS CELL CULTURE ADAPTIVE MUTATIONS ;= /WING TO ITS UNPRECEDENTED LEVEL OF (#6 2.! REPLICATION AND ANTIGEN EXPRESSION THE REPLICON SYSTEM BECAME A VERY IMPORTANT TOOL TO STUDY THE INTRACELLULAR STEPS OF THE VIRAL REPLICATION CYCLE AND PROVIDED THE FIRST FUNC TIONAL CELL BASED PLATFORM FOR SCREENING OF ANTIVIRAL AGENTS THAT TARGET THE 2.! REPLICATION PROCESS (OWEVER THIS SYSTEM DID NOT SUPPORT THE PRODUC TION OF INFECTIOUS VIRUS PARTICLES ;n= WHICH IS DUE TO THE ADAPTIVE MUTA TIONS THAT INTERFERE WITH VIRUS PARTICLE ASSEMBLY AND INFECTIVITY IN VIVO ;= 4HE FIRST SYSTEM ALLOWING STUDIES OF THE (#6 INFECTION PROCESS WAS BASED ON (#6 PSEUDOPARTICLES (#6PP ; = 4HESE PARTICLES ARE COMPOSED OF RETROVIRAL NUCLEOCAPSIDS SURROUNDED BY AN ENVELOPE LIPID BILAYER INTO WHICH AUTHENTIC AND ENTRY COMPETENT % % GLYCOPROTEIN COMPLEXES ARE EMBEDDED &IG " 3INCE THE EARLY STEPS OF INFECTION ARE ORCHESTRATED BY THE ENVELOPE PROTEINS (#6PPS ARE A VERY VALUABLE SURROGATE SYSTEM TO STUDY (#6 INFECTION AND NEUTRALISATION 0RODUCTION OF INFECTIOUS (#6 PARTICLES IN CELL CULTURE ONLY BECAME POSSIBLE WITH THE AVAILABILITY OF A MOLECULAR CLONE CAPABLE OF HIGH LEVEL REPLICATION IN CULTURED CELLS WITHOUT REQUIREMENT FOR CELL CULTURE ADAPTIVE MUTATIONS 4HIS CLONE WAS ISOLATED FROM A *APANESE PATIENT WITH FULMINANT HEPATITIS HENCE THE ACRONYM *&( ;= 3UBGENOMIC *&( REPLICONS ARE SEVERAL ORDERS OF MAGNITUDE MORE EFFICIENT THAN REPLICONS DERIVED FROM OTHER (#6 MOLECULAR CLONES ; = -OST IMPORTANTLY TRANSFECTION OF
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
&IGURE %XPERIMENTAL MODELS TO STUDY (#6 REPLICATION IN CELL CULTURE ! 3TRUCTURE OF A SUBGENOMIC (#6 REPLICON COMPOSED OF THE .42 THICK LINE THE GENE ENCODING THE NEO MYCIN PHOSPHOTRANSFERASE NEO THE )2%3 FROM THE ENCEPHALOMYOCARDITIS VIRUS %-#6 THE (#6 REPLICASE GENES AND THE .42 " !RCHITECTURE OF A (#6PP )T IS COMPOSED OF A LIPID ENVELOPE CONTAINING AUTHENTIC (#6 GLYCOPROTEIN COMPLEXES AND THE CAPSID #! OF ()6 CONTAINING A RETROVIRAL VECTOR 2.! WITH AN INTEGRATED REPORTER GENE MOST OFTEN EITHER THE GFP OR THE LUCIFERASE GENE # 3CHEMATIC REPRESENTATION OF THE (#6CC CELL CULTURE SYSTEM )N VITRO TRANSCRIPTS OF THE *&( GENOME GENERATED BY USING 4 2.! POLYMERASE ARE TRANSFECTED INTO (UH CELLS BY ELECTROPORATION 3UPERNATANTS 3UP HARVESTED FROM THE TRANFECTED CELLS ARE USED FOR INFECTION OF NAÕVE (UH CELLS )NFECTED CELLS ARE DETECTED BY (#6 ANTIGEN SPECIFIC IMMUNOFLUORESCENCE )&
THE FULL LENGTH *&( GENOME INTO (UH CELLS LEADS TO THE PRODUCTION OF (#6 PARTICLES THAT ARE INFECTIOUS FOR NAIVE (UH CELLS ; = FOR CHIM PANZEES ;= AND FOR 3#)$U0! MICE WITH HUMAN LIVER XENOGRAFTS ;= &IG # 6IRUS TITRES ATTAINED WITH *&( ARE RATHER LOW IN THE RANGE OF TO TISSUE CULTURE INFECTIVITY DOSE 4#)$ PER ML ;= BUT THE SYSTEM WAS IMPROVED DRAMATICALLY IN SEVERAL WAYS &IRST BY THE IDENTIFICATION OF HIGHLY
2ALF "ARTENSCHLAGER ET AL
PERMISSIVE (UH CELL CLONES ;= SECOND BY THE CONSTRUCTION OF CHIMERIC *&( GENOMES ; = THIRD BY CELL CULTURE ADAPTATION OF *&( AND *&( CHIMERAS OR THE DEVELOPMENT OF A GENOTYPE A ISOLATE THAT SUPPORTS VIRUS PRODUCTION ALTHOUGH VIRUS TITRES ATTAINED WITH THIS ISOLATE ARE STILL VERY LOW ;n= !DDITIONAL IMPROVEMENTS ARE THE CONSTRUCTION OF REPLICATION COMPETENT REPORTER VIRUS GENOMES CARRYING EG THE LUCIFERASE GENE OR A GENE ENCODING A FLUORESCENT REPORTER 4HE LATTER IS APPLICABLE TO STUDY VIRUS INFECTION IN LIVE CELLS AS WELL AS INTERACTIONS BETWEEN VIRUS GENOMES
(#6 AND THE IMMUNE SYSTEM ! KEY PLAYER THAT BLOCKS THE INDUCTION OF THE EARLY INNATE ANTIVIRAL DEFENCE APPEARS TO BE THE .3 ! PROTEASE THAT CAN INTERFERE WITH THE DS2.! INDUCED ACTIVATION OF )&. REGULATORY FACTOR )2& ;= 7ITHIN A CELL DS2.! IS RECOGNISED BY SEVERAL MOLECULES INCLUDING 4OLL LIKE RECEPTOR 4,2 THE 2.! HELICASES RETINOIC ACID INDUCIBLE GENE ) 2)' ) AND MDA ALSO CALLED (ELICARD ;= 5PON ACTIVATION BY DS2.! BINDING THESE MOLECULES RECRUIT ADAPTOR PROTEINS WHICH ARE 42)& ALSO CALLED 4)#!- IN CASE OF 4,2 AND #ARDIF ALSO CALLED )03 -!63 OR 6)3! IN CASE OF 2)' ) 4HESE ADAPTORS TRIGGER A SIGNALLING CASCADE RESULTING IN THE TRANSCRIP TIONAL ACTIVATION OF )&. ` )T WAS SHOWN THAT BOTH 42)& AND #ARDIF CAN BE CLEAVED BY THE .3 ! PROTEASE ;n= 4HE BLOCK OF THIS PATHWAY MAY CONTRIBUTE TO THE ESTABLISHMENT OF A PERSISTENT (#6 INFECTION )N ADDITION SEVERAL STUDIES SUGGEST THAT (#6 PROTEINS INTERFERE WITH ONE OR SEVERAL STEPS OF THE EFFECTOR PHASE OF THE )&. SYSTEM EG BY BLOCKING *AK3TAT SIGNALLING OR INHIBITION OF INDIVIDUAL EFFECTOR PROTEINS SUCH AS 0+2 ;= (OWEVER IT REMAINS TO BE DETERMINED WHETHER THESE OBSERVATIONS MOST OFTEN MADE IN ARTIFICIAL IN VITRO OR CELL BASED SYSTEMS ALSO OPERATE IN VIVO 4HE ADAPTIVE IMMUNITY ALSO APPEARS TO BE UNDERMINED BY (#6 WITHOUT GLOBALLY AFFECTING IMMUNE RESPONSE TO OTHER INFECTIOUS AGENTS )T IS GENERALLY ACCEPTED THAT THE VIGOUR AND THE BREADTH OF THE IMMUNE RESPONSE MOUNTED UPON (#6 INFECTION DETERMINE THE OUTCOME OF INFECTION ;= 4HEREFORE A SUCCESSFUL IMMUNE RESPONSE TARGETS MULTIPLE -(# #LASS ) RESTRICTED EPITOPES IN THE (#6 POLYPROTEIN AND INDUCES RATHER LARGE NUMBERS OF (#6 SPECIFIC #$ 4 CELLS )N ADDITION A STRONG #$ 4 CELL RESPONSE IS USUALLY ACCOMPANIED BY A STRONG AND MULTI SPECIFIC #$ 4 CELL PROLIFERA TIVE RESPONSE AND PERMANENT LOSS OF THIS RESPONSE IS A STRONG PREDICTOR FOR PERSISTENCE 2ESOLVED INFECTIONS USUALLY LEAVE A DURABLE MEMORY RESPONSE LOWERING THE CHANCE OF PERSISTENCE UPON RE INFECTION 4HE REASON WHY THE STRONG INITIAL 4 CELL RESPONSE IS BLUNTED AT LATER STAGES OF (#6 INFECTION IS NOT UNDERSTOOD /NE POSSIBILITY HOWEVER IS THAT THE INTERFERENCE OF (#6 WITH THE INNATE IMMUNE RESPONSE RESULTS IN #$ 4 CELL IMPAIRMENT EG DUE TO THE LACK OF IMPORTANT CYTOKINES REQUIRED FOR 4 CELL ACTIVATION 3INCE
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
4 CELL HELP IS IMPORTANT FOR #$ 4 CELLS THE DEGREE OF HELPER CELL IMPAIR MENT WOULD BE A CRITICAL DETERMINANT OF VIRUS ELIMINATION OR PERSISTENCE 4HE EXTENT TO WHICH " CELL RESPONSES CONTRIBUTE TO VIRAL CLEARANCE THUS FAR IS NOT KNOWN )T IS GENERALLY ASSUMED THAT 4 CELL IMMUNITY IS THE PRIMARY DETERMI NANT IN CONTROLLING (#6 INFECTION
$IAGNOSIS OF (#6 INFECTION $IAGNOSIS OF HEPATITIS # IS BASED ON SEROLOGICAL ASSAYS WHICH DETECT (#6 SPECIFIC ANTIBODIES ANTI (#6 AND ON MOLECULAR ASSAYS WHICH DETECT (#6 2.! ;= #URRENT ENZYME IMMUNOASSAYS %)!S ARE HIGHLY SENSITIVE AS WELL AS SPECIFIC AND REPRESENT THE PRIMARY DIAGNOSTIC TOOL (#6 2.! DETEC TION BY REAL TIME 24 0#2 IS NOW STANDARDISED RELIABLE AND REPRODUCIBLE AND OFFERS A BROAD DYNAMIC QUANTITATION RANGE (#6 BECOMES POSITIVE BY 24 0#2 AS EARLY AS n WEEKS AFTER INFECTION AND n WEEKS BEFORE ANTI (#6 SEROCONVERSION (#6 2.! TESTING IS USED TO CONFIRM ACTIVE INFECTION IN ANTI (#6 POSITIVE INDIVIDUALS AND TO DIAGNOSE ACUTE HEPATITIS # OR CHRON IC HEPATITIS # IN THE RARE IMMUNOCOMPROMISED PATIENTS THAT DO NOT DEVELOP ANTI (#6 ANTIBODIES (OWEVER THE PRINCIPAL ROLE OF (#6 2.! TESTING IS IN THE TAILORING AND MONITORING OF ANTIVIRAL THERAPY $ETERMINATION OF (#6 GENOTYPE IS IMPORTANT FOR THE SELECTION OF THE OPTIMAL ANTIVIRAL REGIMEN ,IVER BIOPSY ALLOWS DETERMINING THE NECRO INFLAMMATORY ACTIVITY GRAD ING AND THE DEGREE OF FIBROSIS STAGING AS WELL AS TO RECOGNISE OR EXCLUDE COEXISTING LIVER PATHOLOGY SUCH AS ALCOHOLIC LIVER DISEASE IRON OVERLOAD OR .!&,$ ,IVER BIOPSY IS STRONGLY RECOMMENDED BEFORE THE INITIATION OF ANTIVIRAL THERAPY ! NUMBER OF NON INVASIVE TESTS ARE CURRENTLY BEING EXPLORED TO PREDICT LIVER FIBROSIS ; = 4HESE ARE BASED ON DIFFERENT COMBINATIONS OF BLOOD TESTS TRANSIENT ELASTOGRAPHY &IBRO3CAN ;= OR MAGNETIC RESONANCE IMAGING ;= 7HILE PROMISING CURRENT PREDICTION METHODS REMAIN LIMITED WITH RESPECT TO THE DIFFERENTIATION OF INTERMEDIATE FIBROSIS STAGES AND THUS MAY REPLACE LIVER BIOPSY ONLY IN SELECTED PATIENTS
#URRENT AND FUTURE THERAPY #URRENT STANDARD THERAPY CONSISTS OF PEGYLATED INTERFERON _ 0%' )&. _ ADMINISTERED ONCE WEEKLY BY SUBCUTANEOUS INJECTION COMBINED WITH RIBAVIRIN WHICH IS TAKEN ORALLY ON A DAILY BASIS ;= "OTH DRUGS OPERATE THROUGH INCOMPLETELY UNDERSTOOD LIKELY DIRECT ANTIVIRAL AND IMMUNO MODULATORY MECHANISMS ;= 3TANDARD TREATMENT DURATION IS WEEKS FOR GENOTYPE AND WEEKS FOR GENOTYPES AND #URRENT EFFORTS ARE AIMED AT TAILORING DOSES AND TREATMENT DURATION TO THE INDIVIDUAL PATIENT BASED ON BASELINE PARAMETERS EG GENOTYPE VIREMIA FIBROSIS STAGE DEGREE OF
2ALF "ARTENSCHLAGER ET AL
STEATOSIS AND ON TREATMENT VIRAL KINETICS VIREMIA AT AND WEEKS ;n= (ENCE THERAPY MAY BE ABBREVIATED IN SELECTED PATIENTS WITH FAVOURABLE BASELINE PARAMETERS AND A RAPID VIROLOGIC RESPONSE IE NEGA TIVE (#6 2.! AFTER WEEKS OF TREATMENT WHILE OTHERS MAY BENEFIT FROM PROLONGED TREATMENT )N GENERAL TREATMENT IS CURRENTLY RECOMMENDED FOR PATIENTS WITH CHRONIC HEPATITIS # IE PERSISTENTLY ; MONTHS= ELEVATED AMINOTRANSFERASE LEVELS AND ANTI (#6 AS WELL AS 2.! POSITIVITY IN SERUM AND FINDINGS OF FIBROSIS AND AT LEAST MODERATE DEGREES OF INFLAMMATION AND NECROSIS ON LIVER BIOPSY &OR OTHER PATIENTS DECISIONS WILL HAVE TO BE MADE ON AN INDIVIDUAL BASIS &ACTORS ASSOCIATED WITH A FAVOURABLE TREATMENT RESPONSE ARE INFECTION WITH GENOTYPES OR LOW BASELINE VIREMIA AND LOW FIBROSIS STAGE &OR UNKNOWN REASONS !FRICAN !MERICANS RESPOND POORLY TO CURRENT TREATMENT ; = )N ADDITION OVERWEIGHT HAS BEEN ASSOCIATED WITH POOR TREAT MENT OUTCOMES ;= .OVEL AND VERY PROMISING GENOMIC AND PROTEOMIC APPROACHES ARE AIMED AT PREDICTING TREATMENT OUTCOMES ON AN INDIVIDUAL BASIS ; = #ONTRAINDICATIONS TO THERAPY WITH 0%' )&. _ AND RIBAVIRIN INCLUDE DECOMPENSATED LIVER CIRRHOSIS AUTOIMMUNE DISEASES UNCONTROLLED DEPRES SION OR PSYCHOSIS PREGNANCY THE LACK OF A RELIABLE METHOD OF CONTRACEPTION TERATOGENICITY OF RIBAVIRIN CARDIOPULMONARY DISEASES SEVERE LEUKO OR THROMBOCYTOPENIA AND CONDITIONS THAT IMPAIR COMPLIANCE WITH THERAPY 2IBAVIRIN IS IN PRINCIPLE CONTRAINDICATED IN PATIENTS WITH CREATININE CLEAR ANCE MLMIN AND SHOULD BE USED ONLY WITH VERY CLOSE MONITORING UNDER THESE CIRCUMSTANCES !DVERSE EFFECTS OF 0%' )&. _ INCLUDE AMONG OTHERS FLU LIKE SYMPTOMS FATIGUE LEUKO AND THROMBOCYTOPENIA WEIGHT LOSS IRRITABILITY OR DEPRESSION THYROID DYSFUNCTION HAIR LOSS RASH SEIZURES AND SLEEP DISTURBANCES 4HE MOST FREQUENT ADVERSE EFFECT OF RIBAVIRIN IS HAEMOLYTIC ANAEMIA 0ATIENTS WHO BECOME (#6 2.! NEGATIVE DURING THERAPY AND REMAIN SO FOR MORE THAN MONTHS AFTER THE END OF TREATMENT HAVE A SUSTAINED VIROLOGIC RESPONSE 362 AND USUALLY REMAIN NEGATIVE 0ATIENTS WHO ARE (#6 2.! NEGATIVE AT THE END OF TREATMENT BUT BECOME POSITIVE AGAIN AT MONTHS OF FOLLOW UP ARE CLASSIFIED AS RELAPSERS AND PATIENTS WHO DO NOT RESPOND TO TREATMENT AT ALL AS NONRESPONDERS 'ENOTYPE INFECTED PATIENTS WHO DO NOT EXPERIENCE A * LOG REDUCTION OF VIREMIA AT WEEKS EARLY VIROLOGIC RESPONSE WILL FAIL TO ACHIEVE AN 362 ; = 4REATMENT SHOULD BE DISCONTINUED IN THESE PATIENTS 7ITH THE ABOVE TREATMENT n OF GENOTYPE AND ABOUT OF GENOTYPE AND INFECTED PATIENTS ACHIEVE AN 362 ;n= /VERALL ABOUT OF PATIENTS WITH CHRONIC HEPATITIS # CAN BE CURED WITH THE CUR RENT TREATMENT &OR THESE PATIENTS ONGOING EFFORTS ARE AIMED AT TAILORING TREATMENT TO THE INDIVIDUAL NEEDS IN ORDER TO IMPROVE TOLERABILITY &OR THE OTHER PATIENTS AND FOR THE IMPORTANT PROPORTION OF PATIENTS WHO CANNOT TOL ERATE CURRENT TREATMENT NEW THERAPEUTIC STRATEGIES NEED TO BE DEVELOPED
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
)N PRINCIPLE EACH STEP OF THE (#6 LIFE CYCLE REPRESENTS A TARGET FOR ANTIVIRAL INTERVENTION ;= 3PECIFIC INHIBITORS OF THE BIOCHEMICALLY AND STRUCTURALLY WELL CHARACTERISED .3 ! SERINE PROTEASE AND .3" 2D2P ARE CURRENTLY BEING DEVELOPED AS ANTIVIRAL AGENTS AND THE FIRST CANDIDATES HAVE ALREADY BEEN EVALUATED IN CLINICAL TRIALS ; = 3ERINE PROTEASE INHIBITORS SEEM PARTICULARLY PROMISING AS THEY NOT ONLY BLOCK VIRAL POLY PROTEIN PROCESSING BUT MAY ALSO REVERSE THE INHIBITION OF INNATE IMMUNE SENSING BY (#6 )N ADDITION DRUGS AFFECTING HOST FACTORS INVOLVED IN (#6 REPLICATION ARE BEING EXPLORED AS ANTIVIRAL AGENTS 4HE GENETIC VARIABILITY OF (#6 ALLOWING THE RAPID DEVELOPMENT OF ANTIVIRAL RESISTANCE REPRESENTS A MAJOR CHALLENGE TO THE CLINICAL DEVELOPMENT OF SPECIFIC INHIBITORS 4HEREFORE COMBINATION THERAPY WILL BE NECESSARY FOR THERAPEUTIC SUCCESS ;= 7ITH THE INCREASING NUMBER OF NEW COMPOUNDS TARGETING DIFFERENT STEPS OF THE (#6 REPLICATION CYCLE WE CAN EXPECT THAT THE NUMBER OF PATIENTS THAT CAN BE CURED WILL INCREASE FURTHER
!CKNOWLEDGEMENTS 7ORK IN THE AUTHORS LABORATORIES WAS SUPPORTED BY GRANTS FROM THE -INISTRY OF 3CIENCE 2ESEARCH AND THE !RTS OF "ADEN 7àRTTEMBERG !Z THE 3ONDERFORSCHUNGSBEREICH 4EILPROJEKT ! THE $EUTSCHE &ORSCHUNGSGEMEINSCHAFT "A THE #ELL.ETWORKS #LUSTER OF %XCELLENCE (EIDELBERG THE 3WISS .ATIONAL 3CIENCE &OUNDATION ! THE 3WISS #ANCER ,EAGUE/NCOSUISSE /#3 AND THE ,EENAARDS &OUNDATION
2EFERENCES
$AVIS ', !LBRIGHT *% #OOK 3& 2OSENBERG $- 0ROJECTING FUTURE COM PLICATIONS OF CHRONIC HEPATITIS # IN THE 5NITED 3TATES ,IVER 4RANSPL n 7ILLIAMS 2 'LOBAL CHALLENGES IN LIVER DISEASE (EPATOLOGY n 3HEPARD #7 &INELLI , !LTER -* 'LOBAL EPIDEMIOLOGY OF HEPATITIS # VIRUS INFECTION ,ANCET )NFECT $IS n 3TRAMER 3, 'LYNN 3! +LEINMAN 3( 3TRONG $- #AGLIOTI 3 7RIGHT $* $ODD 29 "USCH -0 $ETECTION OF ()6 AND (#6 INFECTIONS AMONG ANTIBODY NEGATIVE BLOOD DONORS BY NUCLEIC ACID AMPLIFICATION TESTING . %NGL * -ED n &RANK # -OHAMED -+ 3TRICKLAND '4 ,AVANCHY $ !RTHUR 22 -AGDER ,3 %L +HOBY 4 !BDEL 7AHAB 9 !LY /HN %3 !NWAR 7 4HE ROLE OF PAR ENTERAL ANTISCHISTOSOMAL THERAPY IN THE SPREAD OF HEPATITIS # VIRUS IN %GYPT ,ANCET n 0RATI $ 4RANSMISSION OF HEPATITIS # VIRUS BY BLOOD TRANSFUSIONS AND OTHER MEDICAL PROCEDURES A GLOBAL REVIEW * (EPATOL n 2OSS 23 6IAZOV 3 'ROSS 4 (OFMANN & 3EIPP (- 2OGGENDORF -
2ALF "ARTENSCHLAGER ET AL
4RANSMISSION OF HEPATITIS # VIRUS FROM A PATIENT TO AN ANESTHESIOLOGY ASSISTANT TO FIVE PATIENTS . %NGL * -ED n &ORNS 8 -ARTINEZ "AUER % &ELIU ! 'ARCIA 2ETORTILLO - -ARTIN - 'AY % .AVASA - 3ANCHEZ 4APIAS *- "RUGUERA - 2ODES * .OSOCOMIAL TRANSMISSION OF (#6 IN THE LIVER UNIT OF A TERTIARY CARE CENTER (EPATOLOGY n -ACEDO D/ 7HITE +, ,ESCHINSKY $0 "EECHAM "$ 6OGT 4- -OOLENAAR 2, 0ERZ *& 3AFRANEK 4* !N OUTBREAK OF HEPATITIS # VIRUS INFECTIONS AMONG OUTPATIENTS AT A HEMATOLOGYONCOLOGY CLINIC !NN )NTERN -ED n #ONRY ## 6AN2ADEN - 'IBBLE * -ELPOLDER * 3HAKIL !/ 6ILADOMIU , #HEUNG , $I"ISCEGLIE ! (OOFNAGLE * 3HIH *7 2OUTES OF INFECTION VIREMIA AND LIVER DISEASE IN BLOOD DONORS FOUND TO HAVE HEPATITIS # VIRUS INFEC TION . %NGL * -ED n -AST %% (WANG ,9 3ETO $3 .OLTE &3 .AINAN /6 7URTZEL ( !LTER -* 2ISK FACTORS FOR PERINATAL TRANSMISSION OF HEPATITIS # VIRUS (#6 AND THE NATURAL HISTORY OF (#6 INFECTION ACQUIRED IN INFANCY * )NFECT $IS n (OOFNAGLE *( #OURSE AND OUTCOME OF HEPATITIS # (EPATOLOGY 3n3 !LTER (* (#6 NATURAL HISTORY THE RETROSPECTIVE AND PROSPECTIVE IN PERSPECTIVE * (EPATOL n 3EEFF ," .ATURAL HISTORY OF CHRONIC HEPATITIS # (EPATOLOGY 3n 3 3EEFF ," -ILLER 2. 2ABKIN #3 "USKELL "ALES : 3TRALEY %ASON +$ 3MOAK ", *OHNSON ,$ ,EE 32 +APLAN %, YEAR FOLLOW UP OF HEPATITIS # VIRUS INFECTION IN HEALTHY YOUNG ADULTS !NN )NTERN -ED n 4ONG -* EL &ARRA .3 2EIKES !2 #O 2, #LINICAL OUTCOMES AFTER TRANS FUSION ASSOCIATED HEPATITIS # . %NGL * -ED n +ENNY 7ALSH % #LINICAL OUTCOMES AFTER HEPATITIS # INFECTION FROM CON TAMINATED ANTI $ IMMUNE GLOBULIN )RISH (EPATOLOGY 2ESEARCH 'ROUP . %NGL * -ED n 7IESE - 'RUNGREIFF + 'UTHOFF 7 ,AFRENZ - /ESEN 5 0ORST ( /UTCOME IN A HEPATITIS # GENOTYPE B SINGLE SOURCE OUTBREAK IN 'ERMANYnA YEAR MULTICENTER STUDY * (EPATOL n &ERENCI 0 &ERENCI 3 $ATZ # 2EZMAN ) /BERAIGNER 7 3TRAUSS 2 -ORBIDITY AND MORTALITY IN PAID !USTRIAN PLASMA DONORS INFECTED WITH HEPATITIS # AT PLASMA DONATION IN THE S * (EPATOL n %L 3ERAG (" (EPATOCELLULAR CARCINOMA AND HEPATITIS # IN THE 5NITED 3TATES (EPATOLOGY 3n3 -ORADPOUR $ "LUM (% 0ATHOGENESIS OF HEPATOCELLULAR CARCINOMA %UR * 'ASTROENTEROL (EPATOL n VAN 2EGENMORTEL -(6 &AUQUET #- "ISHOP $(, #ARSTENS %" %STES -+ ,EMON 3- -ANILOFF * -AYO -! -C'EOCH $* 0RINGLE #2 6IRUS 4AXONOMY 4HE 6))TH 2EPORT OF THE )NTERNATIONAL #OMMITTEE ON 4AXONOMY OF 6IRUSES !CADEMIC 0RESS 3AN $IEGO 0AWLOTSKY *- (EPATITIS # VIRUS GENETIC VARIABILITY PATHOGENIC AND CLINI CAL IMPLICATIONS #LIN ,IVER $IS n
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
2OBERTSON " -YERS ' (OWARD # "RETTIN 4 "UKH * 'ASCHEN " 'OJOBORI 4 -AERTENS ' -IZOKAMI - .AINAN / #LASSIFICATION NOMENCLATURE AND DATABASE DEVELOPMENT FOR HEPATITIS # VIRUS (#6 AND RELATED VIRUSES PRO POSALS FOR STANDARDIZATION )NTERNATIONAL #OMMITTEE ON 6IRUS 4AXONOMY !RCH 6IROL n 3IMMONDS 0 (OLMES %# #HA 4! #HAN 37 -C/MISH & )RVINE " "EALL % 9AP 0, +OLBERG * 5RDEA -3 #LASSIFICATION OF HEPATITIS # VIRUS INTO SIX MAJOR GENOTYPES AND A SERIES OF SUBTYPES BY PHYLOGENETIC ANALYSIS OF THE .3 REGION * 'EN 6IROL n ,OHMANN 6 2OOS ! +ORNER & +OCH */ "ARTENSCHLAGER 2 "IOCHEMICAL AND STRUCTURAL ANALYSIS OF THE .3" 2.! DEPENDENT 2.! POLYMERASE OF THE HEPATITIS # VIRUS * 6IRAL (EPAT n 9OU 3 3TUMP $$ "RANCH !$ 2ICE #- ! CIS ACTING REPLICATION ELE MENT IN THE SEQUENCE ENCODING THE .3" 2.! DEPENDENT 2.! POLYMERASE IS REQUIRED FOR HEPATITIS # VIRUS 2.! REPLICATION * 6IROL n &RIEBE 0 "OUDET * 3IMORRE *0 "ARTENSCHLAGER 2 +ISSING LOOP INTERAC TION IN THE END OF THE HEPATITIS # VIRUS GENOME ESSENTIAL FOR 2.! REPLICATION * 6IROL n "ARTENSCHLAGER 2 &RESE - 0IETSCHMANN 4 .OVEL INSIGHTS INTO HEPATITIS # VIRUS REPLICATION AND PERSISTENCE !DV 6IRUS 2ES n 0ENIN & 3TRUCTURAL BIOLOGY OF HEPATITIS # VIRUS #LIN ,IVER $IS n VII !PPEL . 3CHALLER 4 0ENIN & "ARTENSCHLAGER 2 &ROM STRUCTURE TO FUNC TION NEW INSIGHTS INTO HEPATITIS # VIRUS 2.! REPLICATION * "IOL #HEM n 4ELLINGHUISEN 4, %VANS -* VON (AHN 4 9OU 3 2ICE #- 3TUDYING HEPATITIS # VIRUS MAKING THE BEST OF A BAD VIRUS * 6IROL n 3ANTOLINI % -IGLIACCIO ' ,A -. "IOSYNTHESIS AND BIOCHEMICAL PROPER TIES OF THE HEPATITIS # VIRUS CORE PROTEIN * 6IROL n -C,AUCHLAN * ,EMBERG -+ (OPE ' -ARTOGLIO " )NTRAMEMBRANE PRO TEOLYSIS PROMOTES TRAFFICKING OF HEPATITIS # VIRUS CORE PROTEIN TO LIPID DROPLETS %-"/ * n +LEIN +# $ELLOS 32 ,INGAPPA *2 )DENTIFICATION OF RESIDUES IN THE HEPATITIS # VIRUS CORE PROTEIN THAT ARE CRITICAL FOR CAPSID ASSEMBLY IN A CELL FREE SYSTEM * 6IROL n +LEIN +# 0OLYAK 3* ,INGAPPA *2 5NIQUE FEATURES OF HEPATITIS # VIRUS CAPSID FORMATION REVEALED BY DE NOVO CELL FREE ASSEMBLY * 6IROL n "OULANT 3 4ARGETT !DAMS 0 -C,AUCHLAN * $ISRUPTING THE ASSOCIATION OF HEPATITIS # VIRUS CORE PROTEIN WITH LIPID DROPLETS CORRELATES WITH A LOSS IN PRODUCTION OF INFECTIOUS VIRUS * 'EN 6IROL n -IYANARI 9 !TSUZAWA + 5SUDA . 7ATASHI + (ISHIKI 4 :AYAS - "ARTENSCHLAGER 2 7AKITA 4 (IJIKATA - 3HIMOTOHNO + 4HE LIPID DROPLET IS AN IMPORTANT ORGANELLE FOR HEPATITIS # VIRUS PRODUCTION .AT #ELL "IOL n 'OFFARD ! $UBUISSON * 'LYCOSYLATION OF HEPATITIS # VIRUS ENVELOPE PROTEINS "IOCHIMIE n $ELEERSNYDER 6 0ILLEZ ! 7YCHOWSKI # "LIGHT + 8U * (AHN 93 2ICE #-
2ALF "ARTENSCHLAGER ET AL
$UBUISSON * &ORMATION OF NATIVE HEPATITIS # VIRUS GLYCOPROTEIN COM PLEXES * 6IROL n 'OFFARD ! #ALLENS . "ARTOSCH " 7YCHOWSKI # #OSSET &, -ONTPELLIER # $UBUISSON * 2OLE OF . LINKED GLYCANS IN THE FUNCTIONS OF HEPATITIS # VIRUS ENVELOPE GLYCOPROTEINS * 6IROL n 7EINER !* "RAUER -* 2OSENBLATT * 2ICHMAN +( 4UNG * #RAWFORD + "ONINO & 3ARACCO ' #HOO 1, (OUGHTON - 6ARIABLE AND HYPERVARIABLE DOMAINS ARE FOUND IN THE REGIONS OF (#6 CORRESPONDING TO THE FLAVIVIRUS ENVE LOPE AND .3 PROTEINS AND THE PESTIVIRUS ENVELOPE GLYCOPROTEINS 6IROLOGY n 0ENIN & #OMBET # 'ERMANIDIS ' &RAINAIS 0/ $ELEAGE ' 0AWLOTSKY *- #ONSERVATION OF THE CONFORMATION AND POSITIVE CHARGES OF HEPATITIS # VIRUS % ENVELOPE GLYCOPROTEIN HYPERVARIABLE REGION POINTS TO A ROLE IN CELL ATTACHMENT * 6IROL n #ALLENS . #ICZORA 9 "ARTOSCH " 6U $AC . #OSSET &, 0AWLOTSKY *- 0ENIN & $UBUISSON * "ASIC RESIDUES IN HYPERVARIABLE REGION OF HEPATITIS # VIRUS ENVELOPE GLYCOPROTEIN E CONTRIBUTE TO VIRUS ENTRY * 6IROL n 4ROESCH - -EUNIER ) ,APIERRE 0 ,APOINTE . !LVAREZ & "OUCHER - 3OUDEYNS ( 3TUDY OF A NOVEL HYPERVARIABLE REGION IN HEPATITIS # VIRUS (#6 % ENVELOPE GLYCOPROTEIN 6IROLOGY n 3TEINMANN % 7HITFIELD 4 +ALLIS 3 $WEK 2! :ITZMANN . 0IETSCHMANN 4 "ARTENSCHLAGER 2 !NTIVIRAL EFFECTS OF AMANTADINE AND IMINOSUGAR DERIVATIVES AGAINST HEPATITIS # VIRUS (EPATOLOGY n #ARRERE +REMER 3 -ONTPELLIER 0ALA # #OCQUEREL , 7YCHOWSKI # 0ENIN & $UBUISSON * 3UBCELLULAR LOCALIZATION AND TOPOLOGY OF THE P POLYPEPTIDE OF HEPATITIS # VIRUS * 6IROL n 'RIFFIN 3 #LARKE $ -C#ORMICK # 2OWLANDS $ (ARRIS - 3IGNAL PEPTIDE CLEAVAGE AND INTERNAL TARGETING SIGNALS DIRECT THE HEPATITIS # VIRUS P PROTEIN TO DISTINCT INTRACELLULAR MEMBRANES * 6IROL n 'RIFFIN 3$ (ARVEY 2 #LARKE $3 "ARCLAY 73 (ARRIS - 2OWLANDS $* ! CONSERVED BASIC LOOP IN HEPATITIS # VIRUS P PROTEIN IS REQUIRED FOR AMANTA DINE SENSITIVE ION CHANNEL ACTIVITY IN MAMMALIAN CELLS BUT IS DISPENSABLE FOR LOCALIZATION TO MITOCHONDRIA * 'EN 6IROL n 'RIFFIN 3$ "EALES ,0 #LARKE $3 7ORSFOLD / %VANS 3$ *AEGER * (ARRIS -0 2OWLANDS $* 4HE P PROTEIN OF HEPATITIS # VIRUS FORMS AN ION CHANNEL THAT IS BLOCKED BY THE ANTIVIRAL DRUG !MANTADINE &%"3 ,ETT n 3AKAI ! #LAIRE -3 &AULK + 'OVINDARAJAN 3 %MERSON 35 0URCELL 2( "UKH * 4HE P POLYPEPTIDE OF HEPATITIS # VIRUS IS CRITICAL FOR INFECTIVITY AND CONTAINS FUNCTIONALLY IMPORTANT GENOTYPE SPECIFIC SEQUENCES 0ROC .ATL !CAD 3CI 53! n ,OHMANN 6 +ÚRNER & +OCH */ (ERIAN 5 4HEILMANN , "ARTENSCHLAGER 2 2EPLICATION OF SUBGENOMIC HEPATITIS # VIRUS 2.!S IN A HEPATOMA CELL LINE 3CIENCE n 3TEINMANN % 0ENIN & +ALLIS 3 0ATEL !( "ARTENSCHLAGER 2 0IETSCHMANN 4 (EPATITIS # VIRUS P PROTEIN IS CRUCIAL FOR ASSEMBLY AND RELEASE OF INFEC TIOUS VIRIONS 0,O3 0ATHOG n *ONES #4 -URRAY #, %ASTMAN $+ 4ASSELLO * 2ICE #- (EPATITIS #
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
VIRUS P AND .3 PROTEINS ARE ESSENTIAL FOR PRODUCTION OF INFECTIOUS VIRUS * 6IROL n "LIGHT +* +OLYKHALOV !! 2ICE #- %FFICIENT INITIATION OF (#6 2.! REPLICATION IN CELL CULTURE 3CIENCE n +OLYKHALOV !! !GAPOV %6 "LIGHT +* -IHALIK + &EINSTONE 3- 2ICE #- 4RANSMISSION OF HEPATITIS # BY INTRAHEPATIC INOCULATION WITH TRANSCRIBED 2.! 3CIENCE n 0ALLAORO - ,AHM ! "IASIOL ' "RUNETTI - .ARDELLA # /RSATTI , "ONELLI & /RRU 3 .ARJES & 3TEINKUHLER # #HARACTERIZATION OF THE HEPATITIS # VIRUS .3 PROCESSING REACTION BY USING A PURIFIED PRECURSOR PROTEIN * 6IROL n 'RAKOUI ! -C#OURT $7 7YCHOWSKI # &EINSTONE 3- 2ICE #- ! SECOND HEPATITIS # VIRUS ENCODED PROTEINASE 0ROC .ATL !CAD 3CI 53! n (IJIKATA - -IZUSHIMA ( !KAGI 4 -ORI 3 +AKIUCHI . +ATO . 4ANAKA 4 +IMURA + 3HIMOTOHNO + 4WO DISTINCT PROTEINASE ACTIVITIES REQUIRED FOR THE PROCESSING OF A PUTATIVE NONSTRUCTURAL PRECURSOR PROTEIN OF HEPATITIS # VIRUS * 6IROL n ,ORENZ )# -ARCOTRIGIANO * $ENTZER 4' 2ICE #- 3TRUCTURE OF THE CATA LYTIC DOMAIN OF THE HEPATITIS # VIRUS .3 PROTEASE .ATURE n +IM *, -ORGENSTERN +! ,IN # &OX 4 $WYER -$ ,ANDRO *! #HAMBERS 30 -ARKLAND 7 ,EPRE #! /-ALLEY %4 #RYSTAL STRUCTURE OF THE HEPATITIS # VIRUS .3 PROTEASE DOMAIN COMPLEXED WITH A SYNTHETIC .3! COFACTOR PEPTIDE #ELL n ,OVE 2! 0ARGE (% 7ICKERSHAM *! (OSTOMSKY : (ABUKA . -OOMAW %7 !DACHI 4 (OSTOMSKA : 4HE CRYSTAL STRUCTURE OF HEPATITIS # VIRUS .3 PROTEINASE REVEALS A TRYPSIN LIKE FOLD AND A STRUCTURAL ZINC BINDING SITE #ELL n 9AO . 2EICHERT 0 4AREMI 33 0ROSISE 77 7EBER 0# -OLECULAR VIEWS OF VIRAL POLYPROTEIN PROCESSING REVEALED BY THE CRYSTAL STRUCTURE OF THE HEPATITIS # VIRUS BIFUNCTIONAL PROTEASE HELICASE 3TRUCTURE n 7OLK " 3ANSONNO $ +RAUSSLICH (' $AMMACCO & 2ICE #- "LUM (% -ORADPOUR $ 3UBCELLULAR LOCALIZATION STABILITY AND TRANS CLEAVAGE COM PETENCE OF THE HEPATITIS # VIRUS .3 .3! COMPLEX EXPRESSED IN TETRACYCLINE REGULATED CELL LINES * 6IROL n 4AI #, #HI 7+ #HEN $3 (WANG ,( 4HE HELICASE ACTIVITY ASSOCIATED WITH HEPATITIS # VIRUS NONSTRUCTURAL PROTEIN .3 * 6IROL n (UGLE 4 &EHRMANN & "IECK % +OHARA - +RAUSSLICH (' 2ICE #- "LUM (% -ORADPOUR $ 4HE HEPATITIS # VIRUS NONSTRUCTURAL PROTEIN " IS AN INTE GRAL ENDOPLASMIC RETICULUM MEMBRANE PROTEIN 6IROLOGY n ,UNDIN - -ONNE - 7IDELL ! 6ON (EIJNE ' 0ERSSON -! 4OPOLOGY OF THE MEMBRANE ASSOCIATED HEPATITIS # VIRUS PROTEIN .3" * 6IROL n 'RETTON 3. 4AYLOR !) -C,AUCHLAN * -OBILITY OF THE HEPATITIS # VIRUS .3" PROTEIN ON THE ENDOPLASMIC RETICULUM MEMBRANE AND MEMBRANE ASSOCI ATED FOCI * 'EN 6IROL n %GGER $ 7OLK " 'OSERT 2 "IANCHI , "LUM (% -ORADPOUR $ "IENZ +
2ALF "ARTENSCHLAGER ET AL
%XPRESSION OF HEPATITIS # VIRUS PROTEINS INDUCES DISTINCT MEMBRANE ALTERATIONS INCLUDING A CANDIDATE VIRAL REPLICATION COMPLEX * 6IROL n 9U '9 ,EE +* 'AO , ,AI -- 0ALMITOYLATION AND POLYMERIZATION OF HEPATITIS # VIRUS .3" PROTEIN * 6IROL n "RASS 6 "IECK % -ONTSERRET 2 7OLK " (ELLINGS *! "LUM (% 0ENIN & -ORADPOUR $ !N AMINO TERMINAL AMPHIPATHIC ALPHA HELIX MEDIATES MEMBRANE ASSOCIATION OF THE HEPATITIS # VIRUS NONSTRUCTURAL PROTEIN ! * "IOL #HEM n 0ENIN & "RASS 6 !PPEL . 2AMBOARINA 3 -ONTSERRET 2 &ICHEUX $ "LUM (% "ARTENSCHLAGER 2 -ORADPOUR $ 3TRUCTURE AND FUNCTION OF THE MEMBRANE ANCHOR DOMAIN OF HEPATITIS # VIRUS NONSTRUCTURAL PROTEIN ! * "IOL #HEM n !PPEL . 0IETSCHMANN 4 "ARTENSCHLAGER 2 -UTATIONAL ANALYSIS OF HEPA TITIS # VIRUS NONSTRUCTURAL PROTEIN ! POTENTIAL ROLE OF DIFFERENTIAL PHOSPHORY LATION IN 2.! REPLICATION AND IDENTIFICATION OF A GENETICALLY FLEXIBLE DOMAIN * 6IROL n -ORADPOUR $ %VANS -* 'OSERT 2 9UAN : "LUM (% 'OFF 30 ,INDENBACH "$ 2ICE #- )NSERTION OF GREEN FLUORESCENT PROTEIN INTO NONSTRUCTURAL PROTEIN ! ALLOWS DIRECT VISUALIZATION OF FUNCTIONAL HEPATITIS # VIRUS REPLICATION COMPLEXES * 6IROL n 1UINTAVALLE - 3AMBUCINI 3 $I 0IETRO # $E &RANCESCO 2 .EDDERMANN 0 4HE ALPHA ISOFORM OF PROTEIN KINASE #+) IS RESPONSIBLE FOR HEPATITIS # VIRUS .3! HYPERPHOSPHORYLATION * 6IROL n 1UINTAVALLE - 3AMBUCINI 3 3UMMA 6 /RSATTI , 4ALAMO & $E &RANCESCO 2 .EDDERMANN 0 (EPATITIS # VIRUS .3! IS A DIRECT SUBSTRATE OF CASEIN KINASE ) ALPHA A CELLULAR KINASE IDENTIFIED BY INHIBITOR AFFINITY CHROMATOGRA PHY USING SPECIFIC .3! HYPERPHOSPHORYLATION INHIBITORS * "IOL #HEM n .EDDERMANN 0 1UINTAVALLE - $I 0IETRO # #LEMENTI ! #ERRETANI - !LTAMURA 3 "ARTHOLOMEW , $E &RANCESCO 2 2EDUCTION OF HEPATITIS # VIRUS .3! HYPERPHOSPHORYLATION BY SELECTIVE INHIBITION OF CELLULAR KINASES ACTIVATES VIRAL 2.! REPLICATION IN CELL CULTURE * 6IROL n "RESSANELLI 3 4OMEI , 2OUSSEL ! )NCITTI ) 6ITALE 2, -ATHIEU - $E &2 2EY &! #RYSTAL STRUCTURE OF THE 2.! DEPENDENT 2.! POLYMERASE OF HEPA TITIS # VIRUS 0ROC .ATL !CAD 3CI 53! n ,ESBURG #! #ABLE -" &ERRARI % (ONG : -ANNARINO !& 7EBER 0# #RYSTAL STRUCTURE OF THE 2.! DEPENDENT 2.! POLYMERASE FROM HEPATITIS # VIRUS REVEALS A FULLY ENCIRCLED ACTIVE SITE .AT 3TRUCT "IOL n 7ATASHI + )SHII . (IJIKATA - )NOUE $ -URATA 4 -IYANARI 9 3HIMOTOHNO + #YCLOPHILIN " IS A FUNCTIONAL REGULATOR OF HEPATITIS # VIRUS 2.! POLY MERASE -OL #ELL n 7ATASHI + 3HIMOTOHNO + #HEMICAL GENETICS APPROACH TO HEPATITIS # VIRUS REPLICATION CYCLOPHILIN AS A TARGET FOR ANTI HEPATITIS # VIRUS STRATEGY 2EV -ED 6IROL n "RANCH !$ 3TUMP $$ 'UTIERREZ *! %NG & 7ALEWSKI *, 4HE HEPATITIS # VIRUS ALTERNATE READING FRAME !2& AND ITS FAMILY OF NOVEL PRODUCTS THE
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
ALTERNATE READING FRAME PROTEIN& PROTEIN THE DOUBLE FRAMESHIFT PROTEIN AND OTHERS 3EMIN ,IVER $IS n -C-ULLAN ,+ 'RAKOUI ! %VANS -* -IHALIK + 0UIG - "RANCH !$ &EINSTONE 3- 2ICE #- %VIDENCE FOR A FUNCTIONAL 2.! ELEMENT IN THE HEPATITIS # VIRUS CORE GENE 0ROC .ATL !CAD 3CI 53! n &EINSTONE 3- -IHALIK +" +AMIMURA 4 !LTER (* ,ONDON 74 0URCELL 2( )NACTIVATION OF HEPATITIS " VIRUS AND NON ! NON " HEPATITIS BY CHLORO FORM )NFECT )MMUN n "RADLEY $7 -C#AUSTLAND +! #OOK %( 3CHABLE #! %BERT *7 -AYNARD *% 0OSTTRANSFUSION NON ! NON " HEPATITIS IN CHIMPANZEES 0HYSICOCHEMICAL EVIDENCE THAT THE TUBULE FORMING AGENT IS A SMALL ENVELOPED VIRUS 'ASTROENTEROLOGY n 7AKITA 4 0IETSCHMANN 4 +ATO 4 $ATE 4 -IYAMOTO - :HAO : -URTHY + (ABERMANN ! +RAUSSLICH (' -IZOKAMI - 0RODUCTION OF INFECTIOUS HEPATITIS # VIRUS IN TISSUE CULTURE FROM A CLONED VIRAL GENOME .AT -ED n 9U 8 1IAO - !TANASOV ) (U : +ATO 4 ,IANG 4* :HOU :( #RYO ELECTRON MICROSCOPY AND THREE DIMENSIONAL RECONSTRUCTIONS OF HEPATITIS # VIRUS PARTICLES 6IROLOGY n +ANTO 4 (AYASHI . 4AKEHARA 4 (AGIWARA ( -ITA % .AITO - +ASAHARA ! &USAMOTO ( +AMADA 4 "UOYANT DENSITY OF HEPATITIS # VIRUS RECOVERED FROM INFECTED HOSTS TWO DIFFERENT FEATURES IN SUCROSE EQUILIBRIUM DENSITY GRA DIENT CENTRIFUGATION RELATED TO DEGREE OF LIVER INFLAMMATION (EPATOLOGY n 0RINCE !- (UIMA"YRON 4 0ARKER 43 ,EVINE $- 6ISUALIZATION OF HEPATITIS # VIRIONS AND PUTATIVE DEFECTIVE INTERFERING PARTICLES ISOLATED FROM LOW DENSITY LIPOPROTEINS * 6IRAL (EPAT n .IELSEN 35 "ASSENDINE -& "URT !$ -ARTIN # 0UMEECHOCKCHAI 7 4OMS ', !SSOCIATION BETWEEN HEPATITIS # VIRUS AND VERY LOW DENSITY LIPOPROTEIN 6,$, ,$, ANALYZED IN IODIXANOL DENSITY GRADIENTS * 6IROL n (UANG ( 3UN & /WEN $- ,I 7 #HEN 9 'ALE - *R 9E * (EPATITIS # VIRUS PRODUCTION BY HUMAN HEPATOCYTES DEPENDENT ON ASSEMBLY AND SECRETION OF VERY LOW DENSITY LIPOPROTEINS 0ROC .ATL !CAD 3CI 53! n !NDRE 0 +OMURIAN 0RADEL & $EFORGES 3 0ERRET - "ERLAND *, 3ODOYER - 0OL 3 "RECHOT # 0ARANHOS "ACCALA ' ,OTTEAU 6 #HARACTERIZATION OF LOW AND VERY LOW DENSITY HEPATITIS # VIRUS 2.! CONTAINING PARTICLES * 6IROL n !GNELLO 6 !BEL ' %LFAHAL - +NIGHT '" :HANG 18 (EPATITIS # VIRUS AND OTHER &LAVIVIRIDAE VIRUSES ENTER CELLS VIA LOW DENSITY LIPOPROTEIN RECEPTOR 0ROC .ATL !CAD 3CI 53! n .AHMIAS 9 #ASALI - "ARBE , "ERTHIAUME & 9ARMUSH -, ,IVER ENDO THELIAL CELLS PROMOTE ,$, 2 EXPRESSION AND THE UPTAKE OF (#6 LIKE PARTICLES IN PRIMARY RAT AND HUMAN HEPATOCYTES (EPATOLOGY n 3CARSELLI % !NSUINI ( #ERINO 2 2OCCASECCA 2- !CALI 3 &ILOCAMO ' 4RABONI # .ICOSIA ! #ORTESE 2 6ITELLI ! 4HE HUMAN SCAVENGER RECEPTOR CLASS " TYPE ) IS A NOVEL CANDIDATE RECEPTOR FOR THE HEPATITIS # VIRUS %-"/ * n
2ALF "ARTENSCHLAGER ET AL
(AHN 4 2ICE #- (EPATITIS # VIRUS ENTRY * "IOL #HEM n -ORADPOUR $ 0ENIN & 2ICE #- 2EPLICATION OF HEPATITIS # VIRUS .AT 2EV -ICROBIOL n +OUTSOUDAKIS ' (ERRMANN % +ALLIS 3 "ARTENSCHLAGER 2 0IETSCHMANN 4 4HE LEVEL OF #$ CELL SURFACE EXPRESSION IS A KEY DETERMINANT FOR PRO DUCTIVE ENTRY OF HEPATITIS # VIRUS INTO HOST CELLS * 6IROL n %VANS -* VON (AHN 4 4SCHERNE $- 3YDER !* 0ANIS - 7OLK " (ATZIIOANNOU 4 -C+EATING *! "IENIASZ 0$ 2ICE #- #LAUDIN IS A HEPATITIS # VIRUS CO RECEPTOR REQUIRED FOR A LATE STEP IN ENTRY .ATURE n -EERTENS , "ERTAUX # $RAGIC 4 (EPATITIS # VIRUS ENTRY REQUIRES A CRITI CAL POSTINTERNALIZATION STEP AND DELIVERY TO EARLY ENDOSOMES VIA CLATHRIN COATED VESICLES * 6IROL n 4SCHERNE $- *ONES #4 %VANS -* ,INDENBACH "$ -C+EATING *! 2ICE #- 4IME AND TEMPERATURE DEPENDENT ACTIVATION OF HEPATITIS # VIRUS FOR LOW P( TRIGGERED ENTRY * 6IROL n 'OSERT 2 %GGER $ ,OHMANN 6 "ARTENSCHLAGER 2 "LUM (% "IENZ + -ORADPOUR $ )DENTIFICATION OF THE HEPATITIS # VIRUS 2.! REPLICATION COMPLEX IN HUH CELLS HARBORING SUBGENOMIC REPLICONS * 6IROL n "ARBA ' (ARPER & (ARADA 4 +OHARA - 'OULINET 3 -ATSUURA 9 %DER ' 3CHAFF : #HAPMAN -* -IYAMURA 4 (EPATITIS # VIRUS CORE PROTEIN SHOWS A CYTOPLASMIC LOCALIZATION AND ASSOCIATES TO CELLULAR LIPID STORAGE DROP LETS 0ROC .ATL !CAD 3CI 53! n -ORADPOUR $ %NGLERT # 7AKITA 4 7ANDS *2 #HARACTERIZATION OF CELL LINES ALLOWING TIGHTLY REGULATED EXPRESSION OF HEPATITIS # VIRUS CORE PROTEIN 6IROLOGY n "ARTENSCHLAGER 2 (EPATITIS # VIRUS MOLECULAR CLONES FROM C$.! TO INFECTIOUS VIRUS PARTICLES IN CELL CULTURE #URR /PIN -ICROBIOL n "UKH * ! CRITICAL ROLE FOR THE CHIMPANZEE MODEL IN THE STUDY OF HEPATITIS # (EPATOLOGY n !LTER (* 0URCELL 2( (OLLAND 06 0OPPER ( 4RANSMISSIBLE AGENT IN NON ! NON " HEPATITIS ,ANCET n (OLLINGER &" 'ITNICK ', !ACH 2$ 3ZMUNESS 7 -OSLEY *7 3TEVENS #% 0ETERS 2, 7EINER *- 7ERCH *" ,ANDER ** .ON ! NON " HEPATITIS TRANSMISSION IN CHIMPANZEES A PROJECT OF THE TRANSFUSION TRANSMITTED VIRUSES STUDY GROUP )NTERVIROLOGY n 4ABOR % 'ERETY 2* $RUCKER *! 3EEFF ," (OOFNAGLE *( *ACKSON $2 !PRIL - "ARKER ,& 0INEDA 4AMONDONG ' 4RANSMISSION OF NON ! NON " HEPATITIS FROM MAN TO CHIMPANZEE ,ANCET n #HOO 1, +UO ' 7EINER !* /VERBY ,2 "RADLEY $7 (OUGHTON - )SOLATION OF A C$.! CLONE DERIVED FROM A BLOOD BORNE NON ! NON " VIRAL HEPATITIS GENOME 3CIENCE n 9ANAGI - 0URCELL 2( %MERSON 35 "UKH * 4RANSCRIPTS FROM A SINGLE FULL LENGTH C$.! CLONE OF HEPATITIS # VIRUS ARE INFECTIOUS WHEN DIRECTLY TRANS FECTED INTO THE LIVER OF A CHIMPANZEE 0ROC .ATL !CAD 3CI 53! n ,ANFORD 2% "IGGER # !DVANCES IN MODEL SYSTEMS FOR HEPATITIS # VIRUS RESEARCH 6IROLOGY n &EINSTONE 3- !LTER (* $IENES (0 3HIMIZU 9 0OPPER ( "LACKMORE $ 3LY $
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
,ONDON 74 0URCELL 2( .ON ! NON " HEPATITIS IN CHIMPANZEES AND MARMOSETS * )NFECT $IS n 8IE :# 2IEZU "* ,ASARTE ** 'UILLEN * 3U *( #IVEIRA -0 0RIETO * 4RANSMISSION OF HEPATITIS # VIRUS INFECTION TO TREE SHREWS 6IROLOGY n -ERCER $& 3CHILLER $% %LLIOTT *& $OUGLAS $. (AO # 2INFRET ! !DDISON 72 &ISCHER +0 #HURCHILL 4! ,AKEY *2 (EPATITIS # VIRUS REPLICATION IN MICE WITH CHIMERIC HUMAN LIVERS .AT -ED n "ARTENSCHLAGER 2 4HE HEPATITIS # VIRUS REPLICON SYSTEM FROM BASIC RESEARCH TO CLINICAL APPLICATION * (EPATOL n 0IETSCHMANN 4 ,OHMANN 6 +AUL ! +RIEGER . 2INCK ' 2UTTER ' 3TRAND $ "ARTENSCHLAGER 2 0ERSISTENT AND TRANSIENT REPLICATION OF FULL LENGTH HEPATITIS # VIRUS GENOMES IN CELL CULTURE * 6IROL n )KEDA - 9I - ,I + ,EMON 3- 3ELECTABLE SUBGENOMIC AND GENOME LENGTH DICISTRONIC 2.!S DERIVED FROM AN INFECTIOUS MOLECULAR CLONE OF THE (#6 . STRAIN OF HEPATITIS # VIRUS REPLICATE EFFICIENTLY IN CULTURED (UH CELLS * 6IROL n "LIGHT +* -C+EATING *! -ARCOTRIGIANO * 2ICE #- %FFICIENT REPLICATION OF HEPATITIS # VIRUS GENOTYPE A 2.!S IN CELL CULTURE * 6IROL n "UKH * 0IETSCHMANN 4 ,OHMANN 6 +RIEGER . &AULK + %NGLE 2% 'OVINDARAJAN 3 3HAPIRO - 3T #LAIRE - "ARTENSCHLAGER 2 -UTATIONS THAT PERMIT EFFI CIENT REPLICATION OF HEPATITIS # VIRUS 2.! IN (UH CELLS PREVENT PRODUCTIVE REPLICATION IN CHIMPANZEES 0ROC .ATL !CAD 3CI 53! n (SU - :HANG * &LINT - ,OGVINOFF # #HENG -AYER # 2ICE #- -C+EATING *! (EPATITIS # VIRUS GLYCOPROTEINS MEDIATE P( DEPENDENT CELL ENTRY OF PSEUDOTYPED RETROVIRAL PARTICLES 0ROC .ATL !CAD 3CI 53! n "ARTOSCH " $UBUISSON * #OSSET &, )NFECTIOUS HEPATITIS # VIRUS PSEUDO PARTICLES CONTAINING FUNCTIONAL % % ENVELOPE PROTEIN COMPLEXES * %XP -ED n +ATO 4 &URUSAKA ! -IYAMOTO - $ATE 4 9ASUI + (IRAMOTO * .AGAYAMA + 4ANAKA 4 7AKITA 4 3EQUENCE ANALYSIS OF HEPATITIS # VIRUS ISOLATED FROM A FULMINANT HEPATITIS PATIENT * -ED 6IROL n +ATO 4 $ATE 4 -IYAMOTO - &URUSAKA ! 4OKUSHIGE + -IZOKAMI - 7AKITA 4 %FFICIENT REPLICATION OF THE GENOTYPE A HEPATITIS # VIRUS SUBGENOMIC REPLICON 'ASTROENTEROLOGY n "INDER - 1UINKERT $ "OCHKAROVA / +LEIN 2 +EZMIC . "ARTENSCHLAGER 2 ,OHMANN 6 )DENTIFICATION OF DETERMINANTS INVOLVED IN INITIATION OF HEPATITIS # VIRUS 2.! SYNTHESIS BY USING INTERGENOTYPIC REPLICASE CHIMERAS * 6IROL n :HONG * 'ASTAMINZA 0 #HENG ' +APADIA 3 +ATO 4 "URTON $2 7IELAND 3& 5PRICHARD 3, 7AKITA 4 #HISARI &6 2OBUST HEPATITIS # VIRUS INFECTION IN VITRO 0ROC .ATL !CAD 3CI 53! n ,INDENBACH "$ -EULEMAN 0 0LOSS ! 6ANWOLLEGHEM 4 3YDER !* -C+EATING *! ,ANFORD 2% &EINSTONE 3- -AJOR -% ,EROUX 2OELS ' ET AL #ELL CULTURE GROWN HEPATITIS # VIRUS IS INFECTIOUS IN VIVO AND CAN BE RECULTURED IN VITRO 0ROC .ATL !CAD 3CI 53! n ,INDENBACH "$ %VANS -* 3YDER !* 7OLK " 4ELLINGHUISEN 4, ,IU ##
2ALF "ARTENSCHLAGER ET AL
-ARUYAMA 4 (YNES 2/ "URTON $2 -C+EATING *! ET AL #OMPLETE REPLICATION OF HEPATITIS # VIRUS IN CELL CULTURE 3CIENCE n 0IETSCHMANN 4 +AUL ! +OUTSOUDAKIS ' 3HAVINSKAYA ! +ALLIS 3 3TEINMANN % !BID + .EGRO & $REUX - #OSSET &, ET AL #ONSTRUCTION AND CHAR ACTERIZATION OF INFECTIOUS INTRAGENOTYPIC AND INTERGENOTYPIC HEPATITIS # VIRUS CHIMERAS 0ROC .ATL !CAD 3CI 53! n 9I - 6ILLANUEVA 2! 4HOMAS $, 7AKITA 4 ,EMON 3- 0RODUCTION OF INFECTIOUS GENOTYPE A HEPATITIS # VIRUS (UTCHINSON STRAIN IN CULTURED HUMAN HEPATOMA CELLS 0ROC .ATL !CAD 3CI 53! n $ELGRANGE $ 0ILLEZ ! #ASTELAIN 3 #OCQUEREL , 2OUILLE 9 $UBUISSON * 7AKITA 4 $UVERLIE ' 7YCHOWSKI # 2OBUST PRODUCTION OF INFECTIOUS VIRAL PAR TICLES IN (UH CELLS BY INTRODUCING MUTATIONS IN HEPATITIS # VIRUS STRUCTURAL PROTEINS * 'EN 6IROL n +AUL ! 7OERZ ) -EULEMAN 0 ,EROUX 2OELS ' "ARTENSCHLAGER 2 #ELL CULTURE ADAPTATION OF HEPATITIS # VIRUS AND IN VIVO VIABILITY OF AN ADAPTED VARI ANT * 6IROL n &OY % 7ANG # 3UMPTER 2 )KEKA - ,EMON 3- 'ALE - 2EGULATION OF INTERFERON REGULATORY FACTOR BY THE HEPATITIS # VIRUS SERINE PROTEASE 3CIENCE n (ISCOTT * ,ACOSTE * ,IN 2 2ECRUITMENT OF AN INTERFERON MOLECULAR SIG NALING COMPLEX TO THE MITOCHONDRIAL MEMBRANE DISRUPTION BY HEPATITIS # VIRUS .3 ! PROTEASE "IOCHEM 0HARMACOL n ,I + &OY % &ERREON *# .AKAMURA - &ERREON !# )KEDA - 2AY 3# 'ALE - *R ,EMON 3- )MMUNE EVASION BY HEPATITIS # VIRUS .3! PROTEASE MEDIATED CLEAVAGE OF THE 4OLL LIKE RECEPTOR ADAPTOR PROTEIN 42)& 0ROC .ATL !CAD 3CI 53! n ,IN 2 ,ACOSTE * .AKHAEI 0 3UN 1 9ANG , 0AZ 3 7ILKINSON 0 *ULKUNEN ) 6ITOUR $ -EURS % ET AL $ISSOCIATION OF A -!63)03 6)3!#ARDIF )++EPSILON MOLECULAR COMPLEX FROM THE MITOCHONDRIAL OUTER MEMBRANE BY HEPATITIS # VIRUS .3 ! PROTEOLYTIC CLEAVAGE * 6IROL n -EYLAN % #URRAN * (OFMANN + -ORADPOUR $ "INDER - "ARTENSCHLAGER 2 4SCHOPP * #ARDIF IS AN ADAPTOR PROTEIN IN THE 2)' ) ANTIVIRAL PATHWAY AND IS TARGETED BY HEPATITIS # VIRUS .ATURE n 'ALE - *R &OY %- %VASION OF INTRACELLULAR HOST DEFENCE BY HEPATITIS # VIRUS .ATURE n "OWEN $' 7ALKER #- !DAPTIVE IMMUNE RESPONSES IN ACUTE AND CHRONIC HEPATITIS # VIRUS INFECTION .ATURE n 0AWLOTSKY *- 'ERMANIDIS ' 4HE NON STRUCTURAL ! PROTEIN OF HEPATITIS # VIRUS * 6IRAL (EPAT n #ASTERA , 0AWLOTSKY *- .ONINVASIVE DIAGNOSIS OF LIVER FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS # -ED 'EN -ED 2OCKEY $# "ISSELL $- .ONINVASIVE MEASURES OF LIVER FIBROSIS (EPATOLOGY 3n3 :IOL - (ANDRA ,UCA ! +ETTANEH ! #HRISTIDIS # -AL & +AZEMI & DE ,6 -ARCELLIN 0 $HUMEAUX $ 4RINCHET *# ET AL .ONINVASIVE ASSESSMENT OF LIVER FIBROSIS BY MEASUREMENT OF STIFFNESS IN PATIENTS WITH CHRONIC HEPATITIS # (EPATOLOGY n
#HRONIC HEPATITIS # 0ORTRAIT OF A SILENT EPIDEMIC AND THE ETIOLOGIC AGENT
,EWIN - 0OUJOL 2OBERT ! "OELLE 09 7ENDUM $ ,ASNIER % 6IALLON - 'UECHOT * (OEFFEL # !RRIVE , 4UBIANA *- ET AL $IFFUSION WEIGHTED MAGNETIC RESONANCE IMAGING FOR THE ASSESSMENT OF FIBROSIS IN CHRONIC HEPATITIS # (EPATOLOGY n 3TRADER $" 7RIGHT 4 4HOMAS $, 3EEFF ," $IAGNOSIS MANAGEMENT AND TREATMENT OF HEPATITIS # (EPATOLOGY n &ELD ** (OOFNAGLE *( -ECHANISM OF ACTION OF INTERFERON AND RIBAVIRIN IN TREATMENT OF HEPATITIS # .ATURE n -ANGIA ! 3ANTORO 2 -INERVA . 2ICCI ', #ARRETTA 6 0ERSICO - 6INELLI & 3COTTO ' "ACCA $ !NNESE - ET AL 0EGINTERFERON ALFA B AND RIBAVIRIN FOR VS WEEKS IN (#6 GENOTYPE OR . %NGL * -ED n VON 7AGNER - (UBER - "ERG 4 (INRICHSEN ( 2ASENACK * (EINTGES 4 "ERGK ! "ERNSMEIER # (AUSSINGER $ (ERRMANN % ET AL 0EGINTERFERON ALPHA A +$ AND RIBAVIRIN FOR OR WEEKS IN PATIENTS WITH GENOTYPE OR CHRONIC HEPATITIS # 'ASTROENTEROLOGY n "ERG 4 VON 7AGNER - .ASSER 3 3ARRAZIN # (EINTGES 4 'ERLACH 4 "UGGISCH 0 'OESER 4 2ASENACK * 0APE '2 ET AL %XTENDED TREATMENT DURATION FOR HEPATITIS # VIRUS TYPE COMPARING VERSUS WEEKS OF PEGINTERFERON ALFA A PLUS RIBAVIRIN 'ASTROENTEROLOGY n :EUZEM 3 "UTI - &ERENCI 0 3PERL * (ORSMANS 9 #IANCIARA * )BRANYI % 7EILAND / .OVIELLO 3 "RASS # ET AL %FFICACY OF WEEKS TREATMENT WITH PEGINTERFERON ALFA B PLUS RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS # INFECTED WITH GENOTYPE AND LOW PRETREATMENT VIREMIA * (EPATOL n 3HIFFMAN -, 3UTER & "ACON "2 .ELSON $ (ARLEY ( 3OLA 2 3HAFRAN 3$ "ARANGE + ,IN ! 3OMAN ! ET AL 0EGINTERFERON ALFA A AND RIBAVIRIN FOR OR WEEKS IN (#6 GENOTYPE OR . %NGL * -ED n *EFFERS ,* #ASSIDY 7 (OWELL #$ (U 3 2EDDY +2 0EGINTERFERON ALFA A KD AND RIBAVIRIN FOR BLACK !MERICAN PATIENTS WITH CHRONIC (#6 GENO TYPE (EPATOLOGY n -UIR !* "ORNSTEIN *$ +ILLENBERG 0' 0EGINTERFERON ALFA B AND RIBAVI RIN FOR THE TREATMENT OF CHRONIC HEPATITIS # IN BLACKS AND NON (ISPANIC WHITES . %NGL * -ED n "RESSLER ", 'UINDI - 4OMLINSON ' (EATHCOTE * (IGH BODY MASS INDEX IS AN INDEPENDENT RISK FACTOR FOR NONRESPONSE TO ANTIVIRAL TREATMENT IN CHRONIC HEPATITIS # (EPATOLOGY n #HEN , "OROZAN ) &ELD * 3UN * 4ANNIS ,, #OLTESCU # (EATHCOTE * %DWARDS !- -C'ILVRAY )$ (EPATIC GENE EXPRESSION DISCRIMINATES RESPOND ERS AND NONRESPONDERS IN TREATMENT OF CHRONIC HEPATITIS # VIRAL INFECTION 'ASTROENTEROLOGY n 0ARADIS 6 !SSELAH 4 $ARGERE $ 2IPAULT -0 -ARTINOT - "OYER . 6ALLA $ -ARCELLIN 0 "EDOSSA 0 3ERUM PROTEOME TO PREDICT VIROLOGIC RESPONSE IN PATIENTS WITH HEPATITIS # TREATED BY PEGYLATED INTERFERON PLUS RIBAVIRIN 'ASTROENTEROLOGY n "ERG 4 0ASCU - -OLLER " 0REDICTION OF SPONTANEOUS VIRAL CLEARANCE IN ACUTE HEPATITIS # BY VIRAL LOAD MEASUREMENTS (EPATOLOGY n &RIED -7 3HIFFMAN -, 2EDDY +2 3MITH # -ARINOS ' 'ONCALES &, *R (AUSSINGER $ $IAGO - #AROSI ' $HUMEAUX $ ET AL 0EGINTERFERON
2ALF "ARTENSCHLAGER ET AL
ALFA A PLUS RIBAVIRIN FOR CHRONIC HEPATITIS # VIRUS INFECTION . %NGL * -ED n -ANNS -0 -C(UTCHISON *' 'ORDON 3# 2USTGI 6+ 3HIFFMAN - 2EINDOLLAR 2 'OODMAN :$ +OURY + ,ING - !LBRECHT *+ 0EGINTERFERON ALFA B PLUS RIBAVIRIN COMPARED WITH INTERFERON ALFA B PLUS RIBAVIRIN FOR INITIAL TREAT MENT OF CHRONIC HEPATITIS # A RANDOMISED TRIAL ,ANCET n (ADZIYANNIS 3* 3ETTE ( *R -ORGAN 42 "ALAN 6 $IAGO - -ARCELLIN 0 2AMADORI ' "ODENHEIMER ( *R "ERNSTEIN $ 2IZZETTO - ET AL 0EGINTER FERON ALPHAA AND RIBAVIRIN COMBINATION THERAPY IN CHRONIC HEPATITIS # A RAN DOMIZED STUDY OF TREATMENT DURATION AND RIBAVIRIN DOSE !NN )NTERN -ED n $E &RANCESCO 2 -IGLIACCIO ' #HALLENGES AND SUCCESSES IN DEVELOPING NEW THERAPIES FOR HEPATITIS # .ATURE n ,AMARRE $ !NDERSON 0# "AILEY - "EAULIEU 0 "OLGER ' "ONNEAU 0 "OS - #AMERON $2 #ARTIER - #ORDINGLEY -' ET AL !N .3 PROTEASE INHIBI TOR WITH ANTIVIRAL EFFECTS IN HUMANS INFECTED WITH HEPATITIS # VIRUS .ATURE n 2EESINK (7 :EUZEM 3 7EEGINK #* &ORESTIER . VAN 6LIET ! VAN DE 7ETERING DE 2OOIJ -C.AIR , 0URDY 3 +AUFFMAN 2 !LAM * ET AL 2APID DECLINE OF VIRAL 2.! IN HEPATITIS # PATIENTS TREATED WITH 68 A PHASE )B PLACEBO CONTROLLED RANDOMIZED STUDY 'ASTROENTEROLOGY n 4ROZZI # "ARTHOLOMEW , #ECCACCI ! "IASIOL ' 0ACINI , !LTAMURA 3 .ARJES & -URAGLIA % 0AONESSA ' +OCH 5 ET AL )N VITRO SELECTION AND CHARAC TERIZATION OF HEPATITIS # VIRUS SERINE PROTEASE VARIANTS RESISTANT TO AN ACTIVE SITE PEPTIDE INHIBITOR * 6IROL n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
(EPATITIS ! INFECTION -ANFRED ( 7OLFF AND !XEL 3CHMIDT )NSTITUTE OF -ICROBIOLOGY AND 6IROLOGY 0RIVATE 5NIVERSITY OF 7ITTEN(ERDECKE 3TOCKUMER
3TRASSE 7ITTEN 'ERMANY 0RIVATE 5NIVERSITY OF 7ITTEN(ERDECKE &ACULTY OF -EDICINE !LFRED (ERRHAUSEN 3TR
7ITTEN 'ERMANY
!BSTRACT (EPATITIS ! IS A UBIQUITOUS DISEASE OF MAN WITH ACUTE SELF LIMITING LIVER INFLAMMATION AND A LOW MORTALITY RATE ALSO KNOWN AS @TRAVELLERS HEPATITIS @HEPATITIS EPIDEMICA AND @INFECTIOUS HEPATITIS 4HE CAUSATIVE INFECTIOUS AGENT IS THE HEPATITIS ! VIRUS BELONGING TO THE FAMILY OF THE 0ICORNAVIRIDAE GENUS (EPATOVIRUS 4HE ROUTE OF TRANSMISSION IS MAINLY FAECAL ORAL (EPATITIS ! IS AN ACUTE HEPATITIS THAT DOES NOT BECOME CHRONIC LIKE HEPATITIS " AND # AND IT IS NO RISK FACTOR FOR THE DEVELOPMENT OF HEPATOCELLULAR MALIGNANCIES 4HE SEVERITY OF CLINICAL MANIFESTATION IS OFTEN AGE RELATED WITH PREDOMINANTLY INAPPAR ENT INFECTION IN YOUNG INDIVIDUALS TO MORE SEVERE COURSES OF INFECTION IN THE ADULTS AND ELDERLY (EPATITIS ! IS MOST PREDOMINANT IN COUNTRIES WITH POOR HYGIENIC CONDITIONS AND IS THEREFORE SOMETIMES ATTRIBUTED AS @TRAVELLERS HEPATITIS 0OTENT VACCINES FOR PROTECTION AND DISEASE PREVENTION ARE AVAILABLE AND THE AMBITIOUS MEDICAL AIM n ERADICATING (!6 BY AGGRESSIVE VACCINATION STRATEGIES n APPEARS REALISTIC
)NTRODUCTION (EPATITIS ! IS A UBIQUITOUS DISEASE OF MAN WITH ACUTE SELF LIMITING LIVER INFLAMMATION AND A RELATIVELY LOW MORTALITY RATE 4HE DISEASE IS PREDOMI NANTLY TRANSMITTED BY THE FAECAL ORAL ROUTE AND IN EXTREMELY RARE CASES BY BLOOD DONATION FROM A PROBAND WITH A HEPATITIS ! INFECTION WITH VIREMIA 4HE CAUSATIVE INFECTIOUS AGENT IS THE (EPATITIS ! 6IRUS (!6 (!6 IS A MEMBER OF THE PICORNAVIRUS FAMILY 0ICORNAVIRIDAE WHICH CONTAINS THE GENERA !PHTHOVIRUS #ARDIOVIRUS %NTEROVIRUS %RBOVIRUS (EPATOVIRUS +OBUVIRUS 0ARECHOVIRUS 2HINOVIRUS AND 4ESCHOVIRUS ;= )NFECTIONS WITH DIFFERENT VIRUSES BELONGING TO THIS FAMILY ARE SPREAD IN HUMANS AND A LOT OF OTHER MAMMALS (!6 IS THE ONLY MEMBER OF THE SPECIES (EPATOVIRUS AND HAS THE INTERNA TIONAL 6IRUS #ODE ; = 4HE GENETIC VARIABILITY IS COMPARA TIVELY LOW AND RECOGNISED WILD TYPE ISOLATES ARE THE STRAINS (- WILD TYPE ACCESSION NUMBER - (-# ACCESSION NUMBER -
-ANFRED ( 7OLFF AND !XEL 3CHMIDT
!'- SIMIAN ORIGIN ACCESSION NUMBER $ AND #2 /F FURTHER GENOMICSCIENTIFIC IMPORTANCE ARE THE ISOLATES ,5 ,9 ,! '"- -"" !( AND &( ;= (!6 IS VIRULENT FOR HUMANS AND HIGHER PRIMATES @/LD AND @.EW 7ORLD 4HE MAJOR TISSUE TROPISM IS WITHIN THE LIVER THERE IS ALSO SOME MINOR TISSUE TROPISM FOR INTESTINAL EPITHELIA ! CONSIDERABLY PERSISTENT PRODUCTIVE INFEC TION OVER A PERIOD OF UP TO MONTHS n ESPECIALLY OF LIVER CELLS n IS COMMON 4HE SPECIALITY OF THE (!6(EPATOVIRUS WITHIN THE 0ICORNAVIRIDAE IS THAT THIS VIRUS SHOWS A COMPARABLY LOW LEVEL OF 2.! REPLICATION COMPARED TO MOST OF THE OTHER PICORNAVIRUSES 0REVIOUSLY (!6 WAS CLASSIFIED AS %NTEROVIRUS TYPE ,ATER IT HAS BEEN SHOWN BY SEVERAL STUDIES THAT IT CAN BE DISTINGUISHED FROM OTHER PICORNA VIRUSES WITH REGARD TO NUCLEOTIDE AND AMINO ACID SEQUENCES AND GROWTH IN CELL CULTURE 4HUS IT IS CLOSELY RELATED TO POLIOVIRUS GENUS %NTEROVIRUS COXSACKIEVIRUS GENUS %NTEROVIRUS AND ECHOVIRUS GENUS 0ARECHOVIRUS WHICH ARE OF RELEVANCE FOR HUMAN INFECTIONS (!6 WAS FIRST DISCOVERED BY IMMUNE ELECTRON MICROSCOPY IN ;= AND ISOLATED IN CELL CULTURE IN ;= 4HE CHARACTERISATION OF THE (!6 CAP SID PROTEINS WAS PERFORMED IN ; = AND THE GENOME WAS CHARACTERISED AS SINGLE STRANDED 2.! IN ;= (!6 HAS ONLY ONE MAJOR SEROTYPE ; = AS ONLY ONE NEUTRALISATION SITE IS IMMUNODOMINANT ;= 4HERE IS NO SERO LOGICAL CROSS REACTION BETWEEN (!6 AND OTHER VIRUSES CAUSING HEPATITIS 4HE VIRION IS KNOWN TO BE VERY STABLE RESISTANT TO ELEVATED TEMPERATURE AND ACIDIC P( CONDITIONS )T ALSO HAS A HIGH RESISTANCE TO CHEMICALS AND ENVIRONMENTAL INFLUENCES )T HAS BEEN FOUND TO SURVIVE FOR DAYS TO MONTHS IN EXPERIMENTALLY CONTAMINATED FRESHWATER SEAWATER WASTEWATER AND SOILS AS WELL AS IN LIVE OYSTER AND CREAM FILLED COOKIES ;= (!6 IS AN IMPORTANT PATHOGEN THE INFECTION IS A COMMON FORM OF ACUTE USUALLY SELF LIMITING VIRAL HEPATITIS IN MANY PARTS OF THE WORLD AND CAUSES WORLDWIDE ABOUT MILLION CASES OF ACUTE CLINICAL HEPATITIS EACH YEAR @!CUTE HEPATITIS IS MOST COMMONLY DEFINED AS A HEPATITIS LASTING NO LONGER THAN MONTHS ! CHRONIC DISEASE MANIFESTATION AS IN OTHER FORMS OF INFECTIOUS OR NON INFECTIOUS HEPATITIS IS NOT OBSERVED IN HEPATITIS ! )T IS NOT ONLY A DISEASE IN @DEVELOPING COUNTRIES BUT ACCOUNTS FOR ABOUT OF ALL CASES OF HEPATITIS IN THE @DEVELOPED WORLD WHEREAS MANY CASES HAVE TO BE ATTRIBUTED TO TRAVELLING ACTIVITIES INTO REGIONS WITH HIGH PREVALENCE FOR (!6 INFECTION /UTBREAKS OCCUR PERIODICALLY IN SEVERAL COUNTRIES 4HE INCIDENCE OF HEPATITIS ! IS CLOSELY RELATED TO SOCIOECONOMIC DEVELOPMENT 4HE MAIN VEHICLES OF TRANSMISSION ARE FAECALLY CONTAMINATED FOOD AND WATER ;=
6IRAL STRUCTURE AND REPLICATION (EPATITIS ! VIRUS SHARES THE KEY PROPERTIES OFT THE PICORNAVIRUS FAMILY 4AB 4HE VIRION IS AN ICOSAHEDRAL NUCLEAR CAPSID WITH A DIAMETER FROM
(EPATITIS ! INFECTION
4ABLE (EPATITIS ! VIRUS VERSUS POLIOMYELITIS VIRUS #OMPARISON OF BIOLOGICAL PROPERTIES &AMILY
0ICORNAVIRIDAE
0ICORNAVIRIDAE
'ENUS
(EPATOVIRUS
%NTEROVIRUS
(EPATITIS ! 6IRUS (!6
0OLIOVIRUS TYPES n
3EROTYPES
-ORPHOLOGY
.ON ENVELOPED VIRUS
)COSAHEDRIC SYMMETRY
#APSIDS CONSIST OF DIFFERENT VIRAL PROTEINS 60 n
60 n ARE SURFACE PROTEINS
#APSOMERES PER NUCLEOCAPSID
$IAMETER NM
STABLE TO ACIDIC CONDITIONS
.ON ENVELOPED VIRUS
)COSAHEDRIC SYMMETRY
#APSIDS CONSIST OF DIFFERENT VIRAL PROTEINS 60 n
60 n ARE SURFACE PROTEINS
#APSOMERES PER NUCLEOCAPSID
$IAMETER n NM
STABLE TO ACIDIC CONDITIONS
'ENOME
6IRION CONTAINS NUCLEIC ACIDS
/NE MOLECULE OF LINEAR SS 2.!
,ENGTH OF GENOME NT
END WITH HAIRPIN STRUCTURE WITH GENOME ASSOCIATED PROTEIN 60G
END WITH POLY !
/NE OPEN READING FRAME CODING FOR ONE PRECURSOR PROTEIN
6IRION CONTAINS NUCLEIC ACIDS
/NE MOLECULE OF LINEAR SS 2.!
,ENGTH OF GENOME NT
END WITH HAIRPIN STRUCTURE WITH GENOME ASSOCIATED PROTEIN 60G
END WITH POLY !
/NE OPEN READING FRAME CODING FOR ONE PRECURSOR PROTEIN
,IPIDS
6IRION CONTAINS NO LIPIDS
6IRION CONTAINS SPHINGOSIN APPROX LIPIDS
'ENOME PER SE IS INFECTIOUS
'ENOME PER SE IS INFECTIOUS
n NM WITH CUBIC SYMMETRY AND COMPOSED OF 2.! AND PRO TEIN ;= &IG 4HE CAPSID POSSESSES FOUR MAJOR STRUCTURAL COMPONENTS 60 60 60 60 4HE MOLECULAR WEIGHTS RANGE FROM n K$ 4HE SURFACE PROTEINS 60 AND 60 ARE MAJOR ANTIBODY BINDING SITES 4HE CAPSID CONTAINS BOTH PRECURSOR 60 AND PRODUCT 60 %ARLY STUDIES HAVE SHOWN THE EXISTENCE OF A VERY SMALL PROTEIN n K$ )T WAS NOT POSSIBLE TO IDENTIFY IT AS 60 BY IMMUNOLOGIC REACTIVITY OR SEQUENCE ANALYSIS )N OTHER PICORNAVI RUSES SUCH AS POLIOVIRUS 60 IS APPROXIMATELY K$ AND IS MYRISTOYLATED AT THE . TERMINAL GLYCINE )N POLIOVIRUS 60 IS FOUND ON THE INTERIOR CAPSID SUR FACE AND MAY CONTRIBUTE TO PARTICLE ASSEMBLY AND STABILITY OR TO BINDING AND ENTRY OF VIRUS INTO CELLS ;= 60 HAS NOT BEEN CONCLUSIVELY DEMONSTRATED IN (!6 PARTICLES )F IT EXISTS IT IS MUCH SMALLER THAN OTHER PICORNAVIRAL 60 MOLECULES AND NOT MYRISTOYLATED ;= 4HE NUCLEOCAPSID CONTAINS CAPSOMERES ,IKE OTHER PICORNAVIRUSES (!6 HAS NO ENVELOPE &IG &IRST C$.! CLONES HAVE BEEN PRODUCED IN ;= AND FIRST INFECTIOUS C$.! CLONES OF (!6 WERE SUCCESSFULLY GENERATED IN ;= MAKING THIS VIRUS ACCESSIBLE TO MOLECULAR BIOLOGY 4HE VIRION CONTAINS ONE COPY OF LINEAR POSITIVE SENSE SINGLE STRANDED 2.! WITH A RELATIVELY LOW ' # CONTENT OF 4HE (!6 GENOME IS KB IN SIZE AND CAN BE DIVIDED INTO THREE
124
Manfred H. Wolff and Axel Schmidt
Figure 1. Electron microscopic image of HAV (Hepatitis A virus/strain HM 175); the bar represents 60 nm.
parts: (i) a 5’ non-coding region (NCR) that comprises approximately 10% of the genome, (ii) an open reading frame that encodes all of the viral proteins and (iii) a short NCR [16]. RNA sediments at 33 S and has a buoyant density of 1.33 g/mL [9]. With RNA extracted from cells or transcribed from cloned amplified cDNA cultured cells can be transfected [9, 18]. RNA also has been translated in vitro demonstrating that the viral genome follows the same translation strategy as the monocistronic genomes of the other picornaviruses [19]. The 5’ untranslated region functions as an internal ribosome entry site to which the genome-linked protein VPg is covalently linked. The virus enters the cell by acid-independent receptor-mediated endocytosis. Genomic replication occurs within the cytoplasm, and the corresponding replicase is a virus-encoded 3D RNA-dependent RNA polymerase which generates partially double-stranded replicative intermediate RNA. The egress mechanism after virion assembly within cytoplasmatic membrane vesicles is still unknown and a matter of current research. Although 3–7 genotypes of HAV have been characterised [20, 21], only one major serotype can be defined so that there appears to be no variation detectable by serology in these neutralisation sites.
(EPATITIS ! INFECTION
&IGURE )NACTIVATION OF (!6(EPATITIS ! VIRUS STRAIN (- ! BY HEATTEMPERATURE " WITH DIFFERENT ALCOHOLS # WITH GLUTARALDEHYDE AND $ WITH PERACETIC ACID -( 7OLFF AND 3 0ROBST UNPUBLISHED DATA
6IRUS STABILITY /NE OF THE MAIN PROPERTIES OF (!6 IS ITS HIGH STABILITY NOT ONLY WITH REGARD TO ENVIRONMENTAL INFLUENCES BUT EVEN CHEMICALS ,IKE MANY OTHER VIRUSES (!6 CAN EASILY SURVIVE LOW TEMPERATURE AND FREEZING %VEN IN FRESH OR SALT WATER IT PERSISTS AT LEAST UP TO MONTHS )T CAN SURVIVE SEVERAL HOURS ON HUMAN HANDS AND SEVERAL DAYS ON ENVIRONMENTAL SURFACES INDOORS WHICH CAN LEAD TO TRANSMISSION ESPECIALLY AT PLACES WITH POOR HYGIENE ;n= ,IKE MOST PICORNAVIRUSES WHICH ARE STABLE BETWEEN P( TO OVER A PERIOD OF MANY HOURS (!6 SURVIVES ACID TREATMENT OF LOWER P( 7HEN SUBJECTED TO P( AT ROOM TEMPERATURE THE INFECTIVITY WAS RETAINED FOR UP TO H ;= 4HIS MAKES IT UNDERSTANDABLE THAT THE VIRUS AFTER TRANSMISSION AND PASSING THE STOMACH CAN SURVIVE IN THE FAECES IN WHICH ITS INFECTIVITY CAN BE RETAINED FOR WEEKS EVEN UNDER DRIED CONDITIONS (!6 IS ALSO ASSOCIATED WITH FOOD BORNE OUTBREAKS )N THIS CONNECTION THE TEMPERATURE STABILITY IS OF HIGH INTEREST (!6 IS RELATIVELY RESISTANT TO HEAT ;= 4HE INFECTIVITY IS NOT OR ALMOST NOT AFFECTED WITHIN H IF VIRUS IS INCUBATED AT ª# )NCREASED TEMPERATURES OVER ª# n EG AT ª# n LEAD TO A FAST AND SIGNIFICANT INAC TIVATION OVER SEVERAL LOG STEPS RESPECTIVELY -( 7OLFF 3 0ROBST UNPUB LISHED RESULTS &IG A "Y AUTOCLAVING ULTRAVIOLET IRRADIATION 7 AT A
126
Manfred H. Wolff and Axel Schmidt
Figure 3. HAV: Cytopathic effect (CPE) in FRhK- 4 cells: typical CPE occurs 7 days post infectionem: A) Control (mock-infected), B) HAV-infected: typical CPEs
depth of 0.9 cm for 1 min) or formalin treatment (3% for 5 min) the virus will be destroyed rapidly [27, 28]. Against chemicals, especially such which are contained in disinfectants, HAV is relatively resistant. Inactivation by glutaraldehyde or peracetic acid (Figs 2c and 2d) is possible in a proper time and concentration, whereas alcohols are not able to decrease the infectivity in a suitable time (Fig. 2b).This is problematic because hand disinfectants usually contain alcohols. In our hands none of the tested commercially available disinfectants showed a log 10 reduction factor which satisfies the requirements of the corresponding German authorities (BGA/DVV; M.H. Wolff, S. Probst, unpublished results), internationally representative as key opinion leaders within this field.
Propagation in cell culture It is still difficult to grow HAV in cell culture. Especially the isolation of wild-type virus from the faeces of a patient often fails. HAV shows a strong tissue tropism. Permissive cell lines are the AGMK, FRhK-4, and BSC-1 cell-line. There are several virus strains which are used for research; the cytopathic HAV variant HM 175 characterised by T. Cromeans et al. (1989) [29] is frequently used for studies. This strain can be propagated in foetal rhesus monkey kidney cells (FRhK-4). On these cells a typical cytopathic effect (CPE) is visible 10–14 days after infection (Fig. 3).
Transmission Transmission of HAV usually occurs by the faecal-oral route either by direct close contact with infected persons or by ingestion of virus-contaminated water or food. In these cases the amount of virus incorporated plays an
(EPATITIS ! INFECTION
IMPORTANT PART )NFECTED PEOPLE EXCRETE n VIRUS PARTICLES PER GRAM OF STOOL BUT ALREADY AN INFECTION DOSE OF ONLY TO VIRUS PARTICLES LEADS TO INFECTION )N SO FAR (!6 IS A POTENT PATHOGEN WHICH HAS BEEN RESPONSIBLE FOR MANY FOOD BORNE OUTBREAKS 4HE FOOD IMPLICATED IN THESE OUTBREAKS MAINLY IS SHELLFISH )NFECTIONS ARE ALSO DESCRIBED AFTER CONSUMPTION OF CONTAMINATED RAW OYSTERS MUSSELS AND CLAMS ;n= %VEN IF THE FOOD IS HEATED INFECTIONS ARE POSSIBLE BECAUSE n AS MENTIONED ABOVE n THE USED TEMPERATURE AND HEATING TIME USUALLY IS NOT SUFFICIENT TO INACTIVATE THE VIRUS )NFECTIONS HAVE ALSO BEEN CAUSED BY SALADS FRUITS VEGETABLES AS WELL AS DAIRY PRODUCTS SANDWICHES BAKED PRODUCTS ; = AND CREAM FILLED COOKIES ;= "UT THERE ARE ALSO STUDIES DESCRIBING THE TRANSMISSION IN HOMOSEXUAL MEN AND IT IS EVEN ASSERTED THAT HOMOSEXUAL MEN ARE THE MOST IMPORTANT RISK GROUP FOR THE TRANSMISSION OF (!6 INFECTION ;= %VEN THOUGH (!6 IS AN ENTEROVIRUS AND USUALLY TRANSMITTED BY FAECAL ORAL ROUTE THERE ARE SINGLE OBSERVATIONS WHICH SHOW A TRANSMISSION BY BLOOD OR BLOOD PRODUCTS ; = SO THAT ALSO CASES OF INFECTION IN INDIVIDUALS WITH INTRAVENOUS DRUG ADDICTION HAVE BEEN REPORTED 4HERE IS ALSO A RISK FOR INFECTION FOR PEOPLE WORKING WITH WASTE WATER MANAGEMENT
0ATHOGENESIS AND CLINICAL FEATURES )N CONTRAST TO HEPATITIS " AND # WHICH CONTRIBUTE TO APPROXIMATELY OF ALL CASES OF HUMAN HEPATOCELLULAR CARCINOMA HEPATITIS ! INFECTION IS NOT A PREDISPOSITION FOR HEPATIC MALIGNANCIES ;= !FTER INGESTION (!6 PASSES THE STOMACH BECAUSE OF ITS P( STABILITY AND CAN ENTER THE SMALL INTESTINE AND REACH THE LIVER VIA THE VENA PORTAE 4HE FURTHER STAGES OF THE INFECTION ROUTE STARTING IN THE GASTROINTESTINAL TRACT AND RESULTING IN HEPATITIS ARE STILL NOT COMPLETELY UNDERSTOOD 9ET SOME OBSERVATIONS ARE WELL DOCUMENTED REPLICATION SITE ARE THE HEPATOCYTES MOST PREDOMINANT n WEEKS AFTER INFECTION AND A VIREMIA TYPICALLY VIRUS PARTICLES PER M, BLOOD IS OBSERVED DURING THE INCUBATION TIME OF APPROXIMATELY n WEEKS AFTER INFECTION !T THE SAME TIME INFECTIOUS VIRUS REACHES THE INTESTINAL TRACT IN THE BILE AND OCCURS IN THE FAECES ;= 4HE DAMAGE OF THE HEPATOCYTES RESULTING IN HEPATITIS MIGHT BE CAUSED BY THE CYTOTOXITY OF (!6 LIKE WITH OTHER PICORNAVIRUSES WHICH EXIT THE HOST CELL BY DISINTEGRATION -OST OBVIOUSLY IT IS MAINLY OF IMMUNOLOGICAL ORIGIN NECROTIC APOPTOTIC IN VITRO STUDIES HAVE SHOWN EVIDENCE OF CELL MEDIATED LYSIS OF (!6 INFECTED CELLS BY NATURAL KILLER CELLS AND BY (,! RESTRICTED (!6 SPECIFIC #$ CYTOTOXIC 4 CELLS THAT WERE CLONED FROM LIVER BIOPSIES OBTAINED DURING ACUTE HEPATITIS ! IN PATIENTS WITH HEPATOCELLULAR NECROSIS ; = 4HIS IMMUNOLOGICAL PROCESS IS GENERALLY INITIATED IN THE INFECTED HOST MOSTLY n WEEKS AFTER INFECTION 4HE ISOLATION OF CYTOTOXIC 4 LYMPHOCYTES FROM LIVER TISSUE OF PATIENTS WITH ACUTE HEPATITIS ! INFECTION GIVES SOME EVIDENCE THAT THE HEPATOCELLULAR
-ANFRED ( 7OLFF AND !XEL 3CHMIDT
DAMAGE MIGHT PRIMARILY BE DUE TO A CELLULAR IMMUNE RESPONSE )N THE ACUTE PHASE NECROTIC INFLAMMATORY CHANGES ARE OBSERVED PREDOMINANTLY IN THE PERIPORTAL REGION ALSO CONTAINING INFILTRATES OF PLASMA CELLS (!6 ANTIGEN CAN FURTHER BE FOUND WITHIN THE HEPATOCYTES AND +UPFFER CELLS ;= !CUTE VIRAL HEPATITIS ! " AND # CANNOT BE DISCRIMINATED BY MACROMORPHOLOGICAL AND HISTOPATHOLOGICAL FEATURES LIGHT MICROSCOPY 4HE HISTOPATHOLOGY OF ACUTE VIRAL HEPATITIS IS COMPREHENSIVELY DESCRIBED IN TEXTBOOKS OF PATHOLOGY AND CAN BE REVISITED THERE 4HE INCUBATION PERIOD RANGES FROM n WEEKS AND THE COURSE OF HEP ATITIS ! MAY BE EITHER INAPPARENT OR SUBCLINICAL WHICH MEANS ANICTERIC %SPECIALLY IN CHILDREN THE DISEASE IS MILDER AND IN n OF CASES INAP PARENT )N YOUNG CHILDREN (!6 INFECTION IS USUALLY ASYMPTOMATIC WHEREAS SYMPTOMATIC DISEASE OCCURS MORE COMMONLY AMONG ADULTS WITH ICTERUS IN MORE THAN OF THE INFECTED INDIVIDUALS 0REGNANCY DOES NOT SEEM TO HAVE ANY IMPACT ON INCIDENCE AND SEVERENESS OF THE DISEASE $ESPITE OF THIS FOR THE PATIENTS AND NEWBORNS SAFETY A VACCINATION WITH AN INACTIVATED VAC CINE CAN BE TAKEN INTO CONSIDERATION PRIOR TO INTENDED PREGNANCY IN CASE OF PERSONS WITH RISK FACTORS FOR HEPATITIS ! )N LESS THAN n OF THE CASES CLINICAL SIGNS SUCH AS ICTERUS SERUM BILIRUBIN MGD, FLU LIKE SYMPTOMS FEVER FATIGUE MYALGIA POLYARTHRITIS NAUSEA ABDOMINAL DISCOMFORT JAUN DICE AND GLOMERULONEPHRITIS AUTOIMMUNOLOGICAL ARE OBVIOUS 3YMPTOMS GENERALLY SUBSIDE WHEN THE DISEASE ENTERS THE ICTERIC PHASE INTRAHEPATIC CHOLESTASIS /FTEN A PALE COLOUR OF THE FAECES IS OBSERVED AND A DARKER COLOUR OF THE URINE BILIRUBINURIA 4HE DISEASE IS CLINICALLY DIVIDED INTO THREE PHASES I THE UNSPECIFIC @PRODROMAL PHASE THE II @ICTERIC PHASE AND III THE @RECONVALESCENCE PHASE 7ITHIN THE LAST PHASE THERE IS TYPICALLY AN AVERSION AGAINST CONSUMPTION OF ALCOHOL AND FATTY FOOD WHICH IS KNOWN AS @POSTHEPATIC SYNDROME -OSTLY THE DISEASE IS SELF LIMITING WITHIN A PERIOD OF SOME WEEKS ALTHOUGH n IN RARE CASES n PROLONGED COURSES OF INFECTION OF n YEARS HAVE BEEN REPORTED 2ARE COMPLICATIONS OF HEPATITIS ! INCLUDE RELAPSING HEPATITIS CHOLESTATIC HEPATITIS AND FULMINANT HEPATITIS #HRONIC INFECTION WITH (!6 DOES NOT OCCUR AND INFECTION INDUCES LIFE LONG IMMUNITY 4HE MORTALITY RATE IS VERY LOW IN CHILDREN ABOUT AND IN ADULTS n 4HE MORTALITY RATE CAN BE HIGHER IN IMMUNOSUPPRESSED PATIENTS
,ABORATORY DIAGNOSTICS (ISTORICALLY IMMUNE ELECTRON MICROSCOPY OF STOOL AND SERUM SPECIMENS PLAYED A ROLE IN DIAGNOSTICS OF (!6 INFECTION $UE TO THE RAPID DECLINE OF VIRUS TITRES DURING INFECTION THESE APPROACHES WERE ONLY SUCCESSFUL DURING THE VERY EARLY PHASE OF INFECTIONINCUBATION PERIOD 4HE DIAGNOSIS OF HEPATITIS IN GENERAL IS MADE BY BIOCHEMICAL TESTS OF TRANSAMINASES ESPECIALLY !,4 !,!4 ALANINE AMINOTRANSFERASE AND ALSO
(EPATITIS ! INFECTION
&IGURE $EVELOPMENT OF SPECIFIC VIRUS ANTIGEN AND ANTIBODY TITRES DURING TYPICAL COURSE OF HEPATITIS ! INFECTION
!34 !3!4 ASPARTATE AMINOTRANSFERASE AND SHOULD BE PERFORMED IN PATIENTS AT RISK FOR ACUTE HEPATITIS ! INFECTION )N ACUTE HEPATITIS ! INFECTION THEY REACH VALUES OF LOG OF THE UPPER REFERENCE LEVEL AND THE QUOTIENT !34 !3!4 !,4 !,!4 IS TYPICALLY LOWER THAN IN CASE OF (!6 INFECTION 4HESE ENZYMES ARE A VERY SENSITIVE MARKER OF HEPATOCELLULAR DAMAGE )T SHOULD BE MENTIONED THAT IN FULMINANT CASES OF LIVER FAILURE TRANSAMINASE TITRES MAY EVEN DECLINE AGAIN DUE TO THE LACK OF INTACT LIVER TISSUE HEPA TOCELLULAR @BURNED OUT PHENOMENON "UT WITH THESE BIOCHEMICAL ASSESS MENTS AS WELL AS WITH CLINICAL OBSERVATION A DIFFERENTIATION BETWEEN THE DIFFERENT HEPATITIS VIRUSES AS RESPONSIBLE INFECTIOUS AGENT IS NOT POSSIBLE 4HEREFORE SPECIFIC ASSAYS FOR ANTI (!6 )G- AND ANTI (!6 )G' HAVE TO BE USED !LTHOUGH INFECTIOUS VIRUS OCCURS IN HIGH AMOUNTS IN FAECES AND COULD BE EASILY DETECTED BY IMMUNE ELECTRON MICROSCOPY THE DIRECT PROOF IN STOOL SPECIMENS IS NOT PRACTICAL BECAUSE THE VIRUS EXCRETION REACHES ITS MAXIMUM ALREADY IN THE LATE PHASE OF THE INCUBATION PERIOD &IG 4HE %,)3!%)! )G- ANTI (!6 SHOULD BEBECOME POSITIVE DURING THE APPARENT PHASE OF INFECTION AND MIGHT STAY POSITIVE FOR UP TO YEARS IN CASE OF SEVERE INFECTION )NTERESTINGLY IN RARE CASES THE TOTAL AMOUNT OF SERUM )G- SERUM ELECTROPHORESIS IS UPREGULATED IN (!6 INFECTION A PHENOM ENON WHICH IS NOT SUFFICIENTLY UNDERSTOOD AND MIGHT ALSO CAUSE UNSPECIFIC CROSS REACTIONS WITH OTHER INFECTIOUS ANTIGENS WHICH HAS TO BE TAKEN INTO DIAGNOSTIC CONSIDERATION /N THE OTHER HAND A LACKING %,)3! )G- ANTI (!6 TITRE DOES NOT EXCLUDE AN APPARENT ACUTE HEPATITIS ! IN RARE CASES
-ANFRED ( 7OLFF AND !XEL 3CHMIDT
$URING THE INCUBATION PERIOD SERUM )G- ANTI (!6 IS GENERALLY NEGATIVE 0OSITIVE )G- ANTI (!6 RESULTS HAVE TO BE CONFIRMED BY AN %,)3!%)! DETERMINATION OF TOTAL ANTI (!6 ANTIBODIES )N THE EARLY PHASE OF INFECTION INCUBATION PERIOD (!6 ANTIGEN CAN BE DETERMINED IN STOOL AND SERUM SPECIMEN VIA ANTIGEN %,)3!%)! OR CORRE SPONDING MOLECULAR DIAGNOSTIC APPROACHES SUCH AS 240#2 !FTER AN INFEC TION n WHETHER CLINICALLY APPARENT OR INAPPARENT n THE ANTI (!6 ANTIBODY STATUS GENERALLY REMAINS POSITIVE LIFE LONG AND APPEARS TO OFFER A SUFFICIENT PROTECTION AGAINST RE INFECTION WITH (!6 .EW MOLECULAR APPROACHES FOR DIAGNOSTICS OF HEPATITIS ! INFECTION ARE CURRENTLY UNDER EVALUATION INCLUDING THE ATTEMPT TO OBTAIN A BETTER UNDER STANDING OF HEPATITIS ! PATHOBIOLOGY ITSELF ;=
0ROTECTION AND VACCINATION 3EVERAL INACTIVATED OR LIVE ATTENUATED VACCINES AGAINST (!6 HAVE BEEN DEVELOPED AND CURRENTLY FOUR INACTIVATED VACCINES ARE INTERNATIONALLY AVAIL ABLE #ELL TROPISM AND ATTENUATION ARE REVIEWED BY * 'RAFF ET AL ;= 4HE VACCINES ARE MANUFACTURED FROM A CELL CULTURE ADAPTED VIRUS STRAIN EG (!6 STRAIN ( PROPAGATED IN HUMAN FIBROBLAST ATTENUATION PROCEDURE SERIAL PASSAGES FROM MONKEY KIDNEY CELLS TO HUMAN FIBROBLASTS FOLLOWED BY PURIFICATION FROM CELL LYSATES FORMALIN INACTIVATION AND ADSORPTION TO ALUMINIUM HYDROXIDE ADJUVANT ;= 4HE VACCINES ARE GIVEN PARENTERALLY AS A TWO DOSE SERIES n MONTHS APART 4HEY ARE HIGHLY EFFICACIOUS AND PROVIDE LONG LASTING PROTECTION ; = ! LIFE VACCINE IS ESPECIALLY WIDELY USED AND ACCEPTED IN THE 0EOPLES 2EPUBLIC OF #HINA WITH EG A CUMULATIVE VACCINATION COVERAGE OF OVER IN *IAOJIANG #ITY AMONG CHILDREN WHICH WERE n YEARS OLD ;= %SPECIALLY FROM THE BROAD VACCINATION ATTEMPTS IN THE 0EOPLES 2EPUBLIC OF #HINA THE PROTECTIVE EFFICACY OF THE ( LIFE VACCINE SEEMED EXCELLENT 4HE ATTENUATED ( VACCINE WAS INTRODUCED IN #HINA IN FOLLOWED BY THE INTRODUCTION OF THE INACTIVATED (- VACCINE AND THE INACTIVATED #2 VACCINE IN MANY COUNTRIES WORLDWIDE .ON RESPONDERS LIKE IN CASE OF HEPATITIS " VACCINATION ARE GENERALLY NOT OBSERVED AND IT APPEARS THAT A SUFFICIENT PROTECTION AGAINST INFECTION CAN BE ACHIEVED FOR A PERIOD OF OVER YEARS AFTER A SUFFICIENT VACCINATION WITH A TWO DOSE APPLICATION VACCINATION REGIMEN 4HERE ARE ALSO COMBINATION VACCINES AVAILABLE CONTAINING INACTIVATED (!6 AND RECOMBINANT ("6 4HIS VACCINE IS GIVEN AS A THREE DOSE SERIES USING A MONTH VACCINATION SCHEDULE &URTHER A COMBINATION VACCINE AGAINST HEPATITIS ! AND 3ALMONELLA TYPHI IS AVAILABLE 4HERE IS CONVINCING EVIDENCE THAT THE VACCINE CONFERS HERD IMMUNISATION IF THE MAIN SPREADERS OF (!6 ARE TARGETED FOR IMMUNISATION 4HIS SHOULD ENCOURAGE COUNTRIES TO START MASS VACCINATION PROGRAMMES AGAINST (!6
(EPATITIS ! INFECTION
ESPECIALLY AS PHARMACOECONOMIC CONSIDERATIONS ARE BEGINNING TO DEMON STRATE THAT SUCH A STRATEGY COULD BE A HIGHLY COST EFFECTIVE WAY OF CONTROLLING THIS DISEASE )T IS EVEN CONCEIVABLE TO ERADICATE (!6 4HIS SHOULD EVEN BE EASIER TO ACHIEVE THAN THE ATTEMPT OF POLIO ERADICATION AS (!6 VACCINES SEEM TO CONFER MORE DURABLE IMMUNITY THAN POLIO VACCINES DO 0HYSICIANS SHOULD CONSIDER ROUTINE VACCINATION OF CHILDREN n MONTHS OF AGE BASED ON REC OMMENDATIONS FROM THE #ENTERS FOR $ISEASE #ONTROL AND 0REVENTION #$# !TLANTA 53! ;= &URTHER RESEARCH ON OPTIMISING THE VACCINATION AND DEVELOPING NEW VAC CINES n ESPECIALLY UNDER THE PERSPECTIVE OF REDUCING THE SOMETIMES OCCUR RING MOSTLY MILD ADVERSE REACTIONS n ARE ONGOING
0OST EXPOSURE IMMUNOTHERAPY ! POST EXPOSURE IMMUNOTHERAPY WITH (!6 HYPERIMMUNOGLOBULIN PREPA RATIONS SERA OF HUMAN ORIGIN CAN BE SUCCESSFUL IN PREVENTING INFECTION OR GENERATING A MILDER COURSE OF INFECTION 4HESE PREPARATIONS SHOULD BE ADMIN ISTERED TO THE PATIENT AS SOON AS POSSIBLE AFTER POTENTIAL EXPOSUREINFECTION n DAYS AFTER EXPOSURE AT THE LATEST )N THE LAST TWO DECADES THE AVAILABILITY OF SUCH PREPARATIONS UNFORTUNATELY DECREASED SIGNIFICANTLY MOSTLY DUE TO THE ACTIVITIES AND OPTIONS RELATED TO ACTIVE VACCINATION %MPIRICALLY THE DOSE AIMED BY PHYSICIANS IS n M,KG BODY WEIGHT OF THE HYPERIMMUNO GLOBULIN PREPARATION AS MENTIONED ABOVE ADMINISTERED IM
4HERAPEUTIC OPTIONS (EPATITIS ! SHOULD BE REGARDED AS A PREVENTABLE MEDICAL THREAT AND SUFFI CIENT PRECAUTIONS OF PREVENTION SHOULD BE TAKEN INTO CONSIDERATION AS THERE ARE NO SPECIFIC THERAPEUTIC OPTIONS AGAINST ACUTE HEPATITIS ! 4HIS SHOULD ESPECIALLY BE CONSIDERED BEFORE TRAVELLING INTO ENDEMIC REGIONS )N SEVERE CASES THE PATIENT SHOULD BE HOSPITALISED AND THE CONSUMP TION OF ANY DRUGS SHOULD BE REDUCED TO THE MEDICALLY NECESSARY MINIMUM &URTHER THERE SHOULD BE NO ALCOHOL CONSUMPTION THE PATIENT SHOULD STRICTLY STAY IN BED AND COAGULATION HAS TO BE MONITORED AND n IN CASE OF COAGULO PATHIAS n TO BE TREATED /N THE OTHER HAND n FORTUNATELY n MANY CASES OF HEPATITIS ! INFECTION ARE INAPPARENT OR HAVE A MILD COURSE OF INFECTION ANDOR ARE SELF LIMITING SO THAT NO THERAPEUTIC INTERVENTION IS NECESSARY )N CASE OF LIVE THREATENING FULMINANT ACUTE HEPATITIS ANDOR HEPATIC ENCEPHALOPATHIA DUE TO ACUTE LIVER FAILURE WHICH IS AN UNCOMMON BUT POTENTIAL EVENT IN HEPATITIS ! INFECTION LIVER TRANSPLANTATION IS THE ULTIMA RATIO FOR THERAPEUTIC INTERVENTION #OMPLEMENTARY SELECTIVE GUT DECONTAMI
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NATION BY ANTIBIOTICS MIGHT BE TAKEN INTO CONSIDERATION IN ORDER TO REDUCE TOXIN PRODUCTION WITHIN THE ') TRACT 4HE FREQUENCY OF PATIENTS REQUIRING LIVER TRANSPLANTATION FOR (!6 HAS DECREASED FROM TO IN THE 5./3 DATABASE IN THE TIME PERIOD FROM TO 4HE TRANSPLANTDEATH RATIO IS REPORTED WITHIN THE RANGE OF APPROXIMATELY AND DUE TO DIF FERENT SCORES AND STUDIES ;=
2EFERENCES
4IDONA #! $ARAI ' EDS 4HE 3PRINGER )NDEX OF 6IRUSES 3PRINGER 0UBL "ERLIN !NDERSON $! (EPATOVIRUS )N #! 4IDONA ' $ARAI EDS )N 4HE 3PRINGER )NDEX OF 6IRUSES 3PRINGER 0UBL "ERLIN n -INOR 0 0ICORNAVIRIDAE )N 2)" &RANCKI #- &AUQUET $, +NUDSON & "ROWN EDS )N #LASSIFICATION AND .OMENCLATURE OF 6IRUSES !RCH 6IROL 3 3PRINGER 0UBL 7IEN n (U 9 (U . ,IU ' #OMPLETE GENOMES OF TWO HUMAN HEPATITIS ! VIRUS ISOLATES FROM #HINA ANALYSIS AND COMPARISON WITH OTHER ISOLATES !CTA 6IROL n &EINSTONE 3- +APIKIAN !: 0URCELL 2( (EPATITIS ! $ETECTION BY IMMUNE ELECTRONE MICROSCOPY OF VIRUS LIKE ANTIGEN ASSOCIATED WITH ACUTE ILL NESS 3CIENCE n 0ROVOST 0* (ILLEMANN -2 0ROPAGATION OF HUMAN HEPATITIS ! VIRUS IN CELL CULTURE IN VITRO 0ROC 3OC %XP "IOL -ED n ,OCARNINI 3! #OULEPIS !' &ERRIS !! ,EHMANN .) 'UST )$ 0URIFICATION OF HEPATITIS ! VIRUS FROM HUMAN FECES )NTERVIROLOGY n #OULEPIS !' ,OCARNINI 3! &ERRIS !! ,EHMANN .) 'UST )$ 4HE POLY PEPTIDES OF HEPATITIS ! VIRUS )NTERVIROLOGY n #OULEPIS !' 4ANNOCK '! ,OCARNINI 3! 'UST )$ %VIDENCE THAT THE GENOME OF HEPATITIS ! VIRUS CONSISTS OF SINGLE STRANDED 2.! * 6IROL n ,EMON 3- "INN ,. !NTIGENIC RELATEDNESS OF TWO STRAINS OF HEPATITIS ! VIRUS DETERMINED BY CROSS NEUTRALIZATION )NFECT )MMUN n ,EMON 3- #HAO 3& *ANSEN 27 "INN ,. ,E$UC *7 'ENOMIC HETERO GENEITY AMONG HUMAN AND NON HUMAN STRAINS OF HEPATITIS ! VIRUS * 6IROL n .AINA /6 "RINTON -! -ARGOLIS (3 )DENTIFICATION OF AMINO ACIDS LOCATED IN THE ANTIBODY BINDING SITES OF HUMAN HEPATITIS ! VIRUS 6IROLOGY n 3ATTAR 3! 3PRINGTHORPE 63 +ARIM 9 ,ORO 0 #HEMICAL DISINFECTION OF NON POROUS INANIMATES SURFACES EXPERIMENTALLY INFECTED WITH FOUR HUMAN PATHOGENIC VIRUSES %PIDEMIOL )NFECT n !TMAR 2, -ATCALF 4' .EILL &( $ETECTION OF ENTERIC VIRUSES IN OYSTERS BY USING THE POLYMERASE CHAIN REACTION !PPL %NVIRON -ICROBIOL n #HOW - .EWMAN *&% &ILMAN $ (OGLE *- 2OWLANDS $* "ROWN &
(EPATITIS ! INFECTION
-YRISTYLATION OF PICORNAVIRUS CAPSID PROTEIN 60 AND ITS STRUCTURAL SIGNIFICANCE .ATURE n (OLLINGER &" 4ICEHURST *2 (EPATITIS ! VIRUS )N ". &IELDS $- +NIPE 0- (OWLEY EDS )N &IELDS 6IROLOGY ,IPPINCOTT 2AVEN 0UBL 0HILADELPHIA n 4ICEHURST *2 2ACANIELLO 62 "AROUDY "- "ALTIMORE $ 0URCELL 2( &EINSTONE 3- -OLECULAR CLONING AND CHARACTERIZATION OF HEPATITIS ! VIRUS C$.! 0ROC .ATL !CAD 3CI 53! n #OHEN *, 4ICEHURST *2 &EINSTONE 3- 2OSENBLUM " 0URCELL 2( (EPATITIS ! 6IRUS C$.! AND ITS 2.! TRANSCRIPTS ARE INFECTIOUS IN CELL CULTURES * 6IROL n 'AUSS -UELLER 6 VON DER (ELM + $EINHARDT & 4RANSLATION IN VITRO OF HEPATITIS ! VIRUS 2.! 6IROLOGY n #OSTA -ATTIOLI - $I .APOLI ! &ERRE 6 "ILLAUDEL 3 0EREZ "ERCOFF 2 #RISTINA * 'ENETIC VARIABILITY OF HEPATITIS ! VIRUS * 'EN 6IROL n &UJIWARA + 9OKOSUKA / (EPATITIS ! VIRUS GENOTYPES .IPPON 2INSHO 3 n 3ATTAR 3 4ETRO * "IDAWID 3 &ARBER * &OODBORN SPREAD OF HEPATITIS ! 2ECENT STUDIES ON VIRUS SURVIVAL TRANSFER AND INACTIVATION #AN * )NFECT $IS n -BITHI *. 3PRINGTHORPE 63 "OULET *2 3ATTAR 3 3URVIVAL OF HEPATITIS ! VIRUS ON HUMAN HANDS AND ITS TRANSFER ON CONTACT WITH ANIMATE AND INANIMATE SURFACES * #LIN -ICROBIOL n -BITHI *. 3PRINGTHORPE 63 3ATTAR 3 %FFECT OF RELATIVE HUMIDITY AND AIR TEMPERATURE ON SURVIVAL OF HEPATITIS ! VIRUS ON ENVIRONMENTAL SURFACES !PPL %NVIRON -ICROBIOL n 0ROVOST 0* 7OLANSKI "3 -ILLER 7* )TTENSOHN /, -C!LEER 7* (ILLEMAN -2 0HYSICAL CHEMICAL AND MORPHOLOGIC DIMENSIONS OF HUMAN HEPATITIS ! VIRUS STRAIN #2 0ROC 3OC %XP "IOL -ED n 0ARRY *6 -ORTIMER 00 4HE HEAT SENSITIVITY OF HEPATITIS ! VIRUS DETER MINED BY SIMPLE TISSUE CULTURE METHOD * -ED 6IROL n #OULEPIS !' !NDERSON ". 'UST )$ (EPATITIS ! !DV 6IRUS 2ES n 7OLFF -( 3CHMITT * 2AHAUS - +ÚNIG ! (EPATITIS ! VIRUS A TEST METHOD FOR VIRUCIDAL ACTIVITY * (OSP )NFECT n #ROMEANS 4 &IELDS (! 3OBSEY -$ +INETIC STUDIES OF A RAPIDLY REPLI CATING CYTOPATHIC HEPATITIS ! VIRUS )N !* :UCKERMAN ED 6IRAL (EPATITIS AND ,IVER $ISEASE !LAN 2 ,ISS 0UBL .EW 9ORK n $ESENCLOS *#! +LONTZ +# 7ILDER -( .AINAN /6 -ARGOLIS (3 'UNN 2! ! MULTISTATE OUTBREAK OF HEPATITIS ! CAUSED BY THE CONSUMPTION OF RAW OYSTERS !M * 0UBLIC (EALTH n %NRIQUES 2 &ROSNER '' (OCHSTEIN -INTZEL 6 2IEDMANN 3 2EINHARDT ' !CCUMULATION AND PERSISTENCE OF HEPATITIS ! VIRUS IN MUSCLES * -ED 6IROL n (ALLIDAY -, +ANG ,9 :HOU 4+ (U -$ 0AN 1# &U 49 (UANG 93 (U 3, !N EPIDEMIC OF HEPATITIS ! ATTRIBUTABLE TO THE INGESTION OF RAW CLAMS IN 3HANGHAI #HINA * )NFECT $IS n
-ANFRED ( 7OLFF AND !XEL 3CHMIDT
#ILVER $/ 6IRUS TRANSMISSION VIA FOOD 7ORLD (EALTH 3TAT 1 n &EINSTONE 3- (EPATITIS ! EPIDEMIOLOGY AND PREVENTION %UR * 'ASTROENTEROL (EPATOL n 4JONG ' 8IRIDOU - #OUNTINHO 2 "RUISTEN 3 $IFFERENT TRANSMISSION PATTERNS OF HEPATITIS ! VIRUS FOR TWO MAIN RISK GROUPS AS EVIDENCE BY MOLECULAR CLUSTER ANALYSIS * -ED 6IROL n #HUDY - "UDEK ) +ELLER 3TANISLAWSKI " -C#AUSTLAND +! .EIDHOLD 3 2OBERTSON "( .UBLING #- 3EITZ 2 ,OWER * ! NEW CLUSTER OF HEPATITIS ! INFECTION IN HEMOPHILIACS TRACED TO A CONTAMINATED PLASMA POOL * -ED 6IROL n "RUNDAGE 3# &ITZPATRICK !. (EPATITIS ! !M &AM 0HYSICAN n 'OESER 4 +ERN 0 'ERLICH 7( ,EBER ,IVER )N 2 -ARRE 4 -ERTENS - 4RAUTMANN % 6ANEK EDS )N +LINISCHE )NFEKTIOLOGIE #LINICAL )NFECTIOLOGY 5RBAN &ISCHER 0UBL -àNCHEN n 6ALLBRACHT ! (OFFMANN , 7URSTER +' &LEMIG " 0ERSISTENT INFECTION OF HUMAN FIBROBLASTS BY HEPATITIS ! VIRUS * 'EN 6IROL n 6ALLBRACHT ! -AIER + 3TIERHOF 9$ 7IEDEMANN +( &LEMMIG " &LEISCHER " ,IVER DERIVED CYTOTOXIC 4 CELLS IN HEPATITIS ! VIRUS INFECTION * )NFECT $IS n $IENSTAG *, 4HE PATHOBIOLOGY OF HEPATITIS ! VIRUS )NT 2EV %XP 0ATHOL n .AINAN /6 8IA ' 6AUGHAN ' -ARGOLIS (3 $IAGNOSIS OF HEPATITIS ! VIRUS INFECTION A MOLECULAR APPROACH #LIN -ICROBIOL 2EV n 'RAFF * .ORMANN ! &EINSTONE 3- &LEHMIG " .UCLEOTIDE SEQUENCE OF WILD TYPE HEPATITIS ! VIRUS '"- IN COMPARISON WITH TWO CELL CULTURE ADAPTED VARIANTS * 6IROL n -AO *3 #HAI 3! 8IE 29 #HEN ., *IANG 1 :HU 8: :HANG 39 (UANG (9 -AO (7 "AO 8. ET AL &URTHER EVALUATION OF THE SAFETY AND PROTECTIVE EFFICACY OF LIVE ATTENUATED HEPATITIS ! VACCINE ( STRAIN IN HUMANS 6ACCINE n &EINSTONE 3- 'UST )$ (EPATITIS ! VACCINE )N 3! 0LOTKIN 7! /RESTEIN EDS 6ACCINES 7" 3AUNDERS 0UBL 0HILADELPHIA n )NNIS ", 3NITBHAN 2 +UNASOL 0 ,AORAKPONGSE 4 0OOPATANAKOOL 7 +OZIK #! 3UNTAYAKORN 3 0ROTECTION AGAINST HEPATITIS ! BY AN INACTIVATED VAC CINE *!-! n "RUNDAGE 3# &ITZPATRICK !. (EPATITIS ! !M &AM 0HYSICIAN n 4AYLOR 2- $AVERN 4 -UNOZ 3 (AN 3( -C'UIRE " ,ARSON !- (YNAN , ,EE 7- &ONTANA 2* 53 !CUTE ,IVER &AILURE 3TUDY 'ROUP &ULMINANT HEPATITIS ! VIRUS INFECTION IN THE 5NITED 3TATES )NCIDENCE PROGNOSIS AND OUT COMES (EPATOLOGY n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
(EPATITIS % INFECTION !XEL 3CHMIDT AND -ANFRED ( 7OLFF 0RIVATE 5NIVERSITY OF 7ITTEN(ERDECKE &ACULTY OF -EDICINE !LFRED (ERRHAUSEN 3TR
7ITTEN 'ERMANY )NSTITUTE OF -ICROBIOLOGY AND 6IROLOGY 0RIVATE 5NIVERSITY OF 7ITTEN(ERDECKE 3TOCKUMER
3TRASSE 7ITTEN 'ERMANY
!BSTRACT (EPATITIS % n FORMERLY CALLED @ENTERICALLY TRANSMITTED NON ! NON " HEPATITIS n IS TRANSMITTED BY THE FAECAL ORAL ROUTE 4HE (EPATITIS % 6IRUS (%6 IS A POSITIVE SENSE SINGLE STRANDED 2.! VIRUS AND HAS GREAT SIMILARITIES TO THE CALICIVIRUSES 6IRUS REPLICA TION APPEARS TO BE LIMITED TO THE HEPATOCYTE 4HE DISEASE IS ESPECIALLY ENDEMIC ANDOR EPIDEMIC ON THE )NDIAN SUB CONTINENT %PIDEMICS ARE MOSTLY WATERBORNE INFECTIONS !LSO IN OTHER @DEVELOPING REGIONS OUTBREAKS OF (%6 INFECTION ARE OBSERVED )N INDUSTRIALISED COUNTRIES THIS DISEASE ONLY PLAYS A MINOR ROLE IN HEPATITIS INFECTIONS (%6 CAUSES EPIDEM ICS ENDEMICS AND SPORADIC CASES OF ACUTE HEPATITIS 4HE INCUBATION PERIOD FOR HEPATITIS % VARIES FROM n WEEKS 4HE COURSE OF DISEASE IS USUALLY MILD AND SELF LIMITING AND RESOLVES WITHIN A WEEKS PERIOD &ULMINANT CASES OF INFECTION ARE RARE (%6 INFECTION DOES NOT INDUCE CHRONIC COURSES OF HEPATITIS OR LIVER DISEASE )N CLINICALLY APPARENT CASES OF INFEC TION JAUNDICE PRURITUS CLAY COLOURED FAECES AND GENERALISED LYMPHADENOPATHIA MAY BE OBSERVED &ATAL INFECTIONS OF FULMINANT HEPATITIS % ARE RARE 0REGNANT WOMEN APPEAR TO BE EXCEPTIONALLY SUSCEPTIBLE TO SEVERE DISEASE FORMS WITH AN EXCESSIVE MORTALITY OF INFECTED MOTHERS OF ABOUT IN THIS GROUP (%6 INFECTIONS APPEARINGLY INDUCE MOSTLY LIFE LONG IMMUNITY TO RE INFECTION 4O DATE THERE IS NO THERAPY AGAINST (%6 INFECTION AVAILABLE 4HE ATTEMPTS IN GENERATING A VACCINE AGAINST (%6 INFECTIONS ARE PROMISING )MPROVING THE SOCIOECONOMIC SITUATION n INCLUDING HYGIENIC CONDITIONS n IS THE MOST EFFECTIVE MEASURE OF DISEASE PREVENTION
)NTRODUCTION (EPATITIS % FORMERLY CALLED @ENTERICALLY TRANSMITTED NON ! NON " HEPATI TIS IS TRANSMITTED BY THE FAECAL ORAL ROUTE 4HE (EPATITIS % 6IRUS (%6 IS A STILL UNASSIGNED GENUS WITH GREAT SIMILARITIES TO THE CALICIVIRUSES 4HE MORPHOLOGY OF THE NON ENVELOPED VIRION IS SPHERICAL AND THE GENOME CONSISTS OF A POLYADENYLATED POSITIVE SENSE SINGLE STRANDED LINEAR SEG MENT 2.! OF AN ABOUT KB 2EPLICATION OF THE VIRUS APPEARS TO BE LIMITED TO THE HEPATOCYTE !LSO NON HUMAN PRIMATES ARE SUSCEPTIBLE FOR (%6 INFECTION 4HE DISEASE IS ESPECIALLY ENDEMIC ANDOR EPIDEMIC ON THE
!XEL 3CHMIDT AND -ANFRED ( 7OLFF
)NDIAN SUBCONTINENT %PIDEMICS ARE MOSTLY WATERBORNE INFECTIONS !LSO IN OTHER @DEVELOPING REGIONS EG !SIAN 0ACIFIC 2EGION FORMER 3OVIET 5NION -IDDLE %AST NORTHERNWESTERN PARTS OF !FRICA OUTBREAKS OF (%6 INFECTION ARE OBSERVED )N INDUSTRIALISED COUNTRIES THIS DISEASE ONLY PLAYS A MINOR ROLE IN HEPATITIS INFECTIONS 4HE PATHOPHYSIOLOGY OF (%6 INFECTION IS STILL POORLY UNDERSTOOD (%6 CAUSES EPIDEMICS ENDEMICS AND SPORADIC CASES OF ACUTE HEPATITIS 4HE INCUBATION PERIOD FOR HEPATITIS % VARIES FROM n WEEKS AVERAGE D $URING ACUTE INFECTION A MOSTLY SHORT VIREMIC PERIOD IS OBSERVED ! PERSISTENT INTESTINAL CARRIER STAGE OR PERSISTENT VIRE MIA HAS NOT BEEN REPORTED 4HE COURSE OF DISEASE IS USUALLY MILD AND SELF LIMITING AND RESOLVES WITHIN A WEEKS PERIOD &ULMINANT CASES OF INFECTION ARE RARE (%6 INFECTION DOES NOT INDUCE CHRONIC COURSES OF HEPATITIS OR LIVER DISEASE #LINICALLY APPARENT CASES OF (%6 INFECTION ARE MOST OFTEN SEEN IN YOUNG TO MIDDLE AGED ADULTS n YEARS OLD #LINICALLY (%6 INFECTION IS INDISTINGUISHABLE FROM THE OTHER FORMS OF VIRAL HEPATITIS )N CLINICALLY APPARENT CASES OF INFECTION JAUNDICE PRURITUS CLAY COLOURED FAE CES AND GENERALISED LYMPHADENOPATHIA MAY BE OBSERVED &ATAL INFECTIONS OF FULMINANT HEPATITIS % ARE RARE (%6 EXHIBITS ITS HIGHEST VIRULENCE WITHIN THE THIRD TRIMESTER OF PREGNANCY 0REGNANT WOMEN APPEAR TO BE EXCEPTION ALLY SUSCEPTIBLE TO SEVERE DISEASE FORMS WITH AN EXCESSIVE MORTALITY OF INFECTED MOTHERS OF ABOUT REPORTED IN THIS GROUP 4HERE IS ALSO A HIGH FREQUENCY OF CASES OF INTRAUTERINE DEATHS AND ABORTIONS IN CASE OF MATERNAL INFECTION (%6 INFECTIONS APPEARINGLY INDUCE MOSTLY LIFE LONG IMMUNITY TO RE INFECTION )N CASE OF DIAGNOSTICS SEROLOGICAL AND MOLECULAR APPROACHES ARE COMBINED FOR EARLY AND APPROPRIATE RESULTS 5NTIL NOW THERE IS NO THERAPY AGAINST (%6 INFECTION AVAILABLE 4HE ATTEMPTS IN GENERATING A VAC CINE AGAINST (%6 INFECTIONS ARE PROMISING )MPROVING THE SOCIOECONOMIC SITUATION INCLUDING HYGIENIC CONDITIONS IS THE MOST EFFECTIVE MEASURE OF DISEASE PREVENTION
6IROLOGY 4HE (EPATITIS % 6IRUS (%6 (%6 LIKE VIRUS IS A NON ENVELOPED VIRUS PARTICLE WITH A DIAMETER OF n NM )TS 6IRUS #ODE IS !CCORDING TO THE )NTERNATIONAL #OMMITTEE ON 4AXONOMY OF 6IRUSES )#46 (%6 IS STILL OFFICIALLY UNASSIGNED (OWEVER THE GENUS IS NAMED @(EPEVIRUS AND THE FAMILY @(EPEVIRIDAE IN CERTAIN DATABASES IE THE .#") TAXONOMY DATABASE 4HE MORPHOLOGY IS SPHERICAL AND THE VIRION STRUCTURE VERY SIMILAR TO THAT OF THE CALICIVIRUSES ;= 4HE SEROLOGICALLY RELATED SMALLER PARTICLES OF n NM IN SIZE ARE OFTEN FOUND IN FAECES OF PATIENTS WITH ACUTE HEPATITIS % INFECTION AND ARE RECENTLY PRESUMED TO REPRESENT DEGRADED VIRAL PARTICLES -OLECULAR ANALYSIS OF THE (%6 GENOME HAS SHOWN THAT IT IS A POLYAD ENYLATED POSITIVE SENSE SINGLE STRANDED LINEAR SEGMENT 2.! OF AN ABOUT
(EPATITIS % INFECTION
KB WITH SHORT AND NON CODING REGIONS WHICH CONTAIN THREE SEPARATE OPEN READING FRAMES /2&S ;= 4HE ' # CONTENT IS n AND THE BUOYANT DENSITY GM, RESPECTIVELY 4HE REPLICATION STRATEGY OF (%6 IS POORLY UNDERSTOOD UNTIL NOW APART THAT IT HAS BEEN SHOWN THAT THE TRAN SCRIPTASE AND REPLICASE ARE VIRUS ENCODED 2.! DEPENDENT POLYMERASES ;= 2EPLICATION OF THE VIRUS MAY BE LIMITED TO THE HEPATOCYTE )T HAS BEEN POSTU LATED BY 2EYES ET AL ;= THAT AFTER THE VIRUS ENTERS THE HEPATOCYTE THE POSI TIVE SENSE (%6 2.! IS TRANSLATED TO PRODUCE THE NON STRUCTURAL PROTEINS NEEDED FOR THE GENERATION OF NEGATIVE STRANDED 2.! @ANTIGENOMIC 2.! 4HIS NEGATIVE STRANDED 2.! MAY THEN SERVE AS A TEMPLATE FOR SYNTHESIS OF POSITIVE SENSE 2.! AND SUBGENOMIC 2.!S WHICH ENCODE THE PRODUCTION OF THE STRUCTURAL PROTEINS IN ORDER TO ENCAPSIDATE THE POSITIVE SENSE 2.! FOR THE ASSEMBLY OF NEW VIRAL PARTICLES )T IS YET UNCLEAR IF THERE MIGHT BE ADDITIONAL REPLICATION WITHIN THE GUT !TYPICAL ISOLATES WHICH DIFFER FROM THE TYPE STRAIN HAVE BEEN REPORTED MINOR DIFFERENCES IN RESISTANCE TO INACTIVATION SLIGHT DIFFERENCES IN IMMU NOREACTIVITY BUT IT IS GENERALLY ACCEPTED THAT ONLY ONE SEROTYPE OF (%6 HAS BEEN IDENTIFIED UP TO NOW ;= .EVERTHELESS ISOLATES OBTAINED FROM GEOGRAPHICALLY MORE DISTANT REGIONS TEND TO SHOW HIGHER DIFFERENCES IN THEIR AMINO ACID SEQUENCES 4HESE OBSERVATIONS SHOWED THAT THE 2.! POLY MERASE REGION APPARENTLY IS THE MOST CONSERVED REGION WITHIN THE (%6 GENOME 4ENDENCIES FOR SPONTANEOUS MUTATIONS ARE RARE AND A HOMOLOGOUS IMMUNITY CAN BE POSTULATED AS SECOND INFECTIONS WITH (%6 HAVE NOT BEEN REPORTED SO FAR !LSO NON HUMAN PRIMATES SUCH AS #YNOMOLGUS MACAQUES AND OWL MON KEYS MARMOSETS !OTUS MONKEYS AND CHIMPANZEES CAN BE EXPERIMENTALLY INFECTED WITH (%6 AND AN ACUTE FORM OF HEPATITIS CAN BE INDUCED WITHIN THESE SPECIES ;= 4HE PROPAGATION OF THE VIRUS IN CELL CULTURE IS STILL PROBLEMATIC WHICH COMPLICATES VIROLOGICAL RESEARCH ON THIS INFECTIOUS AGENT 2ECENTLY A #HINESE ISOLATE WAS REPORTED TO BE SUCCESSFULLY CULTIVATED IN HUMAN LUNG CARCINOMA CELLS (UANG ET AL ;= UNCONFIRMED OBSERVATION (%6 SEQUENCES ARE ACCESSIBLE FOR THE STRAINS @-EXICO - @3!2 - @+ , @53 !& @53 !& @GENOTYPE !* @(YDERABAD )NDIA !& @4+ !& @FULMINANT HEPATITIS 8 @5IGH $ @(E"EI - AND THE 4YPE 3TRAIN - 4HE ACCESSION NUMBERS ARE GIVEN IN BRACKETS
(ISTORY )N THE YEARS THE FIRST OUTBREAK OF AN EPIDEMIC ENTERICALLY TRANS MITTED @NON ! NON " HEPATITIS WAS REPORTED FROM $ELHI )NDIA ;= 4HIS FORM OF HEPATITIS BECAME OR ALREADY WAS EPIDEMIC AND ENDEMIC IN )NDIA
!XEL 3CHMIDT AND -ANFRED ( 7OLFF
AND IN 7ONG ET AL REPORTED THE FIRST EVIDENCE FOR THE EXISTENCE OF A @NON ! NON " VIRAL AGENT AS CAUSATIVE INFECTIOUS AGENT ;= )N "ALAYAN ET AL PUBLISHED DEEPER INSIGHTS INTO THIS INFECTIVE AGENT INCLUDING THE SUC CESSFUL EXPERIMENTAL TRANSMISSION OF THE INFECTIOUS AGENT TO NON HUMAN PRI MATES ;= !FTER EXTENSIVE RESEARCH ON THE STRUCTURE OF THE PARTICLE AND THE GENOME THEREAFTER 'OLDSMITH ET AL DEVELOPED THE FIRST %,)3! TEST SYSTEM FOR HEPATITIS % DIAGNOSTICS ;= THE FUNDAMENTAL BASE FOR DIAGNOSTIC ASSESS MENT OF THE DISEASE
%PIDEMIOLOGY )T IS NOT UNLIKELY THAT (%6 INFECTION HAS A CONSIDERABLY LONG HISTORY WITHIN THE GROUP OF THE @NON ! NON " VIRAL HEPATITIS TRANSMITTED BY THE ENTERICAL PATHWAY ;= 4HERE ARE STILL DISCUSSIONS ON (%6 LIKE CASES OF VIRAL HEPATI TIS FROM ENDEMIC REGIONS ESPECIALLY ON THE )NDIAN SUB CONTINENT WHICH ARE REPORTED TO BE SEROLOGICALLY DISTINCT FROM (%6 SO THAT THERE ARE POSTULA TIONS FOR SUBTYPES OR EVEN @THE SIXTH HUMAN HEPATITIS VIRUS WITH A COMPA RABLE PATHOPHYSIOLOGY LIKE (%6 INFECTION ;= (%6 INFECTION IS ONLY A SPORADIC FORM OF INFECTIOUS HEPATITIS IN @DEVELOPING COUNTRIES $ISEASE OUTBREAKS IN ENDEMICEPIDEMIC REGIONS ARE PREDOMINANTLY WATERBORNE INFECTIONS DUE TO POOR HYGIENIC ENVIRONMENTS (%6 INFECTION OCCURS ENDEMICALLY ANDOR EPIDEMICALLY PREDOMINANTLY ON THE )NDIAN SUB CONTINENT !LSO OUTBREAKS IN @DEVELOPING COUNTRIES OF THE !SIAN 0ACIFIC 2EGION THE FORMER 3OVIET 5NION THE -IDDLE %AST AND THE NORTHERN AND WESTERN PARTS OF !FRICA HAVE BEEN REPORTED )T APPEARS THAT (%6 INFEC TION IS ORIGINALLY AN INFECTION OF THE @/LD 7ORLD ALTHOUGH ALSO INFECTIONS IN -EXICO ;= AND SEROPOSITIVITY IN 6ENEZUELA ;= HAVE BEEN REPORTED 3PORADIC INFECTIONS WITHIN THE @DEVELOPED WORLDINDUSTRIALISED COUNTRIES ARE RARE AND MOSTLY IMPORTED TO THESE REGIONS BY INTERNATIONAL TRAVELLING OR IMMIGRANTS FROM ENDEMIC REGIONS !S RELIABLE AND DEMOGRAPHICALLY REPRESENTATIVE EPIDEMIOLOGICAL DATA ON POSITIVE ANTI (%6 SEROPREVALENCE ARE SPARSE n ESPECIALLY FOR THE )NDIAN SUBCONTINENT WHERE (%6 APPEARS TO BE MOST PREVALENT n IT SHOULD BE HIGHLIGHTED THAT POSITIVE ANTI (%6 SEROP REVALENCE WAS REPORTED TO BE EVEN AS HIGH AS IN BLOOD DONORS IN %GYPT ;= WHERE (%6 INFECTION IS OF LOWER ENDEMIC IMPORTANCE THAN EG ON THE )NDIAN SUBCONTINENT 4HIS SHOULD REFLECT THE IMPORTANCE OF (%6 INFECTIONS IN HIGHLY ENDEMIC REGIONS
#LINICS 4HE PATHOLOGY AND PATHOPHYSIOLOGY OF (%6 INFECTION IS STILL POORLY UNDER STOOD (EPATITIS % OR FORMERLY CALLED @ENTERICALLY TRANSMITTED NON ! NON " HEPATITIS IS TRANSMITTED BY THE FAECAL ORAL ROUTE (%6 HAS NOT BEEN ISOLATED
(EPATITIS % INFECTION
FROM FOOD AND NO STANDARDISED METHOD IS CURRENTLY AVAILABLE FOR ROUTINE ANALYSIS OF FOOD CONCERNING (%6 4HE INCUBATION PERIOD FOR HEPATITIS % VARIES FROM TWO TO NINE WEEKS AND IS ON THE AVERAGE APPROXIMATELY DAYS !S ASSESSED IN NON HUMAN PRIMATES IT IS MOST OBVIOUS THAT THE VIRUS IS SHED IN THE FAECES AFTER ITS PAS SAGE FROM THE LIVER TISSUE INTO THE BILE AND INTO THE DUODENUM CONSECUTIVELY $URING ACUTE INFECTION A MOSTLY SHORT VIREMIC PERIOD IS OBSERVED MOSTLY AT THE TIME POINT WHEN JAUNDICE BECOMES OBVIOUS )N A STUDY OF .ANDA ET AL ;= PROLONGED PHASES OF VIREMIA WERE REPORTED IN UP TO OF THE CASES OF ACUTE (%6 INFECTION /NE PATIENT IS REPORTED WHERE VIREMIA BEGAN AS EARLY AS ONE WEEK BEFORE THE ONSET OF JAUNDICE AND LASTED FOR A FURTHER MONTHS .EVERTHELESS A PERSISTENT INTESTINAL CARRIER STAGE OR PERSISTENT VIREMIA HAS NEVER BEEN DESCRIBED 4HE COURSE OF DISEASE IS USUALLY MILD AND SELF LIMITING AND RESOLVES WITHIN A WEEK PERIOD &ULMINANT CASES OF INFECTION ARE RARE (%6 INFEC TION DOES NOT INDUCE CHRONIC COURSES OF HEPATITIS OR LIVER DISEASE SUCH AS CIRRHOSIS OR HEPATIC NEOPLASIA #LINICALLY APPARENT CASES OF (%6 INFECTION ARE MOST OFTEN SEEN IN YOUNG TO MIDDLE AGED ADULTS OF n YEARS OLD )N YOUNGER INDIVIDUALS AND CHILDREN INFECTIONS TEND TO BE ANICTERIC 4O DATE (%6 INFECTION IS THE MOST COMMON FORM OF CLINICALLY APPARENT SPORADIC VIRAL HEPATITIS IN THE YOUNG ADULT POPULATION IN @DEVELOPING COUNTRIES WHEN WE FOCUS ON THE @/LD 7ORLD &ROM THE CLINICAL PERSPECTIVE (%6 INFECTION IS INDISTINGUISHABLE FROM THE OTHER FORMS OF VIRAL HEPATITIS )N CLINICALLY APPARENT CASES OF INFECTION JAUNDICE MOSTLY LASTS FROM ONE UP TO WEEKS !LSO PRURITUS CLAY COLOURED FAECES AND GENERALISED LYMPHADENOPATHIA MAY BE OBSERVED DURING THE COURSE OF DISEASE &ATAL INFECTIONS OF FULMINANT HEPATITIS % ARE RARE AND IN THE RANGE OF n ON THE AVERAGE 4HEY ARE MORE OFTEN OBSERVED IN PREGNANT WOMEN WHO APPEAR TO BE EXCEPTIONALLY SUSCEPTIBLE TO SEVERE DISEASE FORMS WHERE THEY CAN OCCUR IN UP TO OF (%6 INFECTION WITH A LETHAL COURSE OF INFECTION !NYHOW (%6 EXHIBITS ITS HIGHEST VIRULENCE WITHIN THE THIRD TRIMESTER OF PREGNANCY THE REASONS FOR THIS ARE NOT SUFFICIENTLY UNDERSTOOD UNTIL NOW 4HERE IS ALSO A HIGH FREQUENCY OF CASES OF INTRA UTERINE DEATHS AND ABORTIONS IN CASE OF MATERNAL (%6 INFECTION 3URVIVING NEONATES OF INFECTED MOTHERS OFTEN SHOW A CLINICALLY APPARENT ACUTE (%6 INFECTION !N ALTERED STATUS OF HORMONES AND IMMUNITY ARE OBSERVED DURING PREGNANCY BUT THE ACTUAL CAUSE OF THIS HIGH MORTALITY DURING PREGNANCY IS STILL UNKNOWN )T IS SUGGESTED THAT DIMINISHED CELLULAR IMMUNITY n INDI CATED BY A DECREASE IN #$ AN INCREASE IN #$ CELL COUNTS AND A CONSECU TIVELY LOWERED #$#$ CELL RATIO n AND A HIGH LEVEL OF STEROID HORMONES THAT INFLUENCE VIRAL REPLICATIONEXPRESSION DURING PREGNANCY APPEAR TO BE THE MOST PLAUSIBLE REASON FOR SEVERITY OF THIS DISEASE DURING PREGNANCY ; = 4HERE IS MUCH EVIDENCE THAT (%6 INFECTIONS INDUCE A GOOD AND MOSTLY LIFE LONG IMMUNITY TO RE INFECTION BY (%6
!XEL 3CHMIDT AND -ANFRED ( 7OLFF
$IAGNOSTICS 4HE VIRUS CAN BE VISUALISED BY ELECTRON MICROSCOPY EG IN FAECAL SAMPLES 4ODAY MOST OF THE DIAGNOSTICS IS BASED ON IMMUNOLOGICAL METHODS ON THE ANTIBODY LEVEL 3PECIFIC )G- ANTIBODIES TO (%6 OCCUR EARLY n MOSTLY AT THE TIME POINT OF ONSET OF SYMPTOMSJAUNDICE n AND REGULARLY IN (%6 INFECTION AND CAN PERSIST OVER A CONSIDERABLY LONG PERIOD OF TIME OF UP TO MONTHS AFTER THE PEAK OF THE INFECTION ;= !LSO SPECIFIC )G' ANTI (%6 ANTI BODIES OCCUR EARLY AND REGULARLY PEAK APPROXIMATELY n WEEKS AFTER CLINI CAL MANIFESTATIONS ARE OBSERVED AND REMAIN FOR AT LEAST YEARS DETECTABLE 0ATIENTS WITH A DELAYED )G' RESPONSE WERE REPORTED ;= &AECAL (%6 2.! REGULARLY BECOMES POSITIVE BEFORE THE ONSET OF CLINICAL SYMPTOMS AND BEFORE SERUM (%6 2.! BECOMES DETECTABLE START OF POSITIVITY GOES ALMOST IN PARALLEL WITH )G-)G' SEROCONVERSION $UE TO THESE FACTS MOLECULAR 0#2 TECHNIQUES PLAY AN IMPORTANT COMPLIMENTARY ROLE IN UP TO DATE (%6 INFEC TIOLOGICAL DIAGNOSTICS /F COURSE SPECIFIC LIVER PARAMETER SUCH AS EG SERUM ALANINE AMINO TRANSFERASE !,!4 BILIRUBIN ETC ARE ALTERED SUCH AS IN OTHER FORMS OF VIRAL HEPATITIS
$ISEASE MANAGEMENT AND PREVENTION )MPROVING THE SOCIOECONOMIC SITUATION n INCLUDING HYGIENIC CONDITIONS n WITH AN OPTIMAL WASTE WATER MANAGEMENT PROGRAMME ARE THE MOST EFFEC TIVE MEASURES OF DISEASE MANAGEMENT OF PREVENTING (%6 INFECTIONS -OST INFECTIONS APPEAR BEING DUE TO THE CONSUMPTION OF CONTAMINATED @FRESH WATER 4HERE IS MUCH EVIDENCE THAT EVEN INTRA FAMILIAL PERSON TO PERSON TRANSMISSION ONLY PLAYS A VERY MINOR ROLE UNDER ACCEPTABLE HYGIENIC CONDI TIONS WHICH REFLECTS THAT THE DISEASE ON ITS OWN IS NOT EXTREMELY CONTAGIOUS 4HE VIRUS PARTICLE APPEARS BEING RELATIVELY LABILE AND CAN BE INACTIVATED BY HEATING UP TO nª# OVER A PERIOD OF MIN OR EVEN BY CYCLES OF FREEZE THAWING 4O DATE THERE IS NO SPECIFIC THERAPY AGAINST (%6 INFECTION AVAILABLE &URTHER APPROACHES OF PASSIVE IMMUNOTHERAPY WITH HYPERIMMUNGLOBULINE SERA n EVEN WITH HIGH SPECIFIC ANTI (%6 )G' TITRES DERIVING FROM ENDEMIC AREAS n DID NOT LEAD TO CLINICAL IMPROVEMENT OF THE CLINICAL SITUATION ! VACCINE AGAINST (%6 INFECTION IN HUMANS IS NOT YET AVAILABLE ON THE MARKET HOWEVER DEVELOPMENT OF A CANDIDATE VACCINE IS IN PROGRESS WITH A HIGH VISIBILITY OF SUCCESS ;= 2ESEARCH ON THIS ISSUE STARTED WITH THE EARLY SUCCESSFUL APPROACHES IN CYNOMOLGUS MONKEYS PERFORMED BY 4SAREV ET AL IN ;= 4HEY DISCOVERED THAT IMMUNISATION OF #YNOMOLGUS MACAQUES WITH A K$A RECOMBINANT (%6 FUSION PROTEIN DERIVING FROM THE SECOND /2& OF (%6 PROTECTED THE ANIMALS AGAINST EXPERIMENTAL INFECTION WITH (%6 4HESE RESULTS ARE PROMISING FOR THE DEVELOPMENT OF A VACCINE
(EPATITIS % INFECTION
2EFERENCES
+HUDYAKOV 9 &IELDS (! (%6 ,IKE 6IRUSES )N #! 4IDONA ' $ARAI EDS )N 4HE 3PRINGER )NDEX OF 6IRUSES 3PRINGER 0UBL "ERLIN n 'ORBACH 3, "ARTLETT *' "LACKLOW .2 EDS )NFECTIOUS $ISEASES 7" 3AUNDERS 0HILADELPHIA 2EYES '2 (UANG ## 4AM !7 0URDY -! -OLECULAR ORGANIZATION AND REPLICATION OF HEPATITIS % VIRUS (%6 !RCH 6IROL n #HAUHAN ! $ILIWARI *" +AUR 5 'ANGULY .+ "USHNURMATH 3 #HAWLA 9+ !TYPICAL STRAINS OF HEPATITIS % VIRUS (%6 FROM NORTH )NDIA * -ED 6IROL n +RAWCZYNSKI + (EPATITIS % (EPATOLOGY n (UANG 2 ,I $ 7EI 3 ,I 1 9UAN 8 'ENG , ,I 8 ,IU - #ELL CULTURE OF SPORADIC HEPATITIS % VIRUS IN #HINA #LIN $IAGN ,AB )MMUNOL n 6ISWANATHAN 2 3IDHU !3 )NFECTIOUS HEPATITIS CLINICAL FINDINGS )ND * -ED 2ES n 7ONG $# 0URCELL 2( 3REENIVASAN -! 0RASAD 32 0AVRI +- %PIDEMIC AND ENDEMIC HEPATITIS IN )NDIA EVIDENCE FOR A NON ! NON " HEPATITIS VIRUS AETI OLOGY ,ANCET n "ALAYAN -3 !NDJAPARIDZE !' 3AVINSKAYA 33 +ETILADZE %3 "RAGINSKY $- 3AVINOV !0 0OLESCHUK 6& %VIDENCE FOR A VIRUS IN NON ! NON " HEPATI TIS TRANSMITTED VIA THE FECAL ORAL ROUTE )NTERVIROLOGY n 'OLDSMITH 2 9ARBOUGH 0/ 2EYERS '2 &RY +% 'ABOR +! +AMEL - :AKARIA 3 !MER 3 'AFFAR 9 %NZYME LINKED IMMUNOSORBENT ASSAY FOR DIAGNOSIS OF ACUTE SPORADIC HEPATITIS % IN %GYPTIAN CHILDREN ,ANCET n +OFF 23 (EPATITIS % )N 3, 'ORBACH *' "ARTLETT .2 "LACKLOW EDS )N )NFECTIOUS $ISEASES 7" 3AUNDERS 0HILADELPHIA n !RANKALLE 6! #HADHA -3 4SAREV 3! %MERSON 35 2ISBUD !2 "ANERJEE + 0URCELL 2( 3EROEPIDEMIOLOGY OF WATER BORNE HEPATITIS IN )NDIA AND EVIDENCE FOR A THIRD ENTERICALLY TRANSMITTED HEPATITIS AGENT 0ROC .ATL !CAD 3CI 53! n 6ELAZQUEZ / 3TETLER (# !VILA # /RNELAS ' !LVAREZ # (ADLER 3# "RADLEY $7 3EPÞLVEDA * %PIDEMIC TRANSMISSION OF ENTERICALLY TRANSMITTED NON ! NON " HEPATITIS IN -EXICO n *!-! n 0UJOL &( &AVOROV -/ -ARCANO 4 %STÏ *! -AGRIS - ,IPRANDI & +HUDYAKOV 9% +HUDYAKOVA .3 &IELDS (! 0REVALENCE OF ANTIBODIES AGAINST HEPA TITIS % VIRUS AMONG URBAN AND RURAL POPULATIONS IN 6ENEZUELA * -ED 6IROL n .ANDA 3+ !NSARI )( !CHARYA 3+ *AMEEL 3 0ANDA 3+ 0ROTRACTED VIREMIA DURING ACUTE SPORADIC HEPATITIS % VIRUS INFECTION 'ASTROENTEROLOGY n *ILANI . $AS "# (USAIN 3! "AWEJA 5+ #HATTOPADHYA $ 'UPTA 2+ 3ARDANA 3 +AR 0 (EPATITIS % VIRUS INFECTION AND FULMINANT HEPATIC FAILURE DURING PREGNANCY * 'ASTROENTEROL (EPATOL n "OCCIA $ 'UTHMANN *0 +LOVSTAD ( (AMID . 4ATAY - #IGLENECKI ) .IZOU *9 .ICAND % 'UERIN 0* (IGH MORTALITY ASSOCIATED WITH AN OUTBREAK
!XEL 3CHMIDT AND -ANFRED ( 7OLFF
OF HEPATITIS % AMONG DISPLACED PERSONS IN $ARFUR 3UDAN #LIN )NFECT $IS n "RYAN *0 4SAREV 3! )QBAL - 4ICEHURST * %MERSON 3 !HMED ! $UNCAN * 2AFIQUI !2 -ALIK )! 0URCELL 2( %PIDEMIC HEPATITIS % IN 0AKISTAN PATTERNS OF SEROLOGIC RESPONSE AND EVIDENCE THAT ANTIBODY TO HEPATITIS % VIRUS PROTECTS AGAINST DISEASE * )NFECT $IS n +HUROO -3 2USTGI 6+ $AWSON '* -USHAWAR )+ 9ATTOO '. +AMILI 3 +HAN "! 3PECTRUM OF HEPATITIS % VIRUS INFECTION IN )NDIA * -ED 6IROL n ,IN #8 7U 4 7U 8, 8IE -( #HENG 4 ,I 37 :HANG * 8IA .3 0RIMING WITH AN (%6 4H EPITOPE CAN IMPROVE THE HUMORAL IMMUNOGENICITY OF ITS NATIVE PROTEIN #HINESE 3HENG 7U 'ONG #HENG 8UE "AO n 4SAREV 3! 4SAREVA 43 %MERSON 35 'OVINDARAJAN 3 3HAPIRO - 'ERIN *, 0URCELL 2( 3UCCESSFUL PASSIVE AND ACTIVE IMMUNIZATION OF #YNOMOLGUS MONKEYS AGAINST HEPATITIS % 0ROC .ATL !CAD 3CI 53! n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
"ACTERIAL INFECTIONS OF THE LIVER (ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON )NSTITUTE FOR -EDICAL -ICROBIOLOGY )MMUNOLOGY AND (YGIENE 5NIVERSITY OF #OLOGNE #OLOGNE
'ERMANY $EPARTMENT FOR )NTERNAL -EDICINE 6IRGINIA #OMMONWEALTH 5NIVERSITY 2ICHMOND 6! 53!
!BSTRACT "ACTERIAL INFECTIONS OF THE LIVER CAN BE CATEGORISED INTO THREE ENTITIES ACUTE BACTERIAL HEPATITIS BACTERIAL LIVER ABSCESSES AND GRANULOMATOUS LIVER DISEASE CAUSED BY BACTERIA ! BROAD SPECTRUM OF BACTERIA HAS BEEN IMPLICATED IN DIFFERENT FORMS OF HEPATIC INFECTIONS AND A WIDE VARIETY OF SYSTEMIC BACTERIAL INFECTIONS AFFECT THE LIVER DURING THE COURSE OF INFECTION #LINICAL SYMPTOMS CAUSATIVE PATHOGENS AND THERAPEUTIC APPROACHES OVERLAP WIDELY -OST BACTERIAL INFECTIONS THAT AFFECT THE LIVER CAUSE SECONDARY HEPATITIS WITH ONLY DISCRETE CLINICAL AND LABORATORY FINDINGS 3TANDARD DIAGNOSTIC PROCEDURES INCLUDING PHYSI CAL EXAMINATION IMAGING AND MICROBIOLOGICAL CULTURES WILL USUALLY BE SUFFICIENT TO DETECT AND ASCERTAIN THE BACTERIAL CAUSES OF HEPATITIS 4HERAPY OF BACTERIAL INFECTIONS OF THE LIVER USUALLY INCLUDES ANTIMICROBIAL CHEMOTHERAPY ACCORDING TO STANDARD GUIDELINES FOR THE UNDERLYING DISEASE AND THE IDENTIFIED PATHOGEN AS WELL AS ADDITIONAL INVASIVE THERAPY WHICH MAY BE REQUIRED FOR CERTAIN MANIFESTATIONS
)NTRODUCTION 4HE LIVER CAN BE AFFECTED BY A WIDE VARIETY OF SYSTEMIC INFECTIONS )N BAC TERIAL INFECTIONS MOST COMMON FORMS OF LIVER INVOLVEMENT ARE PYOGENIC ABSCESSES ACUTE HEPATITIS AND GRANULOMATOUS LIVER DISEASE "ACTERIA CAN REACH THE LIVER IN SEVERAL WAYS (EMATOGENOUS SPREAD OF BACTERIA INTO THE LIVER DURING BLOODSTREAM INFECTION VIA THE PORTAL VEIN OR THE HEPATIC ARTERY DIRECT SPREAD OF BACTERIA FROM A CONTIGUOUS FOCAL INFEC TION VIA THE BILIARY TREE OR FOLLOWING INTERNAL OR EXTERNAL TRAUMA 4HESE INFECTIONS USUALLY MANIFEST AS SO CALLED PYOGENIC ABSCESSES THAT ARE CLINICALLY INDISTINGUISHABLE FROM OTHER ABSCESSES SUCH AS THE AMOEBIC LIVER ABSCESS CAUSED BY %NTAMOEBA HISTOLYTICA 7HILE VIRUSES ARE THE MOST COMMON CAUSES OF ACUTE HEPATITIS INFECTIONS DUE TO BACTERIA SUCH AS .EISSERIA MENINGITIDIS 3ALMONELLA TYPHI "RUCELLA SPP OR #AMPYLOBACTER SPP HAVE ALSO BEEN ASSOCIATED WITH THIS CLINICAL
(ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON
ENTITY )NFECTIONS DUE TO BACTERIA SUCH AS -YCOBACTERIUM SPP 4ROPHERYMA WHIPPLEI 4REPONEMA PALLIDUM #OXIELLA BURNETII OR 2ICKETTSIA SPP ARE AMONG THE MAJOR CAUSES OF GRANULOMATOUS LIVER DISEASE 4HIS CHAPTER REVIEWS THE DIFFERENT FORMS OF LIVER DISEASES THAT CAN BE CAUSED BY BACTERIA AND SUMMARISES THE CLINICAL FEATURES AND THERAPEUTIC OPTIONS FOR THE MOST COMMON FORMS AND PATHOGENS
2OUTES OF INFECTION 4HERE ARE IN GENERAL FOUR MECHANISMS BY WHICH BACTERIAL INFECTIONS OF THE LIVER DEVELOP HAEMATOGENOUS BILIARY CONTIGUOUS SPREAD AND VIA DIRECT INOCULATION (AEMATOGENOUS SEEDING OF BACTERIA CAN OCCUR VIA THE PORTAL VEIN OR THE HEPATIC ARTERY FROM THE SYSTEMIC CIRCULATION AND ARE FREQUENTLY ASSOCIATED WITH PERITONITIS DIVERTICULITIS OR GENERALISED BLOODSTREAM INFECTION OR SEPSIS )N THE PRE ANTIBIOTIC ERA THE HAEMATOGENOUS ROUTE WAS THE MOST COMMON METHOD OF INFECTION AND INFECTION USUALLY ORIGINATED FROM APPENDICEAL PATHOLOGY ;= 4ODAY BACTERIAL INFECTIONS OF THE LIVER ARE MOST COMMONLY ASSOCIATED WITH BILIARY DISEASE ; = 5NDERLYING CONDITIONS LEADING TO BACTERIAL INFECTIONS OF THE LIVER VIA THE BILIARY TREE ARE MOST COMMONLY CHOLANGITIS CHOLECYSTITIS OR MALIGNANCIES SUCH AS CHOLANGIOCARCINOMA ;= 4RANSLOCATION OF BACTERIA FROM INFECTIOUS PROCESSES IN CLOSE PROXIMITY OF THE LIVER SUCH AS APPENDICITIS DIVERTICULITIS AND OTHER INFLAMMATORY PRO CESSES OF THE INTESTINE ARE LESS FREQUENT ALTHOUGH CONTIGUOUS SPREAD FROM THE LUNG KIDNEY COLON OR THE STOMACH HAS BEEN REPORTED ; n= 4HERE ARE TWO POTENTIAL MECHANISMS OF DIRECT INFECTION IATROGENIC FOL LOWING INVASIVE PROCEDURES SUCH AS %2#0 PERCUTANEOUS LIVER BIOPSY ;= OR ABDOMINAL SURGERY ;= ACCOUNTING FOR APPROXIMATELY OF ALL PYOGENIC ABSCESSES OF THE LIVER OR VIA PENETRATING TRAUMA THROUGH THE SKIN OR SECOND ARY TO ACCIDENTAL INGESTION OF SHARP OBJECTS SUCH AS FISH BONES ;= OR TOOTH PICKS ;= ACCOUNTING FOR APPROXIMATELY ;= #RYPTOGENIC INFECTIONS WHERE THE ROUTE OF INFECTION ANDOR THE UNDERLY ING CONDITION CANNOT BE IDENTIFIED ACCOUNT FOR n OF ABSCESSES BASED ON DATA FROM SEVERAL STUDIES ; =
#LINICAL ENTITIES "ACTERIAL INFECTIONS OF THE LIVER CAN BE CATEGORISED INTO THREE ENTITIES ACUTE BACTERIAL HEPATITIS BACTERIAL PYOGENIC LIVER ABSCESSES AND GRANU LOMATOUS LIVER DISEASE CAUSED BY BACTERIA 7HILE THIS DIFFERENTIATION REMAINS LARGELY THEORETICAL IN MOST INFECTIONS BECAUSE CLINICAL SYMPTOMS CAUSATIVE PATHOGENS AND THERAPEUTIC APPROACHES OVERLAP WIDELY DIFFER
"ACTERIAL INFECTIONS OF THE LIVER
ENCES IN OUTCOME HAVE BEEN REPORTED IN PATIENTS WITH LIVER INFECTION DUE TO ,ISTERIA MONOCYTOGENES ;=
"ACTERIAL HEPATITIS !MONG THE VARIOUS CAUSES OF ACUTE HEPATITIS BACTERIAL INFECTIONS ARE RELA TIVELY RARE "LOODSTREAM INFECTIONS AND SEVERE SEPSIS OR SEPTIC SHOCK CAN CAUSE HEPATIC ISCHAEMIA THAT CAN PRESENT AS AN ACUTE HEPATITIS ! VARIETY OF ORGANISMS HAS BEEN DESCRIBED AS CAUSATIVE AGENTS OF HEPATITIS INCLUDING "ARTONELLA HENSELAE "ORRELIA BURGDORFERI "RUCELLA ABORTUS #HLAMYDIA SPP #OXIELLA BURNETII &RANCISELLA TULARENSIS ,EGIONELLA PNEUMOPHILA ,EPTOSPIRA INTERROGANS SL ,ISTERIA MONOCYTOGENES -YCOBACTERIUM SPP 3ALMONELLA SPP 4REPONEMA PALLIDUM AND 9ERSINIA PESTIS ;=
"ACTERIAL ABSCESSES 0YOGENIC ABSCESSES ARE THE MOST COMMON FORM OF BACTERIAL INFECTIONS OF THE LIVER AND DEVELOP IN n PATIENTS PER HOSPITAL ADMISSIONS ; n= "ACTERIAL ABSCESSES ACCOUNT FOR ABOUT OF ALL LIVER ABSCESSES IN INDUSTRIALISED COUNTRIES WHILE IN COUNTRIES OF THE 4HIRD 7ORLD PARASITIC ABSCESSES ARE MORE FREQUENT ;= ,IVER ABSCESSES FREQUENTLY DEVELOP VIA DIRECT SPREAD FOLLOWING OBSTRUCTION OF THE BILIARY TREE OR INFECTIONS OF THE GASTROINTESTINAL TRACT SUCH AS DIVERTICULITIS OR PEPTIC ULCER DISEASE BUT CAN ALSO BE ASSOCIATED WITH ABDOMINAL SURGERY OR MALIGNANCIES IN THE CLOSE PROXIMITY OF THE LIVER #ONSEQUENTLY INCIDENCE IS HIGHEST IN PATIENTS BETWEEN AND YEARS ; = -OST STUDIES DID NOT IDENTIFY ANY SIG NIFICANT DIFFERENCES IN GENDER AND DID NOT DETECT ANY CLEAR GEOGRAPHIC PAT TERNS ; = 4HE INCIDENCE OF BACTERIAL LIVER ABSCESSES HAS BEEN INCREASING OVER THE PAST DECADE -ORTALITY HAS DECREASED CONSIDERABLY DURING THAT TIME MOSTLY DUE TO ADVANCES IN IMAGING AND ANTIMICROBIAL CHEMOTHERAPY ;= 4HE MOST IMPORTANT DIFFERENTIAL DIAGNOSIS IS LIVER ABSCESS DUE TO OTHER CAUSES MOST COMMONLY AMOEBIC LIVER ABSCESSES CAUSED BY INFECTION WITH % HISTOLYTICA EVEN THOUGH APPROXIMATELY OF AMOEBIC ABSCESSES ALSO YIELD BACTERIA ; =
'RANULOMATOUS HEPATITIS DUE TO BACTERIAL INFECTIONS )NVOLVEMENT OF THE LIVER MOSTLY IN THE FORM OF GRANULOMATOUS LIVER DISEASE CAN BE AN IMPORTANT MANIFESTATION OF CERTAIN BACTERIAL INFECTIONS 4HE DIF FERENTIAL DIAGNOSIS INCLUDES DISEASES CAUSED BY A NUMBER OF VIRAL EG (!6 (#6 #-6 %"6 OR PARASITIC EG ,EISHMANIA 3CHISTOSOMA 4OXOCARA
(ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON
#LONORCHIS AGENTS WHICH ARE DISCUSSED ELSEWHERE IN THIS BOOK AS WELL AS A VARIETY OF NON INFECTIOUS CAUSES SUCH AS DRUG INDUCED LIVER DISEASE PRIMARY BILIARY CIRRHOSIS NEOPLASTIC AND MALIGNANT DISORDERS AS WELL AS SYSTEMIC DIS EASES SUCH AS SARCOIDOSIS
#LINICAL FEATURES -OST BACTERIAL INFECTIONS AFFECTING THE LIVER CAUSE SECONDARY HEPATITIS WITH MILD TO MODERATE ELEVATION OF LIVER ENZYMES MAINLY !,4 !34 ALKALINE PHOSPHATASE AND ONLY DISCRETE CLINICAL SYMPTOMS -ANY SYSTEMIC BACTERIAL INFECTIONS ONLY INVOLVE THE LIVER TO A RELATIVELY MINOR EXTENT AND ARE THERE FORE NOT PRIMARILY CLASSIFIED AS HEPATITIS HOWEVER SOME INFECTIONS SUCH AS LEPTOSPIROSIS 7EILS DISEASE OR SYPHILIS MAY PRESENT WITH THE CLASSICAL SIGNS AND SYMPTOMS OF AN ACUTE HEPATITIS #LINICAL SYMPTOMS SUCH AS ABDOMINAL PAIN TYPICALLY IN THE RIGHT UPPER QUADRANT AND FEVER MAY PRESENT WITH AN ACUTE ONSET AND SEVERE COMPLICA TIONS SUCH AS PNEUMOPERITONEUM FOLLOWING THE RUPTURE OF A GAS CONTAINING ABSCESS HAVE BEEN DESCRIBED ;= -ORE OFTEN HOWEVER SYMPTOMS ARE NON SPECIFIC AND CAN INCLUDE GENERAL WEAKNESS HEADACHE MYALGIA AND NAUSEA ; = 0ATIENTS TYPICALLY PRESENT WITH SLOWLY PROGRESSIVE VAGUE CONSTITU TIONAL SYMPTOMS SUCH AS FATIGUE ANOREXIA AND FEVER ;n= 4IME BETWEEN THE ONSET OF SYMPTOMS AND DIAGNOSIS AVERAGES WEEKS BUT INTERVALS OF GREATER THAN WEEKS HAVE BEEN REPORTED ;= $EPENDING ON THE SIZE AND THE LOCATION OF THE ABSCESS MORE SPECIFIC SYMPTOMS SUCH AS NAUSEA DIFFUSE ABDOMINAL DISCOMFORT PLEURITIC CHEST PAIN REFERRED RIGHT SHOULDER DISCOM FORT CAUSED BY LESIONS NEAR THE DIAPHRAGM OR BILIARY OBSTRUCTION AND MILD JAUNDICE CAUSED BY ABSCESSES COMPRESSING THE BILIARY TREE MAY BE PRESENT ; n= /NLY BETWEEN AND OF PATIENTS PRESENT WITH THE CLAS SICAL TRIAD OF JAUNDICE FEVER AND TENDERNESS IN THE RIGHT UPPER QUADRANT ; = )N A RECENT SERIES FEVER WAS THE MOST COMMON SYMPTOM PRESENTING IN APPROXIMATELY OF CASES FOLLOWED BY ABDOMINAL PAIN NAUSEA WEIGHT LOSS PLEURAL EFFUSIONS AND HEPATOMEGALY AND JAUNDICE n ; = 0HYSICAL EXAMINATION GENERALLY REFLECTS THE CLINICAL SYMPTOMS HIGHLIGHT ING THE NON SPECIFIC NATURE OF THE PRESENTATION IN MANY PATIENTS ; = ,EUKOCYTOSIS PRESENT IN n OF PATIENTS ; = TWO TO THREE FOLD INCREASED ALKALINE PHOSPHATASE AND ELEVATION IN THE SERUM # REACTIVE PRO TEIN #20 OFTEN IN COMBINATION WITH ANAEMIA DECREASED SERUM ALBUMIN AND ELEVATED BILIRUBIN ARE THE MOST COMMONLY SEEN LABORATORY ABNORMALI TIES ; = )N CONTRAST LIVER FUNCTION TESTS CAN BE NORMAL OR SHOW ONLY SLIGHT TO MODERATE DEVIATIONS FROM THE NORMAL VALUES !LKALINE PHOSPHATASE !0 IS MOST COMMONLY ELEVATED ALANINE AMINOTRANSFERASE !,4 AND ASPARTATE AMINOTRANSFERASE !34 ARE ELEVATED MOSTLY IN PATIENTS WITH PRIMARY OR
"ACTERIAL INFECTIONS OF THE LIVER
SECONDARY BILIARY INVOLVEMENT WHILE ALBUMIN AND PROTHROMBIN TIME ARE OFTEN WITHIN NORMAL LIMITS $UE TO THE NON SPECIFIC NATURE OF CLINICAL AND SOMETIMES ALSO LABORA TORY FINDINGS DIAGNOSIS OF BACTERIAL HEPATITIS USUALLY REQUIRES A HIGH DEGREE OF SUSPICION -OST OF THE IMPORTANT DIFFERENTIAL DIAGNOSES SUCH AS AMOEBIC LIVER ABSCESS CHOLECYSTITIS AND PYELONEPHRITIS CANNOT BE RULED OUT ON CLINI CAL SIGNS ALONE 3INCE THERE ARE A VARIETY OF UNDERLYING CONDITIONS THAT CAN LEAD TO ABSCESSES IN THE LIVER DIAGNOSIS MAY BE MISSED INITIALLY ESPECIALLY IN ABSCESSES OCCURRING IN THE WAKE OF ABDOMINAL SURGERY OR OTHER INVASIVE PROCEDURES WHERE SYMPTOMS SUCH AS PAIN AND FEVER MAY WELL BE RELATED TO THE UNDERLYING CONDITION -ORTALITY RATES HAVE DECREASED SUBSTANTIALLY OVER THE PAST SEVERAL DECADES WITH RECENT STUDIES REPORTING RATES OF n ;=
$IAGNOSIS 3TANDARD DIAGNOSTIC PROCEDURES INCLUDING PHYSICAL EXAMINATION IMAGING ULTRASOUND #4 OR -2) SCAN AND MICROBIOLOGICAL CULTURES WILL USUALLY BE SUFFICIENT TO DETECT AND ASCERTAIN THE BACTERIAL CAUSES OF HEPATITIS #HEST 8 RAY IS NOT VERY SENSITIVE BUT MAY REVEAL AN ELEVATED RIGHT HEMIDIAPHRAGM AND PLEURAL EFFUSION ;= $IAGNOSIS CAN USUALLY BE MADE BY ABDOMINAL ULTRASOUND WHERE SINGLE OR MULTIPLE ABSCESSES CAN BE DETECTED ;= )N SOME CASES ULTRASOUND MAY ALSO HELP TO ESTABLISH THE ORIGIN OF INFEC TION FOR EXAMPLE OBSTRUCTION OF THE BILIARY TREE !BSCESSES TOO SMALL TO BE DETECTED BY ULTRASOUND CAN BE DETECTED USING COMPUTED TOMOGRAPHY #4 WITH CONTRAST MAGNETIC RESONANCE IMAGING -2) ;= 4HESE STUDIES CAN ALSO BE HELPFUL IN ESTABLISHING THE PRIMARY SITE OF INFECTION 3ERIES COMPAR ING IMAGING TECHNIQUES FOUND ULTRASOUND SLIGHTLY LESS SENSITIVE VERSUS THAT #4 WITH CONTRAST ;= &URTHER INVASIVE TESTS SUCH AS %2#0 MAY BE INDICATED DEPENDING ON THE UNDERLYING CONDITIONS ;= !LSO NUCLEAR IMAGING TO LOCATE METASTAIC FOCI AND ENSURE ADEQUATE DRAINAGE MAY BE WAR RANTED IN PATIENTS FAILING TO ACHIEVE DEFERVESCENCE ; = !SPIRATION OF THE ABSCESSES SHOULD BE ATTEMPTED IF POSSIBLE IN ORDER TO OBTAIN MATERIAL FOR MICROBIOLOGICAL AND CYTOLOGICAL EXAMINATION AND ALSO AS PART OF THE TREATMENT IN LARGER ABSCESSES !BSCESS MATERIAL FOR MICROBIOLOGICAL EXAMINATION SHOULD BE COLLECTED IN A STERILE TUBE AND TRANSPORTED TO THE LABORATORY AS SOON AS POSSIBLE )N ADDITION SOME MATERIAL CAN BE INOCULATED INTO BLOOD CULTURE BOTTLES "LOOD CULTURES n SETS SHOULD BE OBTAINED TO COMPLETE MICROBIOLOGICAL DIAGNO SIS $URING THE BACTEREMIC PHASE MOST INFECTIONS CAN BE DIAGNOSED BY BLOOD CULTURES WHICH ARE POSITIVE IN ABOUT HALF OF THE CASES BUT MAY YIELD DIFFERENT PATHOGENS THAN ABSCESS MATERIALS RECOVERED FROM THE SAME PATIENT ; = #YTOLOGIC EXAMINATION OF SMEARS FROM THE ABSCESS MATERIAL IS WARRANTED TO EXCLUDE UNDERLYING MALIGNANCIES
(ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON
4HERAPY 4HERAPY OF BACTERIAL INFECTIONS OF THE LIVER USUALLY CONSISTS OF ANTIMICROBIAL CHEMOTHERAPY ACCORDING TO STANDARD GUIDELINES FOR THE UNDERLYING DIS EASE AND THE IDENTIFIED PATHOGEN $UE TO INCREASING RESISTANCE ESPECIALLY IN ENTEROBACTERIACEAE CULTURE OF THE CAUSATIVE PATHOGENS SHOULD ALWAYS BE ATTEMPTED AND SUSCEPTIBILITIES OF IDENTIFIED BACTERIA SHOULD ALWAYS BE ASCERTAINED )N SOME CASES SUCH AS FULMINATE LEPTOSPIROSIS FULL SUPPORTIVE THERAPY IN THE INTENSIVE CARE UNIT MAY BE NECESSARY !LTHOUGH THERE ARE SOME REPORTS OF CURE BY ANTIBIOTIC TREATMENT WITH OUT SURGERY ; = DRAINAGE OF ABSCESSES IS USUALLY ESSENTIAL ;= 0ERCUTANEOUS TRANSHEPATIC DRAINAGE IS A RELATIVELY LOW RISK PROCEDURE THAT HAS REPLACED OPEN SURGERY AS THE METHOD OF CHOICE ; = 0ERCUTANEOUS CATHETER DRAINAGE 0#$ AND PERCUTANEOUS NEEDLE ASPIRA TION 0.! SHOULD BE ATTEMPTED IF THERE IS ONE LARGE AND ACCESSIBLE ABSCESS 4HESE METHODS HAD A HIGH SUCCESS RATE n WHILE MORTALITY WAS RELATIVELY LOW ; = )N COMPARISON OF BOTH TECHNIQUES 9U AND CO WORKERS CONCLUDED THAT INTERMITTENT NEEDLE ASPIRATION IS PROBABLY AS EFFECTIVE AS CONTINUOUS CATHETER DRAINAGE FOR THE TREATMENT OF PYOGENIC LIVER ABSCESS AND RECOMMENDED IT SHOULD BE CONSIDERED AS A FIRST LINE APPROACH DUE TO THE ADDITIONAL ADVANTAGES OF PROCEDURE SIMPLICITY PATIENT COMFORT AND REDUCED PRICE ;= $UE TO THE EQUIVALENT EFFICACY OF 0#$0.! TO SURGICAL THERAPY AND THE HIGHER MORTALITY OF THE LATTER UP TO MOST AUTHORS RECOMMEND AN OPEN SURGICAL APPROACH ONLY IN SELECTED CASES ; = 2ECENT STUDIES ALSO DESCRIBE ENDOSCOPIC DRAINAGE OF PYOGENIC LIVER ABSCESSES WITH SUSPECTED BILIARY ORIGIN AND CONCLUDE THAT %2#0 ENABLES NOT ONLY DEMONSTRATION OF COMMUNICATIONS BETWEEN THE BILIARY TRACT AND LIVER ABSCESSES BUT ALSO THAT AN INTERNAL DRAINAGE OF THE CAVITY IS FEASIBLE AND SAFE ;= )N CONTRAST OTHERS FOUND THAT FOR LARGE LIVER ABSCESSES OF MORE THAN CM OPEN SURGICAL DRAINAGE PROVIDES BETTER CLINICAL OUTCOMES THAN 0#$ IN TERMS OF TREATMENT SUCCESS NUMBER OF SECONDARY PROCEDURES AND HOSPITAL STAY WITH COMPA RABLE MORBIDITY AND MORTALITY RATES ;= 3INCE ABSCESSES ARE OFTEN POLYMICROBIAL INITIAL THERAPY UTILISING BROAD SPECTRUM ANTIBIOTICS WITH ANAEROBIC COVERAGE IS RECOMMENDED !NTIMICROBIAL AGENTS RECOMMENDED AS FIRST LINE DRUGS INCLUDE BETA LACTAMBETA LACTAMASE INHIBITOR COMBINATIONS FOR EXAMPLE AMPICIL LINSULBACTAM OR PIPERACILLINTAZOBACTAM IN COMBINATION WITH A THIRD GENERATION CEPHALOSPORIN OR A FLUROQUINOLONE OR IN CASES OF NOSOCOMIAL INFECTIONS ANDOR PRETREATED PATIENTS CARBAPENEMS FOR EXAMPLE IMIPE NEM MEROPENEM ; = /THER FACTORS SUCH AS UNDERLYING CONDITIONS OR PROBABLE SOURCE OF INFECTION CAN ALSO INFLUENCE THE DECISION ON INITIAL ANTIMICROBIAL THERAPY 4HERAPY SHOULD BE ADJUSTED AS SOON AS RESULTS FROM BLOOD CULTURES AND FROM CULTURES OF THE ABSCESS ARE AVAILABLE
"ACTERIAL INFECTIONS OF THE LIVER
0ATHOGENS ! BROAD SPECTRUM OF BACTERIA HAS BEEN IMPLICATED IN DIFFERENT FORMS OF HEPATIC INFECTIONS AND A WIDE VARIETY OF SYSTEMIC BACTERIAL INFECTIONS AFFECT THE LIVER DURING THE COURSE OF INFECTION !CUTE PERI HEPATITIS CAN BE CAUSED BY BACTERIAL PATHOGENS INCLUDING "ARTONELLA HENSELAE "ORRELIA BURGDORFERI "RUCELLA ABORTUS #HLAMYDIA SPP #OXIELLA BURNETII &RANCISELLA TULARENSIS ,EGIONELLA PNEUMOPHILA ,EPTOSPIRA INTERROGANS SL ,ISTERIA MONOCYTOGENES ;= -YCOBACTERIUM SPP .EISSERIA GONORRHOEAE ;= AND . MENINGITIDES ;= 3ALMONELLA SPP ; = 4REPONEMA PALLIDUM AND 9ERSINIA PESTIS ;= "ACTERIAL PATHOGENS CAN BE RECOVERED FROM ABOUT OF ABSCESSES ;= AND MAY VARY CONSIDERABLY DEPENDING ON THE SOURCE OF THE ABSCESS !BSCESSES ARE POLYMICROBIAL IN n OF CASES AND SOME AUTHORS HAVE SUGGESTED THAT SOLITARY ABSCESSES ARE MORE FREQUENTLY POLYMICROBIAL THAN MULTIPLE ABSCESS ES ; = 4HE MOST FREQUENTLY ENCOUNTERED AEROBIC BACTERIA ARE %NTEROBACTERIACEAE SUCH AS %SCHERICHIA COLI ;= AND +LEBSIELLA PNEUMONIAE ; = INCLUDING EXTENDED SPECTRUM BETA LACTAMASE %3", PRODUCING STRAINS ;= 'RAM POSITIVE ORGANISMS SUCH AS STAPHYLOCOCCI ;= INCLUDING COMMUNITY ACQUIRED METHICILLIN RESISTANT 3TAPHYLOCOCCUS AUREUS ;= AND STREPTOCOCCI ;n= INCLUDING 3 PNEUMONIAE ;= HAVE BEEN ISOLATED FROM THE LIVER AS WELL 4HE PERCENTAGE OF ANAEROBIC MICROORGANISMS VARIES BETWEEN AND IN DIFFERENT SERIES ; = )N ADDITION A VARIETY OF OTHER ORGANISMS HAVE BEEN REPORTED AS CAUSATIVE AGENTS OF LIVER ABSCESSES INCLUDING !CTINOMYCES SPP ; = " HENSELAE ;= #APNOCYTOPHAGA SPP ;= 2HODOCOCCUS EQUI ;= AND 9ERSINIA ENTEROCOLITICA ;= "ACTERIAL INFECTIONS THAT USUALLY MANIFEST AS GRANULOMATOUS LIVER DISEASE INCLUDE INFECTIONS DUE TO -YCOBACTERIUM SPP "URKHOLDERIA PSEUDOMALLEI ;= "RUCELLA SPP ; = ,ISTERIA SPP ; = 4ROPHERRYMA WHIPPLEI ;= 4 PALLIDUM ; = AND # BURNETII ; =
'RAM NEGATIVE BACTERIA %NTEROBACTERIACEAE 'RAM NEGATIVE RODS ESPECIALLY %NTEROBACTERIACEAE ARE THE MOST COMMON BACTERIA ISOLATED FROM LIVER ABSCESSES 0RIOR TO THE MID S %SCHERICHIA COLI WAS THE PREDOMINANT PATHOGEN ; = -ORE RECENTLY THE SPEC TRUM SHIFTED TO +LEBSIELLA PNEUMONIAE WHICH IS NOW THE MOST COMMONLY ISOLATED PATHOGEN FROM PYOGENIC ABSCESSES ; = WITH THE FIRST CASES DUE TO %3", PRODUCING STRAINS REPORTED RECENTLY ;= 4HIS SHIFT WAS FIRST OBSERVED IN 4AIWAN ;= FOLLOWED BY OTHER !SIAN COUNTRIES SUCH AS *APAN ; = 3INGAPORE ; = +OREA ;= )NDIA ;= (ONG +ONG ;= AS WELL AS %UROPE 3PAIN ;= 5+ ;= !USTRALIA ;= AND THE 5NITED 3TATES ; n=
(ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON
#ONCOMITANT BACTERAEMIA IS REPORTED IN ABOUT HALF THE CASES OF BACTE RIAL ABSCESSES ;= BUT SOME AUTHORS REPORTED BLOOD STREAM INFECTION "3) IN UP TO OF PATIENTS WITH LIVER ABSCESSES DUE TO + PNEUMONIAE ;= %XTRAHEPATIC ABSCESSES HAVE BEEN DESCRIBED IN ONLY n OF THESE PATIENTS ; = 3ECONDARY ABSCESSES ARE MOST OFTEN ENCOUNTERED IN THE EYE ; = BUT A VARIETY OF OTHER SITES HAS BEEN DESCRIBED SUCH AS THE LUNGPLEURA ; = KIDNEY ;= PROSTATE ; = #.3MENINGES ; = BONES ;= AND SKIN AND SOFT TISSUE ; = $IABETES MELLITUS AND ALCOHOLISM HAVE BEEN IDENTIFIED AS SIGNIFICANT RISK FACTORS FOR DEVELOPING METASTATIC INFECTIONS FROM PYOGENIC LIVER ABSCESSES ;= )N LIVER INFECTIONS DUE TO + PNEUMONIA RECENT STUDIES FOUND THE + GENOTYPE TO BE ASSOCIATED WITH METASTATIC COMPLICATIONS ;= )N CONTRAST TO OTHER %NTEROBACTERIACEAE 3ALMONELLA SPP MAINLY 3 TYPHI RARELY CAUSE HEPATIC ABSCESSES EVEN THOUGH THERE HAVE BEEN SOME REPORTS INCLUDING ONE RECENT CASE OF SALMONELLOSIS WITH SEPTIC SHOCK AND LIVER ABSCESS IN A DIABETIC AND CIRRHOTIC PATIENT ;= %VEN IN IMMUNOCOMPRO MISED PATIENTS SUCH AS PATIENTS WITH ()6!)$3 WHERE BACTERAEMIA DUE TO NON TYPHI 3ALMONELLA IS MORE FREQUENT THAN IN IMMUNOCOMPETENT HOSTS FOCAL COMPLICATIONS INVOLVING THE LIVER HAVE BEEN RARELY DESCRIBED ;= 'ENERALLY IN PATIENTS WITH TYPHOID FEVER THE USUAL HISTOLOGIC FINDING OF THE LIVER IS NONSPECIFIC REACTIVE HEPATITIS AND OTHER MANIFESTATIONS SUCH AS HEPATIC GRANULOMA ARE RARE COMPLICATIONS OF TYPHOID FEVER ;= 3YSTEMIC INFECTIONS DUE TO 3ALMONELLA SPP OFTEN INVOLVE THE LIVER MAINLY DURING THE BACTEREMIC PHASE OF INFECTION )N ALMOST HALF OF THE INFECTIONS DUE TO 3 TYPHI HEPATOSPLENOMEGALY AND SEVERE IMPAIRMENT OF LIVER FUNCTIONS CAN BE OBSERVED 4HERE HAVE BEEN MORE THAN CASES OF SALMONELLA HEPATITIS REPORTED AND INCIDENCES RANGE FROM LESS THAN TO OF PATIENTS WITH ENTERIC FEVER 7HILE EXTREME HEPATIC DYSFUNCTION IS A RARE COMPLICATION IN 3ALMONELLA HEPATITIS TYPHOID NODULES WITH MARKED HYPERPLASIA OF RETICULO ENDOTHELIAL CELLS IS USUALLY OBSERVED 3PECIFIC ANTIMICROBIAL THERAPY IS USU ALLY EFFECTIVE BUT SEVERE CLINICAL COURSES WITH MORTALITY RATES UP TO HAVE BEEN REPORTED ; = .EISSERIA MENINGITIDIS.EISSERIA GONORRHOEAE 4HE LIVER CAN BE AFFECTED DURING THE BACTERAEMIA THAT MAY OCCUR DURING MENINGOCOCCAL OR GONOCOCCAL INFECTIONS !CUTE PERIHEPATITIS DUE TO . GONORRHOEAE ONE ETIOLOGY OF THE &ITZ (UGH #URTIS SYNDROME IS MAINLY ENCOUNTERED IN FEMALE PATIENTS WITH PELVIC INFLAMMATORY DISEASE AND CAN DEVELOP EVEN MONTHS AFTER THE PRIMARY INFECTION ;= 4HE INCIDENCE OF THIS COMPLICATION OF PELVIC INFLAMMATORY DISEASE WAS RELATIVELY LOW IN RECENT SERIES ;= 2ECENTLY CHOLESTATIC HEPATITIS HAS BEEN REPORTED IN A CHILD IN 4URKEY FOL LOWING CHRONIC MENINGOCOCCAEMIA ;= (EPATITIS DEVELOPED FOUR DAYS AFTER THE INITIAL PRESENTATION THAT INCLUDED FEVER ARTHRALGIA AND A MACULOPAPULAR RASH WHILE THE PATIENT WAS TREATED WITH PENICILLIN CONSISTENT WITH THE SUSCEP
"ACTERIAL INFECTIONS OF THE LIVER
TIBILITIES OF THE . MENINGITIDIS ISOLATES RECOVERED FROM THE BLOOD CULTURES $IAGNOSIS WAS MADE BY CLINICAL AND LABORATORY FINDINGS AND OTHER CAUSES OF HEPATITIS WERE RULED OUT ;= "URKHOLDERIA PSEUDOMALLEI )NFECTIONS DUE TO "URKHOLDERIA PSEUDOMALLEI ARE USUALLY ASSOCIATED WITH MULTIPLE ABSCESSES OR ANDOR GRANULOMATOUS LIVER DISEASE 3EVERAL CASES HAVE BEEN REPORTED AND CLOSE ATTENTION TO THE PATIENTS TRAVEL HISTORY UNDERLY ING CO MORBIDITIES SUCH AS DIABETES RENAL DISEASE AND ALCOHOL ABUSE AND THE PRESENCE OF CONCOMITANT SPLENIC ABSCESS ARE IMPORTANT TO ENABLE EARLY DETECTION OF MELIOIDOSIS 4HE TREATMENT OF CHOICE IS INTRAVENOUS CEFTAZIDIME FOR AT LEAST DAYS OR MORE !N ADEQUATE DURATION OF MAINTENANCE ORAL THERAPY WITH AMOXICILLIN CLAVULANATE OR TRIMETHOPRIM SULFAMETHOXAZOLE FOR n WEEKS IS NECESSARY TO PREVENT RELAPSE ;= "ARTONELLA HENSELAE " HENSELAE ORIGINALLY DESIGNATED 2OCHALIMAEA HENSELAE USUALLY AFFECTS THE REGIONAL LYMPH NODES LEADING TO ABSCESSES CAT SCRATCH DISEASE #3$ )N HIGHLY IMMUNOCOMPROMISED PATIENTS A GRANULOMATOUS INFECTION OF THE LIVER CAN DEVELOP AS A SECOND STAGE OF THE DISEASE !TYPICAL PRESENTATION OF " HENSELAE INFECTION IS REPORTED IN APPROXIMATELY OF PATIENTS INCLUD ING PAEDIATRIC PATIENTS ;= %NDOCARDITIS GRANULOMATOUS HEPATITIS HEPATO SPLENIC INFECTION OR OSTEOMYELITIS ARE THE MOST COMMON MANIFESTATIONS OF BARTONELLOSIS APART FROM #3$ ;= "RUCELLA SPP "RUCELLA SPP ARE USUALLY INGESTED WITH RAW MILK OR CHEESE MANUFACTURED FROM THE MILK OF INFECTED ANIMALS (EPATITIS HAS BEEN REPORTED AS A CLINICAL MANIFESTATION OF INFECTION WITH " MELITENSIS ;= ,OCALISED MANIFESTA TION OF "RUCELLOSIS IN THE LIVER HEPATIC BRUCELLOMA ARE RARE AND LESS THAN CASES HAVE BEEN REPORTED INCLUDING MANIFESTATIONS IN CHILDREN ; = &RANCISELLA TULARENSIS 4ULAREMIA CAUSED BY &RANCISELLA TULARENSIS USUALLY MANIFESTS AS AN ULCERO GLANDULAR OR A TYPHOIAL ILLNESS )N THE LATTER THERE ARE FEW LOCALISED SIGNS AND IT IS OFTEN ASSOCIATED WITH A MILD HEPATITIS ;=
'RAM POSITIVE BACTERIA 3TAPHYLOCOCCUS SPP 3TREPTOCOCCUS SPP %NTEROCOCCUS SPP 'RAM POSITIVE ORGANISMS SUCH AS 3 AUREUS COAGULASE NEGATIVE STAPHYLO COCCI SUCH AS 3 HAEMOLYTICUS ;= BETA HEMOLYTIC STREPTOCOCCI 3 MILLERI ;= AND %NTEROCOCCUS SPP ARE RECOVERED LESS FREQUENTLY FROM BACTERIAL
(ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON
INFECTIONS OF THE LIVER THAN 'RAM NEGATIVE PATHOGENS ; = )N ADDITION THESE ORGANISMS ARE MORE LIKELY TO BE RECOVERED FROM MONOBACTERIAL SEC ONDARY ABSCESSES IN PATIENTS WHERE THE PRIMARY FOCUS OF INFECTION IS USUALLY LOCATED OUTSIDE THE ABDOMEN )N RECENT STUDIES 3 PNEUMONIAE HAS BEEN REPORTED AS THE CAUSE OF LIVER INFECTIONS MAINLY IN IMMUNOCOMPROMISED HOSTS !LCOHOLISM ()6 INFECTION SPLENECTOMY CONNECTIVE TISSUE DISEASE STEROID USE DIABETES MELLITUS AND INTRAVENOUS DRUG USE REMAIN COMMON RISK FACTORS FOR INVASIVE PNEUMOCOC CAL INFECTIONS ;= ,ISTERIA MONOCYTOGENES ,ISTERIA MONOCYTOGENES CAUSES SEPSIS AND MENINGITIS IN IMMUNOCOMPRO MISED PATIENTS AND A DEVASTATING MATERNALFETAL INFECTION IN PREGNANT WOMEN ; = 6ARIOUS OUTBREAKS DEMONSTRATED THAT , MONOCYTO GENES CAN CAUSE GASTROENTERITIS IN OTHERWISE HEALTHY INDIVIDUALS AND MORE SEVERE INVASIVE DISEASE IN IMMUNOCOMPROMISED PATIENTS ; = -ATERNAL LISTERIOSIS USUALLY RESULTS IN A NONSPECIFIC FEBRILE ILLNESS THAT IS RARELY DIAGNOSED PREPARTUM ABOUT ONE THIRD OF PATIENTS HAVE NO SYMPTOMS AT ALL ; = BUT MAY LEAD TO SPONTANEOUS ABORTION STILLBIRTH DEATH OF THE NEWBORN WITHIN HOURS AFTER BIRTH OR NEONATAL SEPSIS OR RESULT IN GRANULOMA TOSIS INFANTISEPTICA CHARACTERISED BY MICROABSCESSES AND GRANULOMAS IN THE LIVER AND SPLEEN ; = )N ADULTS THERE ARE A NUMBER OF ATYPICAL CLINICAL FORMS OF LISTERIOSIS n OF CASES INCLUDING ENDOCARDITIS THE THIRD MOST FREQUENT FORM MYO CARDITIS HEPATITIS COLECYSTITIS LOCALISED ABSCESSES ;= 4O DATE THERE ARE CASES OF HEPATIC LISTERIOSIS DESCRIBED IN THE LITERATURE WITH CLINICAL PRESEN TATIONS INCLUDING SOLITARY LIVER ABSCESSES MULTIPLE ABSCESSES AND DIFFUSE OR GRANULOMATOUS HEPATITIS WHICH DIFFER IN CLINICAL COURSE AND OUTCOME ;= $ETAILS OF THE CLINICAL FEATURES DIAGNOSTIC MODALITIES AND TREATMENT OPTIONS HAVE RECENTLY BEEN REVIEWED IN DETAIL BY 3CHOLING AND COLLEAGUES ;=
!NAEROBIC BACTERIA 4HE INCIDENCE OF ANAEROBIC BACTERIA RECOVERED FROM LIVER ABSCESSES VARIES GREATLY BETWEEN SERIES %VEN IN STUDIES THAT SPECIFICALLY TRIED TO CULTURE ANAER OBIC MICROORGANISMS INCIDENCES BETWEEN AND ARE REPORTED WHILE MORE RECENT SERIES REPORT INCIDENCES BETWEEN AND ; = 2ECOVERY OF ANAEROBIC BACTERIA ESPECIALLY FROM MIXED INFECTIONS IS SOMETIMES CHALLENGING SO THE INCIDENCE OF THESE ORGANISMS MAY WELL BE UNDER REPORTED !NAEROBIC BACTERIA ARE MORE LIKELY TO BE RECOVERED FROM ABSCESS ASPIRATION AND ARE GENERALLY NOT DETECTED IN CONCOMITANT BLOOD CULTURES "ACTEROIDES FRAGILIS IS THE MOST COMMONLY SEEN ANAEROBE IN MOST SERIES ; =
"ACTERIAL INFECTIONS OF THE LIVER
/THER BACTERIA ,EPTOSPIRA ICTEROHAEMORRHAGIAE 7HILE SEVERAL ,EPTOSPIRA SPP CAN CAUSE DISEASE IN MAN , ICTEROHAEMOR RHAGIAE IS THE CAUSATIVE AGENT OF 7EILS DISEASE #HARACTERISTIC SYMPTOMS AND JAUNDICE MAKE THIS ILLNESS AN IMPORTANT DIFFERENTIAL DIAGNOSIS OF VIRAL HEPA TITIS AND SIMILAR HEPATIC ILLNESSES HAVE BEEN DESCRIBED IN PATIENTS INFECTED WITH HANTAVIRUSES ; = 4REPONEMA PALLIDUM 3YPHILIS A SEXUALLY TRANSMITTED DISEASE CAN AFFECT THE LIVER IN SEVERAL WAYS )F UNTREATED 4 PALLIDUM CAN CAUSE ACUTE HEPATITIS IN THE SECOND STAGE OF DISEASE WHILE GUMMATA CAN ALSO BE PRESENT IN THE LIVER DURING THE TERTIARY PHASE OF SYPHILIS ;= 4HE LIVER IS ALSO REGULARLY AFFECTED IN CONGENITAL SYPHI LIS ;= 2ECENTLY SYPHILITIC HEPATITIS HAS ALSO BEEN DESCRIBED IN LIVER TRANS PLANT PATIENTS ;= -YCOBACTERIUM TUBERCULOSIS 4HE LIVER IS AFFECTED MOST COMMONLY IN MILIARY TUBERCULOSIS SPREADING FROM THE LUNG VIA THE HEPATIC ARTERY ;= BUT OTHER ROUTES OF INFECTION SUCH AS LYMPHATIC SPREAD HAVE BEEN REPORTED ; = &OCAL ISOLATED TUBERCULOSIS OF THE LIVER HAS BEEN REPORTED MAINLY IN IMMUNOCOMPROMISED PATIENTS SUCH AS PATIENTS WITH ()6!)$3 ;= (EPATIC TUBERCULOSIS MAY PRESENT AS AN ABSCESS OR A MORE DIFFUSE FORM OF GRANULOMATOUS LIVER DISEASE #LINICAL FEATURES DIAGNOSIS AND MANAGEMENT OF THIS RARE MANIFESTATION HAVE RECENTLY BEEN REVIEWED IN DETAIL ;=
2EFERENCES
/SCHNER ! $E"AKEY - -URRAY 3 0YOGENIC ABSCESS OF THE LIVER )) !N ANALYSIS OF FOURTY SEVEN CASES WITH REVIEW OF THE LITERATURE !M * 3URG n 3EETO 2+ 2OCKEY $# 0YOGENIC LIVER ABSCESS #HANGES IN ETIOLOGY MAN AGEMENT AND OUTCOME -EDICINE "ALTIMORE n 'UNDLING & 3ECKNUS 2 !BELE (ORN - -OSSNER * 0YOGENIC LIVER ABSCESS 3TATE OF THE ART SITUATION FOR DIAGNOSIS AND THERAPY $TSCH -ED 7OCHENSCHR n ,EE ** +IM (* #HUNG )* +OOK ( 0ARK -2 +IM #* 3HIN $( (WANG 4* 2UPTURED +LEBSIELLA PNEUMONIAE LIVER ABSCESS AFTER HIGH DOSE CYCLO PHOSPHAMIDE FOR SEVERE APLASTIC ANEMIA !M * (EMATOL n /KANO ( 3HIRAKI + )NOUE ( +AWAKITA 4 9AMAMOTO . $EGUCHI - 3UGIMOTO + 3AKAI 4 /HMORI 3 -URATA + ET AL #LINICOPATHOLOGICAL ANALYSIS OF LIVER ABSCESS IN *APAN )NT * -OL -ED n 0EREZ -* #ARRILLO *, -ONTIN )- #ASTELLANO !$ ,IVER ABSCESS DUE TO
(ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON
ILEOCECAL PERFORATION A CASE REPORT WITH LITERATURE REVIEW %MERG 2ADIOL n 'ARCIA !RIAS -" 2ODRIGUEZ 'ALINDO # (OFFER &! 7ANG 7# 0YOGENIC HEPATIC ABSCESS AFTER PERCUTANEOUS LIVER BIOPSY IN A PATIENT WITH SICKLE CELL DIS EASE * 0EDIATR (EMATOL /NCOL n #HEN # #HEN 0* 9ANG 0- (UANG '4 ,AI -9 4SANG 9- #HEN $3 #LINICAL AND MICROBIOLOGICAL FEATURES OF LIVER ABSCESS AFTER TRANSARTERIAL EMBOLI ZATION FOR HEPATOCELLULAR CARCINOMA !M * 'ASTROENTEROL n 4HEODOROPOULOU ! 2OUSSOMOUSTAKAKI - -ICHALODIMITRAKIS -. +ANAKI # +OUROUMALIS %! &ATAL HEPATIC ABSCESS CAUSED BY A FISH BONE ,ANCET 3TOICA - 3AFTOIU ! 'HEONEA $) $UMITRESCU $ 3URLIN 6 0YOGENIC LIVER ABSCESS CAUSED BY ACCIDENTAL INGESTION OF A WOODEN TOOTHPICK ROLE OF PREOPERA TIVE IMAGING * 'ASTROINTESTIN ,IVER $IS n 7ANG *( ,IU 9# ,EE 33 9EN -9 #HEN 93 7ANG *( 7ANN 32 ,IN (( 0RIMARY LIVER ABSCESS DUE TO +LEBSIELLA PNEUMONIAE IN 4AIWAN #LIN )NFECT $IS n ,ODHI 3 3ARWARI !2 -UZAMMIL - 3ALAM ! 3MEGO 2! &EATURES DIS TINGUISHING AMOEBIC FROM PYOGENIC LIVER ABSCESS A REVIEW OF ADULT CASES 4ROP -ED )NT (EALTH n 3CHOLING - 3CHNEEBERGER 0- VAN DEN $RIES 0 $RENTH *0 #LINICAL FEATURES OF LIVER INVOLVEMENT IN ADULT PATIENTS WITH LISTERIOSIS 2EVIEW OF THE LITERATURE )NFECTION n 3CHAEFER 3 !RVAND - 'AERTNER " *ILG 7 ,AFRENZ - ,EITRITZ , -ODROW 3 -UELLER ,ANTZSCH . 0ODBIELSKI ! 2OGGENDORF - ET AL +LINIK UND %RREGERSPEKTRUM )N ( -AUCH ! 0ODBIELSKI - (ERMANN % +NIEHL EDS 1UALITAETSSTANDARDS IN DER MIKROBIOLOGISCH INFEKTIOLOGISCHEN $IAGNOSTIK -I1 5RBAN &ISCHER -àNCHEN UND *ENA n 0ITT (! :UIDEMA '$ &ACTORS INFLUENCING MORTALITY IN THE TREATMENT OF PYOGENIC HEPATIC ABSCESS 3URG 'YNECOL /BSTET n -C$ONALD -) 0YOGENIC LIVER ABSCESS DIAGNOSIS BACTERIOLOGY AND TREAT MENT %UR * #LIN -ICROBIOL n -C$ONALD -) #OREY '2 'ALLIS (! $URACK $4 3INGLE AND MULTIPLE PYOGENIC LIVER ABSCESSES .ATURAL HISTORY DIAGNOSIS AND TREATMENT WITH EMPHA SIS ON PERCUTANEOUS DRAINAGE -EDICINE "ALTIMORE n "ECKINGHAM )* +RIGE *% !"# OF DISEASES OF LIVER PANCREAS AND BILIARY SYSTEM ,IVER AND PANCREATIC TRAUMA "-* n (ANSEN 03 3CHONHEYDER (# 0YOGENIC HEPATIC ABSCESS ! YEAR POPU LATION BASED RETROSPECTIVE STUDY !0-)3 n *OHANNSEN %# 3IFRI #$ -ADOFF ,# 0YOGENIC LIVER ABSCESSES )NFECT $IS #LIN .ORTH !M n (UANG #* 0ITT (! ,IPSETT 0! /STERMAN &! *R ,ILLEMOE +$ #AMERON *, :UIDEMA '$ 0YOGENIC HEPATIC ABSCESS #HANGING TRENDS OVER YEARS !NN 3URG n +URLAND *% "RANN /3 0YOGENIC AND AMEBIC LIVER ABSCESSES #URR 'ASTROENTEROL 2EP n 3HIBA ( !OKI ( -ISAWA 4 +OBAYASHI 3 3AITO 2 9ANAGA +
"ACTERIAL INFECTIONS OF THE LIVER
0NEUMOPERITONEUM CAUSED BY RUPTURED GAS CONTAINING LIVER ABSCESS * (EPATOBILIARY 0ANCREAT 3URG n ,EDERMAN %2 #RUM .& 0YOGENIC LIVER ABSCESS WITH A FOCUS ON +LEBSIELLA PNEUMONIAE AS A PRIMARY PATHOGEN AN EMERGING DISEASE WITH UNIQUE CLINICAL CHARACTERISTICS !M * 'ASTROENTEROL n :ENDA 4 !RAKI ) (IRAIWA 9 -IYAYAMA 3 -ASUNAGA 4 4AKEDA 9 5ENO 4 4AKEDA 2 3EPTIC PULMONARY EMBOLI SECONDARY TO PYOGENIC LIVER ABSCESS IN A DIABETIC PATIENT )NTERN -ED n 2AHIMIAN * 7ILSON 4 /RAM 6 (OLZMAN 23 0YOGENIC LIVER ABSCESS RECENT TRENDS IN ETIOLOGY AND MORTALITY #LIN )NFECT $IS n ,EE +4 7ONG 32 3HEEN 0# 0YOGENIC LIVER ABSCESS AN AUDIT OF YEARS EXPERIENCE AND ANALYSIS OF RISK FACTORS $IG 3URG n #HENG $, ,IU 9# 9EN -9 ,IU #9 3HI &7 7ANG ,3 0YOGENIC LIVER ABSCESS CLINICAL MANIFESTATIONS AND VALUE OF PERCUTANEOUS CATHETER DRAINAGE TREATMENT * &ORMOS -ED !SSOC n 7ONG 49 #HIU 3) 3O -+ 4SANG -+ ,AI 34 4SE ++ )O )9 3EPTIC METASTATIC ENDOPHTHALMITIS COMPLICATING +LEBSIELLA PNEUMONIAE LIVER ABSCESS IN A NON DIABETIC #HINESE MAN (ONG +ONG -ED * n #UNNINGHAM 3# .APOLITANO ,- 0YOGENIC LIVER ABSCESS COMPLICATING BILIARY STRICTURE DUE TO CHRONIC PANCREATITIS 3URG )NFECT ,ARCHMT n !LVAREZ *! 'ONZALEZ ** "ALDONEDO 2& 3ANZ , #ARRENO ' *ORGE *) 3INGLE AND MULTIPLE PYOGENIC LIVER ABSCESSES ETIOLOGY CLINICAL COURSE AND OUT COME $IG 3URG n -OHSEN !( 'REEN 34 2EAD 2# -C+ENDRICK -7 ,IVER ABSCESS IN ADULTS TEN YEARS EXPERIENCE IN A 5+ CENTRE 1*- n 7ONG 7- 7ONG "# (UI #+ .G - ,AI +# 4SO 7+ ,AM 3+ ,AI #, 0YOGENIC LIVER ABSCESS RETROSPECTIVE ANALYSIS OF CASES OVER A YEAR PERIOD * 'ASTROENTEROL (EPATOL n 3AINI 3 )MAGING OF THE HEPATOBILIARY TRACT . %NGL * -ED n "ARNES 0& $E #OCK +- 2EYNOLDS 4. 2ALLS 07 ! COMPARISON OF AME BIC AND PYOGENIC ABSCESS OF THE LIVER -EDICINE "ALTIMORE n 3UGIYAMA - !TOMI 9 0YOGENIC HEPATIC ABSCESS WITH BILIARY COMMUNI CATION !M * 3URG n (ERBERT $! &OGEL $! 2OTHMAN * 7ILSON 3 3IMMONS & 2USKIN * 0YOGENIC LIVER ABSCESSES SUCCESSFUL NON SURGICAL THERAPY ,ANCET n 9EOH +' 9AP ) 7ONG 34 7EE ! 'UAN 2 +ANG *9 4ROPICAL LIVER ABSCESS 0OSTGRAD -ED * n 9U 3# (O 33 ,AU 79 9EUNG $4 9UEN %( ,EE 03 -ETREWELI # 4REATMENT OF PYOGENIC LIVER ABSCESS PROSPECTIVE RANDOMIZED COMPARISON OF CATHETER DRAINAGE AND NEEDLE ASPIRATION (EPATOLOGY n "AYRAKTAR 9 !RSLAN 3 3IVRI " %RYILMAZ - !KOVA - 6AN 4HIEL $( +AYHAN " 0ERCUTANEOUS DRAINAGE OF HEPATIC ABSCESSES THERAPY DOES NOT DIFFER FOR THOSE WITH IDENTIFIABLE BILIARY FISTULA (EPATOGASTROENTEROLOGY n 3ERSTE 4 "OURGEOIS . 6ANDEN %YNDEN & #OPPENS % $EVIERE * ,E -OINE / %NDOSCOPIC DRAINAGE OF PYOGENIC LIVER ABSCESSES WITH SUSPECTED BILIARY ORIGIN !M * 'ASTROENTEROL n
(ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON
4AN 9- #HUNG !9 #HOW 0+ #HEOW 0# 7ONG 7+ /OI ,, 3OO +# !N APPRAISAL OF SURGICAL AND PERCUTANEOUS DRAINAGE FOR PYOGENIC LIVER ABSCESS ES LARGER THAN CM !NN 3URG n +RIGE *% "ECKINGHAM )* !"# OF DISEASES OF LIVER PANCREAS AND BILIARY SYSTEM "-* n 6OGL 4* %STIFAN & 0YOGENIC LIVER ABSCESS INTERVENTIONAL VERSUS SURGICAL THERAPY TECHNIQUE RESULTS AND INDICATIONS 2OFO n "ANIKARIM # #HACKO -2 0ELVIC INFLAMMATORY DISEASE IN ADOLESCENTS !DOLESC -ED #LIN n 4OTAN - 9ILDIZ ' +ALAYCI !' !N UNCOMMON PRESENTATION CHRONIC MENINGOCOCCAEMIA ASSOCIATED WITH CHOLESTATIC HEPATITIS IN A 4URKISH CHILD * 4ROP 0EDIATR n #HOU 90 #HANGCHIEN #3 #HIU +7 +UO #- +UO &9 +UO #( 3ALMONELLOSIS WITH LIVER ABSCESS MIMICKING HEPATOCELLULAR CARCINOMA IN A DIA BETIC AND CIRRHOTIC PATIENT A CASE REPORT AND REVIEW OF THE LITERATURE ,IVER )NT n -ERT ! 4ABAK & /ZARAS 2 /ZTURK 2 !KI ( !KTUGLU 9 4YPHOID FEVER AS A RARE CAUSE OF HEPATIC SPLENIC AND BONE MARROW GRANULOMAS )NTERN -ED n "RANUM '$ 4YSON '3 "RANUM -! -EYERS 7# (EPATIC ABSCESS #HANGES IN ETIOLOGY DIAGNOSIS AND MANAGEMENT !NN 3URG n #HEN 3# 9EN #( 4SAO 3- (UANG ## #HEN ## ,EE -# "ELL 72 #OMPARISON OF PYOGENIC LIVER ABSCESSES OF BILIARY AND CRYPTOGENIC ORIGIN !N EIGHT YEAR ANALYSIS IN A 5NIVERSITY (OSPITAL 3WISS -ED 7KLY n #HEN 3# 7U 79 9EH #( ,AI +# #HENG +3 *ENG ," 7ANG 0( ,IN $" #HEN ## ,EE -# ET AL #OMPARISON OF %SCHERICHIA COLI AND +LEBSIELLA PNEUMONIAE LIVER ABSCESSES !M * -ED 3CI n &ANG #4 ,AI 39 9I 7# (SUEH 02 ,IU +, #HANG 3# +LEBSIELLA PNEU MONIAE GENOTYPE + AN EMERGING PATHOGEN THAT CAUSES SEPTIC OCULAR OR CENTRAL NERVOUS SYSTEM COMPLICATIONS FROM PYOGENIC LIVER ABSCESS #LIN )NFECT $IS n ,IN *# 3IU ,+ &UNG #0 9EH +- #HANG &9 .OSOCOMIAL LIVER ABSCESS CAUSED BY EXTENDED SPECTRUM BETA LACTAMASE PRODUCING +LEBSIELLA PNEUMONI AE * #LIN -ICROBIOL n 0ATEL 42 0ATEL +. "OYARSKY !( 3TAPHYLOCOCCAL LIVER ABSCESS AND ACUTE CHOLECYSTITIS IN A PATIENT WITH #ROHNS DISEASE RECEIVING INFLIXIMAB * 'ASTROINTEST 3URG n 3MITH "- :YROMSKI .* !LLISON $# #OMMUNITY ACQUIRED METHICILLIN RESISTANT 3TAPHYLOCOCCUS AUREUS LIVER ABSCESS REQUIRING RESECTION 3URGERY n -ATSUTANI 4 /NDA - -IYASHITA - (AO + 9OKOYAMA 3 -ATSUDA 4 &UTAMI 2 4AKUBO + 3ASAJIMA + ,IVER ABSCESSES ASSOCIATED WITH STROMAL TUMOUR OF THE STOMACH IN A YOUNG WOMAN %UR * 'ASTROENTEROL (EPATOL n -IJNHOUT '3 +LINKENBERG %# ,YCKLAMA ' ,INSKENS 2 -EUWISSEN 3' 3EPSIS AND ELEVATED LIVER ENZYMES IN A PATIENT WITH INFLAMMATORY BOWEL DIS EASE THINK OF PORTAL VEIN THROMBOSIS $IG ,IVER $IS n (IURA ! +IM %# )KEHARA 4 -ATSUMURA 9 -ISHIMA + )SHIDA ) (EPATIC
"ACTERIAL INFECTIONS OF THE LIVER
ABSCESS AS A COMPLICATION OF THE SUMP SYNDROME * (EPATOBILIARY 0ANCREAT 3URG n 4AYLOR 3. 3ANDERS #6 5NUSUAL MANIFESTATIONS OF INVASIVE PNEUMOCOC CAL INFECTION !M * -ED n 3ABBAJ * 3UTTER 6, &INEGOLD 3- !NAEROBIC PYOGENIC LIVER ABSCESS !NN )NTERN -ED n -IEDEMA "7 $INEEN 0 4HE DIAGNOSIS AND TREATMENT OF PYOGENIC LIVER ABSCESSES !NN 3URG n 3UGANO 3 -ATUDA 4 3UZUKI 4 -AKINO ( )INUMA - )SHII + /HE + -OGAMI + (EPATIC ACTINOMYCOSIS CASE REPORT AND REVIEW OF THE LITERATURE IN *APAN * 'ASTROENTEROL n -IYAMOTO -) &ANG &# 0YOGENIC LIVER ABSCESS INVOLVING !CTINOMYCES CASE REPORT AND #LIN )NFECT $IS n $UNN -7 "ERKOWITZ &% -ILLER ** 3NITZER *! (EPATOSPLENIC CAT SCRATCH DISEASE AND ABDOMINAL PAIN 0EDIATR )NFECT $IS * n 7EBER ' !BU 3HAKRA - (ERTZANU 9 "ORER ! 3UKENIK 3 ,IVER ABSCESS CAUSED BY #APNOCYTOPHAGA SPECIES #LIN )NFECT $IS n .APOLEAO & $AMASCO 06 #AMELLO 4# DO 6ALE -$ DE !NDRADE !& (IRATA 2 *R DE -ATTOS 'UARALDI !, 0YOGENIC LIVER ABSCESS DUE TO 2HODOCOCCUS EQUI IN AN IMMUNOCOMPETENT HOST * #LIN -ICROBIOL n "EECHING .* (ART (( 3YNEK "* "REMNER $! ! PATIENT WITH HEMOSID EROSIS AND MULTIPLE LIVER ABSCESSES DUE TO 9ERSINIA ENTEROCOLITICA 0ATHOLOGY n ,EE 9, ,EE 33 4SAI (# #HEN 93 7ANN 32 +AO #( ,IU 9# 0YOGENIC LIVER ABSCESS CAUSED BY "URKHOLDERIA PSEUDOMALLEI IN 4AIWAN * &ORMOS -ED !SSOC n 3ISTERON / 3OUCI * #HEVALLIER 0 #UA % "RUNETON *. (EPATIC ABSCESS CAUSED BY "RUCELLA 53 #4 AND -2) FINDINGS CASE REPORT AND REVIEW OF THE LITERATURE #LIN )MAGING n #OLMENERO *$ 1UEIPO /RTUNO -) -ARIA 2EGUERA * !NGEL 3UAREZ -UNOZ - -ARTIN #ARBALLINO 3 -ORATA 0 #HRONIC HEPATOSPLENIC ABSCESSES IN "RUCELLOSIS #LINICO THERAPEUTIC FEATURES AND MOLECULAR DIAGNOSTIC APPROACH $IAGN -ICROBIOL )NFECT $IS n 3IEGMAN )GRA 9 ,EVIN 2 7EINBERGER - 'OLAN 9 3CHWARTZ $ 3AMRA : +ONIGSBERGER ( 9INNON ! 2AHAV ' +ELLER . ET AL ,ISTERIA MONOCY TOGENES INFECTION IN )SRAEL AND REVIEW OF CASES WORLDWIDE %MERG )NFECT $IS n 7ING %* 'REGORY 3( ,ISTERIA MONOCYTOGENES CLINICAL AND EXPERIMENTAL UPDATE * )NFECT $IS n #ARNEIRO !# ,IMA 0 "ARBOSA )0 #HAVES &# 7HIPPLES DISEASE n A CHAL LENGING DIAGNOSIS !CTA -ED 0ORT n #OOK '# ,IVER INVOLVEMENT IN SYSTEMIC INFECTION %UR * 'ASTROENTEROL (EPATOL n 7ITKOWSKI *! 0ARISH ,# 4HE GREAT IMITATOR MALIGNANT SYPHILIS WITH HEPATITIS #LIN $ERMATOL n +ORMAN 4- 3PELMAN $7 0ERRY '* $OWLING *0 !CUTE GLOMERULO
(ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON
NEPHRITIS ASSOCIATED WITH ACUTE 1 FEVER CASE REPORT AND REVIEW OF THE RENAL COMPLICATIONS OF #OXIELLA BURNETII INFECTION #LIN )NFECT $IS n 2OMERO *IMENEZ -* 3UAREZ ,OZANO ) &AJARDO *- "ENAVENTE ! -ENCHERO ! DE LA )GLESIA ! (EPATITIS AS UNIQUE MANIFESTATION OF 1 FEVER CLINICAL AND EPIDEMIOLOGIC CHARACTERISTICS IN PATIENTS %NFERM )NFECC -ICROBIOL #LIN n ,EE (# #HUANG 9# 9U 7, ,EE .9 #HANG #- +O .9 7ANG ,2 +O 7# #LINICAL IMPLICATIONS OF HYPERMUCOVISCOSITY PHENOTYPE IN +LEBSIELLA PNEUMONIAE ISOLATES ASSOCIATION WITH INVASIVE SYNDROME IN PATIENTS WITH COM MUNITY ACQUIRED BACTERAEMIA * )NTERN -ED n -ATSUSHITA - (AJIRO + /KAZAKI + 4AKAKUWA ( .ISHIO ! %NDOPHTHALMITIS WITH BRAIN LUNG AND LIVER ABSCESSES ASSOCIATED WITH AN OCCULT COLON CANCER !M * 'ASTROENTEROL n ,IM +( 4AN 9- #HOW 0+ ,IVER ABSCESS METASTASIZING TO PROSTATE AND LUNG * 2 3OC -ED n $YLEWSKI *3 $YLEWSKI ) .ECROTIZING FASCIITIS WITH +LEBSIELLA LIVER ABSCESS #LIN )NFECT $IS n #ASANOVA # ,ORENTE *! #ARRILLO & 0EREZ 2ODRIGUEZ % .UNEZ . +LEBSIELLA PNEUMONIAE LIVER ABSCESS ASSOCIATED WITH SEPTIC ENDOPHTHALMITIS !RCH )NTERN -ED 6ALABHJI * 2OBINSON 3 %LKELES 23 (EPATIC ABSCESS IN A DIABETIC PATIENT 0OSTGRAD -ED * n ,INDSTROM 34 (EALEY 02 #HEN 3# -ETASTATIC SEPTIC ENDOPHTHALMITIS COMPLICATING PYOGENIC LIVER ABSCESS CAUSED BY +LEBSIELLA PNEUMONIAE !UST . : * -ED n 3ACCENTE - +LEBSIELLA PNEUMONIAE LIVER ABSCESS ENDOPHTHALMITIS AND MENINGITIS IN A MAN WITH NEWLY RECOGNIZED DIABETES MELLITUS #LIN )NFECT $IS n !YINALA 32 6ULPE - !ZAZ - #OHEN ( $ONELSON 33 ,EE - 0YOGENIC LIVER ABSCESSES DUE TO +LEBSIELLA PNEUMONIAE IN A DIABETIC PATIENT * -ISS 3TATE -ED !SSOC n +IM $* 0RATT $3 +LEBSIELLA LIVER ABSCESS * #LIN 'ASTROENTEROL n #HENG $, ,IU 9# 9EN -9 ,IU #9 7ANG 23 3EPTIC METASTATIC LESIONS OF PYOGENIC LIVER ABSCESS 4HEIR ASSOCIATION WITH +LEBSIELLA PNEUMONIAE BACTE REMIA IN DIABETIC PATIENTS !RCH )NTERN -ED n #HENG (0 3IU ,+ #HANG &9 %XTENDED SPECTRUM CEPHALOSPORIN COM PARED TO CEFAZOLIN FOR TREATMENT OF +LEBSIELLA PNEUMONIAE CAUSED LIVER ABSCESS !NTIMICROB !GENTS #HEMOTHER n 4AN 9- #HEE 30 3OO +# #HOW 0 /CULAR MANIFESTATIONS AND COMPLICA TIONS OF PYOGENIC LIVER ABSCESS 7ORLD * 3URG n 4AN .7 3RIRAM " 4AN +ENDRICK !0 2AJADURAI 63 .EONATAL HEPATIC ABSCESS IN PRETERM INFANTS A RARE ENTITY !NN !CAD -ED 3INGAPORE n 6IDAL *% DA 3ILVA 02 3CHIAVON .OGUEIRA 2 "ONASSER &ILHO & (ERNANDEZ !6 ,IVER ABSCESS DUE TO 3ALMONELLA ENTERITIDIS IN A RETURNED TRAVELER WITH
"ACTERIAL INFECTIONS OF THE LIVER
()6 INFECTION CASE REPORT AND REVIEW OF THE LITERATURE 2EV )NST -ED 4ROP 3AO 0AULO n 0RAMOOLSINSAP # 6IRANUVATTI 6 3ALMONELLA HEPATITIS * 'ASTROENTEROL (EPATOL n #ONNOR "! 3CHWARTZ % 4YPHOID AND PARATYPHOID FEVER IN TRAVELLERS ,ANCET )NFECT $IS n 2ISSER 7, 2ISSER *- "ENJAMINS ,* &ELDMANN *- )NCIDENCE OF &ITZ (UGH #URTIS SYNDROME IN ADOLESCENTS WHO HAVE PELVIC INFLAMMATORY DISEASE * 0EDIATR !DOLESC 'YNECOL n 'AMBERINI 3 !NANIA ' )NCASA % :ANGIROLAMI ! 4AMPIERI - "OARI " "ENEA ' -ANFREDINI 2 3TAPHYLOCOCCUS HEMOLYTICUS LIVER ABSCESS AS AN UNCOM MON PRESENTATION OF SILENT COLONIC CANCER A CASE REPORT * !M 'ERIATR 3OC n .AGATA 3 3UMIOKA - 3ATO / -IYAMOTO - 7ATANABE # 9AMADA ( (IRATA + )MAGAWA - ! CASE OF LIVER ABSCESS CAUSED BY 3TREPTOCOCCUS MILLERI .IPPON 3HOKAKIBYO 'AKKAI :ASSHI n +UO #- +UO #( #HANGCHIEN #3 ,IVER ABSCESS IN PATIENTS WITH CIR RHOSIS OF THE LIVER A YEAR EXPERIENCE * 'ASTROENTEROL n ,ORBER " ,ISTERIOSIS #LIN )NFECT $IS n 6AZQUEZ "OLAND *! +UHN - "ERCHE 0 #HAKRABORTY 4 $OMINGUEZ "ERNAL ' 'OEBEL 7 'ONZALEZ :ORN " 7EHLAND * +REFT * ,ISTERIA PATHOGENESIS AND MOLECULAR VIRULENCE DETERMINANTS #LIN -ICROBIOL 2EV n 2IEDO &8 0INNER 27 4OSCA -, #ARTTER -, 'RAVES ,- 2EEVES -7 7EAVER 2% 0LIKAYTIS "$ "ROOME #6 ! POINT SOURCE FOODBORNE LISTERIOSIS OUT BREAK DOCUMENTED INCUBATION PERIOD AND POSSIBLE MILD ILLNESS * )NFECT $IS n 'ILLESPIE )! -C,AUCHLIN * 'RANT +! ,ITTLE #, -ITHANI 6 0ENMAN # ,ANE # 2EGAN - #HANGING PATTERN OF HUMAN LISTERIOSIS %NGLAND AND 7ALES n %MERG )NFECT $IS n 3ORABJEE *3 4HE LIVER IN ENTERIC FEVER AND LEPTOSPIROSIS )NDIAN * 'ASTROENTEROL n 6AIPHEI + 3URI 6 "HALLA ! &EVER JAUNDICE ALTERED SENSORIUM WITH MULTIPLE SYSTEMIC MANIFESTATIONS )NDIAN * 'ASTROENTEROL n 6ALLEJO *' 3TEVENS !- $UTTON 26 +APLAN 3, (EPATOSPLENIC ABSCESS ES DUE TO "RUCELLA MELITENSIS REPORT OF A CASE INVOLVING A CHILD AND REVIEW OF THE LITERATURE #LIN )NFECT $IS n #AMARA " +AMAR . "ONAFE *, $ANJOUX - 3UC " 2OSTAING , 3YPHILIS HEPATITIS AND LIVER TRANSPLANTATION -ED -AL )NFECT n (OLLIER ,- (ARSTAD 47 3ANCHEZ 0* 4WICKLER $- 7ENDEL '$ *R &ETAL SYPHILIS CLINICAL AND LABORATORY CHARACTERISTICS /BSTET 'YNECOL n 7INDSOR ** #AT SCRATCH DISEASE EPIDEMIOLOGY AETIOLOGY AND TREATMENT "R * "IOMED 3CI n !YGEN " 3UMERKAN " $OGANAY - 3EHMEN % 0ROSTATITIS AND HEPATITIS DUE TO "RUCELLA MELITENSIS A CASE REPORT * )NFECT n 4ERRY 2" 'UNNAR 2- 0RIMARY MILIARY TUBERCULOSIS OF THE LIVER * !M -ED !SSOC n !STON ./ !BDOMINAL TUBERCULOSIS 7ORLD * 3URG n
(ILMAR 7ISPLINGHOFF AND $ARRYN , !PPLETON
#OLMENERO *$ 3UAREZ -UNOZ -! 1UEIPO /RTUNO -) 2EGUERA *- -ORATA 0 ,ATE REACTIVATION OF CALCIFIED GRANULOMA IN A PATIENT WITH CHRONIC SUP PURATIVE BRUCELLOSIS %UR * #LIN -ICROBIOL )NFECT $IS n 3INAN 4 3HEIKH - 2AMADAN 3 3AHWNEY 3 "EHBEHANI ! #4 FEATURES IN ABDOMINAL TUBERCULOSIS YEARS EXPERIENCE "-# -ED )MAGING +IELHOFNER -! (AMILL 2* &OCAL HEPATIC TUBERCULOSIS IN A PATIENT WITH ACQUIRED IMMUNODEFICIENCY SYNDROME 3OUTH -ED * n 3ALUJA 33 2AY 3 0AL 3 +UKERAJA - 3RIVASTAVA $. 3AHNI 0 #HATTOPADHYAY 4+ (EPATOBILIARY AND PANCREATIC TUBERCULOSIS A TWO DECADE EXPERIENCE "-# 3URG %VANS -% 'REGORY $7 3CHAFFNER 7 -C'EE :! 4ULAREMIA A YEAR EXPERIENCE WITH CASES -EDICINE "ALTIMORE n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITES OR THEIR DISTINCT LIFE CYCLE STAGES !CHIM (ARDER AND (EINZ -EHLHORN "AYER (EALTH#ARE !' !NIMAL (EALTH 2$ 0ARASITICIDES !LFRED .OBEL 3TR
-ONHEIM 'ERMANY $EPARTMENT OF 0ARASITOLOGY (EINRICH (EINE 5NIVERSITY $àSSELDORF 'ERMANY
!BSTRACT 4HERE ARE A VARIETY OF PARASITES n PROTOZOANS CESTODES TREMATODES NEMATODES OR PENTASTOMIDES n WHICH RESIDE IN THE LIVER OR INVADE THIS ORGAN AND ARE RESPONSIBLE FOR INFLAMMATION RESULTING IN HEPATITIS !MONG THE 0ROTOZOA %NTAMOEBA HISTOLYTICA IS OF HIGH IMPORTANCE )N THE CYST FLUID OF THE LIVER ABSCESS PURULENT COMPONENTS ARE VISIBLE BUT ALSO SOME AMOEBA SO CALLED MAGNA FORMS &URTHERMORE THE AMASTIGOTE STAGES OF 4RYPANOSOMA CRUZI AND ,EISHMANIA DONOVANI n BOTH ARE 0ROTOZOA WHICH POSSESS A KINETOPLAST n AND THE SCHIZONTS OF 0LASMODIUM SPP WHICH ARE THE CAUSATIVE PATHOGENS OF MALARIA HAVE TO BE MENTIONED AS A PUTATIVE CAUSE OF PARASITE INDUCED HEPATITIS !MONG CESTODES %CHINOCOCCUS GRANULOSUS AND % MULTILOCULARIS PREFERENTIALLY RESIDE IN THE LIVER 7ITHIN THE TREMATODES 3CHISTOSOMA SPP #LONORCHIS SINENSIS /PISTHORCHIS VIVERRINI $ICROCOELIUM DENDRITICUM AND THE JUVENILE STAGES OF &ASCIOLA HEPATICA HAVE TO BE CONSIDERED !MONG THE LARGE GROUP OF HUMAN NEMATODES ONLY #APILLARIA HEPATICA MIGRATING NEMATODE LARVAE SUCH AS LARVA AND THE ADULTS OF !SCARIS LUMBRICOIDES LARVAE OF 3TRONGYLOIDES STERCORALIS HOOKWORMS 4OXOCARA CANIS AND MICROFILARIAE OF DIFFERENT FILARIAE PLAY A ROLE IN INDUCING LIVER INFLAMMATION
(EPATITIS CAUSED BY PROTOZOA %NTAMOEBIASIS %NTAMOEBA HISTOLYTICA ;n= 4AXONOMY 3UBREGNUM 0HYLUM #LASS /RDER &AMILY 'ENUS
0ROTOZOA !MOEBOZOA ,OBOSEA !MOEBIDA %NTAMOEBIDAE %NTAMOEBA
!CHIM (ARDER AND (EINZ -EHLHORN
-ORPHOLOGY 4HE LIFE CYCLE OF %NTAMOEBA HISTOLYTICA COMPRISES TWO MORPHOLOGICALLY DIS TINCT DEVELOPMENTAL STAGES THE VEGETATIVE STAGES MINUTA AND MAGNA FORMS ALSO KNOWN AS TROPHOZOITES AND THE CYST STAGE &IGS AND &IGS n AND &IGS n SEE PP n 4ROPHOZOITES ARE UNINUCLEATE CELLS WITH A DIAMETER OF n +M AND A TYPICAL NUCLEUS SPHERICAL CENTRAL KARYOSOME THEY SHOW PRONOUNCED GLID ING MOVEMENTS BY FORMATION OF A SINGLE APICAL PSEUDOPODIUM CYSTS ARE SPHERICAL QUADRINUCLEATE AND HAVE DIAMETERS FROM n +M
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD %NTAMOEBA HISTOLYTICA IS USUALLY TRANSMITTED BY THE FAECAL ORAL ROUTE BY INGESTION OF INFECTIOUS CYSTS CONTAMINATED FOOD BUT TRANSMISSION THROUGH RELEVANT HOMOSEXUAL PRACTICES IS ALSO POSSIBLE -ULTIPLICATION OF %NTAMOEBA HISTOLYTICA TAKES PLACE ONLY IN THE INTESTINE !FTER INGESTION OF THE TYPICALLY QUADRINUCLEATE CYSTS WHICH UNLIKE THE TRO PHOZOITES CAN REMAIN INFECTIOUS FOR MONTHS OUTSIDE THE BODY AND ARE NOT DESTROYED BY THE ACID CONTENTS OF THE STOMACH THE UNINUCLEATE TROPHOZOITES CAPABLE OF MULTIPLICATION DEVELOP IN THE SMALL INTESTINE )N THE LOWER COLON THERE IS RENEWED ENCYSTMENT WITH TWO SUBSEQUENT NUCLEAR DIVISIONS !N INFECT ED PERSON CAN PASS UP TO MILLION CYSTS PER DAY 4HE INCUBATION PERIOD OF AMOEBIASIS IS VERY VARIABLE 4HE TIME BETWEEN INFECTION AND THE OCCURRENCE OF CLINICAL SYMPTOMS CAN BE A FEW DAYS BUT IN SOME CASES EVEN SEVERAL YEARS 4HE AVERAGE INCUBATION PERIOD FOR AN AMOEBIC LIVER ABSCESS IS UP TO MONTHS
%PIDEMIOLOGY .ATURAL INFECTION WITH %NTAMOEBA HISTOLYTICA IS LIMITED TO MAN AND A FEW /LD 7ORLD MONKEY SPECIES 0EOPLE IN TROPICAL AND SUBTROPICAL COUNTRIES IN WHICH %NTAMOEBA HISTOLYTICA IS ENDEMIC ARE USUALLY ASSOCIATED WITH LOW SOCIOECONOMIC STATUS AND POOR HYGIENIC CONDITIONS TRAVELLERS TO SUCH COUN TRIES AND MALE HOMOSEXUALS ARE ENDANGERED 4HE PREVALENCE OF %NTAMOEBA HISTOLYTICA DEPENDS PRIMARILY ON THE NUM BER OF CYST PASSERS AND THE HYGIENIC CONDITIONS 5NDER THE HYGIENIC CONDI TIONS WHICH ARE STANDARD IN 7ESTERN %UROPE THE INFECTION USUALLY DOES NOT OR IS POORLY SPREAD
$ISEASES AND SYMPTOMS 4HE PATHOGENICITY OF %NTAMOEBA HISTOLYTICA IS BASED PRIMARILY ON THE ABIL
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
ITY TO DESTROY HOST TISSUE AND CELLS 3URFACE RECEPTORS CYSTEINE PROTEINASES AND PORE FORMING PEPTIDES OF THE AMOEBAE PLAY A DECISIVE ROLE IN THIS 4HE VIRULENCE OF INDIVIDUAL AMOEBA ISOLATES CAN VARY DEPENDING ON THE LEVEL OF EXPRESSION OF THESE MOLECULES !NTIGEN VARIABILITY HAS NOT YET BEEN SHOWN FOR %NTAMOEBA HISTOLYTICA !NY INFECTION WITH %NTAMOEBA HISTOLYTICA IS CALLED ENTAMOEBIASIS -OST INFECTIONS OF PREEXPOSED PERSONS ARE ASYMPTOMATIC /RAL UPTAKE OF CYSTS LEADS MAINLY TO INTESTINAL MANIFESTATIONS BUT ALSO AS A RESULT OF SPREAD OF THE AMOEBAE TO OTHER ORGANS TO EXTRAINTESTINAL MANIFESTATIONS )N THE LATTER CASE THERE OCCUR USUALLY BLOODY DIARRHOEA AND SEVERE ILLNESS ACCOMPANIED BY FEVER AND WEIGHT LOSS &IG )NTESTINAL AMOEBIASIS )NTESTINAL AMOEBIASIS IS LINKED WITH ENTERITIS OR COLITIS OF VARYING SEVERITY 4YPICALLY ULCERATIVE MUCOSAL LESIONS WITH DIARRHOEAL STOOLS CONTAINING BLOOD AND MUCUS &IG !MOEBOMA MAY OCCUR AS TUMOUR LIKE GRANULOMATOUS INFLAMMATORY REACTION OF THE COLON CAUSED BY %NTAMOEBA HISTOLYTICA %XTRAINTESTINAL AMOEBIASIS -AGNA FORMS OF THE AMOEBAE CAN SPREAD TO OTHER ORGANS BY HAEMATOGENOUS DISSEMINATION AND LEAD TO ABSCESS FORMATION )N MORE THAN THERE ARE EXTRAINTESTINAL MANIFESTATIONS IN THE LIVER &IG P )N RARE CASES THERE CAN BE COMPLICATIONS SUCH AS PERITONITIS AFTER PERFORATION OF AN AMOEBIC LIVER ABSCESS OR MIGRATION FROM THE LIVER INTO THE LUNG OR PERICARDIUM
)MMUNE RESPONSE )NFECTIONS WITH %NTAMOEBA HISTOLYTICA REGULARLY INDUCE A SPECIFIC " AND 4 CELL RESPONSE %VEN IN THE CASE OF ASYMPTOMATIC INFECTIONS SERUM ANTIBODIES TO %NTAMOEBA HISTOLYTICA CAN BE DETECTED IN MORE THAN OF CASES
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS )N THE CASE OF ENTERITIS OR COLITIS OTHER INTESTINAL INFECTIOUS AGENTS SHOULD ALWAYS BE RULED OUT )N THE CASE OF MARKED MUCOSAL LESIONS ULCERATIVE COLITIS SHOULD BE CONSIDERED !N AMOEBIC LIVER ABSCESS SHOULD BE DIFFERENTIATED FROM A BACTERIAL ABSCESS &URTHER DIFFERENTIAL DIAGNOSES ARE ECHINOCOCCOSIS OR A NECROTIC TUMOUR 4HE DIAGNOSTIC WORKUP OF INVASIVE AMOEBIASIS DEPENDS ON THE SITE OF MANIFESTATION OF THE ILLNESS A )N THE CASE OF INTESTINAL AMOEBIASIS RECTO SCOPIC OR COLONOSCOPIC DETECTION OF APPROPRIATE MUCOSAL LESIONS AND DIRECT DETECTION OF THE PATHOGEN ARE THE PRIMARY MEASURES 4HE LATTER IS PERFORMED BY EXAMINATION OF THE STOOLS &IGS AND OR BY HISTOLOGICAL DETECTION OF
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Achim Harder and Heinz Mehlhorn
Figure 4. Computer tomographies of a liver with an abscess due to E. histolytica amoebae in biopsy material; b) In extraintestinal amoebiasis imaging procedures such as ultrasound and computed tomography are used to detect appropriate organ manifestations and structural defects. At the same time serological detection of specific antibodies to Entamoeba histolytica is an important, often pivotal diagnostic tool. To distinguish it from other apathogenic intestinal amoebae (e.g., Entamoeba dispar), particularly in the case of asymptomatic infections, Entamoeba histolytica should also be characterised immunologically or genetically. Immunological characterisation using monoclonal antibodies to specific epitopes of Entamoeba histolytica is also available as well as the genetic characterisation on the basis of specific DNA sequences, e.g., within the rRNA gene. The genome of Entamoeba histolytica is currently being sequenced. It probably comprises 20 megabases which are distributed over 14 chromosomes.
Treatment Infection with Entamoeba histolytica must always be treated. Asymptomatic intestinal Entamoeba histolytica infections should be treated with diloxanide fuorate or paromomycin for 10 days. All Entamoeba histolytica infections with intestinal or extraintestinal clinical manifestations
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
SHOULD BE TREATED FIRST WITH METRONIDAZOLE MGKG BODY WTDAY DIVIDED INTO THREE DAILY DOSES FOR DAYS TO KILL AMOEBAE WHICH HAVE ALREADY PENETRATED THE TISSUES FOLLOWED BY TREATMENT WITH DILOXANIDE FUORATE OR PAROMOMYCIN TO ELIMINATE THE REMAINING INTRALUMINAL FORMS
2ESISTANCE $RUG RESISTANCE TO METRONIDAZOLE HAS BEEN SUSPECTED IN INDIVIDUAL CASES BUT HAS NOT YET BEEN SCIENTIFICALLY CONFIRMED
0REVENTION 7ORK ON A VACCINE AGAINST %NTAMOEBA HISTOLYTICA IS IN PROGRESS 0ROPHYLAXIS CURRENTLY CONSISTS OF FILTERING DISINFECTING OR COOKING ALL FOOD WHICH MIGHT BE CONTAMINATED WITH INFECTIOUS %NTAMOEBA HISTOLYTICA CYSTS
.OTIFIABLE DISEASE STATUS %NTAMOEBIASIS IS NOT NOTIFIABLE HOWEVER OCCURRENCE IN SCHOOLS REFUGIE CAMPS ETC HAVE TO BE ANNOUNCED TO 0UBLIC (EALTH !UTHORITIES
,EISHMANIASIS ,EISHMANIA SPECIES ;n= 4AXONOMY 3UBREGNUM 0HYLUM #LASS /RDER 'ENUS 3PECIES /LD 7ORLD
0ROTOZOA %UGLENOZOA 4RYPANOSOMATIDEA 4RYPANOSOMATIDA ,EISHMANIA , DONOVANI , INFANTUM , MAJOR , TROPICA , AETHIOPICA ETC 3PECIES .EW 7ORLD , CHAGASI , MEXICANA , AMAZONENSIS , BRASILIENSIS , PANAMENSIS , PERUVIANA ETC
-ORPHOLOGY 4HE SO CALLED AMASTIGOTE FORM OF THE PARASITE IS FOUND IN CELLS OF THE RETICULOENDOTHELIAL SYSTEM OF THE VERTEBRATE HOST &IG )T IS SPHERICAL OR OVOIDAL MEASURES ABOUT n +M IN DIAMETER AND HAS ONLY A SHORT RETRACTED
!CHIM (ARDER AND (EINZ -EHLHORN
FLAGELLUM 4HE NUCLEUS AND KINETOPLAST STAIN STRONGLY WITH THE 2OMANOVSKY STAIN WHICH GIVES THE ORGANISM ITS CHARACTERISTIC APPEARANCE 4HE SO CALLED PROMASTIGOTE FORM IS FOUND IN THE SANDFLY AND IN CULTURE MEDIUM )T HAS AN ANTERIOR FLAGELLUM AND DEVIDES BY BINARY FISSION &IG
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD 4RANSMISSION IS DONE BY SANDFLIES THUS BEING A ZOONOSIS ORIGINATING FROM DOGS OR RODENTS OR OCCURS FROM MAN TO MAN &URTHER TRANSMISSION FROM MAN TO MAN MAY BE DONE BY BLOOD PRODUCTS 4HE AMASTIGOTE FORM IS TAKEN UP FROM THE BLOOD OR TISSUE OF THE MAMMALIAN HOST BY THE FEMALE SANDFLY AND IS TRANSFORMED THERE INTO THE INFECTIOUS PROMASTIGOTE FORM 6ISCERAL LEISHMANI ASIS 6, NEEDS WEEKS TO MONTHS UNTIL CLINICAL SIGNS OCCUR WHILE CUTANEOUS LEISHMANIASIS #, IS MANIFESTED WITHIN DAYS BY BAD HEALING SKIN LESIONS
%PIDEMIOLOGY ,EISHMANIASIS IS USUALLY A ZOONOSIS 2ESERVOIR HOSTS ARE WILD OR PERIDOMESTIC CARNIVORES EG DOGS RODENTS AND ALSO MAN %NDANGERED ARE PEOPLE LIV ING IN ENDEMIC AREAS AND TRAVELLERS RETURNING FROM ENDEMIC AREAS FOREIGN RESIDENTS MIGRATORY WORKERS ASYLUM SEEKERS REFUGEES FROM ENDEMIC REGIONS AS WELL AS PEOPLE INFECTED WITH ()6 OPPORTUNISTIC INFECTION 4HE ANNUAL INCIDENCE OF #, IS AROUND MILLION CASES THAT OF 6, ABOUT CASES ABOUT OF THESE IN )NDIA AND OF THESE IN THE STATE OF "IHAR 4HE NUMBERS ARE INCREASING ON ACCOUNT OF DEFORESTATION "RAZIL IRRIGATION PROJ ECTS AND URBANISATION -IDDLE %AST AS WELL AS THE COLLAPSE OF INFRASTRUC TURE !FGHANISTAN 6, OCCURS IN THE )NDIAN SUBCONTINENT 0AKISTAN .EPAL #ENTRAL AND 3OUTHWEST !SIA #HINA .ORTH AND 3UBSAHARAN !FRICA .EAR AND -IDDLE %AST -EDITERRANEAN COUNTRIES AND #ENTRAL AND 3OUTH !MERICA
$ISEASES AND SYMPTOMS 6ISCERAL LEISHMANIASIS 6, +ALA AZAR /UTSIDE ENDEMIC AREAS PATIENTS WITH 6, OFTEN REMAIN UNDIAGNOSED FOR A LONG TIME 4HE PRIMARY SYMPTOM n FEVER n IS OFTEN MISDIAGNOSED BLOOD CHANGES SUCH AS ANAEMIA LEUCOPENIA OR THROMBOPENIA OR PANCYTOPENIA AND HEPATOSPLENOMEGALY ARE OFTEN MISINTERPRETED )N THE CASE OF INFECTION WITH ,EISHMANIA INFANTUM IN COUNTRIES OF THE -EDITERRANEAN #OAST OR ,EISHMANIA CHAGASI 3OUTH !MERICA SUBCLINICAL COURSES AND SPONTANEOUS RECOVERIES ARE MORE COMMON THAN CLINICALLY MANIFESTED DISEASE )NFECTIONS WITH ,EISHMANIA DONOVANI ON THE OTHER HAND ARE USUALLY CLINICALLY MANI FEST AND INDUCE A HIGH MORTALITY RATE 4HE DISEASE CAN BEGIN INSIDIOUSLY OR
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
ABRUPTLY 4HE PATIENT PRESENTATION DEPENDS TO A LARGE EXTENT ON THE DURATION OF THE DISEASE )T USUALLY CONSISTS OF FEVER ABDOMINAL SYMPTOMS ASSOCIATED WITH AN ENLARGED SPLEEN WEIGHT LOSS COUGH OR DIARRHOEA 0OST KALA AZAR DERMAL LEISHMANIASIS 0+$, 4HIS NODULAR OR HYPOPIGMENTED MACULAR SKIN ERUPTION MAY OCCUR AFTER SUC CESSFUL TREATMENT OF 6, CAUSED BY , DONOVANI
)MMUNE RESPONSE )NBORN RESISTANCE IS BASED ON THE ABILITY OF THE MACROPHAGES TO KILL THE INTRA CELLULAR ,EISHMANIA STAGES BY NITRIC OXIDE PRODUCTION 4HE PARASITE IN TURN HAS DEVELOPED THE ABILITY TO WARD OFF THIS DANGER BY SPECIFIC INHIBITION AND TO MULTIPLY INSIDE THE CYTOPLASM INSTEAD VACUOLES !CQUIRED IMMUNITY IS INITIATED VIA MACROPHAGES AND DENDRITIC CELLS WHICH PRESENT THE ,EISHMANIA ANTIGENS TO 4 LYMPHOCYTES 4HIS RESULTS IN EITHER AN EFFECTIVE CELLULAR OR INEFFECTIVE HUMORAL IMMUNE RESPONSE 4HE EFFECTIVE 4( RESPONSE LEADS TO ACTIVATION OF THE MACROPHAGES WHILE THE 4( RESPONSE INHIBITS THE MACROPHAGES WITH REGARD TO THEIR ABILITY TO KILL THE ,EISHMANIA STAGES 4HE CELLULAR IMMUNE RESPONSE OF THE HOST DETERMINES THE MANIFESTATION OF THE DISEASE CLINICAL n SUBCLINICAL VISCERAL n CUTANEOUS n MUCOCUTANEOUS ETC
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS %XCLUDED MUST BE NUMEROUS DISEASES IN WHICH OCCUR FEVER ANAEMIA LEUCO PENIA THROMBOPENIA AND HEPATOSPLENOMEGALY PARTICULARLY BACTERIAL SEPSIS AND MALIGNANT DISEASES 6ISCERAL LEISHMANIASIS -ANY TYPES OF NON HEALING WOUNDS 3EROLOGY $IRECT AGGLUTINATION TEST $!4 IMMUNOFLUORESCENCE ANTIBODY TESTS )&!4 ENZYME LINKED IMMUNOSORBENT ASSAYS %,)3! 4HE SENSITIVITY OF THE SEROLOGY IS )N ()6 INFECTED PERSONS DEPENDING ON THE ()6 STAGE ANTIBODIES MAY NO LONGER BE DETECTABLE DESPITE THE PRESENCE OF CLINI CALLY MANIFEST 6, /NLY ABOUT OF THE ()6 INFECTED PATIENTS WITH 6, TEST POSITIVE IN ROUTINE SEROLOGICAL TESTING 4HE PROBLEM WITH SEROLOGICAL DIAGNOSIS OF 6, LIES IN THE SPECIFICITY OF THE AVAILABLE TEST SYSTEMS AND IN THE FACT THAT INDIVIDUALS WITH ASYMPTOMATIC INFECTION AND PEOPLE WHO HAVE BEEN TREATED SHOW POSITIVE SEROLOGICAL RESULTS FOR A LONG TIME SEROLOGICAL @SCAR
!CHIM (ARDER AND (EINZ -EHLHORN
$IRECT DETECTION OF THE PARASITE $IRECT DETECTION OF THE PARASITE IS PERFORMED IN 6ENOUS BLOOD n FLUORESCENCE MICROSCOPIC DETECTION OF ,EISHMANIA STAGES IN THE BUFFY COAT LAYER SENSITIVITY UP TO THE IMMUNODEFICIENCY OF !)$3 PATIENTS MEANS THAT PERIPHERAL MONOCYTES ARE MORE LIKELY TO BE INFECTED THAN IN IMMUNOCOMPETENT INFECTED PATIENTS THEREFORE PARTICULARLY HIGH SENSITIVITIES ARE TO BE EXPECTED %XAMINATION OF MATERIAL OBTAINED BY PUNCTURE OF THE SPLEEN THE LIVER OR THE BONE MARROW n THE SMEARS ARE STAINED WITH 'IEMSA 7RIGHT OR ,EISHMAN STAIN SENSITIVITY SPLEEN LIVER OR BONE MARROW n &IG )NOCULATION OF BIOPSY MATERIAL INTO SUITABLE CULTURE MEDIUM AND CULTURE )N POSITIVE CULTURES MICROSCOPICALLY VISIBLE MOTILE PROMASTIGOTE CELLS CAN BE EXPECTED WITHIN WEEKS 4HE CULTURE STEP CAN FURTHER INCREASE THE SENSITIVITY BY UP TO $IAGNOSTIC PROCEDURES FOR DETERMINING THE SEVERITY OF DISEASE "LOOD COUNT PLASMATIC COAGULATION LIVER VALUES PROTEIN ELECTROPHORESIS ULTRASOUND OF THE ABDOMEN )N ADVANCED COMPLICATED COURSES PROCEDURES TO DETECT SECONDARY BACTERIAL INFECTIONS PNEUMONIA TUBERCULOSIS DYSEN TERY
4REATMENT 6ISCERAL LEISHMANIASIS ,IPOSOMAL AMPHOTERICIN " !M"ISONE BELONGS TO THE GROUP OF THE LIPID ASSOCIATED AMPHOTERICINS 4HESE ARE TAKEN UP BY MACROPHAGES WHICH THUS CARRY THE AMPHOTERICIN " DIRECTLY TO THE SITE OF INFECTION 6ERY HIGH LEVELS ARE ACHIEVED IN THE LIVER AND SPLEEN 4HEY ARE LESS TOXIC THAN AMPHOTERICIN " /N THE BASIS OF THE CRITERIA EFFICACY AND SIDE EFFECT PROFILE LIPOSOMAL AMPHOTERICIN " IS CURRENTLY THE BEST DRUG FOR TREATMENT OF 6, (OWEVER THE PRICE IS A PROBLEM 0ENTAVALENT ANTIMONY COMPOUNDS SODIUM STIBOGLUCONATE ;0ENTOSTAM= CONTAINS MG 3B6ML MEGLUMINE ANTIMONIATE ;'LUCANTIME= CONTAINS MG 3B6ML THE TOXICITY IS ASSOCIATED WITH THE CUMULATIVE DOSE OF 3B6 -YALGIA ARTHRALGIA NAUSEA ABDOMINAL SYMPTOMS POSSIBLY INDICATING PAN CREATITIS HEPATITIS HEADACHES REVERSIBLE PERIPHERAL NEUROPATHY DISTURBANC ES OF THE STIMULUS CONDUCTION SYSTEM OF THE HEART &URTHER DRUGS SECOND LINE DRUGS 4HERE ARE A LARGE NUMBER OF FURTHER DRUGS EG PAROMOMYCIN KETO CONAZOLEITRACONAZOLE ALLOPURINOL WHICH ARE USED UNDER CERTAIN CONDITIONS ()6 PATIENTS ,IPOSOMAL AMPHOTERICIN " INITIALLY HAS A HIGH CURE RATE COMPARED WITH ANTIMONY COMPOUNDS BUT RECURRENCES OCCUR HERE TOO $RUGS FOR RELAPSE PROPHYLAXIS ARE GIVEN
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
2ESISTANCE 0ENTAVALENT ANTIMONY COMPOUNDS PRIMARY RESISTANCE IS FOUND IN ABOUT OF THE PATIENTS IN !FRICAN ENDEMIC AREAS AND IN ABOUT n IN )NDIA
0REVENTION 4HERE ARE NO VACCINES AVAILABLE 4HERE IS NO CHEMOPROPHYLAXIS 2EPELLENTS AND CLOTHING ARE USEFUL AS PROTECTION AGAINST THE DIURNALLY EARLY EVENING ACTIVE VECTORS -OSQUITO NETS IMPREGNATED WITH INSECTICIDE PERMETHRIN PROTECT AGAINST NOCTURNALLY ACTIVE VECTORS DURING SLEEPING
3TRATEGIES FOR PREVENTION AND CONTROL OF THE DISEASE 4HESE STRATEGIES ARE CONCENTRATED ON CONTROL OF THE REGIONALLY SIGNIFICANT RESERVOIR HOSTS EG DOGS AND OF THE VECTORS AS WELL AS ACTIVE CASE FINDING AND TREATMENT
.OTIFIABLE DISEASE STATUS ,EISHMANIASIS IS NOT A NOTIFIABLE DISEASE ACCORDING TO THE 'ERMAN ,AW FOR THE 0ROTECTION !GAINST )NFECTIOUS $ISEASES )NFEKTIONSSCHUTZGESETZ
#HAGAS DISEASE 4RYPANOSOMA CRUZI ; = 4AXONOMY 3UBREGNUM 0HYLUM #LASS /RDER 'ENUS 3PECIES
0ROTOZOA %UGLENOZOA 4RYPANOSOMATIDEA 4RYPANOSOMATIDA 4RYPANOSOMA 4RYPANOSOMA CRUZI
-ORPHOLOGY )NFECTION OF MAN AND NUMEROUS RESERVOIR HOSTS IN A SYLVATIC CYCLE EG VIA ARMADILLO OPOSSUM DOG CAT MONKEYS RODENTS TAKES PLACE THROUGH THE BITE OF BLOOD SUCKING REDUVIID BUGS INCLUDING THOSE OF THE GENERA 4RIATOMA AND
!CHIM (ARDER AND (EINZ -EHLHORN
2HODNIUS )N CONTRAST TO THE !FRICAN TRYPANOSOMES HOWEVER TRANSMISSION IS NOT DONE WITH THE SALIVA BUT THROUGH THE TRYPOMASTIGOTE STAGES CONTAINED IN THE FAECES 4HE BUGS PASS THESE BEFORE OR DURING THEIR BLOOD MEAL AND THEY ARE EITHER CARRIED INTO THE BITE WOUNDS BY THE BUGS OR RUBBED INTO THE WOUNDS BY THE HOSTS THROUGH SCRATCHING )N THE BLOOD THESE TRYPOMASTIGOTE STAGES APPEAR # OR 3 SHAPED AND REACH A LENGTH OF n +M &IG 4HEY VERY SOON INVADE THE HOST CELLS PARTICULARLY MACROPHAGES MUSCLE AND NERVE CELLS AND MULTIPLY DIRECTLY IN THE CYTOPLASM BY CONSTANT BINARY FISSION APPEARING FIRST AS AMASTIGOTE LATER AS EPIMASTIGOTE AND FINALLY AGAIN AS TRY POMASTIGOTE STAGES 4HESE INFECTED HOST CELLS ARE ALSO CALLED PSEUDOCYSTS &IG BUT RUPTURE DURING THE MULTIPLICATION PHASE OF THE PARASITES SO THAT WHOLE ORGANS EG HEART SUFFER FROM SUBSTANTIAL LOSS OF TISSUE 4HE MULTIPLICATION TAKES PLACE VERY GRADUALLY OVER SEVERAL YEARS AND GOES LARGELY UNNOTICED BY THE BODY n ON ACCOUNT OF THE MAINLY INTRACELLULAR LOCATION OF THE PARASITE )F A BUG TAKES UP TRYPOMASTIGOTE STAGES WITH THE BLOOD THESE ATTACH TO ITS MIDGUT WALL TRANSFORM INTO EPIMASTIGOTE FORMS AND MULTIPLY INTENSIVELY THROUGH LONGITUDINAL BINARY FISSION 7HEN THEY REACH THE BUGS HIND GUT THEY ARE TRANSFORMED TO THE INFECTIOUS TRYPOMASTIGOTE METACYCLIC FORM
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD 2OUTE OF INFECTION 0ERCUTANEOUSLY THROUGH RUBBING IN TRYPOMASTIGOTE STAGES CONTAINED IN LIQUID BUG FAECES WHICH ARE PASSED DURING OR BEFORE THE USUALLY NOCTURNAL FEEDING STERCORAL INFECTION &URTHERMORE INFECTION MAY OCCUR BY BLOOD TRANSFUSION OR BREAST MILK )NCUBATION PERIOD n DAYS TO OCCURRENCE OF OEDEMA EG OF THE EYELID #HAGOMA 0REPATENT PERIOD n MONTHS 0ATENT PERIOD #AN NEED YEARS IN CHRONIC COURSES
%PIDEMIOLOGY #OUNTRIES OF OCCURRENCE ARE RURAL REGIONS WITH BUGS IN #ALIFORNIA 3OUTHERN 53! 3OUTH AND #ENTRAL !MERICA -EXICO TO !RGENTINA AND .ORTHERN #HILE
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
$ISEASES AND SYMPTOMS 3YMPTOMS OF THE DISEASE #HAGAS DISEASE !MERICAN TRYPANOSOMIASIS !N ACUTE AND A CHRONIC PHASE OF THE DISEASE ARE DISTINGUISHED !FTER INOCULATION THE PARASITES FIRST MULTIPLY AT THE SITE OF INFECTION PRODUCING A SEVERE INFLAM MATORY REACTION CHAGOMA 4HE AREA AROUND THE EYE IS OFTEN AFFECTED THE CHEEK THE EYELIDS AND CONJUNCTIVA OF THE AFFECTED EYE BECOME RED AND SWOL LEN 2OMA×AS SIGN 4HE PRE AURICULAR LYMPH NODES MAY BECOME SWOLLEN !FTER AN INCUBATION PERIOD OF n WEEKS THE HAEMATOGENOUS SPREAD OF THE PARASITES BEGINS WHICH CAN BE CHARACTERISED BY FEVER LYMPH NODE SWELLING HEPATOSPLENOMEGALY OEDEMA OF THE FACE AND THE LEGS -YOCARDITIS OR MENINGOENCEPHALITIS OCCASIONALLY OCCURS PARTICULARLY IN CHILDREN AND CAN LEAD TO DEATH EVEN IN THE ACUTE PHASE /THERWISE ALL THESE SYMPTOMS SUBSIDE IN THE COURSE OF WEEKS OR MONTHS .OTE 4HE PARASITES ARE MORE EASILY OBSERVED IN THE BLOOD DURING THIS PHASE 4HEY ARE # OR 3 SHAPED AND REACH ABOUT n +M IN LENGTH THEIR KINETOPLAST IS VERY LARGE AND LOCATED AT THE POINTED POSTERIOR END OF THE CELL 4HESE FORMS ARE DISTINCT FROM THE APATHOGENIC STAGES OF THE SPECIES 4 RANGELI WHICH ARE ALSO TRANS MITTED BY BUGS $URING THE CHRONIC PHASE OF THE DISEASE WHICH CAN BE COMPLETELY ASYMPTOMATIC FOR YEARS SO CALLED INTERMEDIATE PHASE PARASITES ONLY RARELY APPEAR IN THE BLOOD AS THEY MULTIPLY MAINLY INTRACELLULARLY UNTIL THE CONSEQUENCES OF THE ORGAN DESTRUCTION BECOME MANIFEST AS #HAGAS DISEASE 4HE DISEASE AFFECTS PARTICULARLY THE MYOCARDIUM AND THE STIMULUS CONDUC TION SYSTEM WITH CORRESPONDING SEVERE %#' CHANGES BUT ALSO THE VISCERAL HOLLOW ORGANS !S REGARDS THE PATHOGENESIS IT IS NOT YET CLEAR WHETHER THE DAMAGE IS CAUSED BY THE DIRECT ACTION OF THE PARASITES OR BY AN AUTOIMMUNE MECHANISM 4HE CARDIOMYOPATHY WHICH AFFECTS MAINLY THE RIGHT VENTRICLE LEADS VIA BOUTS OF ACUTE AND CHRONIC INFECTION AND FIBROSIS TO CARDIOMEGALY AND OFTEN TO A SO CALLED APICAL ANEURYSM 4HE CONGESTIVE CARDIOMYOPATHY IS USUALLY FATAL WITHIN A FEW MONTHS 4HE LESIONS OF THE CONDUCTING FIBRES CAUSE CONDUCTION DISTURBANCES AND ARRHYTHMIAS WHICH CAN LEAD TO SUDDEN CARDIAC DEATH )N THE OESOPHAGUS AND COLON BUT ALSO IN OTHER HOLLOW ORGANS DESTRUC TION OF THE NERVE CELLS OF -EISSNERS AND !UERBACHS PLEXUS LEADS TO LOSS OF TONE AND MOTILITY WITH ENORMOUS DILATION MEGAOESOPHAGUS MEGACOLON WITH CORRESPONDING COMPLICATIONS OF DYSPHAGIA AND CONSTIPATION 4HESE PATIENTS CAN DIE OF ASPIRATION PNEUMONIA OR ILEUS
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS $IRECT DETECTION OF TRYPOMASTIGOTE FORMS IN THE BLOOD IS EASIEST DURING THE ACUTE STAGE )N FRESH PREPARATIONS THEY STAND OUT THROUGH THEIR MOTILITY 4HE DETAILS CAN BE EVALUATED BEST IN THE STAINED SMEAR &IG ! CERTAIN AMOUNT OF CONCENTRATION CAN BE ACHIEVED WITH A THICK DROP BUT THE MOR
!CHIM (ARDER AND (EINZ -EHLHORN
PHOLOGY IS USUALLY CONSIDERABLY IMPAIRED /FTEN MORE EFFECTIVE METHODS OF CONCENTRATION ARE REQUIRED FOR DETECTION SUCH AS DIFFERENTIAL CENTRIFUGATION OR THE MICROHAEMATOCRIT METHOD 4HE ,ANHAM METHOD IS LESS SUITABLE FOR 4 CRUZI 4HE SIMPLE METHOD OF 3TROUT IS VERY EFFECTIVE n ML OF BLOOD IS ALLOWED TO CLOT THE SERUM IS CENTRIFUGED FIRST FOR MIN AT G REMOVAL OF REMAINING ERYTHROCYTES THEN FOR MIN AT G THE MOTILE TRYPANOSOMES ARE CONCENTRATED IN THE SEDIMENT )N THE ACUTE STAGE PARTICULARLY IN ACUTE MENINGOENCEPHALITIS TRYPOMASTIGOTE STAGES CAN OCCASIONALLY ALSO BE FOUND IN THE CEREBROSPINAL FLUID )N THE CHRONIC PHASE OF THE DISEASE DIRECT DETECTION IS NOT USUALLY POS SIBLE (OWEVER IN UP TO OF THE CASES XENODIAGNOSIS IS SUCCESSFUL 4HIS IS DONE BY ALLOWING PARASITE FREE LABORATORY BRED REDUVIID BUGS RD AND TH NYMPH STAGE TO FEED ON THE PATIENT ALTERNATIVELY MEMBRANE FEEDING !FTER OR DAYS THE FAECES OR GUT OF THE BUGS ARE THEN EXAMINED FOR THE PRESENCE OF EPIMASTIGOTE AND TRYPOMASTIGOTE PARASITES )N SOME CASES ISOLATION DURING THE CHRONIC PHASE IS ALSO POSSIBLE THROUGH REPEATED HAE MOCULTURES IN DIFFERENT CULTURE MEDIA &INALLY ISOLATION ON RODENTS IS ALSO POSSIBLE )N REGIONS WHERE 4 RANGELI IS WIDESPREAD DIFFERENTIATION FROM THIS APATHOGENIC TRYPANOSOME SPECIES IS NECESSARY &INALLY AMASTIGOTE STAGES CAN SOMETIMES BE FOUND IN BIOPSIES OF VARIOUS ORGANS SUCH AS SKELETAL MUSCLE MYOCARDIUM CATHETER BIOPSIES INTESTINE LIVER ETC HOWEVER HISTOLOGICAL EXAMINATION IS NOT SUITABLE FOR SPECIFIC DIAGNOSIS )N THE CHRONIC STAGE SEROLOGICAL TESTS ARE OFTEN THE ONLY INDICATION OF AN INFECTION .UMEROUS TESTS )&4 %,)3! #"2 )(! DIRECT AGGLUTINATION DETECT )G' ANTIBODIES IN MORE THAN OF THE PATIENTS IN THE ACUTE STAGE AND IN CONGENITAL INFECTIONS )G- ANTIBODIES ARE USUALLY PRESENT 4ESTS MAY BE NEGATIVE IN THE FIRST WEEKS AFTER INFECTION FALSE POSITIVE REACTIONS CAN OCCUR IN PATIENTS WITH LEISHMANIASIS AND 4 RANGELI INFECTIONS 0#2 WHICH HAS ALREADY BEEN USED SUCCESSFULLY FOR DIAGNOSIS WILL PROBABLY ALLOW VERY SENSITIVE DETECTION OF 4 CRUZI $.! IN BLOOD AND IN BIOPSIES IN THE CHRONIC STAGE TOO IN THE FUTURE
4REATMENT 4HE MOST EFFECTIVE TREATMENT IN BOTH THE ACUTE AND THE CHRONIC STAGES IS NIFURTIMOX n MGKG BODY WT CHILDREN n MGKG BODY WT DAILY FOR n MONTHS "ENZNIDAZOLE MGKG BODY WT CHILDREN MGKG BODY WT DAILY FOR DAYS IS ALSO EFFECTIVE )N THE CHRONIC STAGE DAMAGE THAT HAS ALREADY OCCURRED IS NO LONGER INFLUENCED BY THE TREATMENT
0ROPHYLAXIS )NDOOR CONTROL OF BUGS WITH INSECTICIDES
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
-ALARIA -ALARIA PARASITES 0LASMODIUM SPECIES ; = 4AXONOMY 3UBREGNUM 0HYLUM #LASS /RDER 'ENUS 3PECIES
0ROTOZOA !LVEOLATA (AEMATOZOA (AEMOSPORIDA 0LASMODIUM 0 LASMODIUM FALCIPARUM 0LASMODIUM VIVAX 0LASMODIUM MALARIAE 0LASMODIUM OVALE
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD 4HE MALARIA PARASITES ARE 0ROTOZOA BELONGING TO THE GROUP 3POROZOA !PICOMPLEXA WHICH ARE TRANSMITTED FROM MAN TO MAN ONLY NO ANIMAL RESERVOIR BY THE FEMALE MOSQUITOES OF THE GENUS !NOPHELES DURING THE BLOOD MEAL )NFECTION IS HOWEVER ALSO POSSIBLE THROUGH INFECTED BLOOD TRANSFUSIONS THE MEROZOITES REMAIN INFECTIOUS IN COOLED CITRATED BLOOD FOR AT LEAST DAYS AS WELL AS THROUGH USE OF SHARED INJECTION NEEDLES BY DRUG ADDICTS #ONNATAL MALARIA CAN OCCUR AS A RESULT OF TRANSPLACENTAL OR PERINATAL TRANSMISSION OF MEROZOITES ! SPECIAL FORM OF NATURAL TRANSMISSION IS SO CALLED AIRPORT MALARIA WHICH CAN OCCUR IN AIRPORT WORKERS OR PEOPLE LIVING NEAR AIRPORTS IN CASE THEY ARE BITTEN BY @IMPORTED MOSQUITOES 4RANSMISSION OF INFECTIOUS STAGES SPOROZOITES WITH THE MOSQUITO SALIVA IS FOLLOWED BY ASEXUAL MULTIPLICATION EXOERYTHROCYTIC SCHIZOGONY IN CELLS OF THE LIVER PARENCHYMA AND IN THE 2%3 RETICULOENDOTHELIAL SYSTEM &IG )T IS n RARELY WEEKS DEPENDING ON THE SPECIES BEFORE THE ASEXUAL STAGES BEING PRODUCED IN THE LIVER MEROZOITES INVADE THE RED BLOOD CELLS 4HE TIME UP TO THEIR FIRST APPEARANCE IN THE BLOOD IS TERMED THE PREPATENT PERIOD WHILE THE TIME TO APPEARANCE OF THE FIRST CLINICAL SYMPTOMS NOT IDENTICAL IS DEFINED AS THE INCUBATION PERIOD !FTER THE MEROZOITES HAVE PENETRATED INTO THE RED BLOOD CELLS THE PARA SITE APPEARS FIRST AS A SMALL UNICELLULAR TROPHOZOITE WHICH HAS THE APPEARANCE OF A SIGNET RING UNDER THE LIGHT MICROSCOPE AS ITS LARGE CENTRAL FOOD VACUOLE DOES NOT STAIN AND PUSHES THE CELL NUCLEUS TO THE EDGE 4HE TROPHOZOITES GROW BY CELL DIVISION AND AN INCREASE IN CYTOPLASM TO FORM SCHIZONTS WHICH FINALLY OCCUPY MOST OF THE ERYTHROCYTE AND DEPENDING ON THE SPECIES CONSIST OF n NEW MEROZOITES 4HESE ARE RELEASED WHEN THE ERYTHROCYTE BURSTS AND INVADE NEW ERYTHROCYTES )N THE RED CELLS THESE ASEXUAL MULTIPLICATION PRO CESSES ARE REPEATED ERYTHROCYTIC SCHIZOGONY &IGS AND SYNCHRONISED BY HOST INFLUENCES AND LEAD FINALLY TO A RHYTHMIC SPECIES SPECIFIC RELEASE OF NUMEROUS MEROZOITES AND DIGESTED HAEMOGLOBIN PIGMENT )T APPEARS TO
!CHIM (ARDER AND (EINZ -EHLHORN
BE PARTICULARLY THE FREE MEROZOITES RATHER THAN THE PIGMENT WHICH PRODUCE THE TYPICAL FEVER FOLLOWING THEIR RELEASE 4HE PIGMENT WHICH APPEARS BROWN BLACK UNDER THE LIGHT MICROSCOPE IS STORED IN THE ENDOTHELIA OF NUMEROUS ORGANS BRAIN KIDNEY LIVER ETC AND IS CONSIDERED A MARKER FOR AN EXISTING OR PAST INFECTION !S IN THIS CHAPTER THE MAIN AIM TO DEAL WITH THOSE STAGES MULTIPLYING IN THE EXO ERYTHROCYTIC LIVER CELLS FURTHER DESCRIPTIONS OF THE ERYTHROCYTIC STAGES ARE NEGLECTED )NCUBATION PERIOD 0 FALCIPARUM n DAYS 0 VIVAX n DAYS 0 OVALE n DAYS 0 MALA RIAE n DAYS 0REPATENT PERIOD 4HE MINIMUM DURATION OF EXOERYTHROCYTIC SCHIZOGONY APPEARANCE OF THE FIRST STAGES IN THE BLOOD 0 FALCIPARUM DAYS MEAN n 0 VIVAX DAYS MEAN n 0 OVALE DAYS MEAN n 0 MALARIAE n DAYS MEAN n 0ATENT PERIOD 0 FALCIPARUM WITH TREATMENT ABOUT n WEEKS WITHOUT TREATMENT MAXIMUM MONTHS 0 VIVAX n YEARS 0 OVALE UP TO YEARS 0 MALARIAE UP TO YEARS OR MORE
%PIDEMIOLOGY 7ARM HUMID COUNTRIES BETWEEN THE LATITUDES OF ª .ORTH AND ª 3OUTH )N 'ERMANY THERE ARE AROUND MALARIA CASES PER YEAR WITH FALCIPARUM
&IGURE ,IGHT MICROGRAPH ,- OF A MINUTA FORM OF % HISTOLYTICA &IGURE ,- OF CYSTS OF % HISTOLYTICA &IGURE 3LIMY BLOODY DIARRHOEA AS RESULT OF AN INFECTION WITH % HISTOLYTICA &IGURE SEE PAGE &IGURE ,IGHT MICROGRAPH OF AMASTIGOTE STAGES OF ,EISHMANIA DONOVANI IN AND AROUND A MACROPHAGE &IGURE 3CANNING ELECTRON MICROGRAPH OF A DIVIDING PROMASTIGOTE OF ,EISHMANIA SP &IGURE ,IGHT MICROGRAPH OF A BLOOD SMEAR PREPARATION OF 4 CRUZI TRYPOMASTIGOTES &IGURE 3ECTION THROUGH A MUSCLE CELL WITH A PSEUDOCYST CONTAINING 4 CRUZI STAGES &IGURE ,IGHT MICROGRAPH OF A SECTION THROUGH A LIVER SCHIZONT OF 0LASMODIUM FALCIPARUM
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
!CHIM (ARDER AND (EINZ -EHLHORN
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
MALARIA ACCOUNTING FOR !ROUND OF THESE INFECTIONS ARE IMPORTED FROM !FRICA 4HE LETHALITY OF THIS DISEASE DURING THE LAST YEARS HAS BEEN ABOUT 0ROGNOSTICALLY UNFAVOURABLE FACTORS ARE LACK OF OR INADEQUATE CHEMOPROPHYLAXIS FAILURE OF DOCTORS AND PATIENTS TO RECOGNISE THE SYMP TOMS MISDIAGNOSES INFLUENZA HEPATITIS ENCEPHALITIS PYELONEPHRITIS FEBRILE DIARRHOEAL DISEASES ETC AND THE PATIENTS AGE )N PATIENTS OVER YEARS OF AGE THE LETHALITY IS 7ORLDWIDE MORE THAN MILLION PEOPLE ARE INFECTED AND ABOUT n MILLION PEOPLE DIE EVERY YEAR IN TROPICAL COUNTRIES MOSTLY CHILDREN 4HE MALARIA PARASITES AFFECTING MAN HAVE NO SIGNIFICANT RESERVOIRS 7ITH THE EXCEPTION OF A FEW MONKEY SPECIES EXCLUSIVELY INFECTED PEOPLE SERVE AS THE SOURCE OF INFECTIONS OF THE MOSQUITOES )N ENDEMIC AREAS THE INHABIT ANTS HAVE DEVELOPED A SEMI IMMUNITY AFTER REPEATED INFECTIONS WHICH OFTEN PERMITS ONLY MILD CLINICAL SYMPTOMS #ERTAIN DISEASES SUCH AS SICKLE CELL ANAEMIA (B3 THALASSAEMIA OR GLUCOSE PHOSPHATE DEHYDROGENASE DEFI CIENCY PROTECT AGAINST THE EFFECTS OF FALCIPARUM MALARIA AS THE PARASITES ARE EITHER UNABLE TO INVADE THE ERYTHROCYTES OR DO NOT DEVELOP PROPERLY ONCE THEY HAVE DONE SO
$ISEASES AND SYMPTOMS &OUR DIFFERENT SPECIES OF MALARIA PARASITE MAY OCCUR IN ENDEMIC AREAS THEY DIFFER MARKEDLY WITH RESPECT TO THEIR BLOOD STAGES AND WITH REGARD TO THE CLINICAL SYMPTOMS THEY CAUSE
&IGURE 3CANNING ELECTRON MICROGRAPH OF A RED BLOOD CELL INFECTED BY TWO SCHIZONTS OF 0LASMODIUM FALCIPARUM NOTE THE SURFACE KNOBS OF THE RED BLOOD CELLS AND THE PROTRUDING SCHIZONTS &IGURE ,IGHT MICROGRAPH THROUGH A CAPILLARY BLOCKED BY 0 FALCIPARUM INFECTED RED BLOOD CELLS PLUS PIGMENT &IGURE 3CANNING ELECTRON MICROGRAPH OF AN ADULT %CHINOCOCCUS GRANULOSUS WORM &IGURE ,IVER SHOWING SEVERAL CYSTS OF % GRANULOSUS &IGURE 3ECTION OF THREE DIFFERENTLY ADVANCED CYSTS OF % GRANULOSUS TWO OF WHICH SHOW SEPTA LIKE CHAMBERS CONTAINING SMALL BROOD CAPSULES 4HE SEPTA LIKE STRUCTURES MAY INDUCE THE BICYCLE SPOKE APPEARANCE IN COMPUTER TOMOGRAPHY &IGURE ,IGHT MICROGRAPH OF ADULT WORMS OF %CHINOCOOCUS MULTILOCULARIS RIGHT AND %CHINOCOCCUS GRANULOSUS .OTE THE SIZE DIFFERENCE &IGURE 3CANNING ELECTRON MICROGRAPH OF THE SCOLEX OF AN ADULT % MULTILOCULARIS &IGURE (UMAN LIVER WITH NUMEROUS HOLLOWS DUE TO ALVEOLAR CAVERNS OF % MULTILOCULARIS METACESTODE CYSTS
A B C D
!CHIM (ARDER AND (EINZ -EHLHORN
0LASMODIUM VIVAX 0 VIVAX MALARIA BENIGN TERTIAN MALARIA 0 OVALE OVALE TERTIAN MALARIA 0 MALARIAE QUARTAN MALARIA 0 FALCIPARUM FALCIPARUM MALARIA MALIGNANT TERTIAN MALARIA
-OST SYMPTOMS AND PATHOLOGY OF MALARIA ARE RELATED TO HAEMOLYSIS OF ERYTHROCYTES AND THEIR EFFECTS ON DIFFERENT ORGANS 4HESE ARE REVIEWED IN DETAIL IN THE BELOW MENTIONED REFERENCES !FTER INOCULATION OF SPOROZOITES INTO A NEW HUMAN HOST THEY WITH THE NEXT BITE THEY ENTER CELLS OF THE 2%3 WITHIN SECONDS TO MIN )N THE SALI VARY GLAND OF THE MOSQUITOES THESE SPOROZOITES HAVE DEVELOPED A SURFACE COAT WHICH PROTECTS THEM FROM THE HUMAN IMMUNE SYSTEM )N THE CASE OF 0 VIVAX AND 0 OVALE SPOROZOITES CAN REMAIN DORMANT IN LIVER CELLS FOR SEVERAL MONTHS OR EVEN YEARS IN THE FORM OF HYPNOZOITES OR DORMOZOITES BEFORE THEY BEGIN TO MULTIPLY AND LEAD TO RELAPSES 4HE NEW ATTACKS ATTRIBUTABLE TO HYPNOZOITES ARE REFERRED TO AS RELAPSES AND SIGNIFY THE RE INFECTION OF PREVIOUSLY PARASITE FREE BLOOD 4HESE RELAPSES OCCUR MAINLY WITH 0 VIVAX AND CAN VARY IN LENGTH DEPENDING ON THE STRAIN DELAY OF UP TO MONTHS AFTER COMPLETION OF THE PRIMARY PARASITAEMIA IN n DAYS 4HE RECURRENCE OF CLINICAL SYMPTOMS IN CASES WHERE THERE WERE ALWAYS A SMALL NUMBER OF PARASITES IN THE ERYTHROCYTES BUT THE NUMBER DID NOT LEAD TO DISEASE IS DESCRIBED AS RECRUDESCENCE )N 0 MALARIAE THE RECURRING FEVER ATTACKS WHICH CAN GO ON FOR YEARS SEE BELOW ARE ATTRIBUTED TO THIS PHENOMENON OF RECRUDESCENCE 4HE LABORATORY FINDINGS INCLUDE NORMAL OR DECREASED WHITE CELL COUNTS DECREASING PLATELET COUNTS A RAPIDLY INCREASING ERYTHROCYTE SEDIMENTATION REACTION AND INCREASING ANAEMIA 4HE POTENTIALLY FATAL COURSE OF FALCIPARUM MALARIA COMPARED WITH THE OTHER FORMS IS DUE TO THE FACT THAT THE PARASITE CONTAINING ERYTHROCYTES ATTACH TO THE CAPILLARY WALLS SEE ABOVE WHICH IS DUE AMONG OTHER THINGS TO THE @KNOBS ON THE ERYTHROCYTE SURFACE VISIBLE UNDER THE ELECTRON MICROSCOPE 4HIS RESULTS IN IMPAIRMENT OF THE MICROCIR CULATION WITH STASIS ACIDOSIS PERIVASCULAR OEDEMA AND PETECHIAL BLEEDING $EPENDING ON THE VASCULAR REGION PRIMARILY AFFECTED SIGNS OF SEVERE AND INCREASING ORGAN LESIONS BEGIN TO APPEAR ON THE TH TO TH DAY OF ILLNESS IN THE BRAIN AS CEREBRAL MALARIA WITH SEVERE HEADACHES CLOUDING OF CONSCIOUS NESS AND AS A RESULT OF THE INCREASING CEREBRAL OEDEMA SEIZURES EXTENSIVE NEUROLOGICAL DEFICITS UNCONSCIOUSNESS COMA WITH FATAL OUTCOME #EREBRAL MALARIA IS THE MOST COMMON CAUSE OF DEATH IN FALCIPARUM MALARIA 3EVERE ORGAN LESIONS CAN ALSO OCCUR IN THE KIDNEY LEADING TO DIALYSIS DEPENDENT RENAL FAILURE RENAL MALARIA IN THE LUNG WITH INTERSTITIAL AND ALVEOLAR OEDEMA IN THE CARDIOVASCULAR SYSTEM WITH RHYTHM DISORDERS AND MYOCARDIAL DILATATION IN THE LIVER WITH HEPATIC JAUNDICE IN ADDITION TO THE HAEMOLYSIS AS A SIGN OF INCREASING IMPAIRMENT OF ORGAN FUNCTION AND FINALLY IN THE GASTRO INTESTINAL TRACT WITH DIARRHOEA AS THE CARDINAL SYMPTOM 3EVERE HAEMOLYSIS WHICH IS NOT EXPLAINED BY THE DISINTEGRATION OF THE PARASITISED ERYTHROCYTES
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
ALONE CAN RESULT IN BLACK WATER FEVER WITH RENAL FAILURE AND THREATENING TUBULAR NECROSIS
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS 4HE LARGE NUMBER OF SYMPTOMS RESULTING FROM THE ORGAN LESIONS EXPLAINS THE FREQUENT MISDIAGNOSES WHICH ARE OFTEN FATAL FOR THE PATIENT IF THE DOC TOR DOES NOT CONSIDER MALARIA AND INITIATE A COMPETENT DIAGNOSTIC WORK UP SOON ENOUGH $ETECTION OF THE PARASITES IN THE THICK OR THIN BLOOD FILM IS DECISIVE 4HE THICK FILM LEADS TO AN APPROXIMATELY TO FOLD CONCENTRATION DEPEND ING ON THE THICKNESS AND IS THEREFORE MORE SUITABLE FOR THE DETECTION OF LOW LEVELS OF PARASITAEMIA (OWEVER ITS EVALUATION AND PARTICULARLY DIFFERENTIATION OF THE DIFFERENT TYPES OF PLASMODIA IS MORE DIFFICULT IT IS OFTEN ONLY POSSIBLE TO DISTINGUISH BETWEEN FALCIPARUM AND NON FALCIPARUM PLASMODIA $ETECTION OF PLASMODIA OR THEIR COMPONENTS IS ALSO POSSIBLE WITH VARIOUS NEWER METHODS SUCH AS FLUORESCENCE MICROSCOPY OF HAEMATOCRIT CAPILLARIES 1"# QUANTITATIVE BUFFY COAT ANALYSIS OR BLOOD FILMS DETECTION OF CIR CULATING ANTIGENS AND NUMEROUS VARIETIES OF $.! IN SITU HYBRIDISATION AND 0#2 4HESE METHODS ARE IMPORTANT TOOLS FOR RESEARCH AND EPIDEMIOLOGICAL STUDIES (OWEVER THEY ARE BY NO MEANS A SUBSTITUTE FOR PARASITOLOGICAL BLOOD TESTS STAINED SMEAR AND THICK FILM 4HESE ARE FAST CHEAP AND UNI VERSALLY AVAILABLE 4HEY ALSO HAVE A HIGH SENSITIVITY EVEN COMPARED WITH THE MOLECULAR BIOLOGICAL METHODS AND THE UNACHIEVED SPECIFICITY OF THE GOLD STANDARD $EATHS DUE TO MALARIA ARE ALMOST ALWAYS DUE TO THE FACT THAT THESE TESTS WERE NOT PERFORMED OR PERFORMED TOO LATE
0ROPHYLAXIS 'ENERAL MEASURES +EEPING AWAY MOSQUITOES BY SPRAYING SKIN AND CLOTHING WITH REPELLENTS !UTAN 6ITICKS #OOL PLUS ETC SLEEPING UNDER MOSQUITO NETS SPRAYING INSECTICIDES PYRETHRUM DERIVATES IN BEDROOMS AND ON MOSQUITO NETS #HEMOPROPHYLAXIS #HEMOPROPHYLAXIS IS ALWAYS ADVISABLE WHEN TRAVELLING TO MALARIA REGIONS AND CAN CONSIDERABLY REDUCE THE RISK EVEN IN AREAS WITH RESISTANT PARASITES 4HE CHOICE OF PROPHYLAXIS WILL DEPEND ON THE DESTINATION SEASON LENGTH OF STAY AND TYPE OF TRAVEL AND SHOULD BE MADE INDIVIDUALLY ALSO TAKING INTO ACCOUNT AGE PREGNANCY PREVIOUS ILLNESSES INTOLERANCES AND ANY OTHER DRUGS BEING TAKEN )N THE CASE OF INSUFFICIENT PROPHYLAXIS IN AREAS WITH RESISTANT PARASITES A THERAPEUTIC DOSE OF A RESERVE DRUG EG MEFLOQUINE SHOULD
!CHIM (ARDER AND (EINZ -EHLHORN
ALSO BE CARRIED WHICH CAN BE TAKEN IN THE EVENT OF SYMPTOMS SUGGESTIVE OF MALARIA AND IF MEDICAL HELP IS NOT AVAILABLE EMERGENCY OR STANDBY TREAT MENT (OWEVER THIS SHOULD ONLY BE AN EMERGENCY MEASURE UNTIL MEDICAL ASSISTANCE CAN BE OBTAINED #ARRYING A STANDBY DRUG ALONE WITHOUT TAK ING PROPHYLACTIC MEDICATION CAN BE CONSIDERED IN THE CASE OF VERY SHORT EXPOSURE VERY LOW RISK OF MALARIA AND INTOLERANCE OF MALARIA PROPHYLAXIS !TTENTION )F THE PROPHYLAXIS IS TAKEN IRREGULARLY OR IF THERE IS VOMITING OR DIARRHOEA THE EFFECTIVENESS OF THE PROPHYLAXIS MAY BE COMPROMISED
4REATMENT 1UININE 1UININE IS THE MAIN ALKALOID OF THE #INCHONA BARK IN 0ERU KNOWN AS EFFEC TIVE FEBRIFUGE AGAINST INTERMITTENT FEVER SINCE THE EARLY TH CENTURY )T IS USED ESPECIALLY FOR THE THERAPY OF CHLOROQUINE AND MULTIDRUG RESISTANT 0LASMODIUM FALCIPARUM INFECTIONS 4HE COMBINATION WITH TETRACYCLINE IS USED IN CASES OF SEVERE RESISTANCE #HLOROQUINE 2ESOCHIN AND OTHER PREPARATIONS #HLOROQUINE IS THE DRUG OF CHOICE FOR TERTIAN AND QUARTAN MALARIA RESISTANCE OF 0 VIVAX HAS OCCASIONALLY BEEN OBSERVED !CCORDING TO THE 7(/ STANDARD REGIMEN AN INITIAL DOSE OF MG CHLOROQUINE BASE CHILDREN MGKG BODY WT CORRESPONDING TO TABLETS OF 2ESOCHIN MG MG CHLOROQUINE DIPHOSPHATE IS GIVEN FOLLOWED BY MG BASE CHILDREN MGKG BODY WT AFTER H AND ON THE ND AND RD DAY )N TERTIAN MALARIA THIS IS FOLLOWED BY TREATMENT WITH PRIMAQUINE MG CHILDREN MGKG BODY WT DAILY FOR DAYS TO DESTROY THE TISSUE SCHIZONTS RESPONSIBLE FOR RELAPSES CAUTION DANGER OF HAEMOLYSIS IN PATIENTS WITH GLUCOSE PHOSPHATE DEHYDROGENASE DEFICIENCY !MODIAQUINE !MODIAQUINE WAS INVENTED BETWEEN AND AS AN ANTIMALARIAL DRUG AND WAS INTRODUCED IN )TS ANTIMALARIAL ACTIVITY IS COMPARABLE TO THAT OF CHLOROQUINE (ALOFANTRINE (ALOFANTRINE WAS DEVELOPED WITHIN THE 7ALTER 2EED !RMY )NSTITUTE FOR 2ESEARCH ANTIMALARIAL DRUG DEVELOPMENT PROGRAM IN )T WAS INTRO DUCED IN (OWEVER BECAUSE OF SEVERE CARDIOVASCULAR SIDE EFFECTS HALO FANTRINE IS NO LONGER USED
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
0ROGUANIL 0ALUDRINE )N AREAS WITH PARTIAL RESISTANCE AGAINST CHLOROQUINE PROGUANIL 0ALUDRINE CAN BE USED IN ADDITION TO CHLOROQUINE PROPHYLAXIS 4HEREBY AN ADDITIONAL PROTECTION CAN BE ACHIEVED (OWEVER AS MONO PRODUCT PROGUANIL CANNOT BE USED THE DOSAGE FOR PROPHYLAXIS IS MG PER DAY -EFLOQUINE ,ARIAM -EFLOQUINE HAS BEEN MARKETED SINCE 4HE ACTIVITY IS DIRECTED AGAINST MULTIDRUG RESISTANT 0LASMODIUM FALCIPARUM &OR PROPHYLAXIS MG TAB LET IS GIVEN PER WEEK 4HIS STARTS n WEEKS BEFORE AND ENDS UP TO WEEKS AFTER THE VISIT OF A MALARIA AREA 4HERAPY STARTS WITH THE INITIAL DOSE OF MG TABLETS FOLLOWED BY A FURTHER MG TABLETS AFTER n H AFTER A FURTHER n H MG TABLET IS GIVEN $OXYCYLIN $OXYCYCLIN ALONE IS NOT SUITABLE FOR THERAPY )T CAN BE USED FOR PROPHYLAXIS IN AREAS WITH MEFLOQUINE RESISTANCES AS AN ALTERNATIVE TO ATOVAQUONEPRO GUANIL 4HE DOSAGE IS MG PER DAY n DAYS BEFORE AND UP TO WEEKS AFTER THE VISIT TO A MALARIA AREA 3ULFADOXIN 0YRIMETHAMINE &ANSIDAR 3ULFADOXIN 0YRIMETHAMINE &ANSIDAR IS NOT SUITABLE FOR PROPHYLAXIS &OR THERAPY IT IS USED ESPECIALLY IN !FRICA !TOVAQUONE0ROGUANIL -ALARONE !TOVAQUONE0ROGUANIL -ALARONE IS A FIX COMBINATION FOR PROPHYLAXIS AND CHEMOTHERAPY INCLUSIVE THE STANDBY SELF MEDICATION OF UNCOMPLICATED 0 FALCIPARUM INFECTIONS &OR PROPHYLAXIS MG ATOVAQUONE AND MG PROGUANIL TABLET ARE GIVEN DAILY FOR n DAYS UP TO DAYS &OR THERAPY MG ATOVAQUONE AND MG PROGUANIL TABLETS ARE GIVEN IN A SINGLE DOSE ON THREE CONSECUTIVE DAYS !RTEMISININ !RTEMISININ HAS BEEN USED SO FAR FOR THE TREATMENT OF MALARIA IN AT LEAST MILLION PEOPLE 4HE ADVANTAGE OF THIS DRUG IS ITS RAPID ACTION AGAINST CEREBRAL MALARIA 4HE COMBINATION OF ARTEMETHERLUMEFANTRINE 2IAMED #OARTEM IS NOT SUITABLE FOR PROPHYLAXIS BUT IS RECOMMENDED FOR STANDBY SELF MEDICATION 4HE DOSAGE IS MG MG TABLETS INITIALLY FOLLOWED BY FURTHER TABLETS AFTER H AND TABLETS TWO TIMES DAILY ON DAYS AND IN TOTAL TABLETS
!CHIM (ARDER AND (EINZ -EHLHORN
(EPATITIS CAUSED BY CESTODES %CHINOCOCCOSIS %CHINOCOCCIASIS (YDATIDOSIS %CHINOCOCCUS GRANULOSUS ; n= /THER NAME OF THE AGENT OF DISEASE 3MALL DOG TAPEWORM
4AXONOMY 3UBREGNUM 0HYLUM #LASS /RDER &AMILY 'ENUS 3PECIES
!NIMALIA 0LATYHELMINTHES #ESTODA #YCLOPHYLLIDEA 4AENIIDAE %CHINOCOCCUS %CHINOCOCCUS GRANULOSUS
-ORPHOLOGY 4HE RATHER SHORT TAPEWORM WITH ITS n MM LONG STROBILA LIVES IN THE INTESTINE OF THE DOG AND SOME OTHER CARNIVORES IS PROVIDED WITH n +M LONG LARGE AND n +M LONG SMALL HOOKS AT THE ROSTELLUM n n PROGLOTTIDS AND A UTERUS WITH LOBED LATERAL SACCULATIONS &IG 4HE CYSTIC LARVA METACESTODE TAKES THE FORM OF A FLUID FILLED GENERALLY UNILOCULAR CYST HYDATID THAT GROWS BY EXPAN SION &IGS AND IT MAY CONTAIN DAUGHTER CYSTS IN ITS INTERIOR AND IN EXTREME CASES IT ATTAINS A DIAMETER OF UP TO CM 0ROTOSCOLICES BUD FROM BLOOD CAPSULES OF THE INNER GERMINAL LAYER AND MAY BREAK FREE )N THE FLUID THESE TOGETHER WITH CALCAREOUS CORPUSCLES FORM WHAT IS KNOWN AS HYDATID SAND
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD 4RANSMISSION TO HUMANS AND OTHER INTERMEDIATE HOSTS TAKES PLACE BY MEANS OF ORAL INGESTION OF THE EGGS OF % GRANULOSUS ORIGINATING FROM THE FAECES OF DOGS OR OTHER DEFINITIVE HOSTS 4HE ADULT FORMS OF % GRANULOSUS PARASITISING THE INTESTINE OF THE DEFINI TIVE HOST CONTAIN n TAENIID EGGS n = n +M IN THEIR GRAVID PROGLOTTIDS !FTER THE TERMINAL PROGLOTTIDS WITH EGGS ARE EXCRETED WITH THE FAECES THEY ARE ORALLY INGESTED BY AN INTERMEDIATE HOST (ERE OCCURS HATCHING IN THE INTESTINAL TRACT OF THE LARVA ONCOSPHERE PRESENT IN THE EGG MEMBRANE PENETRATION OF THE WALL OF THE INTESTINE /NCOSPHERES SPREAD
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
VIA THE BLOODSTREAM TO THE LIVER WHERE THE MAJORITY SETTLE /THER ONCO SPHERES ARE TRANSPORTED FURTHER TO THE LUNGS AND CONTINUE TO DEVELOP THERE !PPROXIMATELY n PASS THROUGH THE LUNG AND THEN TRAVEL VIA THE SYS TEMIC CIRCULATION TO A WIDE RANGE OF ORGANS 4HE ONCOSPHERE DEVELOPS INTO A VESICULAR STRUCTURE THAT GROWS BY MEANS OF EXPANSION TO FORM A CYST AND INSIDE CONTAINS PROTOSCOLICES 4HE DEFINITIVE HOST IS INFECTED BY INGESTION OF SUCH CYSTS )N THE INTESTINAL TRACT OF THE DEFINITIVE HOST EACH PROTOSCOLEX MATURES INTO AN ADULT TAPEWORM 4HE INCUBATION PERIOD IN HUMANS TO PRO DUCE CYSTS IS ASSUMED TO BE OVER YEARS
%PIDEMIOLOGY %CHINOCOCCOSIS IS PRIMARILY A ZOONOSIS WITH A BROAD SPECTRUM OF DEFINITIVE AND INTERMEDIATE HOSTS 4HE MOST IMPORTANT DEFINITIVE HOST IS THE DOMESTIC DOG ALTHOUGH THE WOLF COYOTE DINGO HYENA JACKAL AND SOME OTHER CARNIVO ROUS MAMMALS MAY ALSO HARBOUR THE ADULT FORM OF % GRANULOSUS -AMMALS WITH A HERBIVOROUS OR OMNIVOROUS DIET SERVE AS INTERMEDIATE HOSTS 4HOSE THAT PLAY THE MOST IMPORTANT ROLE ARE DOMESTIC ANIMALS SUCH AS CATTLE SHEEP GOATS PIGS AND HORSES ! NUMBER OF WILD ANIMALS EG BUFFALOES BISONS ANTELOPES GAZELLES ELKS AND REINDEER MAY ALSO HOST THE METACESTODES OF THIS SPECIES (UMANS CONSTITUTE A DEAD END INTERMEDIATE HOST AS THEY GENER ALLY DO NOT ALLOW TRANSMISSION TO THE DEFINITIVE FINAL HOST $OG OWNERS WHO FEED THEIR DOGS SCRAPS OF RAW MEAT ARE AMONG THOSE MOST AT RISK )N 'ERMANY HOWEVER THE RISK IS VERY LOW AS AUTOCHTHONOUS INFECTIONS ARE RARE 3TATUTORY MEAT INSPECTION PREVENTS MEAT CONTAINING CYSTS BEING SOLD AS DOG FOOD !S A ZOONOSIS THE FORM OF ECHINOCOCCOSIS CAUSED BY % GRANULOSUS IS STILL DISTRIBUTED WORLDWIDE )T IS PARTICULARLY COMMON FOR EXAMPLE IN -EDITERRANEAN COUNTRIES BROAD REGIONS OF #ENTRAL AND 3OUTH !MERICA AND )NDIA $OGS BROUGHT HOME FROM HOLIDAY DESTINATIONS MAY THEREFORE BE INFECT ED #UDDLING OF THESE ANIMALS MAY LEAD TO HUMAN INFECTIONS %CHINOCOCCUS EGGS FROM THE ANIMALS COAT OR MUZZLE CAN ALSO EASILY END UP ON CARPETS CHAIRS ETC WHICH MAY THEN AGAIN LEAD TO INFECTION OF HUMANS TOO
$ISEASES AND SYMPTOMS #YSTIC ECHINOCOCCOSIS )NFESTATION OF HUMANS WITH METACESTODES OF % GRANULOSUS IS KNOWN AS CYSTIC ECHINOCOCCOSIS OR % GRANULOSUS INFECTION 4HE SLOW GROWTH OF THE PARASITE EXPLAINS WHY THE DISEASE GENERALLY DOES NOT BECOME MANIFEST FOR SEVERAL YEARS POST INFECTION !S A RESULT OF THE EXPANSIVE GROWTH OF THE CYST THIS FORM OF ECHINOCOCCOSIS PRESENTS AS A SPACE OCCUPYING LESION PREDOMINANTLY IN THE LIVER OR THE LUNG APPROXIMATELY n OF CASES &IG 7ITH THE
!CHIM (ARDER AND (EINZ -EHLHORN
GRADUAL EXPANSION MAJOR VESSELS AND STRUCTURES MAY BECOME COMPRESSED AND OCCLUDED 4HE CLINICAL PRESENTATION IS EXTREMELY VARIED DEPENDING ON THE NUMBER SIZE AND SITE OF THE CYSTS #YSTIC ECHINOCOCCOSIS MAY GIVE RISE TO FEBRILE SECONDARY INFECTIONS ABSCESSES OR FISTULISATION ! MAJOR CONCERN IS CYST RUPTURE LEADING TO SECONDARY ECHINOCOCCOSIS AS EACH OF THE RELEASED PROTOSCOLICES MAY DEVELOP INTO A NEW CYST 4HE CYSTS USUALLY GROW SLOWLY AND ARE OFTEN DETECTED BY CHANCE DURING ROUTINE INVESTIGATIONS 4HERE IS A BROAD SPECTRUM OF SYMPTOMS DEPENDING ON THE ORGAN AFFECTED )NFESTATION OF THE LIVER FOR EXAMPLE CAUSES A SENSATION OF PRESSURE IN THE UPPER ABDOMEN AND JAUNDICE WHEREAS HAEMOPTYSIS AND EXPECTORATION OF CYST CONTENTS WITH PRO TOSCOLICES MAY OCCUR IF THE SITE OF INFESTATION IS THE LUNG #LINICAL DIFFERENTIATION IS OFTEN MADE AS FOLLOWS DEPENDING ON THE ORGAN INVOLVED (EPATIC CYSTIC ECHINOCOCCOSIS 7ELL DEMARCATED CYSTS &IGS AND USUALLY APPEAR WITH A CHARACTERISTIC HONEYCOMB PARENCHYMAL PATTERN ON AN ULTRASOUND SCAN /N THIS BASIS THE CYSTS ISARE CLASSIFIED AND STAGED IN STAGES TO USING A CLASSIFICATION PROPOSED BY A 7(/ WORKING GROUP 7(/ )F THE CYSTS RUPTURE INTO THE ABDOMINAL CAVITY THIS MAY LEAD TO LIFE THREATENING PERITONITIS &URTHERMORE SEEDING OCCURS IN A PROCESS KNOWN AS SECONDARY ECHINOCOCCOSIS #OMPRESSION OF THE EFFERENT BILE DUCTS LEADS TO POST HEPATIC JAUNDICE )F A CYST RUPTURES IN THE BILIARY TREE THE CYST CONTENTS ARE DISCHARGED AND IF SMALL DAUGHTER CYSTS PASS THROUGH THE PAPILLA YELLOWISH GRAPE LIKE CYSTS WILL BE DETECTABLE IN THE STOOLS #HOLANGITIS OFTEN DEVELOPS AS A COMPLICATION AS A RESULT OF ASCENSION OF THE PATHOGEN 0ULMONARY CYSTIC ECHINOCOCCOSIS #YSTS RANGING IN SIZE FROM THAT OF A TENNIS BALL TO THAT OF A CHILDS HEAD ISARE WELL DEMARCATED AND MAY BE MIS TAKEN FOR CIRCULAR FOCI OF VARYING ORIGIN ON PLAIN 8 RAYS #LINICAL SYMPTOMS OCCUR IF A CYST LATCHES ONTO THE BRONCHIAL SYSTEM (IGH FEVER EOSINOPHILIA AND PULMONARY INFILTRATES ARE CHARACTERISTIC CLINICAL MANIFESTATIONS 4HE CLEAR CYST FLUID WITH MEMBRANE FRAGMENTS AND HYDATID SAND MAY BE EXPECTORATED VIA THE BRONCHIAL TREE 2UPTURE OF THE CYSTS AND COLLAPSE OF THE ENDOCYSTS RESULTS IN THE WATER LILY SIGN AS A RESULT OF AIR PERMEATING BETWEEN ECTOCYSTS AND ENDOCYSTS "ACTERIAL SECONDARY INFECTIONS ARE A COMMON COMPLICATION -ANIFESTATION IN OTHER ORGANS !NY ORGAN IS SUITABLE AS A NESTING SITE FOR THE DEVELOPMENT OF THE METACESTODE 4HE MORPHOLOGICAL CORRELATE IS THE SAME FOR ALL THE LARGE PARENCHYMATOUS ORGANS NAMELY A WELL DEMARCATED MASS WITH A HOST CAPSULE )F THE BONES AND MUSCLES ARE INVOLVED HOWEVER THE PRESENTATION IS POLYCYSTIC $IFFERENTIATION FROM % MULTILOCULARIS IN BONE IS THEREFORE DIFFICULT %XPERT ADVICE SHOULD BE SOUGHT
)MMUNE RESPONSE )T IS CURRENTLY NOT KNOWN WHY THE HUMORAL IMMUNE RESPONSE IS SO SLOW TO RESPOND TO LONGSTANDING INFECTION AND SYMPTOM MANIFESTATION (IGH TITRE
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
ANTIBODIES OCCUR ONLY IN THE EVENT OF CYST RUPTURE AND AN ALLERGIC REACTION 4HE CELLULAR IMMUNE RESPONSE IN PERSISTENT INFECTION IS AS YET POORLY UNDERSTOOD
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS $IFFERENT DIFFERENTIAL DIAGNOSES NEED TO BE CONSIDERED FOR THE INDIVIDUAL STAGES OF THE LIVER CYSTS VISUALISABLE WITH ULTRASOUND "ENIGN LIVER CYSTS MAY BE CONFUSED WITH STAGE OF HEPATIC CYSTIC ECHINOCOCCOSIS #ALCIFIED HAEMA TOMAS CALCIFIED ABSCESSES AND ALSO LIVER METASTASES HAVE TO BE CONSIDERED AS POSSIBLE DIFFERENTIAL DIAGNOSES FOR STAGES AND 7ITH PULMONARY CYSTS THERE IS CHARACTERISTIC BULGING OF THE CIRCULAR FOCI IN WHICH HOMOGENEOUSLY CLEAR CONTENTS POSSIBLY WITH DAUGHTER CYSTS ARE DETECTABLE WITH DIAGNOSTIC IMAGING TECHNIQUES ! TYPICAL PRESENTING FEATURE IN OTHER PARENCHYMATOUS ORGANS IS THE WELL DEMARCATED HOST CAPSULE 7ITH INFECTION OF BONE THE PRE SENTATION IS POLYCYSTIC MAKING DIFFERENTIAL DIAGNOSIS DIFFICULT ! BLOOD COUNT GENERALLY SHOWS ONLY MODERATE EOSINOPHILIA /NCE A CYST HAS BURST EXCESSIVE EOSINOPHILIA IS DETECTABLE )MMUNOGLOBULIN % LEVELS ARE GENERALLY RAISED 4HE FOLLOWING TECHNIQUES ARE USED FOR DETECTION OF CYSTIC ECHINOCOCCOSIS 5LTRASOUND AND COMPUTED TOMOGRAPHY PROVIDE CHARACTERISTIC MORPHO LOGICAL IMAGES OF THE LESION )N THE LIVER THE CYSTS USUALLY SHOW A BICYCLE SPOKE STRUCTURE 4HE 7(/ CLASSIFICATION CHARACTERISES THE STAGE OF THE DISEASE 4HE CYSTS OF % GRANULOSUS ARE WELL DEMARCATED AND ARE EMBEDDED IN A HOST CAPSULE KNOWN AS THE PERICYST 4HE SURROUNDING WALL OF THE PERI CYST VARIES IN THICKNESS DEPENDING ON THE ORGAN INVOLVED #ALCIFICATIONS ARE OCCASIONALLY TO BE FOUND )N THE CASE OF DEGENERATED CYSTS THE TISSUE IS COMPRESSED AND THE LESION MAY CALCIFY COMPLETELY ! NUMBER OF TEST METHODS HAVE BEEN DEVELOPED FOR THE DETECTION OF ANTIBODIES 4HE MOST COMMONLY USED ARE INDIRECT IMMUNOFLUORESCENCE INDIRECT HAEMAGGLUTINATION TESTS AND %,)3! 3EROLOGICAL TESTS GENERALLY ALLOW DIFFERENTIATION OF THIS DISEASE FROM INFESTATION WITH METACESTODES OF % MULTILOCULARIS .EGATIVE RESULTS ARE NEVERTHELESS OBTAINED IN UP TO OF CASES 4HIS APPLIES IN PARTICULAR TO PULMONARY CYSTIC ECHINOCOCCOSIS -ACROSCOPIC FEATURES ARE THE CHARACTERISTIC CYSTS AND DAUGHTER CYSTS $IAGNOSTIC FINE NEEDLE BIOPSY IS CONTRAINDICATED )F THE CYST IS ACCIDENTALLY PUNCTURED PROTOSCOLICES AND HOOKS ARE DETECTABLE IN THE CLEAR CYST FLUID 4HIS CONFIRMS THE DIAGNOSIS 0!3 POSITIVE LAMINATED MEMBRANES ARE FOUND IN DEGENERATED CYSTS ! FEW $.! PROBES FOR % GRANULOSUS HAVE BEEN DESCRIBED 4HEY HAVE NOT YET BEEN VALIDATED ON CLINICAL SPECIMENS HOWEVER
4REATMENT )N THE PAST FEW YEARS THERE HAS BEEN A CONSIDERABLE CHANGE IN THE STRATEGIES
!CHIM (ARDER AND (EINZ -EHLHORN
FOR THE TREATMENT OF HEPATIC CYSTIC ECHINOCOCCOSIS 7HEREAS SURGERY WAS PREVI OUSLY CONSIDERED THE TREATMENT OF CHOICE THIS IS NOWADAYS RESERVED ONLY FOR CERTAIN MORPHOLOGICAL CYST STAGES 7HEN PERFORMING SURGICAL PROCEDURES IT IS RECOMMENDED THAT THE ENDOCYST IS OPENED UP AND THE CYST WALL IS DISINFECTED WITH n .A#L SOLUTION 7ITH MORE RADICAL PROCEDURES THE CYSTS ISARE ENUCLEATED 4HE CYSTS CAN THEN BE RESECTED TOGETHER WITH THE HOST CAPSULE &OR EASILY ACCESSIBLE CYSTS OF THE LIVER AND PARTICULAR CYST STAGES A TECH NIQUE KNOWN AS 0UNCTURE !SPIRATION )NSTILLATION 2EASPIRATION 0!)2 CAN BE USED 4HIS INVOLVES ULTRASOUND GUIDED PUNCTURE OF THE CYST REMOVAL AND ANALYSIS OF THE CYST CONTENTS INJECTION OF A SCOLICIDAL SOLUTION n ALCOHOL OR n .A#L SOLUTION AND REASPIRATION AFTER A BRIEF INCUBATION PERIOD 4HIS METHOD HAS A PROMISING SUCCESS RATE 4HE TREATMENT SHOULD TAKE PLACE AT SPECIALIST CENTRES $RUG THERAPY OF CYSTIC ECHINOCOCCOSIS WITH THE BENZIMIDAZOLE DERIVA TIVES MEBENDAZOLE OR ALBENDAZOLE IS A KEY CORNERSTONE OF THE TREATMENT PLAN 7(/ &OLLOWING CURATIVE SURGERY TREATMENT IS RECOMMENDED FOR MONTHS $RUG THERAPY IS ESSENTIAL BEFORE DURING AND AFTER TREATMENT WITH THE 0!)2 METHOD $RUG THERAPY ALONE HAS PROVED SUCCESSFUL AT VARIOUS TREATMENT CENTRES LEADING AFTER A PERIOD OF MONTHS OR YEARS TO DEGENERATION OF THE CYST AND CURING OF THE DISEASE "OTH ANTHELMINTICS ARE ABLE TO STOP GROWTH OF THE CYSTS GERMINAL LAYER AND THE PROTOSCOLICES ! MONTH PERIOD OF TREATMENT WITH ALBENDAZOLE AT A DOSAGE OF n MGKG "7 PER DAY IS RECOMMENDED ,ONGER TREATMENT PERIODS MAY BE NECESSARY DEPENDING ON WHICH ORGAN IS AFFECTED 4HE ANTHELMINTIC THERAPY IS OFTEN COMMENCED PREOPERATIVELY 4HE LOGIC BEHIND THIS IS THAT IT WILL REDUCE THE HIGH PRES SURE INSIDE THE CYST AND SO PREVENT THE RISK OF SEEDING DURING SURGERY 4HIS THINKING IS NOT BACKED UP BY STUDIES HOWEVER AND THE 7(/ RECOMMENDA TION THAT PRETREATMENT WITH ANTHELMINTICS SHOULD BE CONFINED TO JUST A FEW DAYS BEFORE SURGERY THEREFORE STILL APPLIES 7(/ 4REATMENT CAN BE MONITORED ON THE BASIS OF MEASURED CONCENTRATIONS OF THE ANTHELMINTICS 4HE EXTENT TO WHICH THE DOSE OF THE DRUG CORRELATES WITH EFFECTIVE CONTROL OF GROWTH OF THE PARASITE IN VIVO HAS NOT BEEN PROVEN HOWEVER
2ESISTANCE 2ESISTANCE TO ANTHELMINTICS HAS NOT BEEN DESCRIBED TO DATE
0REVENTION )N ORDER TO PREVENT THE INFECTION BEING TRANSMITTED TO HUMANS MEAT CON TAINING CYSTS MUST NOT BE FED TO DOGS )F A DOG IS ALREADY INFECTED HOWEVER ITS FAECES MUST BE DESTROYED IMMEDIATELY AND THE INFESTED DOG MUST BE GIVEN WORMING TREATMENT UNDER QUARANTINE LIKE CONDITIONS 0RAZIQUANTEL IS THE DRUG OF CHOICE FOR THIS PURPOSE
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
!LVEOLAR ECHINOCOCCOSIS %CHINOCOOCUS MULTILOCULARIS ; n n= 3YNONYM 3MALL FOX TAPEWORM
4AXONOMY 3UBREGNUM 0HYLUM #LASS /RDER &AMILY 'ENUS
!NIMALIA 0LATYHELMINTHES #ESTODA #YCLOPHYLLIDEA 4AENIIDAE %CHINOCOCCUS
-ORPHOLOGY 4HE n MM LONG TAPEWORM IS MAINLY FOUND IN THE INTESTINE OF THE RED FOX 6ULPES VULPES AND DOGS AMONG SOME OTHER CARNIVORES WITH APPROXIMATELY +M LONG LARGE AND APPROXIMATELY +M LONG SMALL HOOKS ON THE ROSTEL LUM n n PROGLOTTIDS AND A SACCIFORM UTERUS &IGS AND 4HE LARVA METACESTODE OF THE ALVEOLAR TYPE &IG TAKES THE FORM OF A STRUCTURE MADE UP OF MULTIPLE SMALL VESICLES THAT GROWS BY INFILTRATION BY MEANS OF EXOGENOUS BUDDING )NDIVIDUAL VESICLES ARE MERE MILLIMETRES IN SIZE WITH A GELATINOUS MATRIX INSIDE AND PROTOSCOLICES FORMED FROM THE GERMINAL LAYER
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD 4RANSMISSION TO HUMANS AMONG OTHER INTERMEDIATE HOSTS TAKES PLACE BY ORAL INGESTION OF THE EGGS OF % MULTILOCULARIS ORIGINATING FROM THE FAECES OF RED FOXES OR OTHER DEFINITIVE HOSTS #ONTACT TO EGG CONTAMINATED HAIR OF FINAL HOSTS AND CONSUMPTION OF WILD BERRIES BLUEBERRIES STRAWBERRIES ETC CON TAMINATED WITH FOX FAECES OR INHALATION OF HELMINTH EGGS SWIRLED UP DURING WORK IN FIELDS ARE THOUGHT TO BE RESPONSIBLE TOO 4HE ADULT FORM OF % MULTILOCULARIS IS A PARASITE IN THE SMALL INTESTINE OF THE DEFINITIVE HOST 4HE NUMBER OF EGGS FORMED IN THE GRAVID PROGLOTTIDS DEPENDS ON THE HOST SPECIES AND THE AGE OF THE INFECTION )N YOUNG WORMS IT IS n PER SEGMENT BUT LATER DECLINES DRAMATICALLY %XCRETION OF TAENIID EGGS n = n +M WITHIN THE PROGLOTTIDS WITH THE FAECES OF THE DEFINI TIVE FINAL HOST !FTER ORAL INGESTION BY AN INTERMEDIATE HOST THE LARVA ONCO SPHERE PRESENT IN THE EGG MEMBRANE IN THE INTESTINAL TRACT HATCH PENETRATE
!CHIM (ARDER AND (EINZ -EHLHORN
THE INTESTINAL WALL /NCOSPHERES SPREAD VIA THE BLOODSTREAM TO THE LIVER LODGE IN THE LIVER AND DEVELOP INTO A MULTIVESICULAR METACESTODE PERMA NENTLY GROWING BY MEANS OF EXOGENOUS BUDDING 0ROTOSCOLICES ARE FORMED INTERNALLY )NFECTION OF THE DEFINITIVE HOST OCCURS AS A RESULT OF CONSUMPTION OF THE INTERMEDIATE HOST ONLY IN THE DEFINITE HOST PARASITES MATURE INTO ADULT WORMS 4HE INCUBATION PERIOD IN HUMANS IS ASSUMED TO BE n YEARS
%PIDEMIOLOGY 4HE PARASITOSIS CAUSED BY % MULTILOCULARIS IS PRIMARILY A ZOONOSIS THOUGH WITH A DISTINCTLY NARROWER HOST SPECTRUM THAN IS THE CASE WITH % GRANULO SUS INFECTION 4HE RED FOX 6ULPES VULPES IS THE PRINCIPAL DEFINITIVE HOST IN #ENTRAL %UROPE WITH INFESTATION RATES FOR % MULTILOCULARIS OF WAY OVER IN THE MAIN ENDEMIC AREAS 4HE !RCTIC FOX !LOPEX LAGOPUS PLAYS A KEY ROLE IN !RCTIC REGIONS )N ADDITION OTHER CANINES DOMESTIC DOG WOLF RACCOON DOG ETC ALSO SERVE AS DEFINITIVE HOSTS (UMANS CONSTITUTE A DEAD END INTER MEDIATE HOST 4HE SPECTRUM OF NATURAL INTERMEDIATE HOSTS INCLUDES IN PARTIC ULAR SPECIES OF THE RODENT FAMILY #RICETIDAE WITH THE FIELD MOUSE -ICROTUS ARVALIS AS THE MOST IMPORTANT SPECIES IN #ENTRAL %UROPE /THER -ICROTUS SPECIES BANK VOLES MUSKRATS LEMMINGS BUT ALSO HOUSE MICE BROWN RATS AND OTHER RODENTS MAY HARBOUR THE METACESTODES OF % MULTILOCULARIS !NYONE WHO WORKS IN THE FARMING AND FORESTRY INDUSTRIES IN ENDEMIC AREAS SHOULD BE CONSIDERED TO BE AT INCREASED RISK 3OME PROFESSIONAL ASSO CIATIONS RECKON THAT AN OCCUPATIONAL DISEASE CLAIM FOR COMPENSATION CAN BE MADE FOR ALVEOLAR ECHINOCOCCOSIS 4HE ZOONOSIS CAUSED BY % MULTILOCULARIS IS LIMITED IN ITS DISTRIBUTION TO PARTICULAR REGIONS OF THE NORTHERN HEMISPHERE )N %UROPE THESE AREAS ARE 3OUTHERN AND %ASTERN &RANCE 'ERMANY AND !USTRIA 4HE DISEASE IS ALSO PREVALENT IN THE #ZECH 2EPUBLIC 3LOVAKIA 0OLAND AND "ULGARIA AS WELL AS 4URKEY FROM WHERE THE ENDEMIC AREA EXTENDS EASTWARDS AS FAR AS 3IBERIA AND THE .ORTHERN )SLANDS OF *APAN )TS GEOGRAPHICAL DISTRIBUTION IS LIKEWISE CONSIDERED TO INCLUDE !LASKA #ANADA AND THE #ENTRAL .ORTHERN STATES OF THE 53! !S THE PREVALENCE IN THE DEFINITIVE HOST POPULATIONS INCREASES SO THE AFFECTED AREA EXPANDS INCREASING THE RISK OF INFECTION FOR HUMANS
$ISEASES AND SYMPTOMS !LVEOLAR ECHINOCOCCOSIS 4HE PRIMARY SITE OF INFECTION WITH %CHINOCOCCUS MULTILOCULARIS IN HUMANS IN OF CASES IS THE LIVER &IG 4HE SLOW GROWTH OF THE MASS IN THE LIVER GENERALLY CAUSES NO SYMPTOMS 4HE DISEASE IS THEREFORE OFTEN ONLY DIAGNOSED BY CHANCE !T ADVANCED STAGES SYSTEMIC SYMPTOMS SUCH AS NIGHT SWEATS WEIGHT LOSS AND FATIGUE ARE EXPERIENCED AND ARE SUGGESTIVE OF A MALIGNANT DISEASE !DDITIONAL SYMPTOMS MAY OCCUR AS A
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
RESULT OF COMPRESSION OF MAJOR VESSELS IN THE LIVER 4HE PATHOGENS GROWTH BY INFILTRATION CAUSES DIFFERENT SIGNS AND SYMPTOMS ACCORDING TO WHICH ORGANS ARE AFFECTED !BDOMINAL ORGANS ARE RECEPTIVE TO GROWTH OF THE ALVEOLAR MASS DROP METASTASES ,YMPH NODES ARE ALSO COLONISED (AEMATOGENOUS DISSEMI NATION OF DETACHED GERMINAL LAYER CELLS EG UNDIFFERENTIATED CELLS ACT LIKE TUMOUR CELLS MAY LEAD TO SEEDING IN OTHER ORGANS 3UCH METASTASIS IS FAVOURED BY IMMUNOSUPPRESSION 4HE SPREAD OF THE PARASITIC MASS AT THE TIME OF DIAGNOSIS IS CURRENTLY DESCRIBED USING AN ANATOMICAL DISTRIBUTION PATTERN SIMILAR TO THE 4.- SYSTEM 0.- CLASSIFICATION OF THE %UROPEAN %CHINOCOCCOSIS 7ORKING 'ROUP
0ATHOGENICITY VIRULENCE AND ANTIGEN VARIABILITY 4HE CHRONIC PERSISTENCE OF THE PARASITIC LESION IS AS YET ONLY LITTLE UNDERSTOOD 4HERE IS 4( WEIGHTED IMMUNOMODULATION AS A RESULT OF WHICH THE PARA SITIC INFILTRATE IS PRESUMABLY TOLERATED BY THE HOST ORGANISM FOR MANY YEARS )MMUNOLOGICAL CONTROL IS ASSUMED TO PLAY A ROLE IN THE CASE OF @ABORTIVE LESIONS )N SUCH CASES THE EFFECTIVE CELLULAR IMMUNE RESPONSE IS ABLE TO KILL THE PARASITE 4HE INFECTION IS CURED LEAVING A CALCIFIED LESION )T IS NOT KNOWN HOW OFTEN THIS HAPPENS 3TUDIES ON IMMUNOGENETIC PREDISPOSITION ARE AVAIL ABLE AND PROVIDE INITIAL INDICATIONS OF POSSIBLE RESISTANCE TO THE PATHOGEN IN THE PRESENCE OF PARTICULAR (,! $2 CHARACTERISTICS 2APID PROGRESSION AND METASTASIS HAVE BEEN DESCRIBED IN THE IMMUNOSUPPRESSED
)MMUNE RESPONSE ! HUMORAL IMMUNE RESPONSE IS GENERALLY DETECTABLE IN CASES OF % MULTILOC ULARIS INFECTION 4HE CELLULAR IMMUNE RESPONSE IS CHARACTERISED BY MARKED EXPRESSION OF ), AND PARTIALLY EXPLAINS THE CHRONIC PERSISTENCE OF THE PATHOGEN
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS 4HE POOR DEFINITION OF THE LIVER LESION WITH CALCIFICATIONS AND CENTRAL NECROT IC CAVITIES IS MORPHOLOGICALLY SIMILAR TO THE PRESENTATION OF HEPATOCELLULAR CARCINOMA %ARLY MANIFESTATIONS MAY GIVE THE IMPRESSION OF HAEMANGIOMAS 4INY INTRAHEPATIC CALCIFICATIONS ARE CURRENTLY CONSIDERED TO BE A MANIFES TATION OF RECOVERY FROM THE PARASITIC DISEASE IE OF THE ABORTIVE FORM OF ALVEOLAR ECHINOCOCCOSIS %OSINOPHILIA WHICH IS RARELY DIAGNOSTICALLY INFORMATIVE DOES NOT OCCUR %LEVATION OF THE IMMUNOGLOBULIN % LEVEL ON THE OTHER HAND IS DETECTABLE
!CHIM (ARDER AND (EINZ -EHLHORN
IN ACTIVE ALVEOLAR ECHINOCOCCOSIS )MAGING AND SEROLOGICAL TECHNIQUES HAVE TO BE USED FOR DIAGNOSIS -ACROSCOPIC AND HISTOPATHOLOGICAL EVIDENCE OF THE % MULTILOCULARIS METACESTODE IS CONCLUSIVE ! DIAGNOSTIC BIOPSY IS NOT RECOMMENDED ON ACCOUNT OF THE RISK OF DISSEMINATION OF LARVAL TISSUE 4HE ALVEOLAR LIVER ECHINOCOCCUS IS SEEN ON ULTRASOUND AND #4 SCANS AS A GRAPE LIKE TUMOUR WITH SCATTERED MARGINAL CALCIFICATIONS )T IS POORLY DIFFERENTIATED FROM THE REST OF THE LIVER TISSUE )T IS NOT UNCOMMON TO SEE CENTRAL NECROTIC CAVITIES THAT GIVE THE IMPRESSION OF A CYST 4HE IRREGULAR TEX TURE THE POOR DIFFERENTIATION AND SCATTERED CALCIFIED DEPOSITS ARE INDICATIVE $IAGNOSTIC CONSIDERATIONS MUST INCLUDE A MALIGNANT LESION $EPENDING ON WHICH ORGANS ARE AFFECTED DIFFERENT IMAGING TECHNIQUES MAY BE INFORMA TIVE 3PECIFIC ANTIBODIES ARE DETECTABLE IN OVER OF CASES ALLOWING DIF FERENTIATION FROM CYSTIC ECHINOCOCCOSIS &ALSE POSITIVE SEROLOGICAL REACTIONS DO OCCUR 6ARIOUS $.! PROBES ARE AVAILABLE 4HEY HAVE NOT YET BEEN VALIDATED HOWEVER FOR CLINICAL DIAGNOSIS
4HERAPY 3URGERY 4HE TREATMENT OF CHOICE IS RADICAL SURGERY FOR CLEARLY CIRCUMSCRIBED LESIONS 7ITH CURATIVE SURGERY THERAPY SHOULD BE SUPPLEMENTED WITH SUBSEQUENT DRUG TREATMENT WITH ALBENDAZOLE OR MEBENDAZOLE FOR A MINIMUM OF YEARS 2ECURRENCES THOUGH ONLY AFTER SOME YEARS ARE COMMON WITH PALLIATIVE PROCEDURES )N CASES OF EXTENSIVE ORGAN INVOLVEMENT AND COMPRESSION OF MAJOR BLOOD VESSELS INTERVENTIONAL MEASURES ARE CRUCIAL 4HESE INCLUDE THE INSERTION OF STENTS RELIEF OF PRESSURE IN NECROTIC CAVITIES OR SEALING OFF NEWLY FORMED CAVITIES ! LIVER TRANSPLANT SHOULD BE CONSIDERED IF THE LIVER IS ADDITIONALLY DAM AGED BY OTHER DISEASES )F THE LIVER IS VERY EXTENSIVELY AFFECTED EVEN WITHOUT SPREAD TO OTHER ORGANS TRANSPLANTATION OFFERS NO ADDITIONAL ADVANTAGE OVER CHEMOTHERAPY ALONE ,ONG TERM SUBSEQUENT TREATMENT WITH ALBENDAZOLE IS NECESSARY TO PREVENT RECURRENCES #HEMOTHERAPY &OR INOPERABLE LESIONS CHEMOTHERAPY ON ITS OWN WITH ALBENDAZOLE OR MEBENDAZOLE LEADS TO CONSOLIDATION AND REGRESSION BY STOPPING THE GROWTH OF THE PARASITE 4HE ACTION OF BOTH DRUGS IS EXCLUSIVELY PARASITOSTATIC /N THE BASIS OF CURRENT KNOWLEDGE TREATMENT THEREFORE HAS TO BE CONTINUED FOR LIFE
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
2ESISTANCE 4HE ACTION OF BENZIMIDAZOLES AGAINST % MULTILOCULARIS INFECTION IS EXCLU SIVELY PARASITOSTATIC 4HE CELLULAR TARGET MOLECULES FOR BENZIMIDAZOLES ARE ` TUBULINS AS ESSENTIAL COMPONENTS OF THE CYTOSKELETON 6ARIABLE SENSITIVITY OF THE %CHINOCOCCUS ` TUBULIN TO BENZIMIDAZOLES COULD EXPLAIN DRUG RESIS TANCE
0REVENTION #ONSUMPTION OF RAW WILD BERRIES HAS TO BE CONSIDERED RISKY AND SHOULD THEREFORE BE AVOIDED )NDIVIDUAL PROPHYLACTIC MEASURES ARE NEVERTHELESS INSUFFICIENT AS A MEANS OF PREVENTION #ONTROL MEASURES MUST BE DIRECTED AT REDUCING INFESTATION WITHIN FOX POPULATIONS
3TRATEGIES FOR DISEASE PREVENTION 4HE FOX POPULATION IN SOME REGIONS OF 3OUTHERN 'ERMANY WAS TREATED FOR PARASITES BY REGULARLY LEAVING OUT BAIT CONTAINING PRAZIQUANTEL 4HIS HAS BEEN SHOWN TO RESULT IN A REDUCTION IN THE HIGH RATE OF INFECTION OF FOXES WITH ADULT FORMS OF % MULTILOCULARIS )T IS HOWEVER UNCLEAR WHAT IMPACT THIS WILL HAVE ON THE POTENTIAL INFECTION OF HUMANS
(EPATITIS CAUSED BY TREMATODES &ASCIOLOSIS &ASCIOLIASIS &ASCIOLA HEPATICA ; = /THER NAME OF THE AGENT OF DISEASE ,ARGE LIVER FLUKE
4AXONOMY 3UBREGNUM 0HYLUM #LASS 3UBCLASS /RDER &AMILY 'ENUS
!NIMALIA 0LATYHELMINTHES 4REMATODA $IGENEA %CHINOSTOMATA &ASCIOLIDAE &ASCIOLA
!CHIM (ARDER AND (EINZ -EHLHORN
-ORPHOLOGY (UMANS ARE INFECTED PREDOMINANTLY WITH THE LARGE LIVER FLUKE &ASCIOLA HEPATICA WHICH GROWS TO A SIZE OF = MM &IG &IGS n n SEE PP n 4HE GIANT LIVER FLUKE & GIGANTICA OCCURS ONLY EXCEPTIONALLY AND WITH A LIMITED GEOGRAPHICAL DISTRIBUTION GROWING TO UP TO MM IN LENGTH IN ITS NATURAL HOST 4HE SURFACE OF THESE WORMS IS FORTIFIED BY NUMEROUS SCALES &IG
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD (UMANS ARE INFECTED AS A RESULT OF ORAL INGESTION OF THE METACERCARIAE THAT ARE USUALLY ATTACHED TO PLANTS )T IS SUFFICIENT FOR SUCH PLANTS TO BE CASUALLY PLACED IN THE MOUTH 4HE EGGS OF THE ADULT FLUKES LIVING IN THE BILE DUCTS &IG ARE EXCRETED VIA THE COMMON BILE DUCT WITH THE FAECES AND NEED TO REACH WATER IN ORDER TO DEVELOP FURTHER 4HIS RESULTS IN THE DEVELOPMENT WITHIN n WEEKS INSIDE THE EGG OF A CILIATED LARVA THE MIRACIDIUM WHICH HATCHES FROM THE EGG MEMBRANE AND ACTIVELY SEEKS OUT THE INTERMEDIATE HOST SNAILS SUCH AS ,YMNAEA (ERE ASEXUAL REPRODUCTION INVOLVING A NUMBER OF STAGES TAKES PLACE LEADING TO THE FORMATION OF CERCARIAE 4HESE LEAVE THE SNAIL SWIM AROUND IN THE WATER ULTIMATELY ATTACH THEMSELVES TO GRASSES AND ENCYST TO FORM THE METACERCARIA THE INFECTIOUS STAGE THAT CAN LIVE FOR MONTHS PRIMAR ILY UNDER MOIST CONDITIONS /NCE ORALLY INGESTED THE YOUNG FLUKES HATCH IN THE SMALL INTESTINE BORE THEIR WAY THROUGH THE INTESTINAL WALL AND MIGRATE THROUGH THE ABDOMINAL CAVITY TO THE LIVER !FTER n WEEKS MIGRATION IN THE HEPATIC PARENCHYMA THE FLUKES BREAK THROUGH INTO THE BILE DUCTS THEIR FINAL RESTING PLACE &IG 3EXUAL MATURITY IS REACHED APPROXIMATELY WEEKS AFTER INFECTION PREPATENCY PERIOD
%PIDEMIOLOGY & HEPATICA OCCURS WORLDWIDE AND IS PARTICULARLY COMMON IN HUMID REGIONS WITH A HIGH RAINFALL THAT MEET THE BIOTOPE REQUIREMENTS OF THE AMPHIBIOUS INTERMEDIATE HOST SNAILS ,YMNAEA SPP ALSO KNOWN AS MUD SNAILS 4HE MAIN HOSTS ARE DOMESTIC AND WILD RUMINANTS )NFECTIONS IN OTHER HERBI VORES AND OMNIVORES ARE ALSO NOT UNCOMMON #LINICALLY AND ECONOMI CALLY SIGNIFICANT OFTEN EPIDEMIC DISEASES MAY BE TRIGGERED IN DOMESTIC RUMINANTS & GIGANTICA OCCURS IN TROPICAL ZONES OF !SIA AND !FRICA IN 3OUTH %AST !SIA AND THE 0ACIFIC REGION OFTEN ALONGSIDE & HEPATICA )SOLATED AREAS OF DISTRIBUTION ARE FOUND IN THE -IDDLE %AST AND IN THE 3OUTHERN REPUB
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
LICS OF THE FORMER 5332 4HE HOST SPECTRUM IS THE SAME AS THAT FOR & HEPATICA )NFECTION OF HUMANS WITH & HEPATICA OCCURS WORLDWIDE AND USUALLY SPORADICALLY 'ROUP INFESTATIONS HAVE BEEN REPORTED IN %NGLAND &RANCE AND .ORTH !FRICA !PPROXIMATELY CASES PER YEAR HAD BEEN DOCUMENTED IN &RANCE BETWEEN AND WITH HIGHER RATES IN SOME REGIONS )NFESTATION OF HUMANS WITH & GIGANTICA IS RARE THOUGH CASES ARE KNOWN FROM THE 0ACIFIC AND !SIAN REGION
$ISEASES AND SYMPTOMS &ASCIOLIASIS IS AN ACUTE OR CHRONIC DISEASE OF THE LIVER FOLLOWING INFESTATION OF HUMANS WITH LIVER FLUKES 4HE DEGREE OF INFESTATION IN HUMANS IS USUALLY ONLY SLIGHT )NFECTIONS ARE THEREFORE OFTEN CLINICALLY INAPPARENT PARTICULARLY IN THE PREPATENT PERIOD )N THE EARLY STAGE APPROXIMATELY WEEKS AFTER INFECTION LARVAL MIGRATION GIVES RISE TO PERIHEPATITIS WITH SYSTEMIC SYMP TOMS SUCH AS FEVER EXHAUSTION AND LOSS OF APPETITE ,EUCOCYTOSIS EOSINO PHILIA AND ELEVATED )G% LEVELS ARE GENERALLY OBSERVED /NCE THE ADULT PARASITES HAVE COLONISED THE BILE DUCTS INFLAMMATION AND LATER FIBROSIS AND CALCIFICATION OF THE LATTER OCCUR 4HE ANAEMIA THAT OCCURS AT A LATER STAGE OF THE DISEASE IS CAUSED BY THE SUSTAINED CONSUMP TION OF BLOOD BY THE FLUKES "ESIDES INTERMITTENT FEVER THE SYMPTOMS EXPERIENCED BY PATIENTS ARE ANOREXIA WEIGHT LOSS PRURITUS AND PAIN USU ALLY LOCALISED UNDER THE RIGHT COSTAL MARGIN /CCASIONAL OBSTRUCTION OF THE BILE DUCTS BY THE MIGRATION OF THE WORMS LEADS TO RECURRENT PERIODS OF JAUNDICE %CTOPIC SITES OF INFECTION WITH THE PARASITE ARE CONNECTIVE TISSUE AND #.3
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS #ONDITIONS THAT MUST BE RULED OUT ARE PERIHEPATITIS OF OTHER AETIOLOGY IN THE ACUTE STAGE AND CHOLESTASIS OF OTHER ORIGIN AND GALLSTONES AT THE CHRONIC STAGE )N THE PREPATENT PERIOD LASTING WEEKS OR MORE SEROLOGICAL METH ODS INDIRECT IMMUNOFLUORESCENCE TEST INDIRECT HAEMAGGLUTINATION AND %,)3! CAN BE USED FOR AETIOLOGICAL CLARIFICATION ALTHOUGH CROSS REACTIONS ARE LIKELY PARTICULARLY WITH OTHER TREMATODES /PISTHORCHIS 3CHISTOSOMA SPP !FTER THE PREPATENT PERIOD CHARACTERISTIC OPERCULATED EGGS MEASUR ING = +M & HEPATICA AND = +M & GIGANTICA ARE DETECTABLE IN THE STOOLS 4HE EGGS ARE NOT REGULARLY EXCRETED 2EPEATED TESTING IS THERE FORE NECESSARY AND EGG DETECTION IS NOT ALWAYS POSSIBLE %GG DETECTION ON A SINGLE OCCASION IS NOT SUFFICIENT AS LIVER FLUKE EGGS CONSUMED WITH CONTAMI NATED BEEF LIVER SAUSAGE ALSO PASS THROUGH THE INTESTINE UNCHANGED
!CHIM (ARDER AND (EINZ -EHLHORN
4REATMENT %FFICIENT TREATMENT IS ACHIEVED WITH TRICLABENDAZOLE SINGLE DOSE OF MG KG 4REATMENT WITH BITHIONOL = MGKG PER DAY EVERY OTHER DAY FOR WEEKS IS ALSO RECOMMENDED &URTHERMORE PRAZIQUANTEL FOR DAYS WHEN THE DAILY DOSE IS GIVEN DEVIDED AT THREE INTERVALS
2ESISTANCE 2ESISTANCE IN TREATMENT OF HUMAN FASCIOLOSIS IS UNKNOWN AT PRESENT "Y CON TRAST THERE ARE SEVERE PROBLEMS IN VETERINARY MEDICINE IN TREATING &ASCIOLA HEPATICA INFECTIONS WITH ALL AVAILABLE COMMON FASCIOLOCIDAL DRUGS
0ROPHYLAXIS 0LANTS GROWING ON WET GROUND AND IN THE VICINITY OF NATURAL WATERS SUBJECT TO OCCASIONAL FLOODING MAY BE CONTAMINATED WITH METACERCARIAE AND SHOULD NOT BE PLACED IN THE MOUTH #ONSUMPTION OF NATURALLY GROWING WATERCRESS SHOULD BE AVOIDED
$ICROCOELOSIS $ICROCOELIASIS $ICROCOELIUM DENDRITICUM ; = /THER NAME OF THE AGENT OF DISEASE 3MALL LIVER FLUKE LANCET FLUKE $ICROCOELIUM LANCEOLATUM
4AXONOMY 3UBREGNUM 0HYLUM #LASS 3UBCLASS /RDER &AMILY 'ENUS
!NIMALIA 0LATYHELMINTHES 4REMATODA $IGENEA 0LAGIORCHIATA $ICROCOELIIDAE $ICROCOELIUM
-ORPHOLOGY 4HE PATHOGENS ARE THE SMALL LIVER FLUKE $ICROCOELIUM DENDRITICUM AND $ HOSPES WHICH BOTH HAVE A SMOOTH NOT SCALY SURFACE &IGS AND 4HE PARASITES REACH A SIZE OF = MM
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD )NFECTION OCCURS AS A RESULT OF ACCIDENTAL INGESTION OF INFECTED SECOND INTER MEDIATE HOSTS PARTICULAR SPECIES OF ANT SUCH AS &ORMICA SPP IN THE CASE OF $ DENDRITICUM AND #AMPONOTUS SPP IN THE CASE OF $ HOSPES ,ARVAE CONTAINING EGGS REACH THE OUTSIDE WORLD WITH THE FAECES OF INFECT ED ANIMALS 4HEY ARE INGESTED BY TERRESTRIAL SNAILS OF THE GENERA (ELICELLA AND :EBRINA IN THE CASE OF $ DENDRITICUM AND ,YMNICOLARIA SPECIES IN THE CASE OF $ HOSPES !SEXUAL REPRODUCTION IN THE SNAILS GIVES RISE TO CERCARIAE THAT ARE DISCHARGED BY THE SNAILS ENCLOSED IN BALLS OF MUCUS !NTS AS THE SECOND INTERMEDIATE HOST EAT THESE BALLS OF MUCUS CONTAINING THE CERCARIAE 4HE INFECTIOUS STAGES METACERCARIAE FORM IN THE ANTS COELOM )NFESTATION OF THE HYPOPHARYNGEAL GANGLION ALTERS THE BEHAVIOUR OF INFECTED ANTS WHICH THEN BITE INTO PLANTS IN THE EVENING AS OUTDOOR TEMPERATURES FALL AND ARE INGESTED ORALLY IN THE MORNING FOR EXAMPLE BY A GRAZING ANIMAL AS THE DEFINITIVE HOST 4HE YOUNG FLUKES ARE RELEASED FROM THE METACERCARIAE IN THE SMALL INTESTINE AND MIGRATE VIA THE COMMON BILE DUCT TO THE SMALL BILE DUCTS 4HERE THEY REACH SEXUAL MATURITY IN n WEEKS AND START TO LAY THE TYPICAL OPERCULATED EGGS PREPATENT PERIOD
%PIDEMIOLOGY $ DENDRITICUM OCCURS IN THE TEMPERATE ZONES OF THE .ORTHERN HEMISPHERE !N INCREASED PREVALENCE IS OFTEN OBSERVED IN CONFINED AREAS AS THE LIVER FLUKE IS DEPENDENT ON THE SIMULTANEOUS PRESENCE OF TWO INTERMEDIATE HOSTS TERRESTRIAL SNAILS AND PARTICULAR SPECIES OF ANT DURING ITS COMPLICATED DEVELOPMENT CYCLE )TS DEFINITIVE HOSTS ARE A NUMBER OF SPECIES OF MAM MAL INCLUDING RUMINANTS AND RABBITS (IGH INFESTATION RATES ARE KNOWN IN DOMESTIC RUMINANTS IN 3OUTHERN %UROPE $ HOSPES IS CONFINED TO %ASTERN AND #ENTRAL !FRICA $ICROCOELIASIS IN HUMANS OCCURS IN CORRELATION WITH INFESTATION IN ANI MALS )N #ENTRAL !SIA 5ZBEKISTAN FOR EXAMPLE THE PREVALENCE IN HUMANS ON THE BASIS OF AUTOPSY REPORTS IS COMPARED WITH BETWEEN n IN DOMESTIC RUMINANTS
$ISEASES AND SYMPTOMS $ICROCOELIASIS IS A CHRONIC DISEASE OF THE LIVER PARTICULARLY THE BILIARY SYSTEM OCCURRING RARELY IN HUMANS FOLLOWING INFECTION WITH THE SMALL LIVER FLUKE 4HE CLINICAL SYMPTOMS ARE DEPENDENT ON THE WORM BURDEN #OLONISATION OF THE BILE DUCTS BY THE PARASITE LEADS TO ACUTE AND LATER CHRONIC CHOLANGITIS ! LATE SEQUELA IS THE DEVELOPMENT OF CIRRHOTIC CHANGES IN THE PERIPORTAL REGION
!CHIM (ARDER AND (EINZ -EHLHORN
3YMPTOMS OBSERVED IN HEAVY INFECTIONS ARE PERSISTENT RIGHT SIDED UPPER ABDOMINAL PAIN JAUNDICE ENLARGEMENT OF THE LIVER AND THE SPLEEN ALTERNAT ING DIARRHOEA AND CONSTIPATION FLATULENCE DIZZINESS VOMITING HEADACHE AND IN ADVANCED CASES ANAEMIA
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS #HOLANGITIS AND CHOLESTASIS OF OTHER ORIGIN 0ATENT INFECTIONS ARE DIAGNOSED BY DETECTION IN THE STOOL OF THE OPERCULATED DARK BROWN EGGS MEASURING APPROXIMATELY = +M 4HE TEST IS REPEATED TO EXCLUDE THE POSSIBILITY OF EGGS THAT ARE MERELY PASSING THROUGH THE INTESTINE HAVING GOT THERE BY CHANCE AS A RESULT OF EATING THE LIVER OF INFECTED ANIMALS
4REATMENT 0RAZIQUANTEL = MGKG ON A SINGLE DAY IS USED AS A CHEMOTHERAPEUTIC AGENT
0ROPHYLAXIS ,OOK OUT FOR THE PRESENCE OF ANTS WHEN EATING WINDFALL FRUIT AND NATURALLY GROWING PLANTS 0EOPLE SHOULD NOT CHEW ON BLADES OF GRASS
#LONORCHOSIS #LONORCHIASIS #LONORCHIS SINENSIS ; = /THER NAME OF THE AGENT OF DISEASE ,ANCEOLATE FLUKE #HINESE LIVER FLUKE /PISTHORCHIS SINENSIS
4AXONOMY 3UBREGNUM 0HYLUM #LASS 3UBCLASS /RDER &AMILY 'ENUS
!NIMALIA 0LATYHELMINTHES 4REMATODA $IGENEA /PISTHORCHIATA /PISTHORCHIIDAE #LONORCHIS
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
-ORPHOLOGY 4HE LANCEOLATE PARASITE #LONORCHIS SINENSIS WHICH IS A TRANSPARENT PINK COLOUR WHILE ALIVE GROWS TO A SIZE OF n =n MM &IGS AND )T HAS CHARACTER ISTIC BRANCHED TESTES ARRANGED IN PAIRS ON THE POSTERIOR THIRD OF THE BODY
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD (UMANS ARE INFECTED BY CONSUMPTION OF RAW OR INADEQUATELY PREPARED FRESHWATER FISH PARTICULARLY CARP THE SECOND INTERMEDIATE HOST IN THE DEVEL OPMENT CYCLE )F THE SMALL OPERCULATED WORM EGGS MAXIMUM +M IN LENGTH FIND THEIR WAY INTO WATER WITH THE FAECES OF INFECTED VERTEBRATES AND ARE INGESTED THERE BY SNAILS "ULINUS AND 0ARAFOSSARULUS SPECIES ASEXUAL REPRODUCTION THEN TAKES PLACE IN THIS FIRST INTERMEDIATE HOST IN THE COURSE OF DEVELOPMENT VIA A NUMBER OF STAGES #ERCARIAE THAT ARE RELEASED FROM THE SNAILS ACTIVELY PENETRATE SMALL FRESHWATER FISH PREDOMINANTLY CYPRINIDS ENCYST IN MUSCLE AND FORM METACERCARIAE !FTER BEING CONSUMED IN RAW FISH THE YOUNG FLUKES HATCH IN THE DUODENUM MIGRATE VIA THE COMMON BILE DUCT TO THE DISTAL BILE DUCTS ATTACH THEMSELVES TO THE EPITHELIUM MATURE INTO ADULT FLUKES AND START TO LAY EGGS AFTER n WEEKS PREPATENCY 4HE PARASITE CAN SURVIVE IN THE DEFINITIVE HOST FOR n YEARS PATENCY
%PIDEMIOLOGY # SINENSIS OCCURS THROUGHOUT !SIA FROM )NDOCHINA TO *APAN "ESIDES HUMANS CATS DOGS PIGS VARIOUS SMALL PREDATORS MUSTELIDS AND RATS ARE ALSO INFESTED THESE ANIMALS CONSTITUTING A RESERVOIR THAT IS DIFFICULT TO CONTROL %NDEMIC AREAS ARE +OREA 6IETNAM 4AIWAN #HINA AND (ONG +ONG WHERE PREVALENCES OF OVER ARE COMMON )N *APAN HOWEVER INFESTATION OF HUMANS HAS TODAY BECOME A RARITY
$ISEASES AND SYMPTOMS #ONFINED TO !SIA CLONORCHIASIS IS A DISEASE OF THE LIVER PRIMARILY THE BILIARY SYSTEM AS A RESULT OF INFECTION WITH THE #HINESE LIVER FLUKE # SINENSIS CAUSES INFLAMMATORY AND PROLIFERATIVE CHANGES IN THE BILE DUCTS THE SEVERITY OF THESE CHANGES BEING DEPENDENT ON THE NUMBER OF FLUKES AND THE DURATION OF THE INFESTATION )NFECTION IS MANIFESTED INITIALLY IN TERMS OF EXHAUSTION LOSS OF APPETITE AND GASTROINTESTINAL SYMPTOMS SUCH AS DIARRHOEA AND METEORISM 3EVERE INFECTIONS ARE FOLLOWED BY PAIN IN THE RIGHT EPIGASTRIC REGION HEPA TOMEGALY FEVER JAUNDICE AND OCCASIONALLY URTICARIA -ASSIVE INFESTATION AS
!CHIM (ARDER AND (EINZ -EHLHORN
A RESULT OF REPEATED INFECTIONS MORE THAN FLUKES PER PATIENT MAY BE SEEN LEADS TO SEVERE DISORDERS OF GENERAL WELLBEING WITH DIZZINESS TREMOR SEIZURES AND WEIGHT LOSS #IRRHOSIS OF THE LIVER OEDEMA AND ASCITES OCCUR WITH PERSISTENT INFECTIONS 0ANCREATITIS AND GALLSTONES ARE COMMON "ACTERIAL SUPERINFECTIONS USU ALLY % COLI AND CHOLECYSTITIS ARE COMMON COMPLICATIONS )NFECTION PREDISPOSES TO CHOLANGIOCARCINOMAS WHICH OCCUR IN CASES OF LONG TERM INFECTIONS
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS #HOLANGITIS AND CIRRHOSIS OF THE LIVER OF OTHER ORIGIN NEED TO BE RULED OUT DEPENDING ON THE STAGE AND THE SEVERITY OF THE INFECTION 4HE CLINICAL PRE SENTATION RESEMBLES THAT SEEN IN CASES OF INFESTATION WITH OTHER /PISTHORCHIS SPECIES OR $ICROCOELIUM SPP 4HE YELLOWISH COLOURED OPERCULATED EGGS APPROX = +M IN SIZE ARE MICROSCOPICALLY DETECTABLE IN STOOLS OR DUODENAL FLUID %GG EXCRETION MAY COMMENCE JUST DAYS AFTER INFECTION "ECAUSE THEY ARE SO SMALL THE EGGS ARE EASILY MISSED IN STOOL SPECIMENS #ONCENTRATION TECHNIQUES SHOULD THEREFORE BE USED 3EROLOGICAL TECHNIQUES AND 0#2 TECHNIQUES HAVE ALSO PROVED USEFUL FOR DIAGNOSTIC PURPOSES %OSINOPHILIA IS OBSERVED IN THE ACUTE STAGE
4REATMENT 4HE DISEASE IS TREATED WITH PRAZIQUANTEL = MGKG PER DAY FOR DAYS OR ALBENDAZOLE MGDAY FOR DAYS !S WITH MOST FLUKE INFECTIONS THE INTRODUCTION OF PRAZIQUANTEL CONSTI TUTED A SIGNIFICANT ADVANCE IN THE TREATMENT ALSO OF CLONORCHIASIS 4HE EGGS DISAPPEAR FROM STOOLS AND DUODENAL FLUID A FEW DAYS AFTER TREATMENT
0ROPHYLAXIS 4HOROUGH COOKING OR FRYING OF FISH IS THE MOST IMPORTANT PROPHYLACTIC MEA SURE IN ENDEMIC AREAS 3INCE CHANGES TO THE EATING PRACTICES OF POPULATION GROUPS THAT TRADITIONALLY EAT RAW FISH ARE ACHIEVABLE ONLY IN THE LONG TERM ATTEMPTS ARE BEING DIRECTED AT MAKING RAW FISH SAFE BY TREATING IT WITH GAMMA IRRADIATION K'Y TO KILL OFF THE METACERCARIAE (UMAN FAECES SHOULD NOT BE ALLOWED TO CONTAMINATE FISH WATERS SO AS TO PREVENT INFECTION OF THE SNAILS LIVING THERE VIA THE EGGS
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
/PISTHORCHOSIS /PISTHORCHIASIS /PISTHORCHIS FELINEUS / VIVERRINI ; n= /THER NAMES OF THE AGENTS OF DISEASE ,IVER FLUKE CAT LIVER FLUKE ORIENTAL LIVER FLUKE
4AXONOMY 3UBREGNUM 0HYLUM #LASS /RDER &AMILY 'ENUS 3PECIES
!NIMALIA 0LATYHELMINTHES $IGENEA /PISTHORCHIIDA /PISTHORCHIIDAE /PISTHORCHIS /PISTHORCHIS FELINEUS / VIVERRINI
-ORPHOLOGY $ORSOVENTRALLY FLATTENED HERMAPHRODITE TREMATODES MEASURE n MM IN LENGTH AND n MM IN WIDTH 4HEY HAVE A BLIND ENDING BRANCHED INTES TINE AND TWO SUCKERS 3OLID TESTES ARE LOCATED IN THE HIND PART OF THE BODY &IG
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD -AN IS INFECTED ALMOST ONLY BY EATING RAW OR UNCOOKED CARP FLESH )N SOME ENDEMIC AREAS FISH FROM OTHER FAMILIES ARE ALSO POSSIBLE SOURCES OF INFECTION 4HE GENUS /PISTHORCHIS BELONGS TO THE GROUP OF TRIHETEROXENOUS HEL MINTHS HAVING ONE DEFINITIVE AND TWO INTERMEDIATE HOSTS $EVELOPMENTAL CYCLE STARTS WITH EXCRETION OF THE EGGS WITH THE STOOLS OF THE DEFINITIVE HOST &URTHER DEVELOPMENT OCCURS ONLY IN FRESHWATER BY INGESTION OF MIRACIDIA CONTAINING EGGS BY THE FIRST INTERMEDIATE HOST SNAILS "ITHYNIIDAE AND OTHER FAMILIES $IFFERENT LARVAL STAGES DEVELOP IN THE SNAIL SPOROCYST REDIA CERCARIA #ERCARIAE ARE RELEASED AND INFECT THE SECOND INTERMEDIATE HOST CARP #YPRINIDAE (ERE DEVELOPMENT OF INFECTIOUS METACERCARIAE OCCUR !FTER INGESTION OF THE METACERCARIAE BY THE DEFINITIVE HOST THE BILE DUCTS ARE COLONISED WITH ADULT WORMS %GG EXCRETION BEGINS ABOUT n WEEKS AFTER INFECTION PREPATENT PERIOD 4HE MAIN MULTIPLICATION PHASE OF THE LIVER FLUKE TAKES PLACE AT THE LARVAE STAGE IN THE FIRST INTERMEDIATE HOST SNAIL )N THE DEFINITIVE HOST MAN MAMMALS THE NUMBER OF ADULT WORMS CORRESPONDS TO THE NUMBER OF
!CHIM (ARDER AND (EINZ -EHLHORN
INFECTIOUS STAGES INGESTED ONE METACERCARIA DEVELOPS TO ONE ADULT WORM -ULTIPLICATION IN THE DEFINITIVE HOST CONSISTS ONLY IN THE PRODUCTION OF EGGS WHICH MUST LEAVE THE BODY IN ORDER TO UNDERGO FURTHER DEVELOPMENT !N INCUBATION PERIOD CANNOT USUALLY BE DEFINED AS THE DEVELOPMENT OF CLINI CAL SYMPTOMS DEPENDS ON THE NUMBER OF n USUALLY CUMULATIVELY n INGESTED METACERCARIAE AND THE DURATION OF THE INFECTION )N THE CASE OF SIMULTANE OUS MASSIVE INFECTION THE FIRST SYMPTOMS CAN BE EXPECTED n WEEKS AFTER INFECTION
%PIDEMIOLOGY -AN IS THE DEFINITIVE FINAL HOST )N ADDITION THERE IS A BROAD SPECTRUM OF RESERVOIR HOSTS IN PISCIVOROUS MAMMALS #ANIDAE &ELIDAE ETC 0EOPLE WHO EAT RAW OR PARTIALLY COOKED CARP FISH OR PARTS OF THESE FISH ARE AT HIGH RISK 4HE DISTRIBUTION OF OPISTHORCHOSIS IS LIMITED TO %URASIA )T OCCURS WHEREVER EATING HABITS ALLOW INFECTION 4HE RANGE OF / FELINEUS EXTENDS FROM 3PAIN EASTWARDS TO 3IBERIA WHILE / SINENSIS OCCURS ONLY IN %AST !SIA AND / VIVER RINI ONLY IN 3OUTH %AST !SIA 4HAILAND ,AOS !UTOCHTHONOUS /PISTHORCHIS INFECTION IS NOW EXTREMELY RARE IN 7ESTERN AND #ENTRAL %UROPE
$ISEASES AND SYMPTOMS /PISTHORCHOSIS 4HE DISEASE IS CAUSED BY BILE DUCT PARASITES WHOSE INFEC TIOUS STAGES METACERCARIAE ARE RELEASED IN THE DUODENUM FROM WHERE THEY MIGRATE DIRECTLY TO THE BILE DUCTS OCCASIONALLY ALSO TO THE PANCREATIC DUCT !DULT WORMS CAUSE DILATION OF THE BILE DUCTS WITH HYPERTROPHY OF THE EPITHE LIUM AND FIBROUS WALL THICKENING 4HE SEVERITY OF THE DISEASE IS DETERMINED BY THE DURATION UNTREATED UP TO YEARS AND THE INTENSITY OF INFECTION AS MANY AS WORMS HAVE BEEN FOUND AT AUTOPSY 4HE ACUTE PHASE ONLY WITH SIMULTANEOUS INTAKE OF NUMEROUS METACERCARIAE IS ASSOCIATED WITH FEVER EPIGASTRIC AND UPPER ABDOMINAL SYMPTOMS AND DIARRHOEA 4HE CHRONIC PHASE IS CHARACTERISED BY FEVER COLICY ABDOMINAL PAINS SOMETIMES BILE DUCT OBSTRUCTION HEPATOMEGALY )N ADDITION THERE MAY BE SECONDARY BACTERIAL INFECTIONS CHOLELITHIASIS ABSCESSES CIRRHOSIS OEDEMA ASCITES AND CHOLANGIOCARCINOMA AS COMPLICATIONS
)MMUNE RESPONSE 4HE IMMUNE RESPONSE PRODUCED BY LIVER FLUKES NEITHER KILLS THE PARASITES NOR PROTECTS AGAINST REINFECTION
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS 4HE DIFFERENTIAL DIAGNOSIS INCLUDES BILE DUCT DISEASES OF OTHER ORIGIN WITH APPROPRIATE SYMPTOMS -ICROSCOPY 4HE ONLY PROOF OF THE PRESENCE OF OPISTHORCHOSIS IS DETECTION OF THE OPERCULATED EGGS MEASURING n +M IN LENGTH AND n +M IN WIDTH IN THE STOOLS OR BILE %XCRETION OF EGGS BEGINS ABOUT n WEEKS AFTER INFECTION PREPATENT PERIOD !S THE DIFFERENTIATION OF EGGS AMONG /PISTHORCHIS SPECIES AND FROM THOSE OF NUMER OUS OTHER SPECIES OF SMALL INTESTINAL FLUKES IS VERY DIFFICULT THE DIAGNOSIS SHOULD BE MADE BY SPECIALISED PARASITOLOGICAL OR TROPICAL MEDICINE LABORATORIES 3EROLOGY .O TESTS OF HIGH SPECIFICITY AND SENSITIVITY ARE CURRENTLY AVAILABLE 0#2 WAS RECENTLY SHOWN TO HELP IN DIAGNOSIS
4REATMENT 4HE DRUG OF CHOICE IS PRAZIQUANTEL "ILTRICIDE $OSAGE MGKG ONCE OR MGKG BODY WEIGHT TIMES ON THE SAME DAY
0REVENTION 4HE ONLY RELIABLE PROTECTION AGAINST INFECTION IS AVOIDING EATING DISHES CON TAINING RAW OR PARTIALLY COOKED FISH PARTICULARLY CARP WHICH COULD CONTAIN INFECTIOUS STAGES
3TRATEGIES FOR PREVENTION AND CONTROL OF THE DISEASE )N ENDEMIC AREAS CAMPAIGNS COMPRISING HEALTH EDUCATION MASS ANTHELMINIC TREATMENT AND PROPER REMOVAL OF EXCREMENT ARE NEEDED (OWEVER BECAUSE OF THE EXISTENCE OF ANIMAL RESERVOIR HOSTS EXTERMINATION IS PRACTICALLY UNACHIEVABLE
3CHISTOSOMIASIS 3CHISTOSOMOSIS "ILHARZIASIS 3CHISTOSOMA SPECIES ; = /THER NAME OF AGENTS OF DISEASE 3 INTERCALATUM 3 JAPONICUM 3 MANSONI 3 MEKONGI "ILHARZIA SPECIES $ISTOMUM BILHARZIASE BLOOD FLUKE INTESTINAL BLOOD FLUKE BLADDER FLUKE *APANESE BLOOD FLUKE COUPLED OR PAIRED WORMS
!CHIM (ARDER AND (EINZ -EHLHORN
4AXONOMY 3UBREGNUM 0HYLUM #LASS 3UBCLASS /RDER &AMILY 'ENUS 3PECIES
!NIMALIA 0LATYHELMINTHES 4REMATODA $IGENEA 3CHISTOSOMATIDA 3CHISTOSOMATIDAE 3CHISTOSOMA 3 MANSONI 3 JAPONICUM 3 MEKONGI 3 INTERCALATUM 3 HAEMATOBIUM
-ORPHOLOGY 3CHISTOSOMES ARE DIECIOUS APPROXIMATELY n CM LONG FLUKES &IGS AND 4HE MALE CARRIES THE FEMALE IN A VENTRAL GROOVE CANALIS GYNAECOPHO RUS OR GYNAECOPHORAL CANAL 4WO SUCKERS ARE USED FOR ATTACHMENT TO AND MOVEMENT WITHIN BLOOD VESSELS VEINS OF THE MESENTERIC OR VESICAL PLEXUS 4HE SIMPLE BLIND ENDING INTESTINE IS FILLED WITH INGESTED ERYTHROCYTES 4HE TEGUMENT CONSISTS OF A SYNCYTIUM WITH A DOUBLE SURFACE MEMBRANE 4HE EGGS MEAN SIZE IN LENGTH n +M ACCORDING TO SPECIES EACH CONTAIN ONE LARVA MIRACIDIUM AND HAVE A CHARACTERISTIC SPINE SEE $IAGNOSIS
&IGURE ,IGHT MICROGRAPH OF AN ADULT &ASCIOLA HEPATICA AS AS SEEN FROM ITS VENTRAL SIDE &IGURE 3CANNING ELECTRON MICROGRAPH OF THE ANTERIOR REGION OF AN ADULT & HEPATICA FLUKE SHOWING THE ORAL AND THE LARGER VENTRAL SUCKER THE IN BETWEEN SITUATED TWO SMALL GENITAL OPEN INGS AND THE TYPICAL SCALY SURFACE BY TOOTHED TEGUMANTAL SCALES &IGURE #UT OFF BILE DUCT WITH ADULT &ASCIOLA FLUKES &IGURE ,IGHT MICROGRAPH OF AN ADULT $ DENDRITICUM FLUKE &IGURE 3CANNING ELECTRON MICROGRAPH OF THE ANTERIOR END OF AN ADULT $ DENDRITICUM FLUKE .OTE THE SMOOTH NOT SCALY SURFACE &IGURE ,IGHT MICROGRAPH OF AN UNSTAINED ADULT #LONORCHIS SINENSIS &IGURE 3CANNING ELECTRON MICROGRAPH OF THE VENTRAL SIDE OF AN ADULT # SINENSIS FLUKE .OTE THE SMOOTH UNSCALY SURFACE &IGURE ,IGHT MICROGRAPH OF AN ADULT /PISTHORCHIS VIVERRINI WORM .OTE THE SOLID POSTERIOR TESTES
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
!CHIM (ARDER AND (EINZ -EHLHORN
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD 4RANSMISSION OF SCHISTOSOMES TO HUMANS IS POSSIBLE IN FRESHWATER CONTAIN ING THE CERCARIAE FORK TAILED LARVAE EXCRETED BY THE SNAILS 4HE CERCARIAE CAN ACTIVELY PENETRATE THE SKIN WITHIN A SHORT SPACE OF TIME 3INCE THE SNAIL SPECIES THAT SERVE AS INTERMEDIATE HOSTS OCCUR ONLY IN SUB TROPICAL CLIMATIC ZONES TRANSMISSION CAN ONLY TAKE PLACE IN WATERS IN THOSE REGIONS #ONSTRUCTION OF IRRIGATION SYSTEMS IN !FRICA IN PARTICULAR HAS LED TO A DRA MATIC INCREASE IN REPRODUCTION OF THE INTERMEDIATE HOST SNAILS RESULTING IN INCREASED TRANSMISSION 3CHISTOSOMES ARE TWO HOST HELMINTHS WITH DIFFERENT DEFINITIVE AND INTER MEDIATE HOSTS ADULT FLUKES RESIDE IN THE DEFINITIVE FINAL HOST HUMANS (ERE EGG EXCRETION WITH STOOLS OR URINE OCCURS n DEPENDING ON THE SPECIES -IRACIDIA HATCH IN FRESHWATER PENETRATE AN INTERMEDIATE HOST PARTICULAR FRESHWATER OR AMPHIBIAN SPECIES OF SNAIL AND LARVAL DEVELOPMENT AND MULTIPLICATION OCCUR INSIDE THE SNAIL SPOROCYSTS CERCARIAE 4HEREAFTER CERCARIAE SWARM INTO THE WATER AND ACTIVELY PENETRATE PERCUTANEOUSLY INTO HUMANS MIGRATE WITHIN THE DEFINITIVE HOST MATURE INTO ADULT WORMS AND COLONISE THE SPECIES SPECIFIC VENOUS PLEXUSES 4HE BLOOD FLUKES PRINCIPAL MULTIPLICATION PHASE TAKES PLACE AT THE LARVAL STAGE IN THE INTERMEDIATE HOST SNAIL 4HE NUMBER OF WORMS HARBOURED BY THE DEFINITIVE HOST MAN IS THE SAME AS THE NUMBER OF PENETRATING CERCARIAE ONE CERCARIA DEVELOPS TO ONE MALE OR FEMALE ADULT WORM ACCORDING TO ITS SEX CHROMOSOMES -ULTIPLICATION IN THE DEFINITIVE HOST CONSISTS SOLELY OF THE PRODUCTION OF EGGS 4HESE MUST FIND THEIR WAY INTO WATER IN ORDER TO DEVELOP FURTHER
&IGURE ,IGHT MICROGRAPH OF A COUPLE OF 3CHISTOSOMA MANSONI &IGURE 3CANNING ELECTRON MICROGRAPH OF A COUPLE OF 3 MANSONI &IGURE ,IGHT MICROGRAPH OF A SECTION THROUGH A LIVER GRANULOME DUE TO A CENTRALLY LOCATED EGG OF 3 MANSONI &IGURE %NDOSCOPY OF THE INNER SURFACE OF A HUMAN BLADDER SHOWING MANY GRANULOMAS DUE TO PROTRUDING EGGS OF 3CHISTOSOMA HAEMATOBIUM &IGURE SEE P &IGURE ,IGHT MICROGRAPH OF A LARVA OF HOOKWORMS &IGURE 'IEMSA STAINED MICROFILARIA FROM BLOOD SMEAR &IGURE !DULT OF !RMILLIFER ANNULATUS &IGURE ! ANNULATUS SCANNING ELECTRON MICROGRAPH OF THE ANTERIOR END WITH MOUTH HOOKS
!CHIM (ARDER AND (EINZ -EHLHORN
!N INCUBATION PERIOD IS DEFINABLE ONLY IF A HOST IS SIMULTANEOUSLY INFEST ED WITH NUMEROUS CERCARIAE 0ENETRATION BY THE CERCARIAE MAY LEAD SHORTLY AFTERWARDS TO CERCARIAL DERMATITIS FOLLOWED A FEW WEEKS LATER BY THE FEBRILE SYSTEMIC DISORDER KNOWN AS +ATAYAMA SYNDROME
%PIDEMIOLOGY 7HILE 3 INTERCALATUM IS ALMOST EXCLUSIVELY A HUMAN PARASITE 3 MANSONI ALSO OCCURS IN A NUMBER OF RODENT SPECIES TOO !LSO THE FORM OF SCHISTOSOMIASIS CAUSED BY 3 JAPONICUM IS A ZOONOSIS WITH CATTLE BUFFALO PIGS RODENTS ETC AS DEFINITIVE HOSTS )N THE CASE OF 3 MEKONGI DOGS AND PIGS ACT AS AN ANIMAL RESERVOIR !NYONE LIVING IN ENDEMIC AREAS WITH OCCUPATIONAL CONTACT WITH WATER EG RICE GROWING LAUNDRY WORK IS EXPOSED TO THE RISK OF 3CHISTOSOMA INFECTION 3IMILARLY ANYONE TRAVELLING TO THE TROPICS IS AT RISK OF CONTRACTING SCHISTOSOMIASIS WHEN SWIMMING OR COMING INTO CONTACT IN SOME OTHER WAY WITH INFECTED WATERS 3CHISTOSOMIASIS CAN ONLY OCCUR IN REGIONS IN WHICH THE VECTOR SNAILS LIVE AND 3CHISTOSOMA EGGS PASS INTO WATERS WITH FAECES ANDOR URINE 4HIS IS THE CASE IN OVER COUNTRIES IN HOT REGIONS )T IS ESTIMATED THAT WAY OVER MILLION PEOPLE ARE INFECTED WORLDWIDE IN !FRICA AND THE -IDDLE %AST WITH 3 HAEMATOBIUM THIS SPECIES DOES NOT AFFECT THE LIVER BUT THE URINARY TRACT OR 3 MANSONI IN ,ATIN !MERICA WITH 3 MANSONI IN #HINA AND THE 0HILIPPINES WITH 3 JAPONICUM IN ,AOS AND #AMBODIA WITH 3 MEKONGI AND IN TROPICAL !FRICA WITH 3 INTERCALATUM
$ISEASES AND SYMPTOMS 4HE SIGNS AND SYMPTOMS OF SCHISTOSOMIASIS BILHARZIASIS VARY ACCORDING TO THE SPECIES AND THE DURATION OF THE DISEASE THOUGH ALL ARE DIRECTLY OR INDIRECTLY A CONSEQUENCE OF MANS IMMUNE RESPONSE TO THE PARASITES DIF FERENT STAGES !CUTE SCHISTOSOMIASIS !CUTE SCHISTOSOMIASIS IS CHARACTERISED BY A TOXAEMIC PHASE INCLUDING FEVER DIARRHOEA EXHAUSTION AND OTHER NON SPECIFIC SYMPTOMS @+ATAYAMA SYNDROME AS A RESULT OF PASSAGE OF THE LARVAE OF 3 JAPONICUM THROUGH THE LUNG AND THEIR RAPID GROWTH IMMUNE RESPONSE TO METABOLIC PRODUCTS IN THE MESENTERIC VEINS &ORMATION OF LARGE GRANULOMAS &IG IS FOUND AROUND EGGS THAT ARE DEPOSITED IN THE CAPILLARIES PARTICULARLY LIVER INTES TINE BLADDER ,EUKOCYTOSIS WITH MARKED EOSINOPHILIA )N MILD INFECTIONS AND ALSO IN TOURISTS EARLY SYMPTOMS EITHER DO NOT OCCUR OR REMAIN UNREC OGNISED
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
#HRONIC SCHISTOSOMIASIS !LL SYMPTOMS ARE A DIRECT OR INDIRECT CONSEQUENCE OF THE GRANULOMATOUS REACTION TO THE PARASITE EGGS &IGS AND 4HOUGH THE GRANULOMAS ARE SMALLER IN THE CHRONIC STAGE THAN IN THE ACUTE STAGE IMMUNOMODULATION THE QUANTITY OF EGGS IE OF WORM PAIRS AND THE DURATION OF THE INFECTION MANY YEARS OR EVEN LIFELONG WITHOUT TREATMENT DETERMINE THE COURSE OF THE DISEASE )N ENDEMIC AREAS BILHARZIASIS IS RELATIVELY RARELY FATAL BUT OFTEN CAUSES INFIRMITY -ILD INFECTIONS ARE NOT THREATENING ! DISTINCTION IS MADE BETWEEN URINARY AND INTESTINAL SCHISTOSOMIASIS DEPENDING ON THE SITE OF THE WORMS AND THE ORGANS IN WHICH THE EGGS ARE DEPOSITED &IG )NTESTINAL SCHISTOSOMIASIS )NTESTINAL SCHISTOSOMIASIS IS CAUSED BY THE EGGS OF 3 MANSONI 3 JAPONICUM 3 MEKONGI AND 3 INTERCALATUM THAT ARE DEPOSITED PRIMARILY IN THE INTESTINE AND THE LIVER &IG OR ARE EXCRETED WITH THE STOOLS 4HE GRANULOMATOUS INFLAMMATORY REACTION AROUND THE EGGS LEADS IN THE LARGE INTESTINE IN PAR TICULAR TO MUCOSAL HYPERAEMIA ULCERATION AND LATER ALSO GRANULOMATOUS PROLIFERATION AND BLEEDING /F EVEN GREATER SIGNIFICANCE WITH THE FIRST TWO OF THE AFOREMENTIONED SPECIES HOWEVER IS THAT THE LIVER IS DAMAGED BY GRANU LOMAS THAT FORM AROUND EGGS THAT ARE CARRIED VIA THE BLOODSTREAM TO THE PRESINUSOIDAL BIFURCATIONS OF THE PORTAL VEIN #HRONIC PHLEBITIS PERIPORTAL FIBROSIS AND FINALLY @PIPESTEM FIBROSIS DEVELOP AS A RESULT OF THE GRANULOMAS IN THE LIVER %VEN THOUGH THE PERIPORTAL FIBROSIS DOES NOT AFFECT THE HEPATIC PARENCHYMA BETWEEN AREAS OF FIBROSIS AND DOES NOT INTERFERE WITH ITS FUNC TIONING IT NEVERTHELESS LEADS TO PORTAL HYPERTENSION #ONSEQUENCES OF THIS MAY BE AS FOLLOWS FORMATION OF ASCITES PARTICULARLY WITH 3 JAPONICUM OESOPHAGEAL VARICES AND HEPATOSPLENOMEGALY 7ORM EGGS MAY ULTIMATELY PASS VIA PORTOSYSTEMIC COLLATERALS INTO THE LUNG AND LEAD TO PULMONARY HYPERTENSION AND COR PULMONALE 4HE SIGNS AND SYMPTOMS ASSOCIATED WITH INTESTINAL SCHISTOSOMIASIS RANGE FOR EXAMPLE FROM EXHAUSTION AND ABDOMI NAL PAIN VIA DIARRHOEA WITH LOSS OF BLOOD AND PROTEIN THROUGH TO MASSIVE VARICEAL BLEEDING AS A CAUSE OF DEATH #HRONIC INTESTINAL SCHISTOSOMIASIS PER SISTS FOR YEARS AND ITS SEVERITY DEPENDS ON THE INTENSITY AND DURATION OF THE INFESTATION /VERALL IT CONSTITUTES A DISEASE THAT IS TRIGGERED BY THE IMMUNE RESPONSE IN HUMANS TO THE WORM EGGS
)MMUNE RESPONSE 2ESPONSES IN THE HOST TAKE THE FORM OF FORMATION OF )G' )G! )G- AND )G% ACTIVATION OF VARIOUS IMMUNOCOMPETENT CELL POPULATIONS AND CIRCULATION OF IMMUNE COMPLEXES 4HE PARASITE PROTECTS ITSELF BY MIMICRY OF HOST PROTEIN AND BY PROTEASES THAT LEAD TO INACTIVATION OF ANTIBODIES AND COMPLEMENT FACTORS )MMUNE PROCESSES AT THE SCHISTOSOMULA STAGE MAY HOWEVER ALSO PROTECT AGAINST RE INFECTION AND SUPERINFECTION
!CHIM (ARDER AND (EINZ -EHLHORN
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS $IFFERENTIAL DIAGNOSES FOR BOTH INTESTINAL AND URINARY SCHISTOSOMIASIS ARE VARIOUS DISEASES OF OTHER ORIGIN EG +ATAYAMA SYNDROME NEEDS TO BE DISTIN GUISHED FROM PARATYPHOID FEVER AND TYPHOID FEVER &URTHERMORE A NUMBER OF PARASITIC AND OTHER INFECTIONS NEED TO BE EXCLUDED BOTH IN THE ACUTE AND THE CHRONIC PHASE OF THE DIFFERENT FORMS OF SCHISTOSOMIASIS $IRECT DETECTION IN SMEARS SEDIMENT OR AFTER CONCENTRATION TAKES PLACE BY MEANS OF MICROSCOPIC EXAMINATION OF STOOLS OR URINE FOR SCHISTOSOME EGGS THE SHAPE OF WHICH IS SPECIES SPECIFIC ! H URINE SPECIMEN OR SEVERAL GRAMS OF STOOL MAY BE NECESSARY FOR THIS PURPOSE 3TOOL MAY CON TAIN THE EGGS OF 3 MANSONI n = n +M WITH LATERAL SPINE 3 INTERCALATUM n = n +M WITH TERMINAL SPINE 3 JAPONICUM n = n +M WITH A SMALL SIZED SPINE AND 3 MEKONGI n = n +M WITH A SMALL SIZED SPINE 1UANTITATIVE METHODS ML URINE FILTRATE STOOL SMEAR USING THE +ATO +ATZ METHOD ARE EPIDEMIOLOGICALLY IMPOR TANT 7HERE VERY FEW EGGS ARE EXCRETED THE MIRACIDIUM HATCHING TEST HAS PROVED SUCCESSFUL 4HIS INVOLVES PLACING THE MIRACIDIA PRESENT IN THE EGGS IN A FLASK TO HATCH "ECAUSE OF THEIR POSITIVE PHOTOTAXIS THESE THEN MIGRATE INTO AN ILLUMINATED ATTACHED SIDE ARM OF THE FLASK FROM WHICH THEY CAN BE REMOVED $ETECTION OF ANTISCHISTOSOMAL ANTIBODIES IN THE SERUM BY INDIRECT IMMUNOFLUORESCENCE INDIRECT HAEMAGGLUTINATION ANDOR %,)3! !LL TESTS ARE GENERALLY BASED ON ANTIGEN PREPARATIONS WORMS OR EGGS OF 3 MANSONI AND CROSS REACT WITH OTHER 3CHISTOSOMA SPECIES %VALUATION OF TITRE STEPS AND POSSIBLE CROSS REACTIONS WITH OTHER PARASITOSES SHOULD BE PERFORMED BY INSTITUTES OF PARASITOLOGY OR TROPICAL MEDICINE 4ESTS FOR CIRCULATING 3CHISTOSOMA ANTIGENS IN SERUM ARE LIKEWISE SUITABLE FOR THE DETECTION OF SCHISTOSOMIASIS
4REATMENT 0RAZIQUANTEL "ILTRICIDE IS THE DRUG OF CHOICE AGAINST ALL 3CHISTOSOMA SPECIES 4HE DOSAGE IS X MGKG BODY WEIGHT "7 3 JAPONICUM OR = MGKG "7 ALL OTHER SPECIES ADMINISTERED ORALLY IN ONE DAY 3IDE EFFECTS IF THEY OCCUR AT ALL ARE ONLY MINOR POSSIBLE EXCEPTIONS MASSIVE INFECTIONS AND CEREBRAL SCHISTOSOMIASIS -ETRIFONATE "ILARZIL AND OXAMNIQUINE -ANSIL ARE ALSO USED IN SOME ENDEMIC AREAS ALTHOUGH THESE ARE EFFECTIVE ONLY AGAINST 3 HAEMATOBIUM AND 3 MANSONI RESPEC TIVELY
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
2ESISTANCE 4HE EFFICACY OF PRAZIQUANTEL AGAINST 3 MANSONI IS REDUCED TO A VARYING DEGREE IN DIFFERENT !FRICAN COUNTRIES AS A RESULT OF DEVELOPMENT OF WRONG USE 4RUE RESISTANCE HAS NOT YET BEEN SHOWN
0REVENTION !VOIDANCE OF SKIN CONTACT WITH CONTAMINATED WATERS RELIABLY PROTECTS AGAINST INFECTION /THER PROPHYLACTIC MEASURES VACCINATION CHEMOPROPHY LAXIS ARE NOT AVAILABLE
3TRATEGIES FOR DISEASE PREVENTION AND CONTROL )NDIVIDUAL PROPHYLAXIS INVOLVES AVOIDANCE OF SKIN CONTACT WITH CONTAMI NATED WATERS RIVERS LAKES PONDS RICE FIELDS IRRIGATION SYSTEMS )N HIGHLY ENDEMIC AREAS MASS TREATMENT OR SELECTIVE TREATMENT OF INFECT ED PERSONS WITH PRAZIQUANTEL IS INDICATED IN ADDITION TO HEALTH EDUCATION MEASURES AND PROPER DISPOSAL OF HUMAN EXCREMENT 5SE OF MOLLUSCICIDES FOR INTERMEDIATE HOST CONTROL IS POSSIBLE ONLY IN LIMITED AREAS
(EPATITIS CAUSED BY NEMATODES #APILLARIASIS #APILLARIA HEPATICA ; = /THER NAME OF THE AGENT OF DISEASE .O OTHER SPECIFIC NAME DISEASE HEPATIC CAPILLARIASIS
4AXONOMY 3UBREGNUM 0HYLUM #LASS 3UBCLASS /RDER &AMILY 'ENUS
!NIMALIA .EMATOZOA .EMATODES !DENOPHOREA 4RICHOCEPHALIDA #APILLARIDAE #APILLARIA
-ORPHOLOGY 4HE PATHOGEN IS #APILLARIA HEPATICA A NEMATODE AS SLENDER AS A HUMAN
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Achim Harder and Heinz Mehlhorn
Figure 30. Light micrograph of a section showing a layer of eggs in the liver
hair, measuring up to approximately 10 cm in length in the adult stage, with marked hepatotropism.
Epidemiology The parasite is prevalent worldwide and its principal hosts are rodents, predominantly rats, in which prevalence rates may be as high as 80% or more. Infection in humans is rare. Approximately 40 confirmed cases, in total, have been reported in North and South America, Africa, Asia and Central Europe, although it is likely that a number of cases remained unreported.
Transmission, multiplication and incubation period Humans are infected by oral ingestion of the parasite’s embryonated (larvacontaining) eggs.
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
# HEPATICA PARASITISES THE HEPATIC PARENCHYMA WITHIN WHICH IT MIGRATES !T THE SAME TIME THE ADULT FEMALE WORMS LAY CHARACTERISTIC EGGS WITH POLAR PLUGS &IG 4HE EGGS WHICH ARE DEPOSITED IN THE BORE HOLES AND ARE LATER ENCAPSULATED IN TUBULAR GRANULOMAS REACH THE OUTSIDE WORLD ONLY BY MEANS OF MACERATION ON THE DEATH OF THE HOST OR IF INFECTED ANIMALS SERVED AS PREY VIA THE DIGESTIVE TRACT OF THE PREDATOR CANNIBALISM ALSO PLAYS A ROLE IN THE CASE OF RATS /NCE IN THE OPEN AN INFECTIVE LARVAL STAGE DEVELOPS INSIDE THE EGG AND THIS IS THEN INGESTED BY HUMANS WITH CONTAMINATED FOOD 4HE LARVA HATCHES FROM THE EGG MEMBRANE IN THE INTESTINE MIGRATES THROUGH THE INTESTINAL WALL AND PASSES VIA THE BLOODSTREAM TO THE LIVER 3EXUAL MATU RITY AND HENCE COMMENCEMENT OF EGG LAYING ARE ATTAINED AFTER n WEEKS PREPATENT PERIOD
$ISEASES AND SYMPTOMS 4HERE ARE ONLY RARE CASES OF DISEASE CAUSED BY SINGLE FEW LIVER SPECIFIC ROUNDWORMS WHILE SERIOUS CONSEQUENCES OCCUR IN THE EVENT OF MASSIVE INFECTIONS 4HE CLINICAL PRESENTATION DEPENDS ON THE BURDEN OF INFECTION ,IGHT INFECTION OCCASIONALLY REPORTED AS A POST MORTEM FINDING WOULD APPEAR TO BE ASYMPTOMATIC )N HEAVY INFECTIONS WHICH IN CHILDREN MAY PROVE FATAL AN ACUTE COURSE IS TO BE EXPECTED AT AROUND THE COMMENCEMENT OF EGG LAYING THESE SYMPTOMS REFLECTING THE DESTRUCTION OF LARGE AREAS OF LIVER PARENCHYMA )N SUCH CASES UNEXPLAINED EXTRAHEPATIC SYMPTOMS EG LUNG DISORDERS HAVE BEEN DESCRIBED IN THE PATHOGENESIS -ODERATE INFECTIONS ARE ASSOCIATED WITH UNCHARACTERISTIC UPPER ABDOMINAL PAIN AND HEPATOMEGALY ,EUCOCYTOSIS EOSINOPHILIA AND HYPERGAMMAGLOBULINAEMIA REGULARLY OCCUR
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS &OCAL OR DISSEMINATED DAMAGE TO THE LIVER PARENCHYMA OF DIVERSE ORIGIN 7ORM NODULES WITH CONVOLUTED PARASITES ANDOR EGG STRINGS ENCAPSULATED IN GRANULOMAS ARE OFTEN TO BE FOUND IN THE SUBCAPSULAR REGION AND ARE LAPA ROSCOPICALLY DETECTABLE )N PATENT INFECTIONS THE DIAGNOSIS CAN BE CONFIRMED BY BIOPSY REVEALING EGGS MEASURING = +M WITH POLAR PLUGS &IG 4HERE ARE NO SEROLOGICAL METHODS AVAILABLE
4REATMENT -EBENDAZOLE IS EFFECTIVE ACCORDING TO FINDINGS IN ANIMAL EXPERIMENTS
!CHIM (ARDER AND (EINZ -EHLHORN
0ROPHYLAXIS !VOID CONTAMINATED FOODS KEEP CHILDREN AWAY FROM AREAS POPULATED BY RATS
,ARVA MIGRANS DISEASE -IGRATING NEMATODES ; = -IGRATING LARVAE OR ADULTS OFTEN PASS VIA THE BLOODSTREAM FROM THE INTES TINE TO THE LIVER 4HESE PARASITES HAVE LEFT THE INTESTINE AND ARE EN ROUTE TO OBLIGATORY PASSAGE THROUGH THE HEART AND LUNGS DURING WHICH THEY MAY BE CARRIED OFF VIA THE BLOODSTREAM TO OTHER ORGANS )F THE LARVAE ARE UNABLE TO REACH SEXUAL MATURITY IN HUMANS MIGRATION CONTINUES UNTIL THEIR DEATH n MONTHS 4HE FOLLOWING NEMATODES HAVE BEEN DETECTED QUITE COMMONLY IN THE LIVER LARVA MIGRANS VISCERALIS
!SCARIS LUMBRICOIDES , LARVA AND ADULT
3TRONGYLOIDES STERCORALIS LARVAE
(OOKWORM LARVAE &IG
4OXOCARA CANIS LARVAE
-ICROFILARIAE OF VARIOUS FILARIAE &IG
4REATMENT !FTER INVASION INTO THE BILIARY SYSTEM ENDOSCOPIC EXTRACTION OF ! LUM BRICOIDES LARVAE CAN BE TRIED BEFORE SURGICAL INTERVENTION &OR REMOVAL OF 3TRONGYLOIDES STERCORALIS LARVAE THE BENZIMIDAZOLES ALBENDAZOLE THIABEN DAZOLE OR MEBENDAZOLE CAN BE APPLIED !LSO THE MACROCYCLIC LACTONE SEEMS TO BE EFFECTIVE !GAINST HOOKWORM LARVAE MEBENDAZOLE AND ALBENDAZOLE MAY BE USED &OR INFECTIONS WITH 4OXOCARA CANIS LARVAE THIABENDAZOLE X MGKG BODY WEIGHT DAILY OVER n DAYS ALBENDAZOLE MGKG BODY WEIGHT OVER DAYS OR DIETHYLCARBAMAZINE ARE RECOMMENDED -ICROFILARIAE OF VARIOUS FILARIAE CAN BE TREATED WITH DIETHYLCARBAMAZINE WITH A TOTAL ORAL DOSE OF MGKG BODY WEIGHT GIVEN OVER n WEEKS !LSO IVERMECTIN AT A SINGLE SUBCUTANEOUS DOSE OF MGKG BODY WEIGHT MAY BE TRIED
0ENTASTOMIDIASIS 0ENTASTOMIDA ; = /THER NAMES OF THE AGENTS OF DISEASE 4ONGUE WORMS ,INGUATULIDAE
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
4AXONOMY 0HYLUM #LASS /RDER &AMILY 'ENUS
0ENTASTOMIDA 0ENTASTOMIDEA 0OROCEPHALIDA !RMILLIFERIDAE !RMILLIFER ,INGUATULA 0OROCEPHALUS
"IOLOGYMORPHOLOGY 4HE ADULTS OF THE GENERA ,INGUATULA !RMILLIFER AND 0OROCEPHALUS LIVE IN THE NASOPHARYNX AND LUNGS OF CARNIVOROUS VERTEBRATES ,INGUATULA SERRATA ALSO IN HUMANS &IGS AND , SERRATA FEMALES ARE UP TO CM LONG MALES UP TO CM LONG AND ARE FOUND MAINLY IN DOGS !RMILLIFER SPECIES REACH A SIM ILAR SIZE 0OROCEPHALUS SPECIES ARE NOT MORE THAN CM LONG 4HE EGGS WHICH MEASURE ABOUT = +M ,INGUATULA OR +M IN LENGTH !RMILLIFER LEAVE THE BODY WITH THE NASAL MUCUS AT THE TIME OF SHEDDING THEY ALREADY CONTAIN A FIRST STAGE LARVA )F THESE EGGS ARE INGESTED BY HERBIVORES OR BY HUMANS THE LARVAE PENETRATE THE GUT WALL AND MIGRATE TO VARIOUS ORGANS INCLUDING LIVER LUNG WHERE THEY UNDERGO SEVERAL MOULTS AND GROW TO A SIZE OF n MM ,INGUATULA SERRATA OR n MM !RMILLIFER ARMILLATUS )F THIS INTERMEDIATE HOST IS EATEN BY A CARNIVORE THE LARVAE BECOME SEXUALLY MATURE IN ITS NASOPHARYNX AFTER UNDERGOING A FURTHER MOULT AND THE FEMALES BEGIN TO LAY THE SOMETIMES PRODIGIOUS NUMBERS OF EGGS AS MANY AS PER DAY
4RANSMISSION MULTIPLICATION AND INCUBATION PERIOD 4HERE ARE VARIOUS ROUTES OF INFECTION IN MAN (UMANS LIKE HERBIVORES CAN BECOME INFECTED BY INGESTING EGGS CONTAINING LARVAE WITH THEIR FOOD 4HE LARVAE THEN HATCH AND MIGRATE THROUGH THE BODY OFTEN INVADING THE LUNG AND LIVER 4HIS ROUTE OF INFECTION PLAYS A PARTICULAR ROLE IN !FRICAN AND !SIAN COUNTRIES AS IN THESE COUNTRIES HUMANS RELATIVELY OFTEN BECOME INFECTED WITH EGGS OF PENTASTOMES OF THE GENERA !RMILLIFER AND 0OROCEPHALUS THE DEFINITIVE HOSTS OF WHICH ARE SNAKES WHEN HANDLING SNAKES AND CONTAMI NATED PLANTS OR PREPARING THEM FOR COOKING AND THEN BECOME THE INTERMEDI ATE HOST "Y INGESTION OF LARVAE WITH INSUFFICIENTLY COOKED OR RAW MEAT FROM INFECTED INTERMEDIATE HOSTS )N THE CASE OF , SERRATA THESE CAN EVEN BECOME SEXUALLY MATURE IN THE NASOPHARYNX )NCUBATION PERIOD $EPENDS ON THE STAGE OF INFECTION !FTER CONSUMPTION OF LARVA INFECTED MEAT THE PRE ADULT WORMS LEAD TO LOCAL REACTIONS WITHIN A FEW DAYS )F TISSUE
!CHIM (ARDER AND (EINZ -EHLHORN
STAGES OCCUR IT CAN BE n MONTHS BEFORE THE MIGRATING LARVAE CAUSE DAMAGE AND SYMPTOMS 0REPATENT PERIOD n MONTHS IN THE CASE OF ,INGUATULA 0ATENT PERIOD MONTHS IN THE CASE OF ,INGUATULA RARELY LONGER
%PIDEMIOLOGY ,INGUATULA SERRATA OCCURS WORLDWIDE SPECIES OF THE GENERA !RMILLIFER AND 0OROCEPHALUS ARE FOUND IN !FRICA AND !SIA
$ISEASES AND SYMPTOMS 4HE FOLLOWING SYMPTOMS CAN OCCUR DEPENDING ON WHETHER THE PERSON IS INFECTED AS AN INTERMEDIATE OR DEFINITIVE HOST -OST INFECTIONS OCCUR IN THE NASAL REGION BY ADULTS OF , SERRATA AND LEAD TO THE SYNDROME KNOWN AS HAL ZOUN 4HE NASAL PASSAGES CAN BECOME COMPLETELY BLOCKED )N ADDITION THERE IS DEAFNESS AND FACIAL SWELLING )F THERE IS PRONOUNCED SNEEZING THESE ADULTS CAN BE EXPELLED SPONTANEOUSLY )NFECTION OF THE ABDOMINAL ORGANS AMONG THEM THE LIVER BY !RMILLIFER ARMILLATUS WITH THE SOMETIMES VERY LARGE LARVAE LEADS TO UNSPECIFIC SYMP TOMS CAUSED BY THE BORING ACTIVITY OF THE MIGRATING LARVAE $EPENDING ON THE LOCATION OF THE DAMAGE THIS CAN LEAD TO THE DEATH OF THE INFECTED PERSON AS HAS BEEN OBSERVED IN NUMEROUS AUTOPSIES IN !FRICA
$IFFERENTIAL DIAGNOSIS AND DIAGNOSIS -ICROSCOPIC DETECTION OF THE EGGS IN NASAL SECRETIONS OR FINDING OF SPONTA NEOUSLY PASSED WORMS IN THE CASE OF ,INGUATULA (ISTOLOGICAL DETECTION OF LARVAE LOCATED IN THE TISSUES $IFFERENTIATION FROM OTHER WORM EGGS
0ROPHYLAXIS !VOIDING TOUCHING SNAKES AND DOGS OR THEIR FAECES PARTICULARLY IN SUBTROPI CAL AND TROPICAL REGIONS !VOIDING INFECTION OF ONESELF AND OF ONES DOG BY EATING ONLY COOKED MEAT 4RAINING DOGS NOT TO EAT RODENTS
#OMPARATIVE HEPATITIS $ISEASES CAUSED BY ADULT PARASITESx
4REATMENT 5NKNOWN 7ORMS IN THE NASAL REGION CAN BE REMOVED BY PROVOCATION OF SNEEZING OR BY SURGICAL PROCEDURES
2EFERENCES
,ANG 7 ,ÚSCHER 4 4ROPENMEDIZIN IN +LINIK UND 0RAXIS 'EORG 4HIEME 6ERLAG 3TUTTGART 7(/ !MOEBIASIS 7EEKLY %PIDEMIOLOGICAL 2ECORD n #OOK '# -ANSONS 4ROPICAL $ISEASES TH %DITION 7" 3AUNDERS #OMPANY ,TD 0HILADELPHIA 2AVDIN *) !MEBIASIS n 3TATE OF THE ART CLINICAL ARTICLE #LIN )NFECT $IS n -EHLHORN ( ED %NCYCLOPEDIA OF 0ARASITOLOGY "IOLOGY 3TRUCTURE &UNCTION $ISEASES 4REATMENT 4HERAPY 4HIRD %DITION 3PRINGER (EIDELBERG .EW 9ORK -EHLHORN ( %ICHENLAUB $ ,ÚSCHER 4 0ETERS 7 $IAGNOSTIK UND 4HERAPIE DER 0ARASITOSEN DES -ENSCHEN !UFLAGE 'USTAV &ISCHER 6ERLAG 3TUTTGART "RYCESON !$- ,EISHMANIASIS )N *'' ,EDINGHAM $! 7ARRELL EDS #ONCISE /XFORD 4EXTBOOK OF -EDICINE /XFORD 5NIVERSITY 0RESS /XFORD n $AVIDSON 2( ,EISHMANIASIS )N $ !RMSTRONG * #OHEN EDS )NFECTIOUS $ISEASES 6OL -OSBY ,ONDON n (ARMS :WINGENBERGER ' "IENZLE 5 ,EISHMANIOSEN )N 7 ,ANG 4 ,ÚSCHER EDS 4ROPENMEDIZIN IN +LINIK UND 0RAXIS RD EDITION 'EORG 4HIEME 6ERLAG 3TUTTGART n 'ERMAN 3OCIETY OF 4ROPICAL -EDICINE $4' RECOMMENDATION FOR MALAR IA PROPHYLAXIS 4HOMPSON 2#! ,YMBERY !* %CHINOCOCCUS AND (YDATIDE $ISEASE #!" )NTERNATIONAL 7ALLINGFORD 5+ 7(/ )NFORMAL 7ORKING 'ROUP ON %CHINOCOCCOSIS 'UIDELINES FOR TREAT MENT OF CYSTIC AND ALVEOLAR ECHINOCOCCOSIS IN HUMANS "ULLETIN OF THE 7ORLD (EALTH /RGANIZATION n 7(/ !RBEITSGRUPPE ZUR %CHINOKOKKOSE 2ICHTLINIEN ZUR "EHANDLUNG DER ZYSTISCHEN UND ALVEOLËREN %CHINOKOKKOSE BEIM -ENSCHEN #HEMOTHER * n 0AWLOWSKI :3 %CKERT * 6UITTON $! !MMANN 27 +ERN 0 #RAIG 03 $AR +& $E 2OS & &ILICE # 'OTTSTEIN " ET AL %CHINOCOCCOSIS IN (UMANS )N 7(//)% -ANUAL ON %CHINOCOCCOSIS IN (UMANS AND !NIMALS 7(/ 'ENEVA n +ERN 0 2EUTER 3 "UTTENSCHOEN + +RATZER 7 $IAGNOSTIK DER ZYSTISCHEN %CHINOKOKKOSE $EUTSCHE -EDIZINISCHE 7OCHENSCHRIFT n +ERN 0 2EUTER 3 +RATZER 7 "UTTENSCHOEN 4HERAPIE DER ZYSTISCHEN %CHINOKOKKOSE $EUTSCHE -EDIZINISCHE 7OCHENSCHRIFT n $ARAI ' (ANDERMANN - (INZ % 3ONNTAG (' ,EXIKON DER
!CHIM (ARDER AND (EINZ -EHLHORN
)NFEKTIONSKRANKHEITEN DES -ENSCHEN %RREGER 3YMPTOME $IAGNOSE 4HERAPIE UND 0ROPHYLAXE !UFLAGE 3PRINGER (EIDELBERG +ERN 0 2EUTER 3 "UTTENSCHOEN + +RATZER 7 !LVEOLËRE %CHINOKOKKOSE $IAGNOSTIK $EUTSCHE -EDIZINISCHE 7OCHENSCHRIFT n +ERN 0 2EUTER 3 +RATZER 7 "UTTENSCHOEN !LVEOLËRE %CHINOKOKKOSE 4HERAPIE $EUTSCHE -EDIZINISCHE 7OCHENSCHRIFT n -EHLHORN ( %CKERT * 4HOMPSON 2#! 0ROLIFERATION AND METASTASES FORMATION OF LARVAL %CHINOCOCCOSIS MULTILOCULARIS )) 5LTRASTRUCTURAL INVESTIGA TIONS 0ARASITOL 2ES n -àLLER " -EHLHORN ( 3CHMIDT * 0#2 DIAGNOSIS OF INFECTIONS WITH DIF FERENT SPECIES OF /PISTHORCHIIDAE USING A RAPID CLEAN UP PROCEDURE FOR STOOL SAMPLES AND SPECIFIC PRIMERS 0ARASITOL 2ES n -àLLER " -EHLHORN ( 3CHMIDT * 3ENSITIVE AND SPECIES SPECIFIC DETEC TION OF #LONORCHIS SINENSIS BY 0#2 IN INFECTED SNAILS AND FISHES 0ARASITOL 2ES n "EAVER 0# *UNG 2# #UPP %7 #LINICAL 0ARASITOLOGY TH %DITION ,EA AND &EBIGER 0HILADELPHIA $ESPOMMIER $$ 'WADZ 27 (OTEZ 0* 0ARASITIC $ISEASES RD %DITION 3PRINGER 6ERLAG .EW 9ORK
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
!UTOIMMUNE HEPATITIS IN HUMANS 3TEFAN ,àTH AND !NSGAR 7 ,OHSE ) $EPARTMENT OF -EDICINE 5NIVERSITY -EDICAL #ENTER (AMBURG %PPENDORF -ARTINISTR (AMBURG 'ERMANY
!BSTRACT !UTOIMMUNE HEPATITIS !)( CAN OCCUR IN ALL AGE GROUPS FROM EARLIEST CHILDHOOD UP UNTIL THE TH DECADE !)( AFFECTS WOMEN MORE COMMONLY THAN MEN #LINICAL PRESENTATION MAY BE AN ACUTE HEPATITIS UP TO FULMINANT LIVER FAILURE BUT CAN ALSO BE ASYMPTOMATIC !)( IS CHARACTERISED BY LYMPHO PLASMACELLULAR INFILTRATES ON LIVER BIOPSY ELEVATED LIVER ENZYMES IN SERUM AND ASSOCIATION WITH THE (,! HAPLOTYPES " $2 AND $2 IN THE ABSENCE OF ACTIVE VIRAL MARKERS 0ATIENTS CHARACTERISTICALLY PRESENT WITH HYPERGAM MAGLOBULINEMIA ELEVATED SERUM LEVELS OF )G' AND AUTOANTIBODIES SUCH AS ANTINUCLEAR ANTIBODIES !.! SMOOTH MUSCLE ANTIBODIES 3-! ANTIBODIES TO SOLUBLE LIVER ANTIGEN LIVER PANCREAS 3,!,0 OR TO LIVER KIDNEY MICROSOMES ,+- #ORTICOSTEROIDS ARE THE DRUG OF CHOICE FOR REMISSION INDUCTION AZATHIOPRINE THE DRUG OF CHOICE FOR MAINTENANCE OF REMISSION 4HE RAPID RESPONSE TO IMMUNOSUPPRESSIVE TREAT MENT SUPPORTS THE DIAGNOSIS OF !)( AND LEADS TO A GOOD LONG TERM PROGNOSIS 4REATMENT DURATION REMAINS CONTROVERSIAL AND CAN BE DISCUSSED AFTER RESOLUTION OF ALL CLINICAL LABO RATORY AND HISTOLOGICAL MANIFESTATIONS OF DISEASE ACTIVITY 4REATMENT SHOULD BE MAINTAINED FOR A MINIMUM OF YEARS
!GENT !UTOIMMUNE HEPATITIS !)( IS A CHRONIC INFLAMMATORY DISORDER OF THE LIVER OF UNKNOWN ORIGIN ASSOCIATED WITH HYPERGAMMAGLOBULINAEMIA AND THE OCCURRENCE OF AUTOANTIBODIES ; = !S IN OTHER AUTOIMMUNE DISORDERS A GENETIC PREDISPOSITION OF THE HOST SUCH AS THE PRESENCE OF (,! #LASS ) " AND (,! #LASS )) $2 $2 AND $2A HAS BEEN FOUND ;= )N ADDITION UNKNOWN ENVIRONMENTAL TRIGGERS SUCH AS VIRAL OR BACTERIAL INFECTION OR DRUGS MAY THEN INDUCE AUTOIMMUNE HEPATITIS IN THE GENETICALLY PREDISPOSED HOST 4HE LOSS OF IMMUNE TOLERANCE TO SELF ANTIGENS MAY BE DUE TO THE RELEASE OF MODIFIED AND PRIMARILY SEQUESTERED NUCLEAR OR CYTOSOLIC PROTEINS WHICH ACTIVATE RESTING BUT NATURALLY OCCURRING AUTO REACTIVE 4 CELLS &OR EXAMPLE HEPATITIS # VIRUS HAS THE POTENTIAL TO INDUCE SUCH AUTO REACTIVE 4 CELLS THAT CROSS REACTIVELY RECOGNISE THE CYTOCHROME 0 ISOFORMS ! AND
3TEFAN ,àTH AND !NSGAR 7 ,OHSE
! WHICH CONTAIN SEQUENCE HOMOLOGY TO (#6 ;= 4HIS CROSS REACTIVITY BETWEEN FOREIGN AND SELF PROTEINS IS COMMONLY REFERRED TO AS @MOLECULAR MIMICRY 5P TO OF PATIENTS WITH CHRONIC (#6 INFECTION DISPLAY AUTOANTIBODIES DIRECTED AGAINST THE CYTOCHROME 0 $ #90$ ;= (OWEVER AUTOIMMUNE HEPATITIS IS ONLY EXTREMELY RARELY ASSOCIATED WITH VIRAL HEPATITIS 4HE #90$ HUMANISED MOUSE MODEL OF !)( EXPRESSES THIS HUMAN ANTIGEN IN THE LIVER AND SHOWS PERSISTENT HEPATITIS AFTER INFEC TION WITH AN !DENOVIRUS #90$ VECTOR ; = -OST OTHER ANIMAL MODELS OF !)( USED TRANSGENIC TARGET ANTIGENS EXPRESSED IN THE LIVER BUT COULD ONLY DEMONSTRATE TRANSIENT HEPATITIS ;n= 4HE PRINCIPAL EFFECTOR CELLS OF !)( ARE #$ AND #$ LYMPHOCYTES MAINLY FOUND IN THE PORTAL TRACTS AND #$ 4 LYMPHOCYTES MAINLY FOUND PERIPORTALLY ;= 4HE REPERTOIRE OF ANTIGENS THAT SENSITISE THESE CELLS SEEMS RESTRICTED )NFILTRATING #$ LYMPHOCYTES SHOW DEFECTS IN THEIR APOPTOTIC PATHWAY WHICH MIGHT BE RESPONSIBLE FOR THE PERPETUATION OF INFLAMMATION ;= #O STIMULATORY MOLECULES LIKE #$ ARE UPREGULATED ON LIVER INFILTRAT ING MONOCYTES IN !)( PATIENTS BUT NOT IN PATIENTS WITH CHRONIC (#6 INFEC TION ;= 2EGULATORY #$ #$ LYMPHOCYTES HAVE BEEN SHOWN TO INHIBIT #$ 4 CELL PROLIFERATION AND ARE DECREASED IN NUMBER AND FUNCTION IN !)( PATIENTS ;= )T HAS BEEN SPECULATED THAT !)( CAN BE TRIGGERED BY CERTAIN DRUGS ! RECENT REPORT ASSOCIATED STATINS USED IN THE TREATMENT OF HYPERCHO LESTERINEMIA WITH THE ONSET OF !)( ;= !LTHOUGH THE EXACT PATHOGENESIS IS NOT UNDERSTOOD YET DIAGNOSING !)( AND PROVIDING ADEQUATE TREATMENT IS EXTREMELY IMPORTANT FOR THE PATIENTS AFFECTED BY THE DISEASE !)( WAS THE FIRST LIVER DISEASE IN WHICH CONTROLLED TRIALS PROVED THE EFFICACY OF A THERAPEUTIC INTERVENTION CORTICOSTEROIDS AND IN WHICH TIMELY DIAGNOSIS AND ADEQUATE THERAPY IS LIFE SAVING AND CAN REVERSE DISEASE PRO GRESSION TO LIVER CIRRHOSIS RESULTING IN A NORMAL LIFE EXPECTANCY IN THE MAJOR ITY OF TREATED PATIENTS ;=
%PIDEMIOLOGY 4HE PREVALENCE OF !)( IS ESTIMATED AROUND n ;= !)( CAN MANIFEST AT ANY AGE FROM VERY EARLY CHILDHOOD UP UNTIL THE TH DECADE AND LIKE MANY OTHER AUTOIMMUNE DISEASES IT IS MORE COMMON IN WOMEN GENDER RATIO /VER OF THE PATIENTS DEVELOP !)( AFTER THE AGE OF YEARS ;= !S MANY AS OF THE PATIENTS PRESENT SUBCLINICALLY ; = LEADING TO DELAYED DIAGNOSIS 4HIS DELAY EXPLAINS THAT MANY PATIENTS ALREADY SHOW CIR RHOSIS AT PRESENTATION ; = 5P TO ONE THIRD OF PATIENTS MAY PRESENT WITH A VERY ACUTE DISEASE AND SOME EVEN WITH FULMINANT HEPATIC FAILURE THEREFORE !)( MUST BE CONSIDERED IN ALL PATIENTS WITH A FULMINANT PRESENTATION ;= !UTOIMMUNE HEPATITIS CAN BE ASSOCIATED WITH CONCURRENT IMMUNE DISEASES SUCH AS SYSTEMIC SCLEROSIS AND POLYMYOSITIS ;= MULTIPLEX NEURITIS ;= AND POLYGLANDULAR AUTOIMMUNE SYNDROME TYPE ))) ;=
!UTOIMMUNE HEPATITIS IN HUMANS
$IAGNOSIS !)( SHOULD BE CONSIDERED IN ANY PATIENT WITH ELEVATED LIVER ENZYMES -OST PATIENTS SHOW A SUBACUTE DISEASE PRESENTING WITH LETHARGY AND OFTEN JAUN DICE WITHOUT A RISK FACTOR FOR VIRAL HEPATITIS /THER CLINICAL SYMPTOMS MAY BE ARTHRALGIAS AND SLIGHT RIGHT UPPER QUADRANT PAIN
$IAGNOSTIC CRITERIA !UTOANTIBODIES ARE THE HALLMARKS OF AUTOIMMUNE HEPATITIS 4HERE IS WITH THE POSSIBLE EXCEPTION OF ANTI 3,!,0 ANTIBODIES NO SINGLE TEST THAT PROVES OR DISPROVES THE DIAGNOSIS OF !)( $IAGNOSIS IS THEREFORE BASED ON THE COM BINATION OF HISTORY CLINICAL EXAMINATION AND A NUMBER OF LABORATORY AND SEROLOGICAL VARIABLES 4HE KEY FEATURES FOR MAKING A DIAGNOSIS OF !)( ARE
HYPERGAMMMAGLOBULINAEMIA WITH A PREFERENTIAL INCREASE OF )G'
DEMONSTRATION OF AUTOANTIBODIES !.! 3-! 3,!,0 ,+-
ABSENCE OF VIRAL HEPATITIS
PORTAL HEPATITIS WITH LYMPHOPLASMACELLULAR INFILTRATES ON HISTOLOGY !DDITIONAL FEATURES MAY BE FURTHER SUPPORTIVE
A PERSONAL OR FAMILY HISTORY OF OTHER AUTOIMMUNE DISEASE
A HISTORY OF A SPONTANEOUSLY FLUCTUATING COURSE
ARTHRALGIAS
PRESENCE OF (,! $2 OR $2 4HE USUALLY VERY PROMPT RESPONSE TO IMMUNOSUPPRESSSION PROVES THE DIAG NOSIS
3CREENING TESTS $IAGNOSIS OF !)( CONSISTS OF THE EXCLUSION OF LIVER DISEASES OF OTHER ORIGIN 6IRAL HEPATITIS " AND # SHOULD BE RULED OUT BY TESTING FOR ("S!G AND ANTI (#6 !LCOHOL CONSUMPTION INTAKE OF HEPATOTOXIC MEDICATION AND HEREDITARY LIVER DISEASES 7ILSON DISEASE HAEMOCHROMATOSIS ALPHA ANTITRYPSIN DEFICIEN CY SHOULD BE EXCLUDED 4HE FIRST HINT TO THE PRESENCE OF !)( IS DEMONSTRATION OF ELEVATED GAMMA GLOBULINS ON A SERUM ELECTROPHORESIS WHICH IS PROBABLY THE CHEAPEST SCREENING TEST FOR !)( (OWEVER AROUND n OF !)( PATIENTS DO NOT DISPLAY ELEVATED GAMMA GLOBULINS AT INITIAL DIAGNOSIS 3OME OF THESE HAVE A RELATIVE ELEVATION OF THEIR PHYSIOLOGICAL GAMMA GLOBULIN LEVELS WHICH ONLY BECOMES APPARENT WHEN UPON IMMUNOSUPPRESSION THE GAMMA GLOBULIN LEVELS FALL FROM THE UPPER NORMAL RANGE TO THE LOWER NORMAL RANGE 3ERUM LIPIDS SHOULD BE TESTED AS FATTY LIVER DISEASE IS AN IMPORTANT DIFFERENTIAL DIAGNOSIS
3TEFAN ,àTH AND !NSGAR 7 ,OHSE
1UANTITATIVE )G! )G' AND )G- LEVELS ARE VERY HELPFUL DIAGNOSTIC MARKERS AS WELL )N !)( THERE IS TYPICALLY A SELECTIVE ELEVATION OF )G' WITH NORMAL LEV ELS FOR )G! AND )G- %LEVATED )G! HINTS TOWARDS A TOXIC CAUSE EG ALCOHOL OF THE LIVER DISEASE WHILE ELEVATED )G- IS A FEATURE OF BILIARY DISEASE SUCH AS PRIMARY BILIARY CIRRHOSIS OR PRIMARY SCLEROSING CHOLANGITIS "OTH THESE CONDI TIONS CAN BE ASSOCIATED WITH !)( SO CALLED /VERLAP SYNDROMES
!UTOANTIBODIES !BOUT OF ALL !)( PATIENTS HAVE PATHOLOGICAL TITRES OF AT LEAST ONE AUTO ANTIBODY 4HE MOST COMMON ANTIBODIES ARE ANTI NUCLEAR ANTIBODIES !.! AND ANTIBODIES TO SMOOTH MUSCLE ANTIGEN 3-! IN n OF CASES EACH SOMETIMES IN COMBINATION !NTIBODIES TO SOLUBLE LIVER ANTIGEN 3,!,0 ARE PRESENT IN ABOUT OF PATIENTS AND IN HALF OF THESE PATIENTS THE SOLE AUTOANTIBODY IS DEMONSTRABLE !NTIBODIES TO LIVER KIDNEY MICROSOMAL ANTI GEN ,+- ARE UNCOMMON n BUT DELINEATE A SEPARATE DISEASE SUB GROUP OFTEN CALLED AUTOIMMUNE HEPATITIS TYPE WHICH IS MORE PREVALENT IN CHILDHOOD WHERE IT MAY BE A VERY SEVERE DISEASE !NTIBODIES TO CYCLIC CITRULLINATED PEPTIDES ANTI ##0S ARE FOUND IN OF PATIENTS WITH AUTOIMMUNE HEPATITIS ;= !UTOANTIBODIES SHOULD BE TESTED BY TWO METHODS ANTI NUCLEAR ANTIBODIES !.! ANTIBODIES TO SMOOTH MUSCLE ANTIGEN 3-! AND ANTIBODIES TO LIVER KIDNEY MICROSOMAL ANTIGEN ,+- ARE BEST TESTED USING IMMUNOFLUORESCENCE ON TISSUE SECTIONS WHICH WILL AT THE SAME TIME DETECT ANTI MITOCHONDRIAL ANTIBODIES !-! AS THE CHARACTERISTIC TEST FOR PRIMARY BILIARY CIRRHOSIS 3,!,0 ANTIBODIES DO NOT SHOW UP ON IMMUNOFLUORESCENCE AND ARE THEREFORE MISSED BY ROUTINE TEST ING 4HESE ANTIBODIES SHOULD BE LOOKED FOR BY SPECIFIC IMMUNOASSAYS SUCH AS %,)3! ANDOR IMMUNOBLOT 7HILE !.! 3-! AND ,+- CAN ALSO BE FOUND IN SOME PATIENTS WITH OTHER LIVER DISEASE AND NON HEPATIC AUTOIMMUNE DISEASE 3,!,0 ANTIBODIES SEEM TO BE HIGHLY SPECIFIC FOR !)( AND THUS DIAGNOSTIC IN THE PATIENTS IN WHICH THEY CAN BE DEMONSTRATED 4HIS SEEMS TO BE ALSO TRUE FOR ANTIBODIES TO DOUBLE STRANDED $.! WHICH ARE DETECTABLE IN OF PATIENTS AND FOR WHICH THE ONLY DIFFERENTIAL DIAGNOSIS IS SYSTEMIC LUPUS ERYTHEMATOSUS 3,%
(ISTOLOGY 4HE DIAGNOSIS OF !)( IS BASED ON LIVER BIOPSY WHICH IS REQUIRED TO DEMON STRATE TYPICAL HISTOLOGICAL !)( FEATURES OF BRIDGING OR MULTIACINAR NECROSIS AND THE PRESENCE OF A LYMPHO PLASMACELLULAR INFILTRATE BUT ALSO IN ORDER TO EXCLUDE IMPORTANT DIFFERENTIAL DIAGNOSES SUCH AS DRUG INDUCED LIVER DISEASE OR NON ALCOHOLIC STEATOHEPATITIS .!3( !S MENTIONED ABOVE ABOUT A QUARTER OF ALL PATIENTS WITH !)( ALREADY HAVE CIRRHOSIS AT THE TIME OF DIAG
!UTOIMMUNE HEPATITIS IN HUMANS
NOSIS ;= #IRRHOSIS IS OFTEN MACRONODULAR WHICH EXPLAINS WHY IN MANY OF THESE PATIENTS CIRRHOSIS MAY BE MISSED BECAUSE OF THE SAMPLING ERROR BIOPSY OF A LARGE REGENERATIVE NODULE WITHOUT FIBROUS SEPTA 3OME AUTHORS THERE FORE FAVOUR LAPAROSCOPY AT INITIAL DIAGNOSIS WHICH CAN NOW BE PERFORMED WITH MINIMAL INVASIVENESS DUE TO THE AVAILABILITY OF MINI INSTRUMENTS
4REATMENT )MMUNOSUPPRESSION DRAMATICALLY IMPROVES THE OUTCOME IN AUTOIMMUNE HEPATITIS AND WITH INDIVIDUALISED IMMUNOSUPPRESSION PATIENTS CAN LOOK FORWARD TO A NORMAL LIFE EXPECTANCY AND GOOD QUALITY OF LIFE 4HE PROMPT RESPONSE TO CORTICOSTEROIDS CAN BE OBSERVED IN NEARLY ALL !)( PATIENTS WHICH MAKES IT THE MOST RELIABLE FINAL DIAGNOSTIC TOOL NON RESPONSE TO IMMUNOSUPPRESSION SUGGESTS ANOTHER DIAGNOSIS PROVIDED THE PATIENT IS COMPLIANT AND THE DOSE IS ADEQUATE #ORTICOSTEROID TREATMENT IS JUSTIFIED EVEN IN ASYMPTOMATIC PATIENTS SINCE THESE PATIENTS WILL USUALLY DEVELOP SYMPTOMS ;= 4HE PREFERRED TREATMENT SCHEDULE IN ADULTS IS PREDNISOLONE COMBINED WITH AZATHIOPRINE
2EMISSION INDUCTION #ORTICOSTEROIDS ARE THE DRUGS USED FOR THE INDUCTION OF REMISSION %XACT TREATMENT DOSES ARE CONTROVERSIAL AND NEED TO BE ADJUSTED ACCORDING TO THE INDIVIDUAL SEVERITY OF THE DISEASE ; = 7E USUALLY RECOMMEND A STARTING DOSE OF MGKG PREDNISOLONE FOR ALL PATIENTS EXCEPT THOSE WITH VERY MILD DIS EASE 3EVERE ICTERIC DISEASE MAY CAUSE MALABSORPTION OF CORTICOSTEROIDS AND THEREFORE INTRAVENOUS APPLICATION OF PREDNISOLONE SHOULD BE FAVOURED )N PATIENTS WITH MILD DISEASE HALF OF THIS DOSE MAY BE SUFFICIENT 4RANSAMINASE LEVELS USUALLY FALL WITHIN DAYS AND THE PREDNISOLONE DOSE CAN SOON BE TAPERED USUALLY IN STEPS OF MG WEEKLY DOSE REDUCTIONS !ZATHIOPRINE SHOULD BE ADDED TO THE TREATMENT AS SOON AS THE DIAGNOSIS OF !)( IS CON FIRMED BECAUSE ITS IMMUNOSUPPRESSIVE EFFECT TAKES SEVERAL WEEKS TO FULLY DEVELOP ;= 4HE SEVERITY OF DISEASE ACTIVITY DETERMINES THE DOSAGE AZA THIOPRINE SHOULD BE ADDED TO CORTICOSTEROIDS AT A DOSE OF MGKGD PATIENTS WITH VERY ACTIVE DISEASE SHOULD BE GIVEN HIGHER DOSES UP TO MGKGD ;= 7HILE CORTICOSTEROIDS ARE TAPERED EARLY AZATHIOPRINE DOSE IS MAINTAINED AT LEAST UNTIL STEROIDS ARE REDUCED BELOW MG PREDNISOLONEDAY ! TYPICAL TREATMENT SCHEDULE FOR A PATIENT WITH A BODY WEIGHT OF KG IS GIVEN IN 4ABLE 4APERING OF STEROIDS CAN BE FASTER IN PATIENTS WITH A VERY PROMPT RESPONSE OR IN MILDER DISEASE (OWEVER RAPID TAPERING OFTEN RESULTS IN EARLY RELAPSE THUS REQUIRING HIGHER OVERALL STEROID DOSES AND THEREFORE THE DOSE SHOULD NOT BE REDUCED TOO QUICKLY 6ITAMIN $ n )%DAY AND CALCIUM
3TEFAN ,àTH AND !NSGAR 7 ,OHSE
4ABLE 3TEPWISE REDUCTION OF STEROIDS AND COMBINED AZATHIOPRINE IMMUNOSUPPRESSIVE THERA PY IN A n KG PATIENT !:4 SHOULD BE ADDED AS SOON AS THE DIAGNOSIS OF !)( IS CONSIDERED DEFINITE #ORTICOSTEROID
!ZATHIOPRINE
7EEK
MGDAY
MGDAY
7EEK
MGDAY
MGDAY
7EEK
MGDAY
MGDAY
7EEK
MGDAY
MGDAY
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MGDAY
MGDAY
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MGDAY
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MGDAY
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7EEK x
MGDAY
MGDAY
MGDAY SHOULD BE GIVEN TO PREVENT DEVELOPMENT OF OSTEOPOROSIS AS LONG AS STEROID DOSE IS ABOVE MGDAY
-AINTENANCE OF REMISSION !ZATHIOPRINE IS THE DRUG OF FIRST CHOICE FOR THE MAINTENANCE OF REMISSION !ZATHIOPRINE WHEN STARTED AFTER THE DIAGNOSIS OF !)( HAS BEEN ESTABLISHED MAY THEN HELP TO SAVE STEROIDS )N ICTERIC PATIENTS THE PHARMACODYNAMICS OF AZATHIOPRINE AND ITS METABOLITES MAY BE CONSIDERABLY ALTERED INCREASING THE DANGER OF TOXICITY )N THESE PATIENTS A FALL OF BILIRUBIN BELOW TIMES THE UPPER LIMIT OF NORMAL SHOULD NORMALLY BE ACHIEVED BEFORE ADDING AZA THIOPRINE AND THE STARTING DOSE OF AZATHIOPRINE IN ICTERIC PATIENTS SHOULD BE LOWER AND GRADUALLY INCREASED TO THE DESIRED DOSE $UE TO THE LOW DOSE OF AZATHIOPRINE IN !)( PATIENTS COMPARED TO HIGHER DOSES IN INFLAMMATORY BOWEL DISEASE TOLERABILITY IS VERY GOOD IN THE MAJOR ITY OF PATIENTS 4OXICITY MAY RESULT IN ABDOMINAL PAIN NAUSEA AND FEVER "ONE MARROW TOXICITY REQUIRES REGULAR BLOOD COUNTS INITIALLY EVERY n WEEKS AND SLOWLY DECREASING TO ONCE EVERY MONTHS 4HE SUPERIORITY OF AZA THIOPRINE OVER CORTICOSTEROIDS IN MAINTAINING REMISSION HAS BEEN CONVINC INGLY DEMONSTRATED BY THE +INGS #OLLEGE GROUP ;= #OMBINATION THERAPY SHOULD BE GIVEN FOR THE FIRST MONTHS AND THEN CORTICOSTEROIDS SHOULD BE TAPERED OUT SLOWLY FOR ALL THOSE PATIENTS WHO ARE IN BIOCHEMICAL REMISSION NORMAL TRANSAMINASES AND NORMAL )G' 3OME GROUPS RECOMMEND INCREAS ING THE DOSE OF AZATHIOPRINE AT THIS STAGE UP TO MGKG IN ORDER TO AVOID RELAPSE UPON STEROID WITHDRAWAL ;= OTHERS LIKE OUR GROUP WOULD RATHER
!UTOIMMUNE HEPATITIS IN HUMANS
THEN CONTINUE LOW DOSE STEROIDS MG AND LOW DOSE AZATHIOPRINE MGKG BECAUSE OF WORRIES ABOUT ONCOGENIC EFFECTS OF LONG TERM HIGH DOSE AZATHIO PRINE )N EACH PATIENT TRANSAMINASES AND )G' LEVELS SHOULD BE MONITORED CLOSELY EVERY TIME IMMUNOSUPPRESSION IS DECREASED SIGNIFICANTLY AS RELAPSE UPON DOSE REDUCTION OCCURS IN n OF PATIENTS ;= AND MAY OFTEN BE PRECEDED BY AN INCREASE OF )G' LEVELS WELL BEFORE THE TRANSAMINASES AND SHOULD LEAD TO IMMEDIATE REINSTITUTION OF THE ORIGINAL REGIMEN 7HENEVER TRANSAMINASES RISE THERE SHOULD BE A SHORT INCREASE OF STEROID DOSAGE %XACT DOSE AND DURATION VERY MUCH DEPENDS ON HOW EARLY RELAPSE IS DETECTED AS EARLY INTERVENTION USUALLY REQUIRES NO MORE THAN A LIMITED SCHEDULE SUCH AS MG FOR WEEK MG FOR WEEK MG FOR WEEKS AND THE ORIGINAL MAINTENANCE DOSE THEREAFTER 4HERAPY FOR AUTOIMMUNE HEPATITIS IS CONTINUED UNTIL REMISSION IS ACHIEVED TREATMENT FAILS OR DRUG TOXICITY OCCURS #OMPLETE CLINICAL BIO CHEMICAL AND HISTOLOGICAL REMISSION OFTEN TAKES YEARS (ISTOLOGICAL REMIS SION LAGS BEHIND CLINICAL AND BIOCHEMICAL REMISSION BY n MONTHS 4HE MAJORITY OF PATIENTS WILL REQUIRE LONG TERM MOST PATIENTS LIFE LONG IMMU NOSUPPRESSION MANY BEING MAINTAINED WITH DOSES BETWEEN AND MG AZATHIOPRINE DAILY )N ALL PATIENTS AZATHIOPRINE SHOULD BE CONTINUED FOR A MINIMUM OF YEARS BEFORE COMPLETE TREATMENT WITHDRAWAL IS CONSIDERED BECAUSE OTHERWISE RELAPSE RATES ARE VERY HIGH WITHIN MONTHS ;= 4REATMENT WITHDRAWAL SHOULD ONLY BE CONSIDERED IN PATIENTS WHO HAVE BEEN FREE OF RELAPSE FOR YEARS AND IN WHOM LIVER BIOPSY HAS DEMONSTRATED ABSENCE OF SIGNIFICANT INFLAMMATION BECAUSE THE STRONGEST PREDICTOR OF RELAPSE AFTER TREATMENT WITHDRAWAL IS THE PRESENCE OF HISTOLOGICAL SIGNS OF CONTINUED INFLAMMATION ;= #OMPLIANCE MAY BECOME A PROBLEM IN SOME LONG TERM PATIENTS AND IT MAY OCCASIONALLY BE JUSTIFIED TO ATTEMPT TREATMENT WITHDRAWAL DESPITE NEGATIVE PREDICTORS FOR STABLE REMISSION AS ONLY THE PROOF OF RELAPSE WILL CONVINCE THE PATIENT TO TAKE A POTENTIALLY TOXIC DRUG FOR MANY YEARS )N THESE PATIENTS CLOSE OBSERVATION FOR THE FIRST n YEARS AFTER TREATMENT WITHDRAWAL IS REQUIRED IN ORDER TO DETECT RELAPSE IN TIME 2ELAPSE MAY SOMETIMES BE DELAYED BY MANY MONTHS SO PATIENTS AND THEIR CAREGIVERS MIGHT BE MISLED BY A STABLE SITUATION EARLY AFTER TREATMENT WITHDRAWAL )N MOST PATIENTS TREATMENT MONITORING CAN BE SOLELY BASED ON LABORATORY INVESTIGATIONS SUCH AS DETERMINATION OF AMINOTRANSFERASES AND GAMMA GLOB ULINES AND LIVER BIOPSY ON FOLLOW UP IS ONLY REQUIRED IF AMINOTRANSFERASES OR GAMMA GLOBULINES OR )G' ALTERNATIVELY FAIL TO NORMALISE
0ATIENTS DIFFICULT TO TREAT &ULMINANT AUTOIMMUNE HEPATITIS ! FEW PATIENTS PRESENT WITH FULMINANT HEPATIC FAILURE 4HIS IS MORE COM MONLY OBSERVED IN CHILDREN AND YOUNG ADULTS 5NFORTUNATELY IMMUNOSUP
3TEFAN ,àTH AND !NSGAR 7 ,OHSE
PRESSION MAY COME TOO LATE FOR SOME OF THESE PATIENTS AND THE STANDARD CRITERIA FOR EMERGENCY LIVER TRANSPLANTATION SHOULD BE USED FOR THE PATIENTS AS WELL DESPITE THE PRESENCE OF AN UNDERLYING CONDITION WHICH IN PRINCIPLE IS VERY RESPONSIVE TO TREATMENT 3OME PATIENTS RAPIDLY DETERIORATE ON STE ROIDS IN THIS SITUATION AND ANY DELAY IN TRANSPLANTATION WILL INCREASE THE RISK OF POTENTIALLY FATAL INFECTION 0ATIENTS WITHOUT ENCEPHALOPATHY HOW EVER SHOULD UNDERGO AN INTENSIVE TRIAL OF IMMUNOSUPPRESSION GIVING UP TO MG PREDNISOLONE IV FOR THE FIRST FEW DAYS !FTER TRANSPLANTATION MORE INTENSIVE IMMMUNOSUPPRESSION INCLUDING AZATHIOPRINE IS RECOMMENDED AS RELAPSE OF !)( IS RECOGNISED IN AT LEAST n OF TRANSPLANTED PATIENTS WITHIN YEARS ;=
0ATIENTS INTOLERANT OF AZATHIOPRINE )NTOLERANCE TO AZATHIOPRINE CAN BE OBSERVED IN UP TO OF THE PATIENTS AND A SIMILAR PROPORTION OF ADDITIONAL PATIENTS WILL DEVELOP SIDE EFFECTS LATER ON MOSTLY DUE TO ARTHRALGIA LYMPHOPENIA MYELOSUPPRESSION HEPATOTOXICITY OR PANCREATITIS REQUIRING EITHER DOSE REDUCTION OR COMPLETE DRUG WITHDRAWAL 7HILE SOME OF THESE PATIENTS CAN BE MANAGED WITH STEROID MONOTHERAPY THE MAJORITY WILL REQUIRE ANOTHER SECOND LINE DRUG 0RIMARILY BECAUSE OF ITS LOW TOXICITY MYCOPHENOLATE MOFETIL NOW HAS EMERGED AS THE STANDARD SECOND CHOICE DRUG FOR THESE PATIENTS 4HREE SMALL CLINICAL STUDIES PROVIDED EVIDENCE THAT ABOUT TWO THIRDS OF PATIENTS FARE WELL ON --& AT A DOSE OF MG TWICE DAILY ;= WHILE ONE THIRD APPEARS TO NOT REALLY BENEFIT FROM THE DRUG )N THESE FEW PATIENTS THE CHOICE BECOMES MORE DIFFICULT /UR PERSONAL PREFERENCE IN DESCENDING ORDER IS CYCLO PHOSPHAMIDE METHOTREXATE OR CYCLOSPORINE #YCLOPHOSPHAMIDE CAN BE GIVEN ORALLY MGDAY INITIALLY OR AS A BOLUS INFUSION LIKE IN 3,% 4HESE PATIENTS HOWEVER SHOULD BE TREATED IN SPECIALISED CENTRES AS SIDE EFFECTS OF THE DRUG NEED TO BE CLOSELY WEIGHED AGAINST THE DANGERS OF PROGRESSIVE DISEASE
0OOR RESPONDERS TO STANDARD IMMUNOSUPPRESSION $ESPITE USING THE SCHEDULE OF HIGH DOSE STEROIDS IN THE INITIATION OF TREAT MENT ABOUT OF THE PATIENTS HAVE WORSENING AMINOTRANSFERASES OR BILI RUBIN LEVELS INDICATING TO FAIL REMISSION ;= )N SOME OF THESE HIGHER THAN USUAL MAINTENANCE DOSES n MG PREDNISOLONEDAY UP TO MGKGDAY AZATHIOPRINE MAY BE THE BEST CHOICE OF MANAGEMENT /NLY EXCEPTIONAL PATIENTS WILL CONTINUE TO SHOW HIGH INFLAMMATORY ACTIVITY AFTER INTENSIFYING IMMUNOSUPPRESSION )N THESE PATIENTS TREATMENT FAILURE WARRANTS REASSESS MENT WITH REGARD TO THE ACCURACY OF THE DIAGNOSIS AND EXCLUSION OF VARIANT SYNDROMES OR OTHER HEPATIC DISEASES EG DRUG INDUCED HEPATOTOXICITY A
!UTOIMMUNE HEPATITIS IN HUMANS
SECOND OPINION BOTH CLINICALLY AND ON THE HISTOLOGY MAY BE HELPFUL 6ARIOUS EXPERIMENTAL PROTOCOLS HAVE BEEN USED IN THESE PATIENTS OUR PERSONAL PREF ERENCE IS CYCLOPHOSPHAMIDE 4HESE PATIENTS SHOULD BE REFERRED AND TREATED IN SPECIALISED CENTRES WITH EXPERTS IN !)( TO EVALUATE NOVEL THERAPEUTIC APPROACHES IN PATIENTS DIFFICULT TO TREAT )N CONCLUSION IT HAS TO BE EMPHASISED THAT INDIVIDUALISED THERAPY IS TAI LORED TO THE INDIVIDUAL REQUIREMENTS OF EACH PATIENT 7ITH SUCH CAREFUL MAN AGEMENT LIFE EXPECTANCY OF TREATED PATIENTS EXCEEDS AT YEARS AND IS COMPARABLE WITH TO THOSE IN AGE AND SEX MATCHED NORMAL POPULATION ;=
/VERLAP SYNDROMES WITH 0"# OR 03# !BOUT n OF PATIENTS PRESENT AT SOME STAGE OF THEIR DISEASE WITH OVER LAPPING FEATURES WITH EITHER PRIMARY SCLEROSING CHOLANGITIS 03# ;= OR MORE COMMONLY PRIMARY BILIARY CIRRHOSIS 0"# ;= )N THESE PATIENTS MANAGEMENT SHOULD BE PRIMARILY DIRECTED BY THE AUTOIMMUNE HEPATITIS COMPONENT OF THEIR DISEASE AS THIS IS THE CONDITION LEADING MOST RAPIDLY TO LIVER DESTRUCTION AND CIRRHOSIS AND AT THE SAME TIME CAN BE TREATED EFFEC TIVELY )N OVERLAP PATIENTS IT APPEARS SENSIBLE TO ADD URSODEOXYCHOLIC ACID 5$#! TO THE TREATMENT SCHEDULE EVEN THOUGH THE EVIDENCE FOR THIS APPROACH IS WEAK 0ATIENTS WITH !)(03# OVERLAP SEEM TO RUN A LESS FAVOUR ABLE COURSE THAN PATIENTS WITH !)( ONLY WHILE !)(0"# OVERLAP PATIENTS SEEM TO HAVE A SIMILARLY GOOD PROGNOSIS
2EFERENCES
-ACKAY )2 7EIDEN 3 5NGAR " 4REATMENT OF ACTIVE CHRONIC HEPATITIS AND LUPOID HEPATITIS WITH -ERCAPTOPURINE AND !ZATHIOPRINE ,ANCET n /"RIEN %. 'OBLE !* -ACKAY )2 0LASMA TRANSAMINASE ACTIVITY AS AN INDEX OF THE EFFECTIVENESS OF CORTISONE IN CHRONIC HEPATITIS ,ANCET n +RAWITT %, !UTOIMMUNE (EPATITIS . %NGL * -ED n +AMMER !2 VAN DER "URG 3( 'RABSCHEID " (UNZIKER )0 +WAPPENBERG +- 2EICHEN * -ELIEF #* #ERNY ! -OLECULAR MIMICRY OF HUMAN CYTOCHROME 0 BY HEPATITIS # VIRUS AT THE LEVEL OF CYTOTOXIC 4 CELL RECOGNITION * %XP -ED n -IYAKAWA ( +ITAZAWA % +IKCHI + &UJIKAWA ( +AWAGUCHI . !BE + -ATSUSHITA ( )GARASHI 4 (ANKINS 27 +AKO - )MMUNOREACTIVITY TO VARIOUS HUMAN CYTOCHROME 0 PROTEINS OF SERA FROM PATIENTS WITH AUTOIM MUNE HEPATITIS CHRONIC HEPATITIS " AND CHRONIC HEPATITIS # !UTOIMMUNITY n #ORCHERO * 'RANVIL #0 !KIYAMA 4% (AYHURST '0 0IMPRALE 3 &EIGENBAUM , )DIE *2 'ONZALEZ &* 4HE #90$ HUMANIZED MOUSE EFFECT OF THE
3TEFAN ,àTH AND !NSGAR 7 ,OHSE
HUMAN #90$ TRANSGENE AND (.& ALPHA ON THE DISPOSITION OF DEBRISOQUINE IN THE MOUSE -OL 0HARMACOL n (OLDENER - (INTERMANN ( 2HODE ! 7OLFE 4 'ONZALEZ &* *OHNSON %& -ANNS - VON (ERRATH -' #HRISTEN 5 ! NOVEL MODEL FOR HUMAN AUTOIMMUNE HEPATITIS "REAKING TOLERANCE TO HUMAN #90$ BY VIRAL INFECTION 3UBMITTED FOR PUBLICATION !NDO + 'UIDOTTI ,' 7IRTH 3 )SHIKAWA 4 -ISSALE ' -ORIYAMA 4 3CHREIBER 2$ 3CHLICHT (* (UANG 3. #HISARI &6 #LASS ) RESTRICTED CYTOTOXIC 4 LYMPHOCYTES ARE DIRECTLY CYTOPATHIC FOR THEIR TARGET CELLS IN VIVO * )MMUNOL n 3ACHER 4 +NOLLE 0 .ICHTERLEIN 4 !RNOLD " (AMMERLING '* ,IMMER ! #P' /$. INDUCED INFLAMMATION IS SUFFICIENT TO CAUSE 4 CELL MEDIATED AUTOAG GRESSION AGAINST HEPATOCYTES %UR * )MMUNOL n $JILALI 3AIAH ,APIERRE 0 6ITOZZI 3 !LVAREZ & $.! VACCINATION BREAKS TOLERANCE FOR A NEO SELF ANTIGEN IN LIVER A TRANSGENIC MURINE MODEL OF AUTOIM MUNE HEPATITIS * )MMUNOL n $E "IASIO -" 0ERIOLO . !VAGNINA ! 'ARCIA DE $AVILA -4 #IACCA - 'ONI * DE -ATTEO % 'ALOPPO # #ANERO 6ELASCO -# &AINBOIM ( ET AL ,IVER INFILTRATING MONONUCLEAR CELLS IN CHILDREN WITH TYPE ) AUTOIMMUNE HEPATITIS * #LIN 0ATHOL n +UROKOHCHI + !RIMA + -ASAKI 4 $EGUCHI ! .AKAI 3 -ORISHITA ! 9ONEYAMA ( /HGI 4 /NO - 9OSHITAKE ! ET AL !NALYSIS OF #$ AND BCL EXPRES SION ON PERIPHERAL BLOOD AND LIVER INFILTRATING MONONUCLEAR CELLS IN PATIENTS WITH AUTOIMMUNE HEPATITIS * #LIN )MMUNOL n +UROKOHCHI + -ASAKI 4 (IMOTO 4 $EGUCHI ! .AKAI 3 -ORISHITA ! 9ONEYAMA ( +IMURA 9 7ATANABE 3 +URIYAMA 3 5SEFULNESS OF LIVER INFILTRATING #$ POSITIVE MONONUCLEAR CELLS FOR DIAGNOSIS OF AUTOIMMUNE HEPATITIS 7ORLD * 'ASTROENTEROL n ,ONGHI -3 (USSAIN -* -ITRI 22 !RORA 3+ -IELI 6ERGANI ' 6ERGANI $ -A 9 &UNCTIONAL STUDY OF #$ #$ REGULATORY 4 CELLS IN HEALTH AND AUTOIMMUNE HEPATITIS * )MMUNOL n !LLA 6 !BRAHAM * 3IDDIQUI * 2AINA $ 7U '9 #HALASANI .0 AND "ONKOVSKY (, !UTOIMMUNE HEPATITIS TRIGGERED BY STATINS * #LIN 'ASTROENTEROL n #ZAJA !* &REESE $+ $IAGNOSIS AND TREATMENT OF AUTOIMMUNE HEPATITIS (EPATOLOGY n !L #HALABI 4 "OCCATO 3 0ORTMANN "# -C &ARLANE )' (ENEGHAN -! !UTOIMMUNE HEPATITIS IN THE ELDERLY A SYSTEMATIC ANALYSIS OF A LARGE GROUP OF CONSECUTIVE PATIENTS WITH DEFINITE !)( FOLLOWED AT A TERTIARY REFERRAL CENTRE * (EPATOL n &ELD ** $INH ( !RENOVICH 4 -ARCUS 6! 7ANLESS )2 (EATHCOTE %* !UTOIMMUNE HEPATITIS EFFECT OF SYMPTOMS AND CIRRHOSIS ON NATURAL HISTORY AND OUTCOME (EPATOLOGY n +OGAN * 3AFADI 2 !SHUR 9 3HOUVAL $ )LAN 9 0ROGNOSIS OF SYMPTOMATIC VERSUS ASYMPTOMATIC HEPATITIS ! STUDY OF PATIENTS * #LIN 'ASTROENTEROL n
!UTOIMMUNE HEPATITIS IN HUMANS
2OBERT 3+ 4HERNEAU 4 #ZAJA !* 0ROGNOSIS OF HISTOLOGICAL CIRRHOSIS IN TYPE AUTOIMMUNE HEPATITIS 'ASTROENTEROLOGY n -IYAKE 9 )WASAKI 9 4ERADA 2 /NISHI 4 /KAMOTO 2 3AKAI . 3AKAGUCHI + 3HIRATORI 9 #LINICAL CHARACTERISTICS OF FULMINANT TYPE AUTOIMMUNE HEPA TITIS AN ANALYSIS OF ELEVEN CASES !LIMENT 0HARMACOL 4HER n ,IS 3WIETY ! "RZEZINSKA 7EISLO , 0IERZCHALA % 7CISLO $ZIADECKA $ 3YSTEMIC SCLEROSIS POLYMYOSITIS OVERLAP SYNDROME ACCOMPANIED BY AUTOIM MUNE HEPATITIS AND SARCOIDOSIS OF MEDIASTINAL LYMPH NODES * %UR !CAD $ERMATOL 6ENEROL n ,UTH 3 "IRKLEIN & 3CHRAMM # (ERKEL * (ENNES % -ULLER &ORELL 7 'ALLE 02 ,OHSE !7 -ULTIPLEX NEURITIS IN A PATIENT WITH AUTOIMMUNE HEPATITIS A CASE REPORT 7ORLD * 'ASTROENTEROL n /KI + 9AMANE + +OIDE * +OIDE * -ANDAI + .AKANISHI 3 &UJIKAWA 2 +OHNO . ! CASE OF POLYGLANDULAR AUTOIMMUNE SYNDROME TYPE ))) COMPLICATED BY AUTOIMMUNE HEPATITIS %NDOCR * n -ONTANO ,OZA ! #ZAJA !* #ARPENTER (! 0IETTE ! -URPHY $ 3HUMS : "URLINGAME 2 .ORMAN ', &REQUENCY AND SIGNIFICANCE OF ANTIBODIES TO CYCLIC CITRULLINATED PEPTIDE IN TYPE ) AUTOIMMUNE HEPATITIS !UTOIMMUNITY n (ENEGHAN -! -C&ARLANE )' #URRENT AND NOVEL IMMUNOSUPPRESSIVE THERAPY FOR AUTOIMMUNE HEPATITIS (EPATOLOGY n *OHNSON 0* )MMUNOSUPPRESSIVE DRUG MECHANISMS )N )' -C&ARLANE 2 7ILLIAMS EDS )N -OLECULAR BASIS OF AUTOIMMUNE HEPATITIS 2' ,ANDES !USTIN n *OHNSON 0* -C&ARLANE )' 7ILLIAMS 2 !ZATHIOPRINE FOR LONG TERM MAIN TENANCE OF REMISSION IN AUTOIMMUNE HEPATITIS . %NGL * -ED n #ZAJA !* 4REATMENT STRATEGIES IN AUTOIMMUNE HEPATITIS #LIN ,IVER $IS n +ANZLER 3 ,ÚHR ( 'ERKEN ' 'ALLE 02 ,OHSE !7 ,ONG TERM MANAGE MENT AND PROGNOSIS OF AUTOIMMUNE HEPATITIS !)( ! SINGLE CENTER EXPERI ENCE : 'ASTROENTEROL n +ANZLER 3 'ERKEN ' ,OHR ( 'ALLE 02 -EYER ZUM "àSCHENFELDE +( ,OHSE !7 $URATION OF IMMUNOSUPPRESSIVE THERAPY IN AUTOIMMUNE HEPATITIS * (EPATOL n 'AUTAM - #HERUVATTATH 2 "ALAN 6 2ECURRENCE OF AUTOIMMUNE LIVER DISEASE AFTER LIVER TRANSPLANTATION A SYSTEMATIC REVIEW ,IVER 4RANSPL n #HATUR . 2AMJI ! "AIN 6' -A -- -AROTTA 0* 'HENT #. ,ILLY ," (EATHCOTE %* $ESCHENES - ,EE 33 ET AL 4RANSPLANT IMMUNOSUPPRES SIVE AGENTS IN NON TRANSPLANT CHRONIC AUTOIMMUNE HEPATITIS THE #ANADIAN ASSOCIATION FOR THE STUDY OF THE LIVER #!3, EXPERIENCE WITH MYCOPHENOLATE MOFETIL AND TACROLIMUS ,IVER )NT n 2OBERTS 3+ 4HERNEAU 4- #ZAJA !* 0ROGNOSIS OF HISTOLOGICAL CIRRHOSIS IN TYPE ) AUTOIMMUNE HEPATITIS 'ASTROENTEROLOGY n 'OHLKE & ,OHSE !7 $IENES (0 ,OHR ( -ARKER (ERMANN % 'ERKEN ' -EYER ZUM "USCHENFELDE +( %VIDENCE FOR AN OVERLAP SYNDROME OF
3TEFAN ,àTH AND !NSGAR 7 ,OHSE
AUTOIMMUNE HEPATITIS AND PRIMARY SCLEROSING CHOLANGITIS * (EPATOL n ,OHSE !7 ZUM "USCHENFELDE +( &RANZ " +ANZLER 3 'ERKEN ' $IENES (0 #HARACTERIZATION OF THE OVERLAP SYNDROME OF PRIMARY BILIARY CIRRHOSIS 0"# AND AUTOIMMUNE HEPATITIS EVIDENCE FOR IT BEING A HEPATITIC FORM OF 0"# IN GENETICALLY SUSCEPTIBLE INDIVIDUALS (EPATOLOGY n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
(EPATITIS IN DOGS *AN 2OTHUIZEN $EPARTMENT OF #LINICAL 3CIENCES OF #OMPANION !NIMALS &ACULTY OF 6ETERINARY -EDICINE 5NIVERSITY 5TRECHT 9ALELAAN 4$ 5TRECHT 4HE .ETHERLANDS
!BSTRACT ,IVER DISEASES ARE A MAJOR FOCUS OF RESEARCH IN THE &ACULTY OF 6ETERINARY -EDICINE )N A CLINICAL POPULATION OF THE DOGS HAS A FORM OF HEPATITIS 4HERE ARE SEVERAL ASPECTS OF CANINE HEPATITIS WHICH MAKE COMPARISON WITH HUMAN HEPATITIS VERY USEFUL !S A WHOLE LIVER DISEASES AND ESPECIALLY DIFFERENT FORMS OF HEPATITIS IN DOGS DEVELOP HIGHLY SIMILAR TO HUMAN HEPATITIS FULMINANT ACUTE CHRONIC 4HIS MAKES DOG DISEASES INTERESTING TO STUDY IMPORTANT ASPECTS IN THE PATHOGENESIS OF THE DISEASE 7E HAVE SHOWN THAT IN HUMANS AND DOGS IDENTICAL PROCESSES WITH RESPECT TO FORMATION OF FIBROSIS REGENERATION STEM CELL ACTIVATION AND OXIDATIVE DAMAGE OCCUR )N MOST ASPECTS IDENTICAL PATHOGENESIS AND PATHOPHYSIOLOGY OF CANINE AND HUMAN HEPATITIS MAKE THESE SPONTANEOUS DOG DISEASES IDEAL MODELS TO STUDY THE EFFECT OF NEW MODES OF INTERVENTION TO STIMULATE REGENERATION AND REDUCE OR PREVENT CIRRHOSIS
)NTRODUCTION (EPATITIS IS A FREQUENT LIVER DISEASE IN DOGS 4HE PRIMARY INFLAMMATORY DIS EASE IN DOGS AFFECTS THE PARENCHYME HEPATITIS WHICH IS DIFFERENT FROM THE SITUATION IN CATS WHERE IT IS PRIMARILY OF BILIARY ORIGIN CHOLANGITIS ;= &OLLOWING DESTRUCTION OF HEPATIC PARENCHYMA APOPTOSIS OR NECROSIS AN INFLAMMATORY REACTION REGENERATION OF PARENCHYMA FIBROSIS AND DUCTULAR PROLIFERATION MAY OCCUR 7HEN HEPATOCYTIC DESTRUCTION IS LIMITED AND THE RETICULIN NETWORK REMAINS INTACT REGENERATION WITH COMPLETE RESTITUTION OF THE LIVER STRUCTURE CAN OCCUR 3EVERE PARENCHYMAL DESTRUCTION WITH EXTEN SIVE LOSS OF HEPATOCYTES OFTEN IS FOLLOWED BY DUCTULAR PROLIFERATION -ANY OF THESE STRUCTURES CONTAIN BOTH LIVER CELL AND BILE DUCT ELEMENTS AND MAY REFLECT REGENERATIVE PROLIFERATION OF AN HEPATIC STEM CELL POPULATION ANALO GOUS TO OVAL CELLS IN THE RAT OR TRANSFORMATION OF REGENERATING HEPATOCYTES INTO DUCTULAR LIKE STRUCTURES 4HESE STRUCTURES GENERALLY ARE MOST PROMINENT IN THE PERIPORTAL AREAS ,IKE IN MAN THESE ARE #+ POSITIVE LIVER PROGENITOR CELLS 7ITH CHRONIC PARENCHYMAL DAMAGE OR EXTENSIVE LOSS OF HEPATOCYTES FIBROSIS AND POSTNECROTIC SCARRING MAY OCCUR WITH THE FORMATION OF INTRAHE
*AN 2OTHUIZEN
PATIC PORTOVENOUS SHUNTS IN THESE CASES PROLONGED REGENERATIVE EFFORT WILL RESULT IN REGENERATIVE PARENCHYMAL NODULES 4HE DIAGNOSIS OF HEPATITIS AND ITS CLASSIFICATION ACUTE CHRONIC ETC IS ONLY POSSIBLE WITH HISTOLOGY OF THE LIVER 4HE HISTOPATHOLOGIC DIAGNOSIS INCLUDES THE TYPE PATTERN AND EXTENT OF THE NECROSIS AND INFLAMMATION AND THE POSSIBLE CAUSE AND IN MORE CHRONIC CASES THE PRESENCE PATTERN AND EXTENT OF FIBROSIS AND REGENERATION 4HE ACTIVITY OF THE INFLAMMATION IS DEFINED BY THE AMOUNT OF HEPATOCELLULAR NECROSIS AND INFLAMMATION AND THE CHRONICITY IS DETERMINED BY THE AMOUNT OF FIBROSIS &OR VETERINARY MEDICINE THERE IS A LIVER CONSENSUS GROUP OF THE 7ORLD 3MALL !NIMAL 6ETERINARY !SSOCIATION 73!6! 4HIS GROUP HAS RECENTLY PUBLISHED A CONSENSUS FOR THE NOMENCLATURE AND THE CLINICAL AND HISTOLOGICAL DIAGNOSTIC CRITERIA IN THE DIAGNOSIS OF LIVER DISEASES ;= 4HESE WORLD STAN DARDS AND THE ACCEPTED NOMENCLATURE HAS BEEN USED IN THIS CHAPTER
!CUTE HEPATITIS IN DOGS %TIOLOGY !CUTE HEPATITIS CAN BE CAUSED BY CHEMICALS THE MOST FAMILIAR ARE ORGAN IC SOLVENTS SUCH AS ##L AND PHOSPHOROUS VIRAL INFECTION ;= INFECTIOUS CANINE HEPATITIS DUE TO THE #ANINE !DENOVIRUS ;#!6 = AND MYCOTOXINS ESPECIALLY AFLATOXIN " !CUTE HEPATITIS MAY ALSO BE CAUSED BY VARIOUS TOXINS SUCH AS MUSHROOM TOXINS !MANITUM OR BLUE GREEN ALGAE TOXINS #YANOPHYCEAE $RUGS ALSO MAY CAUSE ACUTE HEPATITIS IN DOGS $RUG INDUCED HEPATITIS HAS BEEN REPORTED AFTER TREATMENT WITH NALIDIXINE ACID ; = !DDITIONAL FORMS OF DRUG INDUCED HEPATITIS IN DOGS HAVE BEEN REPORTED IN DOGS LIKE IDIOSYNCRATIC DRUG TOXICITY SULFONAMIDES CARPROFEN AND AMIODA RONE OR DOSE DEPENDENT DRUG TOXICITY ACETAMINOPHEN ; = #!6 IS SO FAR THE ONLY KNOWN HEPATITIS VIRUS IN DOGS BUT THE SIMILARITY OF FORMS OF ACUTE AND CHRONIC HEPATITIS BETWEEN DOGS AND MAN INDICATES THAT LIKE IN MAN THERE MAY BE MORE HEPATITIS VIRUSES IN IDIOPATHIC CASES OF CANINE HEPATITIS 4HERE ARE THREE FORMS OF #!6 CAUSED HEPATITIS PERACUTE ACUTE AND CHRONIC (EPATITIS RESULTING FROM SEPSIS NON SPECIFIC REACTIVE HEPATITIS AND HYPOXIA HAEMOLYSIS SHOCK ARE NOT DISCUSSED HERE
0ATHOGENESIS AND PATHOLOGY $EPENDING ON THE EXTENT OF THE LIVER CELL NECROSIS INTRACELLULAR ENZYMES WILL BE RELEASED AND BILE WILL LEAK BACK INTO THE CIRCULATION )N ACUTE HEPATITIS ALL OF THE ENZYMES !,4 !34 AND BILE ACIDS ARE USUALLY HIGHLY ELEVATED &EVER CAN BUT DOES NOT ALWAYS OCCUR AS A RESULT OF PYROGENS FROM NECROTIC TISSUE AND FROM REDUCED REMOVAL OF ENDOTOXINS AND BACTERIA FROM THE PORTAL
(EPATITIS IN DOGS
BLOOD $IFFUSE INTRAVASCULAR COAGULATION IS OFTEN SEEN 6ERY EXTENSIVE LIVER CELL NECROSIS WITH LOSS OF A GREAT AMOUNT OF LIVER FUNCTION FULMINANT HEPA TITIS SEEMS TO BE QUITE RARE BUT MAY BE MISSED BECAUSE SUCH CASES MAY NOT REACH REFERRAL CENTRES )T LEADS TO THE DEVELOPMENT OF HEPATIC ENCEPHALOPA THY DISSEMINATED INTRAVASCULAR COAGULOPATHIA $)# JAUNDICE AND HYPOGLY CAEMIA VIA LOSS OF GLYCOGEN SYNTHESIS AND GLYCONEOGENESIS 4HIS SEVERE FORM PROGRESSES RAPIDLY TO COMA AND DEATH !CUTE HEPATITIS IS CHARACTERISED BY LIVER NECROSIS FOLLOWED BY AN INFLAM MATORY REACTION $EPENDING ON THE SEVERITY OF THE HEPATITIS THERE MAY BE APOPTOSIS FOCAL NECROSIS AND CONFLUENT OR BRIDGING NECROSIS 4HE INFLAMMA TORY INFILTRATE CONSISTS OF ROUND CELLS AND NEUTROPHILS )NFECTION WITH #!6 IS USUALLY CHARACTERISED BY CONFLUENT AND BRIDGING NECROSIS IN THE CENTRI LOBULAR ZONE AND BY THE PRESENCE OF INTRANUCLEAR INCLUSIONS IN HEPATOCYTES AND +UPFFER CELLS 4HE VIRUS CAN ALSO BE DEMONSTRATED HISTOLOGICALLY BY THE INTRANUCLEAR INCLUSION BODIES OR IMMUNOFLUORESCENCE
3YMPTOMS 3YMPTOMS COMPRISE ACUTE ILLNESS APATHY SOMETIMES FEVER ANOREXIA VOMIT ING DEHYDRATION SOMETIMES ICTERUS AND IN SEVERE CASES $)# )N FULMINANT HEPATITIS THERE IS RAPID WORSENING WITH HEPATIC ENCEPHALOPATHY ICTERUS AND BLEEDING 4HE CLINICAL PICTURE IS ENTIRELY DEPENDENT ON THE SEVERITY AND EXTENT OF THE LIVER DAMAGE )N MOST CASES ACUTE HEPATITIS IS NOT A SEVERE DIS EASE -OST DOGS RECOVER COMPLETELY WITHOUT TREATMENT
$IAGNOSIS )F THERE IS NO JAUNDICE THE SYMPTOMS ARE NON SPECIFIC "LOOD EXAMINATION REVEALS INCREASED LIVER ENZYMES ESPECIALLY !,4 SOMETIMES HYPERBILIRUBI NAEMIA 5LTRASONOGRAPHICALLY THE LIVER IS USUALLY NOT ABNORMAL IN SIZE ARCHI TECTURE OR ECHODENSITY /NLY IN CASES OF VERY SEVERE OR FULMINANT HEPATITIS THE LIVER MAY APPEAR TOO SMALL AND IRREGULAR 4HE DIAGNOSIS IS ESTABLISHED BY LIVER BIOPSY )N DOGS BIOPSY NEEDLES OF ' MAY BE USED TO OBTAIN LARGE ENOUGH SAMPLES TO BE DIAGNOSTIC #OAGULATION SHOULD BE CHECKED FIRST IN CASE OF $)# IT IS OFTEN ABNORMAL $IAGNOSIS OF #!6 INFECTION MIGHT BE PERFORMED WITH PAIRED SERUM TITRE TESTS AND CAN BE CONFIRMED ETIOLOGICALLY USING MOLECULAR TESTS
4REATMENT 5SUALLY NO SPECIFIC TREATMENT IS NEEDED )N MORE SEVERE CASES SUPPORT IVE TREATMENT MAY EXTEND TO IV FLUID INFUSION TO CORRECT HYPOVOLEMIA
*AN 2OTHUIZEN
SHOCK ACIDOSIS OR ALKALOSIS HYPOGLYCAEMIA AND ELECTROLYTE DISTURBANCES #ORTICOSTEROIDS ARE CONTRAINDICATED BECAUSE OF THE SUSPICION OF VIRAL ETIOLO GIES )N SEVERE LIVER DAMAGE AN ANTIBIOTIC AMOXYCILLIN MAY BE A HELPFUL SUPPORT TO ELIMINATE BACTERAEMIA DUE TO INADEQUATE HEPATIC CLEARANCE OF THE PORTAL CIRCULATION 0HALLOIDINE AND ACETAMINOPHEN INTOXICATION CAUSE OXIDATIVE DAMAGE AND MAY BE TREATED WITH SILYMARIN MGKGDAY FOR n DAYS !CETAMINOPHEN INTOXICATION MAY ALSO BE TREATED WITH THE COMBINA TION OF . ACETYLCYSTEINE MGKG 0/ EVERY H DURING DAYS VITAMIN # n MGKG 0/ EVERY H FOR DAYS AND CIMETIDINE MGKGBID FOR DAYS )F ACETAMINOPHEN TOXICITY HAS CAUSED HEMOLYSIS BLOOD TRANSFUSION MAY BE REQUIRED !CUTE HEPATITIS RECOVERS SPONTANEOUSLY AS A RULE HOWEVER IN ABOUT OF THE CASES IT PROGRESSES TO CHRONIC HEPATITIS #HRONIC DISEASE DOES NOT GIVE CLINICAL SIGNS IN THE FIRST MONTHS AND MAY BECOME CLINICALLY APPARENT AFTER SEV ERAL MONTHS WITH LIVER DYSFUNCTION )T IS THEREFORE RECOMMENDED TO PERFORM A CONTROL LIVER BIOPSY OR AT LEAST TO MEASURE PLASMA !,4 n WEEKS AFTER THE DIAGNOSIS OF ACUTE HEPATITIS TO DETECT CHRONIC HEPATITIS IN AN EARLY PHASE
,EPTOSPIROSIS %TIOLOGY ,EPTOSPIROSIS IS A DISEASE RESULTING FROM INFECTION WITH ,EPTOSPIRACEAS 4HE GENUS ,EPTOSPIRA IS DETERMINED BY ITS SEROVAR $UE TO THEIR PATHOGENICITY VIRULENCE DIFFERENT GROUPS OF SEROVARS HAVE BEEN SUBSUMED UNDER DIFFER ENT @NOMEN SPECIES $OGS ARE THE MAIN HOST FOR ONE THE MAJOR CAUSES OF LEPTOSPIROSIS THE , INTERROGANS SEROVAR ,EPTOSPIRA CANICOLA /THER SEROVARS LIKE , ICTEROHAEMORRHAGIAE AND , GRIPPOTYPHOSA ALSO CAUSE LEPTOSPIROSIS ,EPTOSPIRA ARE TRANSMITTED VIA DIRECT CONTACT OR URINE AND CONTAMINATED WATER FROM DOGS AND RODENTS LIKE RATS AND MICE RESPECTIVELY ; = )T IS NOTEWORTHY THAT LEPTOSPIROSIS IS AN ANTHROPOZOONOSIS ,EPTOSPIROSIS IS A FREQUENT CAUSE OF HEPATITIS IN DOGS ACCOUNTING FOR A SIGNIFICANT NUMBER OF ACUTE HEPATITIS CASES IN DOGS WITH APPROXIMATELY MORTALITY 0ROPHYLACTIC VACCINES ARE AVAILABLE $OGS MAY BE ASYMPTOMATIC CARRIERS WHICH TRANSMIT THE INFECTION WITHOUT BEING ILL %XPERIMENTAL INFECTION CAUSES DISEASE IN YOUNG DOGS BUT OLDER DOGS MAY REMAIN NON SYMPTOMATIC )N SPONTANEOUS CLINICAL CASES ILLNESS DEVELOPS AFTER AN INCUBATION OF n WEEKS ;= 4HE SYMPTOMS ARE DOMINATED BY THE URAEMIA )CTERUS IF PRESENT IS CAUSED BY INTRAHEPATIC CHOLESTASIS -YOSITIS MAY CAUSE PAINFUL PALPATION AND GAIT 7ITHOUT TREATMENT RENAL INSUFFICIENCY IS FATAL 4HE LIVER LESIONS ARE NOT SEVERE AND RECOVER SPONTANEOUSLY )N THE LIVER THERE IS A NON SPECIFIC REACTIVE HEPATITIS "ACTERIAL ENZYMES CAUSE DETACHMENT OF THE TIGHT JUNCTIONS WHICH STIMULATE HEPATOCYTES INTO MITO SIS 4HEREFORE AN INCREASED NUMBER OF MITOTIC FIGURES IN THE HEPATOCYTES IS
(EPATITIS IN DOGS
CHARACTERISTIC $UE TO INTRAHEPATIC CHOLESTASIS NEARLY ALL CASES ARE DISTINCTLY JAUNDICED 3YMPTOMS ARE MAINLY DETERMINED BY ACUTE RENAL FAILURE
3YMPTOMS 4HE SYMPTOMS COMPRISE MALAISE OFTEN FEVER VOMITING JAUNDICE SOMETIMES DIARRHOEA MUSCLE PAIN SOMETIMES PETECHIAE DUE TO THROMBOCYTOPENIA AS A RESULT OF $)#
$IAGNOSIS 4HE DISEASE IS CHARACTERISED BY ACUTE ONSET AND ICTERUS (OWEVER SINCE SYMPTOMS MIGHT BE UNSPECIFIC DIAGNOSIS IS SUPPORTED BY LABORATORY TESTING "LOOD EXAMINATION REVEALS URAEMIA AND CHOLESTASIS WITH ELEVATED BILIRUBIN !0 GAMMA'4 AND BILE ACIDS #0+ REFLECTING MYOSITIS IS OFTEN ELEVATED AND MANY CASES HAVE THROMBOCYTOPENIA 5RINE EXAMINATION MAY REVEAL TUBULAR EPITHELIAL CELLS IN THE SEDIMENT ANDOR PROTEINURIA ,IVER HISTOLOGY USUALLY SHOWS NON SPECIFIC REACTIVE HEPATITIS WHICH MAY OCCUR IN ANY TYPE OF SEPSIS 4HE DIAGNOSIS CAN BE MADE BY SEROLOGY 4HE RAPID )G- PEAK IS MAXIMAL AFTER DAYS FOLLOWED AT LEAST n DAYS LATER BY A LONG LASTING )G' PEAK )'- STAYS HIGH FOR n WEEKS AND SPECIFIC MEASURE MENT OF )G- IN SERUM IS THE ONLY METHOD TO CONFIRM THE DIAGNOSIS IN AN EARLY STAGE )G' MAY INDICATE CHRONIC INFECTION OR MAY BE DUE TO VACCINA TION )NCREASING )G' OVER TIME INDICATES ACTIVE INFECTION 3INCE SEROLOGY IS NOT ALWAYS A RELIABLE METHOD ETIOLOGICAL DIAGNOSIS SHOULD BE CONFIRMED BY EITHER DETECTION OF THE AGENS IN LIVER BIOPSIES ,EVADITI OR 7ARTHIN 3TARRY STAINING OR BACTERIAL CULTURE IE /XOID 3ELECTIVE ,EPTOSPIRA "ROTH $IAGNOSTIC 0#2 IS ALSO AVAILABLE
4REATMENT AND PROPHYLAXIS 0ENICILLIN IS GIVEN UNTIL KIDNEY FUNCTION HAS RECOVERED OR STABILISED AND THEN STREPTOMYCIN IS GIVEN ON TWO CONSECUTIVE DAYS !LTERNATIVELY CEPHALOSPORINS ARE WELL EFFECTIVE ;= 4HIS PREVENTS THE CONTINUING EXCRETION OF ,EPTOSPIRA IN THE URINE 4HE URINARY SHEDDING OF ,EPTOSPIRA STOPS TWO DAYS AFTER THE START OF PENICILLIN ADMINISTRATION AND REMAINS ABSENT AS LONG AS PENICILLIN IS CONTINUED 0REVENTION BY VACCINATION IS IMPORTANT FOR DOGS AT RISK SUCH AS HUNTING DOGS OR DOGS WHICH LIKE TO SWIM 4HE PROGNOSIS DEPENDS ON THE DEGREE OF KIDNEY FAILURE $ESPITE GOOD THERAPY THE INFECTION IS USUALLY FATAL !CUTE DISEASE WITH JAUNDICE AND URAE MIA SHOULD IMMEDIATELY BE TREATED AS IF IT IS LEPTOSPIROSIS UNTIL THE DIAGNOSIS IS DEFINITELY MADE
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#HRONIC HEPATITIS AND CIRRHOSIS #HRONIC HEPATITIS IN DOGS ;n= IS CHARACTERISED BY PERIPORTAL FIBRO SIS INFILTRATION OF LYMPHOCYTES AND PLASMA CELLS AND PERIPORTAL LIVER CELL APOPTOSIS OR NECROSIS 4HE APOPTOTIC HEPATOCYTES SHRINK AND ARE ACIDIPHI LIC 0ARENCHYMAL EXPANSION OF THE INFLAMMATION AND FIBROSIS MAY CAUSE PORTO PORTAL OR PORTO CENTRAL BRIDGING SEPTA 0ORTO CENTRAL FIBROSIS CAUSES CIRRHOSIS AS THE END STAGE OF CHRONIC HEPATITIS -ACRONODULAR CIRRHOSIS IS THE COMMON FORM IN DOGS BUT MICRONODULAR CIRRHOSIS IS ESPECIALLY SEEN IN DIF FERENT FORMS OF CHRONIC HEPATITIS DUE TO COPPER STORAGE !DVANCED FIBROSIS EXTENDS TO CIRRHOSIS IN A NEGATIVE VICIOUS CIRCLE REGARDLESS OF THE UNDERLYING CAUSE #URATIVE INTERVENTION IS MORE SUCCESSFUL IF INITIATED IN EARLY STAGES OF THE DISEASE 4HEREFORE FAST AND ACCURATE DIAGNOSIS MAY BE PIVOTAL #HRONIC HEPATITIS AND CIRRHOSIS CAUSE INTRAHEPATIC CHOLESTASIS BUT IN ONLY SOME OF THE CASES THERE IS ICTERUS
%TIOLOGY #HRONIC ACTIVE HEPATITIS MAY BE THE RESULT OF A VIRAL INFECTION #ANINE !DENOVIRUS IS THE ONLY KNOWN CANINE HEPATITIS VIRUS (OWEVER IT IS LIKELY THAT THERE ARE MORE DIFFERENT YET UNKNOWN HEPATITIS VIRUSES IN DOGS ; n= !LTHOUGH INFECTION WITH #!6 MIGHT BECOME CHRONIC IN VACCINATED ANIMALS #!6 INFECTION RESULTS IN FULMINANT HEPATITIS IN ALL NON VACCINATED ANIMALS ; = #!6 TITRES ARE USUALLY LOW IN DOGS WITH CHRONIC HEPATITIS 4HE LYMPHOCYTIC AND PLASMACELLULAR INFLAMMATION AND THE GOOD RESPONSE TO IMMUNOSUPPRESSIVE DRUGS INDICATE THAT A SELF PERPETUATING IMMUNE COMPONENT OF LIVER CELL DESTRUCTION IS INVOLVED IN THE CHRONIC PROGRESSION #HRONIC HEPATITIS IN DOGS MAY ALSO BE CAUSED BY TOXINS SUCH AS AFLATOXICOSIS )NHERITED COPPER ACCUMULATION ALSO LEADS TO DAMAGE OF HEPATOCYTES WITH SECONDARY HEPATITIS AND FIBROSIS ;n= SEE BELOW #OPPER ACCUMULATION AND INFLAMMATION HOWEVER BEGIN IN ZONES OF THE LIVER LOBULES AND NOT IN ZONE AS IN OTHER TYPES ;=
0ATHOGENESIS 'RADUALLY PROGRESSIVE LIVER CELL NECROSIS MAY CAUSE A CONTINUING ELEVATION OF ALL LIVER ENZYMES AND THE BILE ACIDS (OWEVER IN NOT VERY ACTIVE HEPATITIS AND IN END STAGES IN WHICH CIRRHOSIS HAS DEVELOPED THE RELEASE OF ENZYMES INTO THE PLASMA MAY BE INSIGNIFICANT AND THEN THE ENZYMES MAY BE NORMAL OR SLIGHTLY ELEVATED )CTERUS DOES NOT ALWAYS DEVELOP #HRONIC HEPATITIS IS ALWAYS A DIFFUSE PROCESS THROUGHOUT THE LIVER ,IVER FUNCTION IS DIMINISHED BY THE LOSS OF FUNCTIONAL TISSUE AND REDUCED PORTAL BLOOD FLOW 4HERE ARE OFTEN LOW ALBUMIN AND FIBRINOGEN LEVELS (EPATIC ENCEPHALOPATHY MAY
(EPATITIS IN DOGS
DEVELOP IF PORTOSYSTEMIC COLLATERALS ARE FORMED 4HE END STAGE IS USUALLY CIRRHOSIS (YPOALBUMINAEMIA AND PORTAL HYPERTENSION MAY CAUSE ASCITES #HRONIC HEPATITIS MAY OCCUR AT ANY AGE )N THE BREEDS IN WHICH AN ABNOR MAL COPPER METABOLISM CAUSES HEPATITIS THE GRADUAL ACCUMULATION OF COP PER USUALLY LEADS TO CLINICAL SIGNS AT AN AGE OF n YEARS #HRONIC HEPATITIS OCCURS IN ALL BREEDS BUT THE MOST FREQUENTLY AFFECTED BREEDS ARE ,ABRADOR 2ETRIEVERS 'OLDEN 2ETRIEVERS TO A LESSER EXTENT $OBERMANN 0INSCHERS ALL 3PANIEL BREEDS "EDLINGTON 4ERRIERS AND 7EST (IGHLAND 7HITE 4ERRIERS SEE ALSO HEPATITIS DUE TO COPPER STORAGE 4HE INCIDENCE OF CHRONIC HEPATITIS IS RELATIVELY HIGH IT IS ONE OF THE MOST COMMON LIVER DISEASES IN COMPANION ANIMALS AND ACCOUNTS FOR ABOUT OF THE CASES IN A REFERRAL CLINIC
3YMPTOMS 4HE MOST FREQUENT SYMPTOMS ARE APATHY REDUCED APPETITE VOMITING POOR ENDURANCE POLYDIPSIA AND IN ABOUT OF THE CASES ICTERUS )N ADVANCED CASES WITH DECOMPENSATION OF THE LIVER FUNCTIONS AND PORTAL HYPERTENSION THERE MAY BE ASCITES AND HEPATIC ENCEPHALOPATHY 3O CALLED @BLUE EYES THAT ARE A RESULT OF STRUCTURAL CHANGES IN THE SCLERA CAN FREQUENTLY BE OBSERVED IN DOGS WITH CHRONIC #!6 INFECTION
$IAGNOSIS 0HYSICAL EXAMINATION USUALLY REVEALS NO SPECIFIC FINDINGS !LL OF THE LIVER ENZYMES ARE MORE OR LESS INCREASED BUT !,4 IS THE MOST SENSITIVE PARAM ETER ALSO IN EARLY STAGES )N ADVANCED CASES THERE MAY BE HYPOALBUMINAE MIA 4HE DIAGNOSIS CAN ONLY BE MADE BY LIVER BIOPSY 5LTRASONOGRAPHY MAY REVEAL A SMALL LIVER WITH AN IRREGULAR SURFACE AND STRUCTURE )N LESS ADVANCED CASES THERE ARE NO ULTRASONOGRAPHIC ABNORMALITIES 2EGARDING THE VERY HIGH FREQUENCY OF COPPER STORAGE DISEASES IN DOGS IT IS ADVISABLE TO PERFORM HIS TOCHEMICAL COPPER STAINING IN ALL CASES EG RUBEANIC ACID STAIN $IAGNOSIS OF #!6 INFECTION CAN ONLY BE CONFIRMED USING LAB TESTS
4REATMENT 4HERE IS NO SPECIFIC TREATMENT AVAILABLE TO DATE )MMUNOSUPPRESSION MAY SLOW THE IMMUNE COMPONENT OF THE PATHOGENESIS 0REDNISOLONE MGKG DAY IS THE USUAL DRUG GIVEN FOR AT LEAST WEEKS AND IN MORE ACTIVEADVANCED STAGES FOR n WEEKS )F THE SIDE EFFECTS OF STEROIDS ARE INTOLERABLE MG AZATHIOPRINEKG DAY MAY BE USED )T IS IMPORTANT TO EVALUATE THE RESPONSE TO TREATMENT BY LIVER BIOPSIES -EDICATION IS AIMED TO ACHIEVE COMPLETE HISTOLOGICAL REMISSION OF THE INFLAMMATORY PROCESS AND OF HEPATOCYTE APOP
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TOSIS WHICH OCCURS USUALLY AFTER n WEEKS 7ITHOUT TREATMENT THE DISEASE PROGRESSES TO CIRRHOSIS )N CASES WITH COPPER ACCUMULATION THE MOST EFFECTIVE DRUG IS PENICILLA MINE GIVEN IN TWO DOSES PER DAY MGKGDAY 4HE USUAL TREATMENT PERIOD IS WEEKS AFTER WHICH A FOLLOW UP HISTOLOGICAL EVALUATION SHOWS IF PENICIL LAMINE MAY BE DISCONTINUED AND BE REPLACED BY ZINC GLUCONATE TO PREVENT REACCUMULATION OF COPPER 4HERE ARE EFFECTIVE HEPATIC SUPPORT COMMERCIAL DIETS WHICH CONTAIN LITTLE COPPER AND SEVERAL ANTIOXIDANTS !PART FROM SPECIFIC TREATMENT DIRECTED AT THE HEPATITIS ADVANCED STAGE CASES NEED SUPPORTIVE CARE TO PREVENT OR TREAT DEHYDRATION ASCITES AND MANAGEMENT OF (% 4HE PRESENCE OF PORTOSYSTEMIC COLLATERAL CIRCULATION AS A PREREQUISITE FOR (% CAN BE PREDICTED WITH AN AMMONIA TOLERANCE TEST 4HE PROGNOSIS OF CHRONIC HEPATITIS IS GUARDED THE DISEASE CAN BE STOPPED COMPLETELY IN MANY DOGS (OWEVER IN MANY CASES THERE ARE RECURRENCES WHICH FINALLY DETERMINE A GUARDED PROGNOSIS #OPPER STORAGE DISEASES MAY BE TREATED WITH COMPLETE SUCCESS AND HAVE A MUCH BETTER PROGNOSIS $EPENDING ON THE PRESENCE OF COLLATERALS DOGS MAY REQUIRE PERMANENT SUP PORT WITH A LIVER SUPPORT DIET AND LACTULOSE
#HRONIC HEPATITIS DUE TO HEPATIC COPPER STORAGE %TIOLOGY (EPATITIS IN COPPER STORAGE DISEASES OCCURS AS A RESULT OF AN INHERITED DEFECT OF HEPATIC COPPER METABOLISM &OOD CONTAINS AN EXCESS OF COPPER WHICH IS ABSORBED IN THE SMALL INTESTINES AND CLEARED FROM THE PORTAL BLOOD BY THE LIVER 4HE EXCESS IS NORMALLY EXCRETED INTO THE BILE BY THE HEPATOCYTES #OPPER IS ALSO AN ESSENTIAL ELEMENT AND IT IS DISTRIBUTED TO THE BODY BY THE LIVER AFTER INCORPORATION IN CERULOPLASMIN 4HE NORMAL METABOLIC PATHWAYS OF COPPER IN THE HEPATOCYTES ARE ONLY IN PART KNOWN INTRACELLULAR TRAFFICK ING IS ONLY IN PROTEIN BOUND FORM &REE COPPER CAUSES OXIDATIVE DAMAGE TO THE CELLS RESULTING IN LIVER CELL APOPTOSIS AND AN INFLAMMATORY REACTION !CCUMULATION OF COPPER AND INFLAMMATION OCCUR AROUND THE CENTRAL VEINS IN ZONE OF THE LIVER LOBULES #HOLESTASIS MAY ALSO CAUSE SOME COPPER ACCU MULATION WHICH IS ALWAYS LOCALISED IN THE PORTAL AREAS ZONE AND ALSO IS MUCH LESS PRONOUNCED THAN THE ZONE ACCUMULATION IN PRIMARY COPPER STORAGE DISEASES ;= #OPPER RELATED HEPATITIS IF UNTREATED PROGRESSES TO CHRONIC HEPATITIS AND CIRRHOSIS 4HE GRADUAL ACCUMULATION LEADS TO CLINICAL DISEASE TYPICALLY AT AN AGE OF n YEARS IN MOST DOGS (IGH HEPATIC COPPER CONCENTRATIONS MGG DRY TISSUE INDICATE AN INHERITED FORM OF COPPER STORAGE DISEASE NORMAL DOGS HAVE LEVELS MGG (ISTOCHEMICAL STAINING WITH RUBEANIC ACID SHOWS THE ZONAL DISTRIBUTION WHICH IS AN ESSENTIAL CLUE TO THE DIAGNOSIS
(EPATITIS IN DOGS
4HIS DISEASE OCCURS IN DIFFERENT BREEDS ;n= "EDLINGTON 4ERRIERS ,ABRADOR 2ETRIEVERS $OBERMANN 0INSCHERS ALL 3PANIEL BREEDS 7EST (IGHLAND 7HITE 4ERRIERS $ALMATIAN DOGS !NATOLIAN 3HEPHERDS AND 3KYE 4ERRIERS /NLY IN "EDLINGTON 4ERRIERS WHICH HAVE AN AUTOSOMAL RECESSIVE DISEASE THE UNDERLYING GENE DEFECT A DELETION IN THE #/--$ GENE HAS BEEN FOUND 6ERY RECENTLY RELIABLE $.! TESTS FOR THE DELETION IN THE #/--$ GENE HAVE BEEN REPORTED ; = &OR NONE OF THE OTHER BREEDS THE CAUSATIVE GENE OR A $.! MARKER IS KNOWN BUT ONGOING RESEARCH IN SEV ERAL BREEDS WILL REVEAL NEW GENE MUTATIONS WITHIN A FEW YEARS )T HAS RECENTLY BEEN SHOWN ; = THAT $OBERMANN 0INSCHERS AND ,ABRADOR 2ETRIEVERS HAVE AN INHERITED FORM OF COPPER STORAGE DISEASE WHICH AFFECTS ABOUT OF THESE POPULATIONS )N $OBERMANN 0INSCHERS THIS CHRONIC HEPATITIS IS VERY AGGRESSIVE AND NEARLY EXCLUSIVELY LINKED TO FEMALES #OPPER ASSOCIATED HEPATITIS OCCURS ALSO IN DIFFERENT 3PANIEL BREEDS AND $ALMATIAN DOGS )N GENERAL WE HAVE RECENTLY SHOWN NOT YET PUBLISHED THAT OF ALL DOGS WITH HEPATITIS HAVE AN UNDERLYING DISORDER OF COPPER METABOLISM
0ATHOGENESIS 4HE INCREASED COPPER CONCENTRATION DUE TO GRADUAL ACCUMULATION IS AFTER YEAR OF AGE /XIDATIVE DAMAGE CAUSES LIVER CELL DEATH ACTIVATION OF THE +UPFFER CELLS AND AN INFLAMMATORY REACTION IN ZONE #HRONIC PERSISTENT HEPATITIS LEADS TO LOSS OF REGENERATIVE CAPACITY AND FIBROSIS )N THE END STAGE CIRRHOSIS MAY DEVELOP )N COPPER STORAGE DISEASES THIS IS ALWAYS MICRONODU LAR CIRRHOSIS WHEREAS IN NON COPPER ASSOCIATED FORMS OF CHRONIC HEPATITIS THE REGENERATIVE NODULES ARE MACRONODULAR $OGS WITH COPPER ACCUMULATION MAY DEVELOP AN ACUTE HAEMOLYTIC ANAE MIA PROBABLY DUE TO RELEASE OF HIGHLY ACCUMULATED COPPER FROM NECROTISING HEPATOCYTES "ECAUSE LIVER FUNCTIONS ARE ALREADY REDUCED SUCH DOGS ALWAYS HAVE DISTINCT JAUNDICE (ETEROZYGOTE CARRIERS CANNOT BE DISTINGUISHED PHENOTYPICALLY FROM HEALTHY ANIMALS )N $OBERMANNS THE DISEASE AFFECTS ONLY FEMALES TYPICALLY AT AN AGE OF n YEARS )N ALL OTHER FORMS OF HEPATITIS THERE IS A FEMALE OVER REPRESENTATION USUALLY FEMALES REPRESENT n OF ALL CASES
3YMPTOMS 4HE SYMPTOMS ARE IDENTICAL TO THOSE SEEN IN NON COPPER ASSOCIATED CHRONIC HEPATITIS
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$IAGNOSIS /N THE BASIS OF PHYSICAL AND BLOOD EXAMINATIONS IT IS NOT POSSIBLE TO DIF FERENTIATE THIS DISEASE FROM HEPATITISCIRRHOSIS OR HAEMOLYSIS DUE TO OTHER CAUSES %ARLY SUBCLINICAL CASES CAN BE DISCOVERED BY AN INCREASE OF !,4 IN BLOOD OTHER ENZYMES OR BILE ACIDS ARE MUCH LESS SENSITIVE AND BECOME ABNORMAL ONLY IN ADVANCED CASES 4HE DIAGNOSIS HEPATITIS IS BASED ON HISTO LOGICAL EXAMINATION AND COPPER STAINING OF LIVER BIOPSIES THE CENTROLOBULAR COPPER ACCUMULATION IS ASSOCIATED WITH +UPFFER CELL ACTIVATION AND INFLAM MATION AND IN ADVANCED STAGES WITH FIBROSIS
4REATMENT #OPPER STORAGE DISEASE CAN BE TREATED WITH A COPPER BINDING CHELATING DRUG ;= 0ENICILLAMINE IS WIDELY AVAILABLE AND IS GIVEN IN TWO DAILY DOSES MIN BEFORE EACH MEAL IN A DAILY DOSE OF n MGKG 5RINARY EXCRETION OF THE PENICILLAMIN COPPER COMPLEX REDUCES FREE COPPER FOLLOWED BY THE COP PER BOUND METAL 4HE RESPONSE TO TREATMENT IS EVALUATED BY FOLLOW UP LIVER BIOPSIES AND IS IN MOST CASES SEEN AFTER MONTHS )F THE HEPATITIS IS CURED RECURRENCE SHOULD BE PREVENTED BECAUSE THE UNDERLYING GENE DEFECT CANNOT BE TREATED AND THE DISEASE WILL REOCCUR UPON DISCONTINUATION OF TREATMENT ,ONG TERM PREVENTION MAY BE ACHIEVED WITH ZINC MGKGDAY IN DIVIDED DOSES WITH EACH MEAL :INC INDUCES THE INTESTINAL METALLOTHIONEIN PRODUC TION WHICH BINDS COPPER AND PREVENTS ITS ABSORPTION 2ECENTLY COMMERCIAL LOW COPPER LIVER SUPPORT DIETS HAVE BECOME AVAILABLE WHICH ARE VERY EFFEC TIVE IN PREVENTING THE DISEASE
,OBULAR DISSECTING HEPATITIS %TIOLOGY 4HE ETIOLOGY OF THIS DISEASE IS UNKNOWN 4HE AUTHOR HAS SEEN THIS FORM OF HEPATITIS IN KENNELS WHERE ONE DOG AFTER ANOTHER GOT ILL AT DIFFERENT AGES 7E CONSIDERED THIS SUGGESTIVE FOR AN UNKNOWN INFECTIOUS ORIGIN
0ATHOGENESIS 4HIS IS A SEVERE DISEASE WITH PERICELLULAR FIBROSIS AROUND ALL HEPATOCYTES 4HE AMOUNT OF FIBROUS TISSUE IS EXCESSIVE CAUSING SEVERE PORTAL HYPERTEN SION ASCITES PORTOSYSTEMIC ACQUIRED COLLATERALS AND HEPATIC ENCEPHALOPATHY 4HE PROGRESSION IS USUALLY QUITE FAST CIRRHOSIS IS FORMED WITHIN n WEEKS TIME WHEREAS FOR OTHER FORMS OF CHRONIC HEPATITIS THIS IS SEVERAL MONTHS OR
(EPATITIS IN DOGS
YEARS 7ITH SPECIFIC STAININGS #+ AN ABUNDANT BUT APPARENTLY INADEQUATE PROLIFERATION OF HEPATIC PROGENITOR CELLS IS SEEN THIS DISEASE SHOWS THE MOST PROMINENT PROGENITOR CELL ACTIVATION OF ALL CANINE LIVER DISEASES AND MAY BE AN EXCELLENT MODEL TO STUDY SIGNALS INVOLVED IN THIS PROCESS
3YMPTOMS 3YMPTOMS ARE WEIGHT LOSS VOMITING POLYURIA FOLLOWED BY ASCITES AND HEPATIC ENCEPHALOPATHY
$IAGNOSIS !BDOMINAL FLUID IS CLEAR COLOURLESS OR YELLOW IN CASE OF ICTERUS !T BLOOD EXAMINATION LIVER ENZYMES MAY OR MAY NOT BE INCREASED BUT BILE ACIDS ARE !MMONIA IS OFTEN INCREASED AND THE AMMONIA TOLERANCE TEST IS USUALLY ABNORMAL ,IVER BIOPSY REVEALS THE CHARACTERISTIC CHANGES ESPECIALLY WITH COLLAGEN STAINS
4REATMENT )N OUR EXPERIENCE ALL CASES DIE BECAUSE OF LIVER DECOMPENSATION
#OMPARATIVE ASPECTS OF HEPATITIS IN DOGS AND MAN ,IVER DISEASES ARE A MAJOR FOCUS OF RESEARCH IN THE &ACULTY OF 6ETERINARY -EDICINE 0ROGRAM 4ISSUE 2EPAIR 4HERE ARE SEVERAL ASPECTS OF CANINE HEP ATITIS WHICH MAKE COMPARISON WITH HUMAN HEPATITIS VERY USEFUL !S A WHOLE LIVER DISEASES AND ESPECIALLY DIFFERENT FORMS OF HEPATITIS IN DOGS DEVELOP HIGHLY SIMILAR TO HUMAN HEPATITIS FULMINANT ACUTE CHRONIC 4HIS MAKES DOG DISEASES INTERESTING TO STUDY IMPORTANT ASPECTS IN THE PATHOGENESIS OF THE DISEASE 7E HAVE SHOWN THAT IN HUMANS AND DOGS IDENTICAL PROCESSES WITH RESPECT TO FORMATION OF FIBROSIS REGENERATION STEM CELL ACTIVATION AND OXIDATIVE DAMAGE OCCUR ;n= )N MOST ASPECTS IDENTICAL PATHOGENESIS AND PATHOPHYSIOLOGY OF CANINE AND HUMAN HEPATITIS MAKE THESE SPONTANEOUS DOG DISEASES IDEAL MODELS TO STUDY THE EFFECT OF NEW MODES OF INTERVENTION TO STIMULATE REGENERATION AND REDUCE OR PREVENT CIRRHOSIS /NE UPCOMING ASPECT OF INTEREST TO UNDERSTAND NEW POSSIBILITIES FOR TREATMENT OF PRESENTLY UNTREATABLE STAGES OF HEPATITIS IS THE LIVER STEM CELL 0RECISE UNDERSTAND ING OF THE STEM CELL NICHE OF THE LIVER IS ESSENTIAL IN ORDER TO DEVELOP NEW THERAPIES AIMED AT STIMULATING THE PROLIFERATION AND DIFFERENTIATION OF THESE PROGENITOR CELLS 7E HAVE SHOWN UNPUBLISHED RESULTS THAT STEM CELL ACTIVA
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TION IN DOGS AND MAN OCCURS IN A HIGHLY COMPARABLE WAY IN THE DEVELOP MENT OF HEPATITIS ;= )T IS ALSO POSSIBLE TO DRAW BENEFICIAL CONCLUSIONS FROM DISTINCTLY DIFFERENT FORMS OF HEPATITIS SUCH AS LOBULAR DISSECTING HEPATITIS ,$( WHICH IS MOST COMPARABLE WITH NEONATAL HEPATITIS IN HUMANS 4HE LIVERS OF DOGS WITH ,$( ARE LOADED WITH ACTIVATED PROGENITOR CELLS WHICH IN THE FACE OF EXCESSIVE FIBROSIS IS FUNCTIONALLY INEFFECTIVE 4HIS DISEASE OFFERS CHANCES TO STUDY STEM CELL ACTIVATION AND THE RELATIONS WITH FIBROSIS AND STEL LATE CELL ACTIVATION USING TECHNIQUES SUCH AS MICRODISSECTION MICROARRAY AND IMMUNOHISTOCHEMISTRY 4HE VERY FREQUENT OCCURRENCE OF COPPER STORAGE DISEASES AS A CAUSE OF HEPATITIS IN DOGS IS A SPECIFIC FEATURE OF CANINE HEPATITIS 0UREBRED DOG BREEDS HAVE BEEN FORMED OVER THE PAST n YEARS BY CONTINUOUS SELECTION OF DESIRED CHARACTERISTICS REGARDING BEHAVIOUR AND EXTERIOR 4HIS STRINGENT SELECTION AND INBREEDING HAS CAUSED ACCUMULATION OF ORIGINALLY SPORADIC DISEASE GENES IN ALL BREEDS SO THAT NOWADAYS EACH DOG BREED HAS SEVERAL HIGHLY FREQUENT BREED SPECIFIC DISEASES )N THIS WAY DEFECTS IN THE FUNCTION OF GENES INVOLVED IN COPPER METABOLISM HAVE ALSO BY CHANCE BEEN SEGREGATED OVER DOG BREEDS 4HIS HAS CAUSED THE PRESENCE OF MANY DIFFERENT COPPER METABOLISM DISEASES IN DIFFERENT DOG BREEDS !LSO DUE TO THE FACT THAT TRADI TIONALLY DOG FOODS CONTAIN A QUITE HIGH COPPER CONCENTRATION THE DIFFERENT DOG BREEDS PRESENT AN EXCELLENT OPPORTUNITY TO DETECT YET UNRESOLVED PARTS OF THE CELLULAR PATHWAYS OF COPPER HANDLING )N THE DOG BREEDS MENTIONED BEFORE AS AFFECTED BY COPPER STORAGE LIVER DISEASE WE HAVE EXCLUDED ALL PRESENTLY KNOWN CANDIDATE GENES INVOLVED IN COPPER METABOLISM 4HEREFORE BY DEFINITION THESE DOGS WILL ELUCIDATE NEW ELEMENTS OF COPPER PATHWAYS 4HE HIGH LEVEL OF INBREEDING OF PUREBRED DOGS HAS SIMPLIFIED COMPLEX DIS EASES TO SEEMINGLY MONOGENEOUS DISEASES SO THAT COMPLEX COPPER DISORDERS OF WHICH THE GENETIC BACKGROUND WOULD NOT BECOME APPARENT OR RESOLVABLE IN HUMANS MAY BE UNRAVELLED RELATIVELY EASILY IN DOGS
2EFERENCES
2OTHUIZEN * "UNCH 3% #HARLES *! #ULLEN *- $ESMET 6* 3ZATMARI 6 4WEDT $# VAN DEN )NGH 43'!- VAN 7INKLE 4* 7ASHABAU 2* 73!6! ,IVER 3TANDARDIZATION 'ROUP 73!6! 3TANDARDS FOR #LINICAL AND (ISTOLOGICAL $IAGNOSIS OF #ANINE AND &ELINE ,IVER $ISEASE 3AUNDERS %LSEVIER %DINBURGH $ECARO . #AMPOLO - %LIA ' "UONAVOGLIA $ #OLAIANNI -, ,ORUSSO ! -ARI 6 "UONAVOGLIA # )NFECTIOUS CANINE HEPATITIS AN hOLDv DISEASE REEMERG ING IN )TALY 2ES 6ET 3CI n 3OLLEVELD (! VAN :WIETEN -* VAN +ESSEL !# (EIDT 0* .ALIDIXIC ACID INTOXICATION IN TWO PREGNANT BITCHES 4IJDSCHR $IERGENEESKD n $UFFELL 3* ,ETTER 5NEXPECTED REACTION TO NALIDIXIC ACID 6ET 2EC 4REPANIER ,! )DIOSYNCRATIC TOXICITY ASSOCIATED WITH POTENTIATED SULFON AMIDES IN THE DOG * 6ET 0HARMACOL 4HER n
(EPATITIS IN DOGS
4WEDT $# $IEHL +* ,APPIN -2 'ETZY $- !SSOCIATION OF HEPATIC NECROSIS WITH TRIMETHOPRIM SULFONAMIDE ADMINISTRATION IN DOGS * 6ET )NTERN -ED n 'HNEIM '3 6IERS *( #HOMEL "" +ASS 0( $ESCOLLONGES $! *OHNSON -, 5SE OF A CASE CONTROL STUDY AND GEOGRAPHIC INFORMATION SYSTEMS TO DETERMINE ENVIRONMENTAL AND DEMOGRAPHIC RISK FACTORS FOR CANINE LEPTOSPIRO SIS 6ET 2ES n -OORE '% 'UPTILL ,& 'LICKMAN .7 #ALDANARO 2* !UCOIN $ 'LICKMAN ,4 #ANINE LEPTOSPIROSIS 5NITED 3TATES n %MERG )NFECT $IS n 'REENLEE ** !LT $0 "OLIN #! :UERNER 2, !NDREASEN #" %XPERIMENTAL CANINE LEPTOSPIROSIS CAUSED BY ,EPTOSPIRA INTERROGANS SEROVARS POMONA AND BRATISLAVA !M * 6ET 2ES n &AUCHER *& (OEN " %STAVOYER *- 4HE MANAGEMENT OF LEPTOSPIROSIS %XPERT /PIN 0HARMACOTHER n 3HIH *, +EATING *( &REEMAN ,- 7EBSTER #2 #HRONIC HEPATITIS IN ,ABRADOR 2ETRIEVERS CLINICAL PRESENTATION AND PROGNOSTIC FACTORS * 6ET )NTERN -ED n 7ATSON 0* #HRONIC HEPATITIS IN DOGS A REVIEW OF CURRENT UNDERSTANDING OF THE AETIOLOGY PROGRESSION AND TREATMENT 6ET * n 2OTHUIZEN * #ANINE CHRONIC LIVER DISEASE WHERE ARE WE NOW &OUR POINTERS FOR FUTURE RESEARCH 6ET * "OISCLAIR * $ORE - "EAUCHAMP ' #HOUINARD , 'IRARD # #HARACTERIZATION OF THE INFLAMMATORY INFILTRATE IN CANINE CHRONIC HEPATITIS 6ET 0ATHOL n 6ITRAL #, 0INTO -! ,EWIS 8IMENEZ ,, +HUDYAKOV 9% DOS 3ANTOS $2 'ASPAR !- 3EROLOGICAL EVIDENCE OF HEPATITIS % VIRUS INFECTION IN DIFFER ENT ANIMAL SPECIES FROM THE 3OUTHEAST OF "RAZIL -EM )NST /SWALDO #RUZ n "OOMKENS 39 3LUMP % %GBERINK (& 2OTHUIZEN * 0ENNING ,# 0#2 SCREENING FOR CANDIDATE ETIOLOGICAL AGENTS OF CANINE HEPATITIS 6ET -ICROBIOL n "OOMKENS 39 0ENNING ,# %GBERINK (& VAN DEN )NGH 43 2OTHUIZEN * (EPATITIS WITH SPECIAL REFERENCE TO DOGS ! REVIEW ON THE PATHOGENESIS AND INFECTIOUS ETIOLOGIES INCLUDING UNPUBLISHED RESULTS OF RECENT OWN STUDIES 6ET 1 n -ORRIS 41 'OCKE $* -ODIFIED ACUTE CANINE VIRAL HEPATITIS n A MODEL FOR PHYSIOLOGIC STUDY 0ROC 3OC %XP "IOL -ED n 'OCKE $* 0REISIG 2 -ORRIS 41 -C+AY $' "RADLEY 3% %XPERIMENTAL VIRAL HEPATITIS IN THE DOG PRODUCTION OF PERSISTENT DISEASE IN PARTIALLY IMMUNE ANIMALS * #LIN )NVEST n 2OLFE 4WEDT #OPPER ASSOCIATED HEPATOPATHIES IN DOGS 6ET #LIN . !M 3MALL !NIMAL 0RACTICE n (OFFMANN ' VAN DEN )NGH 43 "ODE 0 2OTHUIZEN * #OPPER ASSOCIATED CHRONIC HEPATITIS IN ,ABRADOR 2ETRIEVERS * 6ET )NTERN -ED n -ANDIGERS VAN DEN )NGH "ODE 4ESKE % 2OTHUIZEN * !SSOCIATION
*AN 2OTHUIZEN
BETWEEN LIVER COPPER CONCENTRATION AND SUBCLINICAL HEPATITIS IN $OBERMAN 0INSCHERS * 6ET )NTERNAL -ED n 3PEETI %RIKSSON 3AARI 7ESTERMARCK ,ESIONS OF SUBCLINICAL DOBERMAN HEPATITIS 6ET 0ATHOLOGY n 3PEE " !RENDS " VAN DEN )NGH 43 0ENNING ,# 2OTHUIZEN * #OPPER METABOLISM AND OXIDATIVE STRESS IN CHRONIC INFLAMMATORY AND CHOLESTATIC LIVER DISEASES IN DOGS * 6ET )NTERN -ED n -ANDIGERS 0* "ODE 0 VAN 7EES !- VAN DEN "ROM 7% VAN DEN )NGH 43 2OTHUIZEN * (EPATIC #U EXCRETION IN $OBERMANNS WITH SUBCLINICAL HEPATITIS 2ES 6ET 3CI n -ANDIGERS 0* VAN DEN )NGH 43 "ODE 0 2OTHUIZEN * )MPROVEMENT IN LIVER PATHOLOGY AFTER MONTHS OF $ PENICILLAMINE IN DOBERMAN PINSCHERS WITH SUBCLINICAL HEPATITIS * 6ET )NTERN -ED n 3PEE " !RENDS " VAN 7EES !- "ODE 0 0ENNING ,# 2OTHUIZEN * &UNCTIONAL CONSEQUENCES OF 2.! INTERFERENCE TARGETING #/--$ IN A CANINE HEPATIC CELL LINE IN RELATION TO COPPER TOXICOSIS !NIM 'ENET n &AVIER 20 3PEE " 0ENNING ,# "RINKHOF " 2OTHUIZEN * 1UANTITATIVE 0#2 METHOD TO DETECT A KB DELETION IN THE -522 GENE ASSOCIATED WITH COPPER TOXICOSIS AND ()6 REPLICATION -AMM 'ENOME n (AYWOOD 3 2UTGERS (# #HRISTIAN -+ (EPATITIS AND COPPER ACCUMULA TION IN 3KYE TERRIERS 6ET 0ATHOLOGY n 4HORNBURG ,0 2OTTINGHAUS ' $ENNIS ' #RAWFORD 3 4HE RELATIONSHIP BETWEEN HEPATIC COPPER CONTENT AND MORPHOLOGIC CHANGES IN THE LIVER OF 7EST (IGHLAND 7HITE 4ERRIERS 6ET 0ATHOLOGY n 4HORNBURG ,0 2OTTINGHAUS ' +OCH * (AUSE 72 (IGH LIVER COPPER LEV ELS IN $OBERMAN 0INSCHERS WITH SUBACUTE HEPATITIS * !M !NIMAL (OSP !SSOC n 4HORNBURG ,0 3HAW $ $OLAN - 2AISBECK - #RAWFORD 3 $ENNIS ', /LWIN $" (EREDITARY COPPER TOXICOSIS IN 7EST (IGHLAND 7HITE TERRIERS 6ET 0ATHOLOGY n 7EBB #" 4WEDT $# -EYER $* #OPPER ASSOCIATED LIVER DISEASE IN $ALMATIANS A REVIEW OF DOGS n * 6ET )NTERNAL -ED n &ORMAN /0 "OURSNELL -% $UNMORE "* 3TENDALL . VAN DEN 3LUIS " &RETWELL . *ONES # 7IJMENGA # 2OTHUIZEN * VAN /OST "! ET AL #HARACTERIZATION OF THE #/--$ -522 MUTATION CAUSING COPPER TOXICOSIS IN "EDLINGTON TERRIERS !NIM 'ENET n -ANDIGERS 0* VAN DEN )NGH 43 "ODE 0 2OTHUIZEN * )MPROVEMENT IN LIVER PATHOLOGY AFTER MONTHS OF $ PENICILLAMINE IN DOBERMAN PINSCHERS WITH SUBCLINICAL HEPATITIS * 6ET )NTERN -ED n 3PEE " !RENDS " VAN DEN )NGH 43 2OSKAMS 4 2OTHUIZEN * 0ENNING ,# -AJOR ('& MEDIATED REGENERATIVE PATHWAYS ARE SIMILARLY AFFECTED IN HUMAN AND CANINE CIRRHOSIS #OMP (EPATOL n 3PEE " !RENDS " VAN DEN )NGH 43 "RINKHOF " .EDERBRAGT ( )JZER * 2OSKAMS 4 0ENNING ,# 2OTHUIZEN * 4RANSFORMING GROWTH FACTOR BETA SIGNAL LING IN CANINE HEPATIC DISEASES NEW MODELS FOR HUMAN FIBROTIC LIVER PATHOLOGIES ,IVER )NT n 3PEE " 0ENNING ,# VAN DEN )NGH 43 !RENDS " ))ZER * VAN 3LUIJS &* 2OTHUIZEN
(EPATITIS IN DOGS
* 2EGENERATIVE AND FIBROTIC PATHWAYS IN CANINE HEPATIC PORTOSYSTEMIC SHUNT AND PORTAL VEIN HYPOPLASIA NEW MODELS FOR CLINICAL HEPATOCYTE GROWTH FACTOR TREATMENT #OMP (EPATOL n )JZER * 2OSKAMS 4 -OLENBEEK 2& 5LTEE 4 0ENNING ,# 2OTHUIZEN * VAN DEN )NGH 43 -ORPHOLOGICAL CHARACTERISATION OF PORTAL MYOFIBROBLASTS AND HEPATIC STELLATE CELLS IN THE NORMAL DOG LIVER #OMP (EPATOL n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
(EPATITIS IN HORSES !NDY % $URHAM 4HE ,IPHOOK %QUINE (OSPITAL &OREST -ERE ,IPHOOK (AMPSHIRE '5 *' 5NITED +INGDOM
!BSTRACT 4HE MAIN CAUSES OF HEPATITIS IN HORSES INCLUDE SERUM HEPATITIS CHOLANGIOHEPATITIS AND CHRONIC ACTIVE HEPATITIS WITH OCCASIONAL CASES OF HAEMATOGENOUS BACTERIAL HEPATITIS EG 4YZZERS DISEASE IN FOALS ABSCESSES VIRAL HEPATITIS PARASITISM AND CHRONIC INFILTRATIVE INFLAMMATORY DISEASE .OT ALL CASES OF HEPATITIS WILL BE CLINICALLY APPARENT DUE TO THE LARGE RESERVE CAPACITY OF THE LIVER (OWEVER SIGNS OF MARKED HEPATIC INSUFFICIENCY AND HEPATIC ENCEPHALOPATHY REDUCE THE LIKELIHOOD OF A SUCCESSFUL OUTCOME 3ERUM ENZYMES INCLUD ING ALKALINE PHOSPHATASE ASPARTATE AMINOTRANSFERASE GAMMA GLUTAMYLTRANFERASE AND GLUTAMATE DEHYDROGENASE OFFER AN APPROXIMATE REFLECTION OF HEPATIC DAMAGE WHEREAS FUNCTIONAL INDICATORS SUCH AS BILE ACIDS BILIRUBIN ALBUMIN GLOBULINS UREA AND AMMONIA MAY PROVIDE MORE PROGNOSTICALLY USEFUL INFORMATION .EVERTHELESS ALL SERUM BIOCHEMICAL PARAMETERS HAVE SIGNIFICANT LIMITATIONS IN TERMS OF SENSITIVITY OR SPECIFICITY ,IVER BIOPSY WHEN GUIDED BY ULTRASONOGRAPHIC IMAGES OFFERS THE OPTIMAL SAFE AND EFFECTIVE MEANS OF INVESTIGATING SUSPECTED HEPATITIS IN HORSES AND WILL PROVIDE USEFUL DIAGNOSTIC AND PROG NOSTIC INFORMATION IN ADDITION TO AIDING SELECTION OF THERAPEUTIC CHOICE 'ENERAL AND SUPPORTIVE CARE FOR EQUINE HEPATITIS CASES INCLUDES FLUID THERAPY ANTI PYRETICS AND DIETARY MANAGEMENT COMPRISING SMALL FREQUENT FEEDS OF LOW FAT GOOD QUALITY PROTEIN AND CEREAL BASED FEEDS SUCH AS GRASS GOOD GRASS HAY DRIED PROPRIETARY CHAFFS ALFALFA PROCESSED WHEATMAIZE AND " VITAMIN SUPPLEMENTS #ARE SHOULD BE TAKEN TO ENSURE THAT SUPPLEMENTS DO NOT CONTAIN POTENTIAL HEPATOTOXINS EG IRON 3PECIFIC THERAPY IS USUALLY SELECTED ON THE BASIS OF BIOPSY FINDINGS AND MAY COMPRISE ANTIBACTERI ALS ANTHELMINTICS GLUCOCORTICOIDS AND LACTULOSE
!ETIOLOGIES 4HERE ARE SIGNIFICANT GEOGRAPHIC VARIATIONS IN THE PREVALENCE OF HEPATITIS IN HORSES 0UBLISHED REVIEWS OF EQUINE HEPATIC DISEASE SUGGEST THAT HEPATITIS IS RELATIVELY COMMON IN THE 53! LARGELY AS A RESULT OF SO CALLED @SERUM HEPA TITIS ;n= /THER COMMON CAUSES OF EQUINE HEPATITIS COMPRISE CHOLANGIO HEPATITIS AND CHRONIC ACTIVE HEPATITIS BOTH OF WHICH HAVE SIMILAR PREVALENCE IN 53! AND 5+ 4AB 3EVERAL SPECIFIC TYPES AND CAUSES OF HEPATITIS IN
!NDY % $URHAM
4ABLE 2ELATIVE PREVALENCE OF EQUINE HEPATITIDES DERIVED FROM FOUR LARGE SURVEYS OF LIVER DISEASE CASES $ISEASE TYPE
53! STUDIES N ; =
5+ STUDIES N ; =
OF TOTAL HEPATOPATHY CASES OF TOTAL HEPATOPATHY CASES 3ERUM HEPATITIS
#HOLANGIOHEPATITIS
#HRONIC ACTIVE HEPATITIS
!BSCESS 4OTAL HEPATITIS CASES
HORSES ARE DISCUSSED BELOW AND ARE ASSOCIATED WITH SPECIFIC CLINICAL CLINI COPATHOLOGICAL GROSS PATHOLOGICAL OR HISTOPATHOLOGICAL DIAGNOSTIC FEATURES (OWEVER IN THE AUTHORS EXPERIENCE SUCH CLEAR DIAGNOSTIC CATEGORISATION IS IMPOSSIBLE IN MANY CLINICAL CASES SEEN IN PRACTICE 4HIS VIEW IS SUPPORTED BY THE MORE GENERAL CATEGORISATION APPEARING IN PUBLISHED REVIEWS OF EQUINE LIVER DISEASE CASES ;n= #ASES OF ACUTE HEPATITIS AND NECROSIS IN ADULT HORSES KNOWN AS SERUM HEPATITIS OR 4HEILERS DISEASE ARE SEEN FREQUENTLY IN SOME GEOGRAPHIC LOCA TIONS SUCH AS THE 53! ; = 0ROGNOSIS IS GUARDED TO POOR WITH THE MAJORITY OF AFFECTED HORSES SUCCUMBING ;= ! SIMILAR DISEASE HAS ALSO BEEN REPORTED FROM &RANCE ;= AND 4URKEY ;= 4HE CONDITION IS RARE IN THE 5+ ALTHOUGH SEVERAL CASES HAVE BEEN SEEN BY THIS AUTHOR EITHER AS ISOLATED CASES OR OUT BREAKS !LTHOUGH MOST CASES HAVE NO OBVIOUS TRIGGER FACTORS SOME MAY FOLLOW BETWEEN n WEEKS AFTER TETANUS ANTITOXIN ADMINISTRATION AND HAVE ALSO BEEN REPORTED FOLLOWING USE OF OTHER EQUINE BIOLOGICALS SUCH AS PLASMA ; = $ESPITE THE SIMILARITIES WITH HUMAN HEPATITIS " VIRUS INFECTION ;= AND THE LONG HELD SUSPICION OF A HAEMATOGENOUS INFECTION CAUSING THIS CONDITION NO INFECTIOUS AGENT HAS YET BEEN IDENTIFIED ; = )NSECT VECTORS HAVE BEEN SUGGESTED AS AN EXPLANATION OF THE SUMMER AND AUTUMN PEAKS OF DISEASE ;= !LTHOUGH NOT REPORTED AS A SPECIFIC ENTITY THE COMMONEST FORM OF HEPA TITIS IN HORSES SEEN BY THIS AUTHOR IS ASSOCIATED WITH LYMPHOCYTIC PORTAL INFIL TRATES WITHOUT OTHER HEPATOPATHIC FINDINGS SUCH AS NECROSIS BILIARY HYPERPLA SIA AND FIBROSIS 3UCH CASES ARE SEEN SPORADICALLY OR AS OUTBREAKS AND HAVE EPIDEMIOLOGIC AND HISTOPATHOLOGIC RESEMBLANCE OF VIRAL HEPATITIDES IN OTHER SPECIES ALTHOUGH SEROLOGIC EXAMINATIONS ARE USUALLY UNPRODUCTIVE #AUTION SHOULD BE EXERCISED HOWEVER WHEN MAKING A DIAGNOSIS OF HEPATITIS ON THE BASIS OF MILD PORTAL LYMPHOCYTIC INFILTRATES AS ONE STUDY FOUND SUCH CHANGES TO BE PRESENT IN OF LIVER SPECIMENS FROM NORMAL HORSES ;= 6IRAL HEPATITIDES ARE NOT WELL RECOGNISED IN HORSES ALTHOUGH EQUINE HERPES VIRUS INFECTION MAY RESULT IN SEVERE HEPATIC NECROSIS IN NEONATES ;= AND SOMETIMES HEPATITIS IN OLDER HORSES ; = (EPATIC MONONUCLEAR PHAGO
(EPATITIS IN HORSES
CYTES +UPFFER CELLS ARE AN IMPORTANT SITE OF VIRAL REPLICATION AND LATENCY IN EQUINE INFECTIOUS ANAEMIA VIRUS INFECTION AND LYMPHOID HEPATITIS IS CHARAC TERISTIC OF ACTIVE INFECTION ; = )N A RECENT STUDY OF %GYPTIAN HORSES WERE FOUND TO BE SEROPOSITIVE FOR HUMAN HEPATITIS % VIRUS ALTHOUGH THERE WAS NO SPECIFIC EVIDENCE OF LIVER DISEASE IN THESE CASES ;= "ACTERIAL HEPATITIS MAY ARISE HAEMATOGENOUSLY AND IS WELL RECOGNISED IN ASSOCIATION WITH NEONATAL SEPTICAEMIA CAUSED BY SEVERAL BACTERIAL SPE CIES ;= ,ESS COMMONLY HAEMATOGENOUS BACTERIAL HEPATITIS HAS BEEN REPORTED AS PART OF A MULTISYSTEMIC INFECTION WITH SPECIFIC PATHOGENS SUCH AS 2HODOCOCCUS EQUI !CINETOBACTER CALCOACETICUS %HRLICHIA RISTICII AND 9ERSINIA ENTEROCOLITICA ;n= #LOSTRIDIAL HEPATITIS IS BEST RECOGNISED AS SPO RADIC CASES OR OUTBREAKS OF @4YZZERS DISEASE IN FOALS BETWEEN n WEEKS OF AGE ;= 4HIS ACUTE BACTERIAL HEPATITIS AND NECROSIS IS CAUSED BY #LOSTRIDIUM PILIFORME AND A FAECAL ORAL ROUTE OF SPREAD IS SUSPECTED 4HE CONDITION IS FREQUENTLY RAPIDLY FATAL BUT TREATMENT CAN BE SUCCESSFUL ;= ! SIMILARLY SEVERE ACUTE CLOSTRIDIAL HEPATITIS HAS ALSO BEEN REPORTED IN ADULT HORSES IN ASSOCIATION WITH # NOYVI AND # HAEMOLYTICUM ;n= ,IVER ABSCESSES ARE REPORTED RARELY IN HORSES BUT MAY BE CAUSED BY A WIDE VARIETY OF BACTERIAL SPECIES INCLUDING "ACTEROIDES FRAGILIS #ORYNEBACTERIUM PSEUDOTUBERCULOSIS % COLI 3TAPHYLOCOCCUS AUREUS 3TREPTOCOCCUS EQUI SUBSP EQUI AND SUBSP ZOOEPIDEMICUS ; n= 3EPTIC BACTERIAL CHOLANGIOHEPATITIS IN ADULT HORSES AND FOALS IS SUSPECTED TO RESULT FROM REFLUX OF DUODENAL CONTENTS ALONG THE HEPATIC DUCT AND IS USU ALLY ASSOCIATED WITH 'RAM NEGATIVE ENTERIC BACTERIA SUCH AS !CTINOBACILLUS EQUULI "ACTEROIDES VULGATUS #ITROBACTER SP %SCHERICHIA COLI +LEBSIELLA PNEUMONIAE AND 3ALMONELLA SP ALTHOUGH 'RAM POSITIVE ISOLATES SUCH AS 3TREPTOCOCCUS SP ARE ALSO REPORTED ; n= 3EPTIC CHOLANGIOHEPATITIS HAS ALSO BEEN REPORTED IN ASSOCIATION WITH HEPATIC NEOPLASIA AND TREMATODE INFESTATION ; = "ILIARY INFECTION MAY PROVIDE FAVOURABLE CONDITIONS COM PRISING NIDUS FORMATION AND BILIARY STASIS THAT PREDISPOSES TO CHOLELITHIASIS /CCASIONAL REPORTS OF VEGETABLE MATTER FOUND WITHIN CHOLELITHS ALSO SUPPORT THIS SEQUENCE OF EVENTS ;= #HOLELITHIASIS CASES APPEAR TO HAVE GEOGRAPHIC PREDISPOSITION WITH MORE CASES REPORTED FROM THE 53! THAN OTHER COUNTRIES !S MOST EQUINE CHOLELITHS ARE COMPOSED OF CALCIUM SALTS BILIRUBINATE AND PHOSPHATE ;= THE PRACTICE OF ALFALFA FEEDING MAY HAVE RELEVANCE TO THEIR AETIOLOGY 3TONES AS LARGE AS CM DIAMETER ARE REPORTED AND PROGNOSIS FOR RECOVERY WITH MEDICAL OR SURGICAL MANAGEMENT IS POOR ;= /THER ORGANISMS OCCASIONALLY REPORTED IN ASSOCIATION WITH HEPATITIS IN HORSES INCLUDE THE PROTIST 0YTHIUM INSIDIOSUM ;= PROTOZOANS INCLUDING #YCLOPOSTHIUM SP 0OLYMORPHELLA AMPULLA AND 3ARCOCYSTIS SP ; = AND HELMINTHS SUCH AS %CHINOCOCCUS GRANULOSUS HYDATID CYSTS ;= &ASCIOLA HEPATICA ;n= &ASCIOLOIDES MAGNA ;= AND 3CHISTOSOMA SP ;= /THER LARVAL NEMATODES INCLUDING 0ARASCARIS EQUORUM 3TRONGYLUS EDENTATUS AND 3 EQUINUS MAY CAUSE HEPATITIS DURING TRANSIT THROUGH THE LIVER AS PART OF THEIR NORMAL MIGRATORY AND DEVELOPMENTAL LIFECYCLE ;n=
!NDY % $URHAM
#HRONIC ACTIVE HEPATITIS IS A POORLY UNDERSTOOD CONDITION CHARACTERISED BY PERSISTENT AND PROGRESSIVE PERIPORTAL INFLAMMATORY INFILTRATES FIBROPLASIA AND BILIARY HYPERPLASIA AND IS OCCASIONALLY SEEN IN ADULT HORSES ; = 4HE AETIOL OGY OF SUCH CASES IS SPECULATIVE 3OME CASES APPEAR TO DEVELOP FROM UNTREAT ED OR NON RESPONSIVE CASES OF SEPTIC CHOLANGIOHEPATITIS OR 4HEILERS DISEASE ;= WHEREAS OTHERS APPEAR TO BE CONSISTENTLY LYMPHOCYTIC WITHOUT EVIDENCE OF PRIOR SEPSIS OR NECROSIS #HRONIC HEPATOTOXICITY VIRAL INFECTION AND IMMUNE MEDIATED DISEASE HAVE BEEN PROPOSED TO EXPLAIN SOME CASES ; = #HRONIC HEPATITIS HAS BEEN REPORTED IN SEVERAL HORSES AS PART OF A MULTISYSTEMIC INFILTRATIVE INFLAMMATORY DISEASE PROCESS OFTEN ADDITIONALLY INVOLVING SKIN LUNG INTESTINE AND OTHER ORGANS -ULTIFOCAL GRANULOMATOUS INFLAMMATION WITH OR WITHOUT EVIDENCE OF -YCOBACTERIA ;n= AND MUL TISYSTEMIC EOSINOPHILIC EPITHELIOTROPHIC DISEASE -%%$ ; n= ARE THE COMMONEST FORMS OF CHRONIC MULTIFOCAL INFLAMMATORY DISEASE IN HORSES #ASES USUALLY PRESENT WITH SIGNS OF WEIGHT LOSS POSSIBLY IN ASSOCIATION WITH SKIN LESIONS (EPATITIS IS MORE OFTEN DISCOVERED FOLLOWING SERUM BIOCHEMI CAL ANALYSIS THAN ON THE BASIS OF CLINICAL SIGNS
$IAGNOSIS 4HERE ARE THREE FUNDAMENTAL AIMS OF THE INVESTIGATION OF CASES OF SUSPECTED LIVER DISEASE FIRSTLY TO DIFFERENTIATE SUBJECTS GENUINELY SUFFERING FROM LIVER DISEASE FROM THOSE WHICH ARE NOT SECONDLY TO DETERMINE THE TYPE OF LIVER DISEASE AFFECTING THE SUBJECT AND THEREFORE APPROPRIATE THERAPY AND THIRDLY TO DIFFERENTIATE THOSE SUBJECTS WHICH ARE LIKELY TO SURVIVE FROM THOSE WHICH ARE NOT
#LINICAL SIGNS 3IGNS OFTEN ASSOCIATED WITH HEPATITIS CASES IN HORSES INCLUDE DEPRESSION WEIGHT LOSS COLIC PYREXIA ANOREXIA PHOTOSENSITISATION NEUROLOGICAL SIGNS SEE BELOW DIARRHOEA JAUNDICE OEDEMA PRURITUS EPISTAXIS POLYDIPSIA POLYURIA DIFFUSE SKIN DISEASE AND CORONITIS ; = 4HE PRESENCE OF SEVERE CLINICAL SIGNS OF HEPATIC INSUFFICIENCY HAS MAJOR PROGNOSTIC RELEVANCE ;= (OWEVER HEPATIC DISEASE IS MORE COMMON THAN HEPATIC INSUFFICIENCY AND MANY CASES OF LIVER DISEASE IN HORSES ARE SUBCLINICAL ; n= )N ONE STUDY OF SUSPECTED EQUINE HEPATOPATHY CASES WERE CONFIRMED BY BIOPSY TO HAVE SIGNIFICANT LIVER DISEASE BUT ONLY OF THESE WERE SHOWING SPECIFIC CLINICAL SIGNS OF SUCH ;= 4HEREFORE ABSENCE OF SPECIFIC CLINICAL SIGNS IN A SUBJECT SUSPECTED TO BE AFFECTED BY HEPATITIS EG ON THE BASIS OF LABORA TORY RESULTS IS OF LIMITED REASSURANCE (EPATITIDES HOWEVER WITH ASSOCIATED SYSTEMIC INFLAMMATORY RESPONSE MAY BE MORE LIKELY TO BE CLINICALLY PERCEPTIBLE PRIOR TO ONSET OF HEPATIC
(EPATITIS IN HORSES
INSUFFICIENCY THAN NON INFLAMMATORY HEPATOPATHIES 3OME SPECIFIC CAUSES OF HEPATITIS HAVE A SUGGESTIVE CLINICAL PRESENTATION 3ERUM HEPATITIS CAUSES ACUTE HEPATIC INSUFFICIENCY AND HAS AN ACUTE PRESENTATION OF MARKED DEPRES SION OFTEN WITH NEUROLOGIC SIGNS ;= #HOLANGIOHEPATITIS CASES WITH CHOLELITH FORMATION ARE ALSO READILY DIAGNOSED CLINICALLY WITH THE TYPICAL SIGNS OF COLIC PYREXIA AND JAUNDICE ; = -ULTISYSTEMIC INFLAMMATORY DISEASES ARE USUALLY SUSPECTED AS A RESULT OF THEIR INTESTINAL OR SKIN SIGNS RATHER THAN FROM HEPATITIS ALTHOUGH LABORATORY EVIDENCE OF LIVER DISEASE IN A HORSE WITH PROTEIN LOSING ENTEROPATHY AND CHRONIC DERMATITIS IS STRONGLY SUGGESTIVE OF THIS CONDITION ;= 4HE SYNDROME OF HEPATIC ENCEPHALOPATHY (% ENCOMPASSES A WIDE VARIETY OF NEUROLOGIC SIGNS IDENTIFIED IN SUBJECTS WITH HEPATIC INSUFFICIENCY AND PORTAL SYSTEMIC BYPASS ;= 3IGNS OF (% ARE USUALLY SUDDEN IN ONSET WHETHER THE UNDERLYING HEPATIC DISEASE IS ACUTE OR CHRONIC $IFFUSE CEREBRAL AND BRAIN STEM DYSFUNCTION IS MOST COMMONLY RECOGNISED WITH DEPRESSION DISORIENTATION CIRCLING COMPULSIVE WALKING HEAD PRESSING DYSPNOEA LARYN GEAL AND PHARYNGEAL PARESIS BLINDNESS YAWNING AND COMA BEING OBSERVED MOST FREQUENTLY /CCASIONALLY EXCITATION INCLUDING AGGRESSION AND SEIZURES ARE SEEN BUT THESE SIGNS ARE FAR LESS FREQUENT THAN SIGNS OF DEPRESSED NEU ROLOGIC FUNCTION /THER RARER SIGNS ATTRIBUTED TO (% INCLUDE PRURITUS FOOT STAMPING DYSPHAGIA AND GASTRIC IMPACTION ; =
(AEMATOLOGY 2EPORTS OF HORSES WITH LIVER DISEASE HAVE FOUND HIGHLY VARIABLE AND NON SPECIFIC HAEMATOLOGICAL FINDINGS WITH NEUTROPHILIA AND LYMPHOPAENIA BEING FAIRLY COMMON AND BOTH ANAEMIA AND ERYTHROCYTOSIS ALSO REPORTED ; n= .EUTROPHILIA IS A COMMON FINDING IN BACTERIAL HEPATITIS CASES AS PART OF THE SYSTEMIC INFLAMMATORY RESPONSE ALTHOUGH ONE STUDY FOUND LEU COCYTOSIS AND NEUTROPHILIA TO BE ASSOCIATED WITH SEVERE NON INFLAMMATORY HEPATOPATHIES ALSO ;= %RYTHROCYTOSIS WAS ALSO RELATIVELY COMMON IN THOSE CASES WITH A WORSE CLINICAL STATUS PROBABLY SECONDARY TO DEHYDRATION ;= !BSOLUTE ERYTHROCYTOSIS IS RECOGNISED AS A PARANEOPLASTIC SYNDROME IN CASES OF HEPATOBLASTOMA AND HEPATOCELLULAR CARCINOMA IN HORSES ;n= ALTHOUGH THIS HAS NOT BEEN REPORTED IN HEPATITIS CASES
3ERUM BIOCHEMISTRY "IOCHEMICAL SUBSTANCES MEASURED IN THE BLOOD OF SUSPECTED EQUINE HEPA TITIS CASES CAN BE SUBDIVIDED INTO INTRACELLULAR ENZYMES REFLECTING DAMAGED LIVER CELLS AND SUBSTANCES REFLECTING IMPAIRED LIVER FUNCTION !LTHOUGH VERY USEFUL DIAGNOSTIC AND PROGNOSTIC INFORMATION IS OBTAINED FROM LABORATORY ANALYSIS OF BLOOD SAMPLES NO BIOCHEMICAL TESTS ARE ABSOLUTELY ACCURATE AND
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THE CLINICIAN WILL SOMETIMES BE MISLED IF ABSOLUTE RELIANCE IS PLACED ON SUCH INFORMATION ;= .EVERTHELESS INCREASED SERUM ENZYME CONCENTRATIONS ARE A REASONABLY RELIABLE INDICATOR OF HEPATIC DISEASE ESPECIALLY WHEN CORROBO RATED BY INCREASES IN SEVERAL DIFFERENT ENZYMES &URTHERMORE ABNORMAL LIVER FUNCTION TESTS SUGGEST HEPATIC INSUFFICIENCY IN A SUBJECT WITH INCREASED SERUM ENZYME CONCENTRATIONS ; =
3ERUM ENZYMES 3EVERAL INTRACELLULAR ENZYMES FOUND IN HEPATOCYTES AND BILIARY EPITHELIA CAN BE USED TO INFER LIVER DISEASE INCLUDING ALANINE AMINOTRANSFERASE !,4 ALKALINE PHOSPHATASE !0 ARGINASE ASPARTATE AMINOTRANSFERASE !34 GAMMA GLUTAMYLTRANFERASE a'4 GLUTAMATE DEHYDROGENASE ',$( IDITOL DEHYDROGENASE AND LACTATE DEHYDROGENASE ; n= WITH !0 !34 a'4 AND ',$( BEING IN THE MOST COMMON USAGE !0 HAS BEEN FOUND TO BECOME ELEVATED WITHIN H OF ACUTE HEPATIC INSULT ALTHOUGH SIGNIFICANT ELEVATIONS HAVE NOT BEEN CONSISTENTLY REPORTED IN ACUTE ; = OR CHRONIC ;n= HEPATOPATHIES )NCREASED SERUM CONCENTRA TIONS OF !0 MAY ALSO BE DERIVED FROM INTESTINE INFLAMMATORY CELLS BONE AND PLACENTA ;= !0 HAS BEEN SHOWN HOWEVER TO BE SUPERIOR TO MOST OTHER ENZYMES FOR PREDICTION OF PROGNOSIS IN CASES OF LIVER DISEASE ; = !LTHOUGH OFTEN CONSIDERED TO REFLECT CHRONIC HEPATOPATHIES ; = a'4 HAS BEEN SHOWN TO BE A SENSITIVE INDICATOR OF ACUTE HEPATIC INSULT ALSO ; = a'4 AND !34 ARE PROBABLY THE MOST SENSITIVE INDICATORS OF HEPATITIS BUT LACK SPECIFICITY ;= )N CONTRAST TO A GENERALLY HIGH REGARD FOR a'4 AS THE MOST CLINICALLY USEFUL LIVER DERIVED ENZYME IN COMMON USAGE ; = CASES ARE FREQUENTLY SEEN WITH INCREASED a'4 IN WHICH LIVER BIOPSY FAILS TO IDENTIFY SIGNIFICANT LIVER DISEASE ;= #ONVERSELY CASES OF HEPATOPATHY WITH NORMAL SERUM a'4 CONCENTRATIONS ARE LESS COMMONLY REPORTED ;n= a'4 WAS FOUND TO BE PROGNOSTICALLY USEFUL ONLY IN SUBJECTS WITH MARKEDLY INCREASED LEVELS IUL ; = 4HE PANCREAS AND RENAL TUBULES ARE ALSO RICH SOURCES OF a'4 ALTHOUGH RENALLY DERIVED a'4 IS WIDELY ACCEPTED TO APPEAR IN URINE AND NOT SERUM ;= )T HAS BEEN SUGGESTED THAT RELATIVE DIFFERENCES IN SERUM CONCENTRATIONS OF LIVER DERIVED ENZYMES MAY INFER THE UNDERLYING NATURE OF THE LIVER DISEASE ; = %XPERIMENTAL STUDIES HAVE SUGGESTED A PRIMARILY BILIARY SOURCE FOR a'4 HEPATOCELLULAR SOURCES FOR !,4 !34 ',$( AND )$( AND BOTH BILI ARY AND HEPATOCELLULAR SOURCES FOR !0 ;n= !LTHOUGH THE ASSOCIATION OF ENZYME PATTERNS WITH SUBTYPES OF HEPATITIS MAY BE AN IMPERFECT GENERALISA TION HEPATOCELLULAR DISEASES SUCH AS SERUM HEPATITIS WILL USUALLY BE ASSOCIAT ED WITH SIMILARLY MARKED INCREASES IN ALL ENZYMES ALTHOUGH CHOLANGIOHEPATI TIS CASES ESPECIALLY WITH BILIARY OBSTRUCTION WILL SHOW THE GREATEST INCREASES IN a'4 AND !0 ; = (OWEVER ELEVATIONS IN SERUM a'4 HAVE BEEN REPORTED IN ASSOCIATION WITH ACUTE HEPATOCELLULAR NECROSIS IN THE ABSENCE OF
(EPATITIS IN HORSES
NOTABLE BILIARY INSULT AND OCCASIONAL CASES OF LIVER DISEASE ARE SEEN WHERE INCREASING CONCENTRATIONS OF SERUM a'4 MAY BE NOTED DESPITE EVIDENCE OF IMPROVEMENT OF THE HEPATOPATHY ; = 4HESE PARADOXICAL FINDINGS HAVE BEEN EXPLAINED AS BEING CONSEQUENCES OF BILIARY HYPERPLASIA ;= AND ONE STUDY FOUND A HIGHLY SIGNIFICANT ASSOCIATION BETWEEN THE SEVERITY OF BILIARY HYPERPLASIA AND THE SERUM CONCENTRATIONS OF !0 AND a'4 ;= !LTHOUGH ',$( IS CONSIDERED TO BE LIVER SPECIFIC THIS AUTHOR HAS ENCOUNTERED MANY CASES IN WHICH HIGH ',$( CONCENTRATIONS WERE NOT SUPPORTED BY LIVER BIOPSY FINDINGS ;= 4HIS MIGHT POSSIBLY BE EXPLAINED BY HISTOPATHOLOGICALLY INSIGNIFICANT HEPATIC INSULTS RESULTING IN INCREASED SERUM ',$( CONCENTRATIONS 4HE PROGNOSTIC VALUE OF ',$( IS DISPUTED ; =
"IOCHEMICAL INDICATORS OF HEPATIC FUNCTION &URTHER SERUM BIOCHEMICAL TESTS MAY PROVIDE EVIDENCE OF ADEQUATE COM PENSATION VERSUS INSUFFICIENCY OF HEPATIC FUNCTION IN SUSPECTED HEPATITIS CASES AND GENERALLY OFFER GREATER DIAGNOSTIC AND PROGNOSTIC VALUE THAN SERUM ENZYMES ; = 4HE MONITORING OF SUBSTANCES THAT ARE USUALLY EXTRACTED FROM SERUM BY THE LIVER EG BILE ACIDS AND BILIRUBIN OR WHOSE SERUM LEVELS ARE MAINTAINED BY A NORMALLY FUNCTIONING LIVER EG ALBUMIN GLOBULINS AND UREA FORM THE BASIS FOR THESE @FUNCTIONAL TESTS 3UCH PARAMETERS ARE LIKELY TO BE MORE EFFECTIVE THAN SERUM ENZYMES IN THE DIFFERENTIATION OF COMPEN SATED HEPATITIS FROM DECOMPENSATED HEPATIC FAILURE 4HOSE IN MOST COMMON USAGE ARE LISTED ABOVE BUT MAY ADDITIONALLY INCLUDE VARIOUS AMINO ACIDS AMMONIA FIBRINOGEN GLUCOSE COAGULATION TESTS ACTIVATED PARTIAL THROM BOPLASTIN TIME ;!044= AND PROTHROMBIN TIME ;04= AND HALF LIFE OF PLASMA BROMOSULPHTHALENE INDOCYANINE GREEN AND RADIONUCLEIDES ; = &AILURE OF NORMAL EXTRACTIVE PROCESSES BY DAMAGED HEPATOCYTES OFTEN LEADS TO INCREASED SERUM BILE ACID CONCENTRATION AND THIS IS STRONGLY ADVO CATED AS AN EXCELLENT DIAGNOSTIC AND PROGNOSTIC INDICATOR OF HEPATIC INSUF FICIENCY IN THE HORSE ; = 4HE MAIN LIMITATION OF SERUM BILE ACID MEASUREMENT IS ITS INSENSITIVITY AND EARLY OR MILD HEPATITIS CASES WILL USUALLY HAVE NORMAL RESULTS ;= )N ONE STUDY ONLY OF BIOPSY CONFIRMED LIVER DISEASE CASES HAD INCREASED SERUM BILE ACIDS ;= 3ERUM BILE ACID CON CENTRATIONS GREATER THAN +MOLL ARE PROGNOSTICALLY CONCERNING IN CHRONIC HEPATOPATHIES ;= AND CASES WITH VALUES ABOVE +MOLL ARE INVARIABLY FATAL (OWEVER BILE ACIDS ARE LESS PROGNOSTICALLY CONCERNING IN ACUTE HEPA TITIS CASES AND FAR HIGHER LEVELS +MOLL ARE OFTEN SEEN IN SUBJECTS THAT LATER RECOVER 5NCONJUGATED INDIRECT BILIRUBIN IS ALSO EXTRACTED FROM PLASMA BY FUNC TIONAL HEPATOCYTES AND THEN CONJUGATED PRIOR TO BILIARY EXCRETION !NOREXIA ;= AND HAEMOLYSIS ; = ARE ADDITIONAL CAUSES OF UNCONJUGATED INDIRECT HYPERBILIRUBINAEMIA WITH VALUES IN ANOREXIC SUBJECTS SOMETIMES EXCEEDING +MOLL IN THE ABSENCE OF LIVER DISEASE ;= 4HE MAJORITY OF EQUINE LIVER
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DISEASE CASES HAVE NORMAL OR ONLY MODERATE INCREASES IN SERUM BILIRUBIN CONCENTRATION ; = AND THE UNCONJUGATED FRACTION USUALLY COMPRISES OF THE TOTAL ;= CREATING INTERPRETIVE PROBLEMS IN ANOREXIC SUBJECTS /CCASIONAL CASES OF HEPATITIS IN THE HORSE IN WHICH SERUM CONJUGATED BILI RUBIN REPRESENTS GREATER THAN OF TOTAL BILIRUBIN ARE VERY LIKELY TO BE SUFFERING FROM OBSTRUCTION OF THE BILIARY TRACT ; = -ARKED HYPOALBUMINAEMIA GL IS RARELY SEEN AS A RESULT OF HEPATITIS IN HORSES DUE TO THE LONG SERUM HALF LIFE OF ALBUMIN AND THE LARGE RESERVE CAPACITY OF THE LIVER ; = ALTHOUGH EVEN MILD TO MODERATE HYPOALBUMINAEMIA EG n GL SUGGESTS A GUARDED PROGNOSIS ; = 3ERUM ALBUMIN CONCENTRATIONS BELOW GL ARE VERY RARELY ENCOUNTERED EVEN IN SEVERE HEPATOPATHIES AND SUCH LOW VALUES SHOULD CREATE A SUSPICION OF A MULTISYSTEMIC PROCESS EG -%%$ AND PROTEIN LOSING ENTEROPATHY ;= (YPERGLOBULINAEMIA IS A VERY USEFUL DIAGNOSTIC AND PROGNOSTIC TEST IN EQUINE LIVER DISEASE ; = AND MAY RESULT FROM THE SYSTEMIC INFLAMMA TORY RESPONSE ASSOCIATED WITH HEPATITIS OR PERHAPS FROM SYSTEMIC IMMUNO STIMULATION BY INTESTINAL DERIVED ANTIGENIC MATERIAL FOLLOWING LOSS OF THE PROTECTIVE BARRIER OF HEPATIC MONONUCLEAR MACROPHAGES +UPFFER CELLS ;= (YPERGLOBULINAEMIA GL HAS BEEN DEMONSTRATED TO BE SUPERIOR TO OTHER SERUM BIOCHEMICAL PARAMETERS IN PREDICTING NON SURVIVAL OF LIVER DISEASE CASES ;= 4HE LIVER IS THE MAIN SITE OF DETOXIFICATION OF AMMONIA .( AND ITS BIOTRANSFORMATION INTO UREA AND THIS HAS BEEN USED TO EXPLAIN THE ASSO CIATION OF LOW SERUM UREA AND HYPERAMMONAEMIA WITH LIVER FAILURE ; = !LTHOUGH MOST CASES OF LIVER DISEASE HAVE NORMAL SERUM UREA CONCENTRA TIONS ; = LOW SERUM UREA LEVELS HAVE FREQUENTLY BEEN DESCRIBED IN EQUINE HEPATOPATHIES ; = /NE STUDY QUESTIONED THE ABOVE EXPLANATION OF LOW SERUM UREA BY FINDING NO SIGNIFICANT ASSOCIATION BETWEEN SERUM UREA AND .( CONCENTRATIONS ;= !NOTHER STUDY ALSO FOUND LOW SERUM CREATININE TO BE ASSOCIATED WITH SEVERE LIVER DISEASE AND PROPOSED POLYDIPSIA AND RENAL WASHOUT AS A CAUSAL FACTOR IN HEPATOPATHY CASES WITH LOW UREA AND CREATININE ;= 7HATEVER THE MECHANISM IT IS WELL ESTABLISHED THAT LOW SERUM UREA IS ASSOCIATED WITH HEPATIC INSUFFICIENCY AND HAS PROGNOSTIC RELEVANCE ;= (YPERAMMONAEMIA IS A FAIRLY CONSISTENT FINDING IN EQUINE SUBJECTS WITH (% ; = ALTHOUGH THE ASSOCIATION BETWEEN PLASMA .( AND SIGNS OF (% WAS ONLY OF BORDERLINE SIGNIFICANCE IN ONE STUDY ;= !NOTHER INVESTIGATION FOUND THAT ALTHOUGH PLASMA .( CONCENTRATION WAS INCREASED IN NEARLY ALL CASES SHOWING SIGNS OF (% THE CONCENTRATIONS VARIED AND DID NOT CORRELATE WITH SEVERITY OF THE DISEASE ;= &URTHERMORE OCCASIONAL CASES WERE FOUND TO HAVE INCREASED PLASMA .( WITHOUT SHOWING SIGNS OF (% ;= !DDITIONAL DOUBTS ABOUT THE PATHOGENIC ROLE OF .( IN (% HAVE BEEN RAISED BY THE CONTRASTING EFFECTS OF EXPERIMENTALLY INDUCED HYPERAMMONAEMIA SUPPORT ING THE VIEW THAT OTHER FACTORS ARE OFTEN INVOLVED IN THE PATHOGENESIS OF (% ; = !DDITIONAL AND SOMETIMES INTERACTING PATHOGENIC ROLES ARE PROPOSED FOR TUMOUR NECROSIS FACTOR _ AROMATIC AMINO ACIDS MANGANESE
(EPATITIS IN HORSES
COPPER PHENOLS BENZODIAZEPINE LIKE SUBSTANCES MERCAPTANS SHORT CHAIN FATTY ACIDS MONOAMINES NEUROSTEROIDS BILIRUBIN AND ELECTROLYTES ;n= !N ALTERNATIVE EXPLANATION OF THE WEAK ASSOCIATION BETWEEN PLASMA .( AND (% IS THAT THE ABILITY OF .( TO CROSS THE BLOOD BRAIN BARRIER IS INCREASED IN SUBJECTS WITH (% ; n= /NE STUDY IDENTIFIED A HIGH CONCENTRATION OF .( IN THE CEREBROSPINAL FLUID OF A HORSE WITH (% ;= !STROCYTIC GLUTAMINE SYNTHESIS FROM .( IS GREATLY INCREASED IN (% CASES AND THE OSMOTIC EFFECT OF INCREASED GLUTAMINE IS THE LIKELY ULTIMATE CAUSE OF ASTROCYTE SWELLING A KEY PATHOLOGICAL EVENT IN (% ; = (EPATITIS AND ACUTE PHASE PROTEINS !00S HAVE AN UNPREDICTABLE ASSO CIATION -OST !00S ARE SYNTHESISED BY THE LIVER AND SUBSEQUENTLY DECREASED HEPATIC BIOSYNTHESIS OF FIBRINOGEN HAS OFTEN BEEN REPORTED IN ASSOCIATION WITH EQUINE HEPATITIDES ; = (OWEVER THE SYSTEMIC INFLAMMA TORY RESPONSE FREQUENTLY SEEN IN ASSOCIATION WITH HEPATIC INSUFFICIENCY EG HYPERGLOBULINAEMIA NEUTROPHILIA TUMOUR NECROSIS FACTOR _ AND MORE ESPECIALLY HEPATITIDES PROVIDES A POSSIBLE EXPLANATION OF THE ASSOCIATION BETWEEN HIGHER PLASMA FIBRINOGEN AND FAILURE TO SURVIVE FOUND IN ONE STUDY OF EQUINE HEPATIC DISEASE ;= "ACTERIAL HEPATITIDES SEPTIC CHLOLANGITIS ABSCESSES ETC ARE CERTAINLY EXPECTED TO PROVOKE SIGNIFICANT HEPATIC !00 SYNTHESIS AND HIGHER CONCENTRATIONS OF FIBRINOGEN EG GL OR SERUM AMYLOID ! MGL SUGGEST A BACTERIAL AETIOLOGY 4HEORETICALLY THE EFFECT OF HEPATIC INSUFFICIENCY ON BLOOD COAGULATION IS HARD TO PREDICT AS THE LIVER IS THE MAJOR SITE OF SYNTHESIS OF MOST PROCO AGULANT ANTICOAGULANT AND FIBRINOLYTIC PROTEINS AND PLATELET DYSFUNCTION IS ALSO REPORTED ;= (OWEVER LABORATORY MEASURES OF HAEMOSTASIS !044 AND 04 ARE INVARIABLY PROLONGED IN ASSOCIATION WITH HEPATIC FAILURE ;= !LTHOUGH CLINICOPATHOLOGIC EVIDENCE OF COAGULOPATHY IS SEEN RELATIVELY FREQUENTLY IN SEVERE HEPATITIS CASES CLINICAL SIGNS OF BLEEDING ARE QUITE RARE ; = (EPATIC INSUFFICIENCY IS ASSOCIATED WITH INCREASED SERUM CONCENTRATIONS OF METHIONINE AND AROMATIC AMINOACIDS TYROSINE TRYPTOPHAN AND PHENYL ALANINE DUE TO REDUCED HEPATIC CLEARANCE ! SIMILAR INCREASE IS NOT SEEN IN BRANCHED CHAIN AMINOACIDS VALINE LEUCINE AND ISOLEUCINE THAT CONTINUE TO BE METABOLISED IN OTHER TISSUES SUCH AS MUSCLE ;= 4HE ALTERED BALANCE OF SERUM AMINOACIDS MAY CONTRIBUTE TO THE SIGNS OF (% BY LEADING TO INCREASES IN FALSE NEUROTRANSMITTERS ;= -EASUREMENT OF SERUM AMINO ACIDS DOES NOT APPEAR TO BE POPULAR IN EQUINE PRACTICE ALTHOUGH IT HAS A GOOD EVIDENCE BASIS ; = (EPATIC GLUCONEOGENESIS IS THE MAIN MECHANISM MAINTAINING FASTING EUGLYCAEMIA AND HYPOGLYCAEMIA IS OCCASIONALLY ENCOUNTERED IN ACUTE AND TERMINAL HEPATITIS CASES PRESUMABLY AS A RESULT OF FAILURE OF THIS PROCESS ;= (OWEVER THIS IS FAR MORE LIKELY TO BE ENCOUNTERED IN FOALS THAN IN ADULT HORSES )N MOST CLINICAL CASES NORMO TO HYPER GLYCAEMIA ARE MORE COMMON PERHAPS AS A RESULT OF A STRESS RESPONSE TO ILLNESS WITH ACUTE INSULIN RESIS TANCE ; =
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4HE ABILITY OF THE LIVER TO REMOVE EXOGENOUS AGENTS SUCH AS BROMOSUL PHTHALENE INDOCYANINE GREEN AND RADIOPHARMACEUTICALS FORMS THE BASIS FOR DYNAMIC TESTS OF LIVER FUNCTION ; = ,OGISTICS OF DYNAMIC TESTING AND LACK OF AVAILABILITY OF TESTING FACILITIES IN COMPARISON TO EASILY MEASURED ALTERNATIVES ABOVE HAVE LIMITED THEIR USE AND NONE ARE POPULAR IN EQUINE PRACTICE 3TUDIES HAVE ESTABLISHED THE PROGNOSTIC IMPORTANCE OF HEPATIC FIBROPLA SIA IN HORSES ;= BUT UNLIKE HUMAN MEDICINE NO SERUM MARKERS OF FIBROSIS HAVE BEEN INVESTIGATED IN EQUINE HEPATITIS CASES (YALURONAN A PARAMETER REFLECTING HEPATIC FIBROSIS IN HUMANS ; = HAS BEEN MEASURED SUCCESS FULLY IN HORSES IN EXPERIMENTAL STUDIES OF JOINT AND LUNG DISEASES ;= AND MERITS FURTHER INVESTIGATION IN THE CONTEXT OF EQUINE LIVER DISEASE
5LTRASONOGRAPHY %XCEPT IN RARE CASES OF MARKED HEPATIC ATROPHY A PROPORTION OF THE EQUINE LIVER IS AMENABLE TO TRANSCUTANEOUS ULTRASONOGRAPHY USING TO -(Z TRANSDUCERS ;= 4HE NORMAL LIVER IS ENTIRELY WITHIN THE BOUNDARIES OF THE RIBCAGE AND AERATED LUNG POSES THE MAIN ULTRASONOGRAPHIC OBSTRUCTION AND SIGNIFICANTLY LIMITS THE VALUE OF THE TECHNIQUE IN HORSES 4HE LUNG MARGINS REPRESENT THE CRANIO DORSAL LIMITS OF THE HEPATIC IMAGE ON BOTH SIDES )N ALMOST ALL CASES THE RIGHT HEMITHORAX ALLOWS IMAGING OF A GREATER QUANTITY OF LIVER OFTEN BETWEEN THE TH AND TH RIBS ALTHOUGH THERE IS CONSIDER ABLE INDIVIDUAL VARIATION IN THE NUMBER OF INTERCOSTAL SPACES VIA WHICH AN IMAGE CAN BE OBTAINED 4HE IMAGE OF THE RIGHT LIVER LOBE IS APPROXIMATELY TRIANGULAR ! HYPERECHOIC CURVILINEAR IMAGE OF THE RIGHT COLON DORSAL AND VENTRAL IS CONSISTENTLY IMAGED DEEP TO THE RIGHT LIVER LOBE AND A SMALLER MOTILE DUODENUM IS FREQUENTLY IMAGED ON THE MEDIAL SURFACE BETWEEN THE LIVER AND COLON IN THE MORE CAUDAL INTERCOSTAL SPACES EG n /N THE LEFT SIDE LIVER CAN ONLY USUALLY BE IMAGED VIA OR INTERCOSTAL SPACES IMME DIATELY CAUDAL TO THE LEFT VENTRICLE #ARE SHOULD BE TAKEN NOT TO CONFUSE THE HEPATIC IMAGE WITH THE ADJACENT SPLEEN 4HE LATTER IS MORE CAUDAL MORE ECHOGENIC AND EXTENDS FROM THE MEDIAL ASPECT OF THE LIVER CRANIALLY TO THE LATERAL ABDOMINAL WALL CAUDALLY OVER MANY MORE INTERCOSTAL SPACES THAN THE RELATIVELY SMALL AND HYPOECHOIC LIVER 3TUDIES HAVE ESTABLISHED SIGNIFICANT DIAGNOSTIC AND PROGNOSTIC CLINICAL USEFULNESS OF HEPATIC ULTRASONOGRAPHY ; = )MAGES CLASSIFIED AS ABNORMAL HAVE A HIGH SPECIFICITY FOR THE PRESENCE OF SIGNIFICANT LIVER DISEASE ;= AND ARE ASSOCIATED WITH POORER CLINICAL OUTCOMES ;= ALTHOUGH LOW SENSITIVITY FOR DETECTING LIVER DISEASE IS THE MAIN LIMITATION AND MANY HORSES WITH NORMAL ULTRASONOGRAPHIC HEPATIC IMAGES WILL BE CONFIRMED TO HAVE SIG NIFICANT LIVER DISEASE IN BIOPSY SPECIMENS ;= &REQUENTLY SUSPECTED ULTRA SONOGRAPHIC ABNORMALITIES SUCH AS ABNORMAL ECHOGENICITY SIZE AND SHAPE ARE SUBJECTIVELY ASSESSED ALTHOUGH CYSTS CHOLELITHS NEOPLASMS ABSCESSES
(EPATITIS IN HORSES
HAEMATOMA AND HEPATIC RUPTURE MAY BE MORE OBJECTIVELY DEFINED ; = )NCREASED HEPATIC ECHOGENICITY HAS BEEN REPORTED PREVIOUSLY IN CASES OF HEPATIC FIBROSIS HAEMOSIDEROSIS AND LIPIDOSIS AND ROUNDING OF HEPATIC MARGINS MAY SUGGEST HEPATOMEGALY ; = )N THIS AUTHORS VIEW THE MAIN VALUE OF HEPATIC ULTRASONOGRAPHY IS AS AN IMPORTANT ADJUNCT TO BIOPSY 5LTRASONOGRAPHIC GUIDANCE ALLOWS MORE CAREFUL SELECTION OF A BIOPSY SITE THAT PROBABLY IMPROVES THE SAFETY AND DIAGNOSTIC SUCCESS OF THE BIOPSY PROCEDURE SEE BELOW
,APAROSCOPY 2ARELY HEPATOPATHY CASES ARE SEEN IN WHICH NO LIVER TISSUE CAN BE IMAGED ULTRASONOGRAPHICALLY AND LAPAROSCOPY CAN THEN BE USED TO VISUALISE THE LIVER AND GUIDE BIOPSY COLLECTION 4HIS HAS PROVEN VERY VALUABLE IN SEVERAL CASES SEEN BY THIS AUTHOR 4HE READER IS REFERRED TO SURGICAL TEXTS FOR FURTHER DESCRIPTION OF THE TECHNIQUE ;=
,IVER BIOPSY )N THE ABSENCE OF NON INVASIVE TESTS THAT CAN RELIABLY DISTINGUISH HORSES WITH SIGNIFICANT LIVER DISEASE FROM THOSE WITHOUT EVIDENCE OF SIGNIFICANT LIVER DISEASE ;= HISTOPATHOLOGICAL EXAMINATION OF LIVER BIOPSIES HAS BECOME ESTABLISHED AS THE ANTE MORTEM TEST OF GREATEST VALUE IN COMMON USAGE ; = (ISTOPATHOLOGIC ASSESSMENT OF BIOPSY SPECIMENS IS OF GREAT PROGNOSTIC VALUE AND GUIDES THE CHOICE OF SPECIFIC THERAPY IN INDIVIDUAL CASES )T IS ALSO THE DIAGNOSTIC TECHNIQUE MOST LIKELY TO PROVIDE A SPECIFIC DIAGNOSIS AND AETIOLOGIC INFORMATION !DDITIONALLY GIVEN THE LACK OF ABSOLUTE RELIABILITY OF SERUM BIOCHEMICAL DATA WHEN MONITORING RESPONSE TO TREATMENT IN HEPA TITIS CASES REPEAT BIOPSY MAY BE THE BEST TECHNIQUE TO ESTABLISH ADEQUATE RECOVERY AND INDEED THE PRESENCE OR ABSENCE OF FURTHER SECONDARY CHANGES FOLLOWING INITIAL BIOPSY ,IVER BIOPSY IS AN EASY SAFE AND HIGHLY INFORMATIVE DIAGNOSTIC PROCEDURE IN CASES OF SUSPECTED HEPATITIS ; = !LTHOUGH ADVERSE EFFECTS SUCH AS HAEMORRHAGE COLIC PERITONITIS PLEURITIS AND PNEUMOTHORAX ARE ALL REPORTED ;= THESE PROBLEMS ARE VERY RARELY ENCOUNTERED 4HE IMPORTANCE AND USE FULNESS OF THE INFORMATION OBTAINED BY BIOPSY INVARIABLY OUTWEIGHS THE ASSO CIATED RISKS IN THIS AUTHORS VIEW ESPECIALLY WHEN THE TECHNIQUE IS PERFORMED UNDER ULTRASONOGRAPHIC GUIDANCE !LTHOUGH MANY RECOMMEND PRE BIOPSY COAGULATION ASSESSMENT ; = THE REQUIREMENT FOR THIS IS QUESTIONABLE ;= /NE STUDY REPORTED SIGNS OF INTRA ABDOMINAL HAEMORRHAGE AT AUTOPSY FOLLOWING LIVER BIOPSY IN THREE HORSES WITH PROLONGED CLOTTING TIMES ALTHOUGH QUANTITY AND ASSOCIATED CLINICAL SIGNS WERE NOT DESCRIBED ;= ! FURTHER REPORT DESCRIBED A SINGLE CASE OF POST BIOPSY HAEMORRHAGE OUT OF LIVER BIOPSIES IN
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HORSES 4HE CASE IN QUESTION WAS KNOWN TO HAVE MARKEDLY PROLONGED 04 BUT CLINICAL SIGNS OF THE HAEMORRHAGE OR OUTCOME WERE AGAIN NOT DESCRIBED ;= -ANY FURTHER REPORTS EXIST DESCRIBING LIVER BIOPSIES PERFORMED IN HORSES WITH BOTH SUBCLINICAL AND CLINICAL COAGULOPATHIES WITHOUT SUBSEQUENT CLINICAL SIGNS OF HAEMORRHAGE ; = .O COMPLICATIONS WERE REPORTED FOLLOWING LIVER BIOPSIES IN MORE THAN HORSES AND RUMINANTS ;= AND NOT A SINGLE CASE OF CLINICALLY SIGNIFICANT HAEMORRHAGE HAS BEEN SEEN BY THIS AUTHOR FOLLOWING MORE THAN LIVER BIOPSY PROCEDURES /THER CLINICIANS HAVE ALSO DESCRIBED THE RISKS OF LIVER BIOPSY IN THE HORSE AS MINIMAL ;= 4HE ONLY ADVERSE EFFECTS OF LIVER BIOPSY OBSERVED BY THIS AUTHOR WERE TWO HORSES THAT SHOWED LOW GRADE ABDOMINAL PAIN FOLLOWING BIOPSY THAT WAS IMMEDIATELY RESPONSIVE TO PHENYLBUTAZONE )T IS NOW THIS AUTHORS ROUTINE PRACTICE TO ADMINISTER n G PHENYLBUTAZONE IV PRIOR TO THE BIOPSY PROCEDURE -OST ULTRASONOGRAPHIC TRANSDUCERS CAN BE FITTED WITH A NEEDLE GUIDE THAT FIXES THE BIOPSY NEEDLE IN THE PLANE OF THE ULTRASONOGRAPHIC IMAGE SO THAT PROGRESS OF THE BIOPSY NEEDLE CAN BE OBSERVED IN REAL TIME 4HIS AUTHOR USUALLY USES A -(Z TRANSDUCER ALTHOUGH OCCASIONALLY OR -(Z TRANS DUCERS MAY BE USED DEPENDING ON BODY SIZE AND SUBCUTANEOUS FAT DEPTH ! SUITABLE SITE FOR BIOPSY IS CHOSEN ULTRASONOGRAPHICALLY ON THE BASIS OF REASONABLE TARGET SIZE AND ABSENCE OF LARGE VESSELS !LTHOUGH THE RIGHT SIDE IS USUALLY CHOSEN LEFT SIDED BIOPSIES ARE SOMETIMES COLLECTED 2OUTINE SEDA TION IS PERFORMED WITH DETOMIDINE MG KG IV AND BUTORPHANOL n MG KG IV AND THE CHOSEN SITE IS PREPARED SURGICALLY AND INFILTRATED WITH LOCAL ANAESTHETIC ! SMALL STAB INCISION IN THE SKIN FACILITATES THE PROCEDURE 3TERILE COUPLING GEL OR ALCOHOL IS APPLIED TO THE AREA AND A GAUGE n CM SEMI AUTOMATIC SPRING LOADED BIOPSY NEEDLE IS FITTED TO THE BIOPSY GUIDE AND INTRODUCED THROUGH THE STAB INCISION AND INTO THE LIVER -OST BIOPSIES ARE COLLECTED AT A DEPTH OF n CM FROM THE SKIN SURFACE )T IS IMPORTANT NOT TO ALLOW EVEN MILD BENDING OF THE NEEDLE AS THIS WILL PREVENT THE NORMAL FIRING MECHANISM FROM CUTTING A BIOPSY SPECIMEN !T LEAST TWO BIOPSIES ARE USUALLY COLLECTED /NE IS PLACED IN FORMOL SALINE FOR HISTOPATHOLOGY AND THE OTHER IN A STERILE CONTAINER FOR BACTERIOLOGIC CULTURE ALTHOUGH THE LATTER IS OFTEN UNSUCCESSFUL EVEN WHEN A BACTERIAL AETIOLOGY IS SUSPECTED $ETERMINATION OF THE PRESENCE OR ABSENCE OF DISEASE IS THE MOST FUNDA MENTAL QUESTION THAT MAY BE ANSWERED FOLLOWING EXAMINATION OF LIVER BIOP SY SPECIMENS BUT THIS REQUIRES CLEAR HISTOPATHOLOGIC CRITERIA WITH WHICH TO DISTINGUISH DISEASED FROM NORMAL LIVERS $ESCRIPTIONS OF MICROSCOPICAL STRUC TURE OF HEALTHY AND DISEASED LIVERS CAN BE FOUND IN HISTOLOGY AND PATHOLOGY TEXTS ; = ALTHOUGH IN PRACTICE THE DISTINCTION MAY BE LESS CLEAR /NE STUDY EXAMINED LIVER SPECIMENS FROM NORMAL HORSES AND FOUND THAT HAD UP TO FIVE LEUCOCYTES PRIMARILY LYMPHOCYTES IN REPRESENTATIVE PORTAL TRACTS ;= 3IGNIFICANT HEPATITIS WOULD THUS BE DEFINED BY THE PRESENCE OF INFLAMMATORY CELLS PER PORTAL TRACT AND POSSIBLY IN ADDITION SECONDARY CHANGES INCLUDING ANY DEGREE OF FIBROPLASIA BILIARY HYPERPLASIA OR NECROSIS HAEMOSIDEROSIS AFFECTING OF HEPATOCYTES AND HYDROPIC DEGENERATION
(EPATITIS IN HORSES
4ABLE 3UMMARY OF SCORES ASSIGNED TO THE SEVERITY OF FIVE HISTOPATHOLOGICAL CRITERIA CON TRIBUTING TO A TOTAL PROGNOSTIC LIVER BIOPSY SCORE MINIMUM SCORE MAXIMUM SCORE )RREVERSIBLE CYTOPATHOLOGY NECROSIS MEGALOCYTOSIS OR AMYLOIDOSIS ;= SEVERITY MILD
MODERATE
SEVERE
&IBROSIS
n
)RREVERSIBLE CYTOPATHOLOGY
)NFLAMMATORY INFILTRATE
n
(AEMOSIDERIN ACCUMULATION
n
n
"ILIARY HYPERPLASIA
n
CLOUDY CHANGE OR CYTOPLASMIC GRANULARITY OF HEPATOCYTES AFFECTING OF A REPRESENTATIVE LOBULE ;= ! POTENTIAL MAJOR CAUSE OF INSENSITIVITY OF LIVER BIOPSY IS THE COLLECTION OF AN UNREPRESENTATIVE SPECIMEN OF LIVER 4HIS IS ILLUSTRATED FOR EXAMPLE IN REPORTS OF EIGHT CASES OF HEPATIC NEOPLASIA OUT OF WHICH ONLY THREE SHOWED EVIDENCE OF TUMOUR DEPOSITS IN LIVER BIOPSY SPECIMENS ; = AND ONE WAS INITIALLY MISDIAGNOSED AS CHOLANGIOHEPATITIS ;= (OWEVER THIS IS NOT A COMMON SCENARIO AND OTHERS HAVE FOUND THAT ALMOST ALL SERIOUS EQUINE HEPATIC DISEASE AFFECTS THE LIVER DIFFUSELY AND THE CORRELATION BETWEEN HIS TOPATHOLOGIC FINDINGS IN BIOPSY SPECIMENS AND SUBSEQUENT AUTOPSY MATERIAL IS EXCELLENT ; = &IBROSIS IS A COMMON AND NON SPECIFIC RESPONSE TO LIVER INJURY ;= AND ALTHOUGH USUALLY ASSOCIATED WITH CHRONIC HEPATOPATHIES FIBROSIS HAS BEEN DETECTED AS SOON AS DAYS FOLLOWING ACUTE HEPATIC INSULTS IN HORSES ;= -ARKED PERIPORTAL AND BRIDGING FIBROSIS IDENTIFIED IN BIOPSY SPECI MENS HAVE LONG BEEN REGARDED AS POOR PROGNOSTIC INDICATORS ; = AND A MORE RECENT STUDY CONFIRMED FIBROSIS AS THE SINGLE MOST PROGNOSTICALLY RELEVANT HISTOPATHOLOGIC VARIABLE ;= (OWEVER IN A PUBLISHED SERIES OF CHOLANGIOHEPATITIS CASES LONG TERM SURVIVAL OF THREE HORSES FOUND TO HAVE SEVERE PERIPORTAL AND BRIDGING FIBROSIS WAS DESCRIBED SUGGESTING THAT OTHER FACTORS ARE ALSO PROGNOSTICALLY IMPORTANT ;= ! SCORING SYSTEM WAS THERE FORE DEVELOPED IN ORDER TO ATTEMPT TO ATTRIBUTE A PROGNOSTICALLY USEFUL BROAD INDEX OF HISTOPATHOLOGIC SEVERITY COMPRISING SEVERAL HISTOPATHOLOGIC VARIABLES COMPRISING FIBROSIS BILIARY HYPERPLASIA MEGALOCYTOSIS NECROSIS AMYLOIDOSIS INFLAMMATORY INFILTRATES AND HAEMOSIDEROSIS ;= !PPLICATION OF THIS PROGNOSTIC BIOPSY SCORE 4AB INDICATED A VERY GOOD PROGNOSIS WITH SCORES OF n SURVIVAL A GUARDED PROGNOSIS WITH SCORES OF n SURVIVAL AND A POOR PROGNOSIS WITH SCORES OF n SURVIVAL ;= "IOPSIES SCORED IN THE HIGHEST CATEGORY WERE ASSOCIATED WITH A TIMES INCREASED RISK OF DEATH WITHIN MONTHS REPRESENTING A FAR HIGHER RISK FACTOR THAN ANY NON INVASIVE TEST RESULTS ; =
!NDY % $URHAM
$IFFERENTIAL DIAGNOSES (EPATITIS CASES RARELY PRESENT WITH ABSOLUTELY SPECIFIC CLINICAL SIGNS AND THEREFORE DIFFERENTIAL DIAGNOSES SHOULD ALWAYS BE CONSIDERED 4HE MAIN PRESENTING SIGNS OF HEPATITIS IN HORSES ARE NON SPECIFIC AND COMPRISE COLIC DEPRESSION NEUROLOGIC SIGNS AND WEIGHT LOSS ; = #OLIC AND DIAR RHOEA IS A COMMON CLINICAL SIGN OF BOTH ENTERITIDES AND HEPATITIDES AND PYREXIA MAY ALSO BE A FEATURE OF BOTH $IFFERENTIAL DIAGNOSES OF ACUTE CEN TRAL NEUROLOGIC SIGNS ;= PRIMARILY COMPRISE HEPATIC FAILURE ENCEPHALITIDES ;= NEUROTOXINS EG MOXIDECTIN FLUPHENAZINE ; = TRAUMA ;= AND PRIMARY INTESTINAL HYPERAMMONAEMIA ; = #LINICAL SIGNS COM MONLY OBSERVED THAT ARE MORE SUGGESTIVE OF HEPATITIS INCLUDE PHOTOSENSITI SATION AND JAUNDICE ALTHOUGH IN PRACTICE MOST HORSES SEEN WITH THESE SIGNS WILL HAVE NORMAL LIVERS WITH PRIMARY PHOTODERMATITIS AND ANOREXIA RESPEC TIVELY BEING THE COMMONEST CAUSES OF THESE SIGNS )N MOST CASES SERUM BIOCHEMISTRY WILL PROVIDE THE STRONGEST INITIAL EVI DENCE OF HEPATITIS ALTHOUGH CASES OF PRIMARY INTESTINAL DISEASE ARE SOMETIMES SEEN WITH MILD TO MODERATE INCREASES IN LIVER DERIVED ENZYMES ;n= 4HIS COULD BE CAUSED BY HEPATIC PORTAL TRANSFER OF NOXIOUS SUBSTANCES SUCH AS LIPOPOLYSACCHARIDES FROM COMPROMISED INTESTINAL MUCOSAE OR PERHAPS FROM PRESSURE FROM A DILATED STOMACH OR COLON !DDITIONAL CONFUSION MAY ARISE IN SOME CASES AS A RESULT OF LACK OF ABSOLUTE SENSITIVITY AND SPECIFICITY OF LABORATORY INDICES OF HEPATITIS ;= AND BIOPSY WILL BE REQUIRED IN ORDER TO MAKE A CERTAIN DIAGNOSIS OF HEPATITIS 4HIS AUTHOR HAS SEEN SEVERAL SUBJECTS WITH ACUTE NEUROLOGIC SIGNS CAUSED BY (% THAT WERE MISDIAGNOSED AS TRAU MATIC CRANIAL INJURIES ON THE BASIS OF EVIDENCE OF EXTERNAL SKIN ABRASIONS THAT ACTUALLY RESULTED FROM FALLS CAUSED BY (%
4REATMENT 'ENERAL AND SUPPORTIVE CARE CAN BE SUPPLIED FOR ANY SUBJECT SUSPECTED TO BE SUFFERING FROM HEPATITIS INCLUDING FLUID THERAPY AND ANTIPYRETICS BUT SPECIFIC THERAPY CANNOT BE LOGICALLY APPLIED IN THE ABSENCE OF A CLEAR SPE CIFIC DIAGNOSIS !LTHOUGH BIOPSY IS USUALLY A PREREQUISITE CERTAIN CONDITIONS SUCH AS SERUM HEPATITIS CHOLELITHIASIS AND 4YZZERS DISEASE MAY BE STRONGLY SUSPECTED ON THE BASIS OF HISTORY CLINICAL SIGNS ULTRASONOGRAPHY AND SERUM BIOCHEMISTRY )N PRACTICE MANY HEPATITIS CASES MAY NOT BE CLEARLY REPRESEN TATIVE OF THE CLEAR CATEGORICAL AETIOLOGIC DIAGNOSES DESCRIBED ABOVE EVEN FOL LOWING BIOPSY ;= .EVERTHELESS INTUITIVELY INDICATED THERAPY CAN BE APPLIED SUCH AS ANTIBACTERIALS IN CASES OF PREDOMINANTLY NEUTROPHILIC HEPATITIDES OR GLUCOCORTICOIDS IN CASES OF PREDOMINANTLY LYMPHOCYTIC EOSINOPHILIC OR PLASMACYTIC HEPATITIDES 3URGICAL MANAGEMENT OF SOME CONDITIONS HAS BEEN REPORTED ;= ALTHOUGH THE MAJORITY OF EQUINE HEPATITIDES WILL BE MANAGED MEDICALLY
(EPATITIS IN HORSES
!NTIMICROBIAL DRUGS ARE INDICATED IN ALL CASES OF BACTERIAL HEPATITIS EG CHOLANGIOHEPATITIS CHOLELITHIASIS HEPATIC ABSCESSATION AND 4YZZERS DISEASE ; = "ACTERIAL ISOLATION AND SENSITIVITY TESTING IS IDEAL ALTHOUGH WILL INTRODUCE A DELAY IN THERAPY AND MAY OFTEN BE UNPRODUCTIVE OR POTEN TIALLY MISLEADING WHEN BIOPSY SPECIMENS ARE SUBMITTED FOR CULTURE ;= )NTUITIVE PREDICTION OF INDICATED SPECTRA OF ACTIVITY MAY BE APPROPRIATE IN MANY CASES #LOSTRIDIAL HEPATITIS EG 4YZZERS DISEASE SHOULD BE TREATED AGGRESSIVELY WITH SODIUM BENZYL PENICILLIN IUKG IV QID OR OXYTET RACYCLINE MGKG IV BID 3UPPURATIVE HEPATITIS IN ADULT HORSES USUALLY INVOLVES ENTERIC BACTERIA AND THEREFORE 'RAM NEGATIVE POTENCY IS IMPOR TANT (OWEVER ANAEROBIC AND 'RAM POSITIVE PATHOGENS ARE WELL RECOGNISED SUGGESTING THAT BROAD SPECTRUM COVER IS ADVISABLE 0ROLONGED ANTIBACTERIAL THERAPY IN EXCESS OF WEEKS IS USUALLY REQUIRED IN CHOLANGIOHEPATITIS CASES ;= WHICH OFTEN PRECLUDES PARENTERAL THERAPY AND RESTRICTS THE CHOICE OF AVAILABLE PRODUCTS 0OTENTIATED SULPHONAMIDES MGKG COMBINED PRODUCT PER OS BID DOXYCYCLINE MGKG PER OS SID BID AND RIFAMPIN MGKG PER OS BID HAVE BROAD SPECTRUM ACTIVITY ALTHOUGH THE LATTER DRUG SHOULD ONLY BE USED IN COMBINATION WITH ANOTHER ANTIBACTERIAL %RYTHROMYCIN MGKG PER OS TID HAS BEEN USED SUCCESSFULLY IN ADULT HORSES ALTHOUGH MAY POSE AN UNACCEPTABLE RISK OF COLITIS ;= %NROFLOXACIN MGKG PER OS 3ID HAS LIMITED 'RAM POSITIVE AND NEGLIGIBLE ANAEROBIC ACTIVITY WHEREAS THE ACTIVITY OF METRONIDAZOLE MGKG PER OS LOADING DOSE FOLLOWED BY MGKG PER OS QID IS RESTRICTED TO ANAEROBIC PATHOGENS ONLY ,IVER FLUKE &ASCIOLA HEPATICA IS A RARE CAUSE OF HEPATITIS IN HORSES AND DONKEYS BUT HAS BEEN TREATED SUCCESSFULLY WITH TRICLABENDAZOLE AT A DOSE OF MGKG PER OS ; = %CHINOCOCCUS GRANULOSUS HYDATID CYSTS ARE MORE FREQUENTLY ENCOUNTERED BUT THEIR PATHOGENIC RELEVANCE IS OFTEN QUESTIONABLE UNLESS LARGE NUMBERS ARE PRESENT OR INTERVENING HEPATIC PARENCHYMA IS SHOWN TO BE DISEASED 4HIS AUTHOR HAS TREATED SUCH CASES WITH ALBENDAZOLE MGKG PER OS SID FOR DAYS REPEATED SIX TIMES AT WEEK INTERVALS ;= AND ALSO BY CYST ASPIRATION AND INJECTION OF STERILE SATURATED SALINE INTO THE CYST CAVITY 'LUCOCORTICOIDS ARE INDICATED IN CASES OF EOSINOPHILIC OR LYMPHOPLASMA CYTIC HEPATITIS AND FOR HEPATITIDES WITH SIGNIFICANT FIBROPLASIA EG CHRONIC ACTIVE HEPATITIS 0REDNISOLONE AT A DOSE OF n MGKG PER OS SID FOR AT LEAST WEEKS IS USUALLY CHOSEN ALTHOUGH MORE AGGRESSIVE THERAPY WITH DEXA METHASONE AT TO MGKG IV SID OR ON ALTERNATE DAYS MAY BE INDICATED IN MORE SEVERE OR NON RESPONSIVE CASES $ESPITE COMMON ANECDOTALLY HELD VIEWS TO THE CONTRARY HEPATIC FIBROSIS IS A POTENTIALLY REVERSIBLE CHANGE AND EXISTS AS A DYNAMIC BALANCE OF FIBROPLASIA AND FIBRINOLYSIS CONTROLLED BY HEPATIC STELLATE CELLS (3#S ;= 4HE ANTIINFLAMMATORY EFFECT OF GLUCOCOR TICOIDS ON ACTIVATED (3#S IS THE ONLY COMMONLY APPLIED ANTIFIBROTIC STRATEGY IN EQUINE HEPATITIS CASES .ON STEROIDAL ANTIINFLAMMATORY DRUGS ARE ONLY USUALLY USED IN PYREXIC HEPATITIS CASES SUCH AS SEPTIC CHOLANGIOHEPATITIS AND CHOLELITHIASIS EG &LUNIXIN MEGLUMINE MGKG SID BID ALTHOUGH BENEFITS IN CASES OF (% HAVE BEEN PROPOSED ;=
!NDY % $URHAM
3EVERAL PREVIOUS STUDIES HAVE REPORTED THAT (% IS A POOR PROGNOSTIC SIGN IN HORSES ; = (OWEVER THE FINDING THAT OF HORSES SHOWING SIGNS OF (% DID SURVIVE FOR AT LEAST MONTHS IN ONE STUDY ;= DOES JUSTIFY ATTEMPTS AT TREATMENT ESPECIALLY IN CASES OF ACUTE HEPATITIS AND DECOMPENSA TION /CCASIONALLY INSTANCES OF EXCITABLE OR AGGRESSIVE (% WARRANTS SEDATION WITH SLIGHTLY REDUCED DOSES OF COMMONLY USED SEDATIVES AND TRANQUILISERS EG 8YLAZINE MGKG IV $ETOMIDINE +GKG IV !CEPROMAZINE +GKG IV $IAZEPAM MAY BE CONTRAINDICATED DUE TO THE PROPOSED INVOLVEMENT OF BENZODIAZEPINE LIKE SUBSTANCES IN THE PATHOPHYSIOLOGY OF (% ;= 4HERE IS LITTLE EVIDENCE BASIS FOR THE SELECTION OF THERAPEUTIC AGENTS FOR TREATMENT OF (% AND SELECTION IS LARGELY BASED ON PERSONAL ANECDOTAL EXPERI ENCE 4HIS AUTHOR GENERALLY FAVOURS LACTULOSE MLKG PER OS WHICH CAN BE GIVEN INITIALLY EVERY n H IN (% CASES AND REDUCED IN FREQUENCY ACCORDING TO RESPONSE $IARRHOEA IS A RARE COMPLICATION &AILURE TO CLINICALLY IMPROVE WITHIN n H OF LACTULOSE TREATMENT REFLECTS A POOR PROGNOSIS IN CHRONIC HEPATITIS CASES ALTHOUGH SUBJECTS WITH ACUTE HEPATITIS AND (% MAY IMPROVE MORE SLOWLY ,ACTULOSE IS A NON ABSORBABLE INDIGESTIBLE DISACCHARIDE THAT IS METABOLISED BY COLONIC BACTERIA TO ACETIC AND LACTIC ACIDS THUS REDUCING LUMINAL P( 4HIS COLONIC ACIDIFICATION IS ASSOCIATED WITH REDUCED ABSORPTION OF IONISED AMMONIUM SUPPRESSION OF FAECAL UREASE AND PROTEASES INCREASED BACTERIAL .( UTILISATION AND DEATH OF MANY PROTEOLYTIC BACTERIA ; = 4HE AUTHORS OF ONE STUDY SUGGESTED THAT ORAL ANTIBIOTICS HAD A SUBJECTIVELY BETTER INFLUENCE ON (% THAN LACTULOSE ALTHOUGH LONG TERM THERAPY IS LESS SUITABLE WITH ANTIBACTERIALS THAN LACTULOSE ;= .EOMYCIN MGKG PER OS QID OR METRONIDAZOLE MGKG PER OS LOADING DOSE FOLLOWED BY MGKG PER OS QID HAVE BOTH BEEN WIDELY USED IN EQUINE (% CASES EITHER ALONE OR IN COMBINATION WITH LACTULOSE /THER PRODUCTS SUCH AS , ORNITHINE , ASPARTATE MAY BE WORTHY OF INVESTIGATION IN EQUINE (% CASES 4HIS PRODUCT REDUCES PLASMA .( CONCENTRATION BY PROMOTING BIOTRANSFORMATION INTO UREA AND GLUTAMINE IN OTHER TISSUES SUCH AS INTESTINE MUSCLE AND KIDNEY AND HAS A GOOD EVIDENCE BASIS IN HUMAN MEDICINE ; =
$IETARY MANAGEMENT 3UBJECTS SUFFERING FROM HEPATITIS AND HEPATIC INSUFFICIENCY MAY BENEFIT FROM SPECIFIC NUTRITIONAL ADVICE 7EIGHT LOSS IS A COMMON FEATURE OF HEPATIC INSUF FICIENCY AND AFFECTED SUBJECTS TEND TO CATABOLISE BODILY PROTEIN MORE READILY THAN HEALTHY SUBJECTS ; = !DEQUATE DIETARY DIGESTIBLE ENERGY INTAKE K*KGDAY ;= IS ESSENTIAL BUT MAY BE HARD TO MAINTAIN IN ANORECTIC SUBJECTS "ALANCED PARENTERAL NUTRITION HAS BEEN SUCCESSFULLY SUPPLIED BY THIS AUTHOR TO HORSES WITH ACUTE HEPATIC FAILURE COMPRISING EQUAL VOLUMES OF GLUCOSE AMINOACIDS )NTRAFUSIN &RESENIUS +ABI AND LIPID EMULSION )NTRALIPID &RESENIUS +ABI AT A RATE OF MLKGHOUR %XCESS DIETARY PROTEIN MIGHT INCREASE AMMONIAGENESIS AND PRECIPITATE (% WHEREAS
(EPATITIS IN HORSES
INADEQUATE PROVISION OF DIETARY PROTEIN POTENTIATES FURTHER CATABOLISM ;= 0ROBABLE OPTIMAL PROTEIN CONTENT WILL APPROXIMATE n GKGDAY BUT WILL DEPEND CONSIDERABLY ON PROTEIN QUALITY ;= 'RASS OR GOOD QUALITY GRASS HAY SHOULD FORM THE BASIS OF HEPATITIS DIETS 3UPPLEMENTARY FEEDS CAN BE OFFERED IN AT LEAST n DAILY MEALS ;= ! LOW !!!"#!! RATIO IN THE DIET OR A "#!! SUPPLEMENT MAY BE OFFERED ; = 7HEAT SOYA BEET PULP AND OATS ARE ALL RELATIVELY RICH IN !!!S WHEREAS ALFALFA WHEAT BRAN MAIZE AND MILO SORGHUM HAVE A RELATIVELY HIGH "#!! CONTENT ; = !DEQUATE PROVISION OF DIETARY GLUCOSE MAY COMPENSATE FOR REDUCED HEPATIC GLYCOGEN SYNTHESIS AND STORAGE ; = AND LIMIT GLUCONEOGENESIS FROM ENDOGENOUS PROTEINS 0ROCESSED MAIZE AND PERHAPS MOLASSES MAY PROVIDE GOOD READILY DIGESTIBLE CARBOHYDRATE FOR THIS PURPOSE ;= $ESPITE THE POPULARITY OF HIGH FAT DIETS FOR THE SAFE PROVISION OF ADDITION AL DIETARY CALORIES IN EQUINE DIETS THIS MAY BE INADVISABLE IN SUBJECTS WITH HEPATIC INSUFFICIENCY DUE TO THE CENTRAL ROLE OF THE LIVER IN TRIAGLYCEROL PRO CESSING AND BILE SYNTHESIS 6ITAMIN SUPPLEMENTATION INCLUDING " VITAMINS $ % AND + ;n= IS WIDELY ADVOCATED FOR SUBJECTS WITH HEPATIC INSUFFICIEN CY AND IS OF ANECDOTAL BENEFIT ESPECIALLY IN SUBJECTS WITH POOR APPETITE :INC SUPPLEMENTATION HAS ALSO BEEN ADVOCATED ; = 4HE ALMOST UNIVERSAL INCLUSION OF IRON IN EQUINE MULTIVITAMIN SUPPLEMENTS COULD BE HARMFUL TO A FAILING LIVER AS HAEMOSIDEROSIS IS A COMMON FINDING IN DISEASED LIVERS IN HORSES AND MAY PRESENT A SIGNIFICANT OXIDATIVE CHALLENGE ;= #OPPER MAN GANESE AND VITAMIN ! ARE ALSO POTENTIALLY HEPATOTOXIC ;= AND THIS AUTHOR HAS RECOGNISED INCREASED MANGANESE ACCUMULATION IN HORSES WITH HEPATIC INSUFFICIENCY ,ACK OF SAFETY STUDIES OF MANY PROPRIETARY FEED SUPPLEMENTS AND HERBAL REMEDIES IS OF POTENTIAL CONCERN WITH SEVERAL KNOWN TO HAVE HEPATOTOXIC PROPERTIES INCLUDING GERMANDER GENTIAN !SAFOETIDA MISTLETOE SENNA CHAPARRAL VALERIAN COMFREY PENNYROYAL $ICTAMNUS AND 0AEONIA ; =
2EFERENCES
0ARRAGA -% #ARLSON '0 4HURMOND - 3ERUM PROTEIN CONCENTRATIONS IN HORSES WITH SEVERE LIVER DISEASE A RETROSPECTIVE STUDY AND REVIEW OF THE LITERA TURE * 6ET )NTERN -ED n 4ENNANT "# "ALDWIN " %VANS #$ +ANECKO ** $ISEASES OF THE EQUINE LIVER 0ROC !!%0 n -C'ORUM "# -URPHY $ ,OVE 3 -ILNE %- #LINICOPATHOLOGICAL FEATURES OF EQUINE PRIMARY HEPATIC DISEASE A REVIEW OF CASES 6ET 2EC n 3MITH -27 3TEVENS +" $URHAM !% -ARR #- %QUINE HEPATIC DIS EASE THE EFFECT OF PATIENT AND CASE SPECIFIC VARIABLES ON RISK AND PROGNOSIS %QUINE 6ET * n "YARS 4$ #HRONIC LIVER FAILURE IN HORSES #OMP #ONTIN %DUC 0RACT 6ET 3n3
!NDY % $URHAM
7EST (* #LINICAL AND PATHOLOGICAL STUDIES IN HORSES WITH HEPATIC DISEASE %QUINE 6ET * n 'UGLICK -! -AC!LLISTER #' %LY 27 %DWARDS 7# (EPATIC DISEASE ASSOCIATED WITH ADMINISTRATION OF TETANUS ANTITOXIN IN EIGHT HORSES * !M 6ET -ED !SSOC n 0EARSON %' ,IVER DISEASE IN THE MATURE HORSE %QUINE VET %DUC n :IENTARA 3 4RAP $ &ONTAINE ** 'ICQUEL " 3AILLEAU # 0LATEAU % 3URVEY OF EQUINE HEPATIC ENCEPHALOPATHY IN &RANCE IN 6ET 2EC n 3AHAL - !LTINTAS ! !RSLAN (( 5RAL + !KSOY % 3ERUM (EPATITIS ASSOCIATED WITH ADMINISTRATION OF TETANUS TOXIN IN SERUM PRODUCING HORSES AND THERAPY 2EVUE -ÏD 6ÏT n $IVERS 4* "ERNARD 76 2EEF 6" %QUINE LIVER DISEASE AND LIVER FAILURE n CAUSES DIAGNOSIS AND TREATMENT 0ROC "AIN &ALLON -EM ,ECT n !LEMAN - .IETO *% #ARR %! #ARLSON '0 3ERUM HEPATITIS ASSOCIATED WITH COMMERCIAL PLASMA TRANSFUSION IN HORSES * 6ET )NTERN -ED n "ARTON -( -ORRIS $$ $ISEASES OF THE LIVER )N 3- 2EED 7- "AYLY EDS )N %QUINE )NTERNAL -EDICINE 7" 3AUNDERS #OMPANY ,ONDON n $URHAM !% 3MITH +# .EWTON *2 (ILLYER -( (ILLYER ,, 3MITH -2 -ARR #- $EVELOPMENT AND APPLICATION OF A SCORING SYSTEM FOR PROGNOSTIC EVALUATION OF EQUINE LIVER BIOPSIES %QUINE 6ET * n 0ERKINS ' !INSWORTH $- %RB (. $EL 0IERO & -ILLER - 7ILKINS 0! 0ALMER * &RAZER - #LINICAL HAEMATOLOGICAL AND BIOCHEMICAL FINDINGS IN FOALS WITH NEONATAL %QUINE HERPESVIRUS INFECTION COMPARED WITH SEPTIC AND PREMA TURE FOALS %QUINE 6ET * n 7HITWELL +% "LUNDEN !3 0ATHOLOGICAL FINDINGS IN HORSES DYING DURING AN OUTBREAK OF THE PARALYTIC FORM OF %QUID HERPESVIRUS TYPE %(6 INFEC TION %QUINE 6ET * n (AMIR !. 6AALA 7 (EYER ' -OSER ' $ISSEMINATED EQUINE HERPESVI RUS INFECTION IN A TWO YEAR OLD FILLY * 6ET $IAGN )NVEST n 3QUIRE 2! %QUINE INFECTIOUS ANEMIA A MODEL OF IMMUNOPROLIFERATIVE DISEASE "LOOD n 3ELLON $# 0ERRY 34 #OGGINS , &ULLER &* 7ILD TYPE EQUINE INFECTIOUS ANEMIA VIRUS REPLICATES IN VIVO PREDOMINANTLY IN TISSUE MACROPHAGES NOT IN PERIPHERAL BLOOD MONOCYTES * 6IROL n 3AAD -$ (USSEIN (! "ASHANDY -- +AMEL (( %ARHART +# &RYAUFF $* 9OUNAN - -OHAMED !( (EPATITIS % VIRUS INFECTION IN WORK HORSES IN %GYPT )NFECT 'ENET %VOL n 2OBINSON *! !LLEN '+ 'REEN %- &ALES 7( ,OCH 7% 7ILKERSON #' ! PROSPECTIVE STUDY OF SEPTICAEMIA IN COLOSTRUM DEPRIVED FOALS %QUINE 6ET * n 3ZEREDI , -OLNAR 4 'LAVITS 2 4AKAI 3 -AKRAI , $ENES " $EL 0IERO & 4WO CASES OF EQUINE ABORTION CAUSED BY 2HODOCOCCUS EQUI 6ET 0ATHOL n $ICKIE #7 2EGNIER */ %QUINE MYOSITIS AND SEPTICEMIA CAUSED BY !CINETOBACTER CALCOACETICUS INFECTION * !M 6ET -ED !SSOC n ,ONG -4 'OETZ 4% +AKOMA ) 7HITELEY (% ,OCK 4% (OLLAND #* &OREMAN
(EPATITIS IN HORSES
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#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION "UD # 4ENNANT 7ILLIAM % (ORNBUCKLE AND *OHN , 'ERIN $EPARTMENT OF #LINICAL 3CIENCES .EW 9ORK 3TATE #OLLEGE OF 6ETERINARY -EDICINE #ORNELL
5NIVERSITY )THACA .9 53! $EPARTMENT OF -OLECULAR 6IROLOGY AND )MMUNOLOGY 'EORGETOWN 5NIVERSITY -EDICAL 3CHOOL
7ASHINGTON $# 53!
!BSTRACT 3INCE DISCOVERY OF THE HEPATITIS " VIRUS ("6 CLOSELY RELATED VIRUSES HAVE BEEN DESCRIBED IN SEVERAL ANIMAL SPECIES 4HE FIRST OF THESE WAS THE WOODCHUCK HEPATITIS VIRUS 7(6 IDENTIFIED IN WOODCHUCKS -ARMOTA MONAX THAT WERE MAINTAINED AT THE 0HILADELPHIA :OOLOGICAL 'ARDEN AND WHICH HAD EXPERIENCED A HIGH PREVALENCE OF CHRONIC HEPATITIS AND HEPATOCELLULAR CARCINOMA (## /N THE BASIS OF MORPHOLOGICAL AND MOLECULAR ANALYSES IT WAS CONCLUDED THAT 7(6 WAS CLOSELY RELATED TO ("6 3INCE DESCRIPTION OF 7(6 INFECTION WITH VIRUSES THAT BELONG TO THE FAMILY (EPADNAVIRIDAE HAVE BEEN DESCRIBED IN THE #ALIFORNIA GROUND SQUIRREL 3PERMOPHILUS BEECHEYI AND THE !RCTIC GROUND SQUIRREL 3PERMOPHILUS PARRYI TWO SPECIES CLOSELY RELATED PHYLOGENETICAL LY TO WOODCHUCKS AND IN SIX AVIAN SPECIES ! TOTAL OF FOUR WELL CHARACTERIZED MAMMALIAN HEPADNAVIRUSES NOW HAVE BEEN ASSOCIATED WITH DEVELOPMENT OF (## 4HESE OBSERVATIONS ON NATURALLY ACQUIRED HEPADNAVIRUS INFECTIONS COMBINED WITH THE DEVELOPMENT OF (## IN WOODCHUCKS FOLLOWING EXPERIMENTAL INFECTION WITH 7(6 OR WITH THE #ALIFORNIA GROUND SQUIRREL VIRUS '3(6 PROVIDES BY ANALOGY CONVINCING COMPARATIVE MEDICAL EVIDENCE FOR THE HEPATOCARCINOGENICITY OF ("6 4HE WOODCHUCK HAS BECOME USEFUL AS AN EXPERIMENTAL ANIMAL MODEL FOR RESEARCH ON THE PATHOGENESIS OF ("6 INFECTION AND FOR INVESTIGATION OF THE MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS 4HE WOODCHUCK ALSO HAS BEEN USEFUL IN THE DISCOVERY AND PRECLINICAL DEVELOPMENT OF ANTIVIRAL DRUGS FOR TREATMENT OF ("6 INFECTION AND FOR TESTING NEW FORMS OF IMMUNOTHERAPY USING CYTOKINES AND THERAPEUTIC VACCINATION )N PARTICULAR THE WOODCHUCK HAS BEEN VALUABLE FOR DETERMINING THE IMPACT OF LONG TERM ANTIVIRAL TREATMENT ON THE OUTCOME OF CHRONIC HEPADNAVIRUS INFECTION IN PLACEBO CONTROLLED LIFETIME SURVIVAL STUDIES WHICH HAVE BEEN PREDICTIVE OF THE RESULTS OF SUBSEQUENT CLINICAL TRIALS
)NTRODUCTION )DENTIFICATION OF THE VIRUS OF HEPATITIS " ("6 WAS ONE THE MOST IMPORTANT MEDICAL ADVANCES OF THE TH #ENTURY AND HAS LED TO SIGNIFICANT ADVANCES IN THE DIAGNOSIS TREATMENT CONTROL AND PREVENTION OF ONE OF THE WORLDS MOST WIDESPREAD AND DEVASTATING INFECTIOUS DISEASES 3INCE DISCOVERY OF ("6
"UD # 4ENNANT ET AL
CLOSELY RELATED VIRUSES HAVE BEEN DESCRIBED IN SEVERAL MAMMALIAN AND AVIAN SPECIES 0ROF (EINZ 3CHALLER TO WHOM THIS VOLUME IS DEDICATED HAS UTILIZED NATURALLY OCCURRING ANIMAL MODELS TO INVESTIGATE THE PATHOGENESIS OF ("6 INFECTION AND THE MECHANISMS OF ("6 REPLICATION )N SO DOING HE HAS IN SIGNIFICANT WAYS ENHANCED OUR UNDERSTANDING OF THE PATHOGENESIS OF ("6 INFECTION HAS IMPROVED THE CARE OF PATIENTS INFECTED WITH ("6 AND HAS TRAINED SOME OF THE MOST DISTINGUISHED MEMBERS OF THE CURRENT GENERATION OF HEPATITIS VIROLOGISTS (IS RESEARCH WITH ANIMAL MODEL SYSTEMS REPRESENTS AN IMPRESSIVE CONTRIBUTION TO MODERN COMPARATIVE MEDICINE
.ATURAL HISTORY OF WOODCHUCK HEPATITIS VIRUS INFECTION 4HE WOODCHUCK HEPATITIS VIRUS 7(6 WAS DESCRIBED ORIGINALLY BY 3UMMERS AND COLLEAGUES IN A COLONY OF WOODCHUCKS -ARMOTA MONAX MAINTAINED AT THE 0HILADELPHIA :OOLOGICAL 'ARDEN AND THAT FOR SOME YEARS HAD EXPERI ENCED AN UNUSUALLY HIGH RATE OF CHRONIC HEPATITIS AND HEPATOCELLULAR CARCI NOMA (## ;= /N THE BASIS OF MORPHOLOGICAL AND MOLECULAR ANALYSES IT WAS CONCLUDED THAT 7(6 WAS CLOSELY RELATED TO THE HEPATITIS " VIRUS ("6 FAMILY OF VIRUSES AND THE WOODCHUCK HEPATITIS VIRUS 7(6 NOW IS CLASSI FIED AS A MEMBER OF THE FAMILY (EPADNAVIRIDAE GENUS /RTHOHEPADNAVIRUS OF WHICH THE PROTOTYPE MEMBER IS ("6 4AB 4HE NATURAL HABITAT OF THE WOODCHUCK EXTENDS FROM NORTH 'EORGIA !LABAMA AND -ISSISSIPPI IN THE SOUTHERN 5NITED 3TATES WEST TO /KLAHOMA +ANSAS .EBRASKA AND )OWA NORTH TO 1UEBEC AND ,ABRADOR ACROSS #ANADA TO "RITISH #OLUMBIA AND THE 9UKON 4ERRITORY AND INCLUDES AN AREA OF SOUTHEASTERN !LASKA ! COMPREHENSIVE SEROEPIDEMIOLOGIC STUDY OF 7(6 INFECTION THROUGHOUT THIS RANGE HAS NEVER BEEN PERFORMED 7(6 INFECTION IS KNOWN TO BE HYPERENDEMIC IN THE MID !TLANTIC REGION OF THE 5NITED 3TATES AND THE WOODCHUCKS STUDIED ORIGINALLY BY 3UMMERS ET AL WERE FROM 0ENNSYLVANIA ;= )N SUBSEQUENT STUDIES REPORTED BY 4YLER ET AL ;= OF THE WOODCHUCKS FROM 0ENNSYLVANIA .EW *ERSEY AND -ARYLAND TESTED POSITIVE FOR THE 7(6 SURFACE ANTIGEN 7(S!G AND WERE POSITIVE FOR ANTIBODY TO THE 7(6 SURFACE ANTIGEN ANTI 7(S FOR A OVERALL RATE OF INFECTION 3IMILAR HIGH RATES OF 7(6 INFECTION HAVE BEEN CONFIRMED BY OTH ERS IN WOODCHUCKS FROM THE -ID !TLANTIC 3TATES ;= )N CONTRAST THE PREVA LENCE OF 7(6 INFECTION IN CENTRAL .EW 9ORK 3TATE IS APPROXIMATELY BASED ON THE DETECTION OF ANTI 7(S ANTIBODY ;= AND THE RATE OF PERSISTENT 7(S ANTIGENEMIA IS ESTIMATED TO BE LESS THAN !LTHOUGH THE NUMBER OF WOODCHUCKS TESTED IS SMALL NO SEROLOGIC EVIDENCE OF 7(6 INFECTION HAS BEEN FOUND IN 6ERMONT AND -ASSACHUSETTS ;n= 3IMILARLY WE HAVE FOUND WOODCHUCKS FROM )OWA TO BE ANTI 7( CORE ANTIBODY ANTI 7(C NEGA TIVE 7E HAVE HOWEVER EXAMINED HEPATIC TISSUES OF WOODCHUCKS FROM THE 0ROVINCE OF 1UEBEC AND /HIO THAT DIED OF HEPATOCELLULAR CARCINOMA (## .ON NEOPLASTIC LIVER TISSUE WAS EXAMINED IMMUNOHISTOLOGICALLY FOR THE
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
4ABLE (EPADNAVIRUSES OF ANIMALS 6IRUS
(OST
3CIENTIFIC .AME
(UMAN 7OODCHUCK GROUNDHOG #ALIFORNIA GROUND SQUIRREL
(OMO SAPIENS -ARMOTA MONAX 3PERMOPHILUS BEECHEYI
!RCTIC GROUND SQUIRREL
3PERMOPHILUS PARRYII
7OOLLY MONKEY
,AGOTHRIX LABOTRICHA
'ENUS /RTHOHEPADNAVIRUS (EPATITIS " VIRUS ("6
7OODCHUCK HEPATITIS VIRUS 7(6 #ALIFORNIA GROUND SQUIRREL HEPATITIS VIRUS '3(6 !RCTIC GROUND SQUIRREL HEPATITIS VIRUS !'3(6 7OOLLY MONKEY HEPATITIS " VIRUS 7-("6 'ENUS !VIHEPADNAVIRUS $UCK HEPATITIS " VIRUS $("6 (ERON HEPATITIS " VIRUS (("6 3NOW GOOSE HEPATITIS " VIRUS 3'("6 2OSSS GOOSE HEPATITIS " VIRUS 2'("6 3TORK HEPATITIS " VIRUS 3("6 #RANE HEPATITIS " VIRUS #("6
$OMESTIC DUCK 0EKIN DUCK !NUS DOMESTICUS 'REY HERON !RDEA CINERIA 3NOW GOOSE !NSER CAERULESCENS 2OSSS GOOSE
!NSER #HEN ROSSII
7HITE STORK 'REY CROWNED CRANE AND $EMOISELLE CRANE
#ICONIA CICONIA "ALEARICA REGULORUM AND !NTHROPOIDES VIRGO
.ATURALLY ACQUIRED INFECTION WITH ("6 ALSO HAS BEEN DETECTED IN THE CHIMPANZEE GORILLA GIBBON AND ORANGUTAN
PRESENCE OF 7( CORE ANTIGEN 7(C!G AND BOTH WERE POSITIVE INDICATING WITH REASONABLE CERTAINTY THAT AT THE TIME OF DEATH BOTH WOODCHUCKS WERE INFECTED WITH 7(6 UNPUBLISHED (EPATIC NEOPLASMS OF WOODCHUCKS FROM THE 0HILADELPHIA :OOLOGICAL 'ARDEN WERE REPORTED EARLY IN THE TH #ENTURY -ULTIPLE HEPATIC ADENO MAS RANGING IN SIZE UP TO CM IN DIAMETER WERE DESCRIBED ; = ,ATER TWO WOODCHUCKS ONE FROM THE 7ASHINGTON :OOLOGICAL 0ARK AND THE OTHER TRAPPED IN "ETHESDA -ARYLAND WERE REPORTED WITH PRIMARY HEPATIC NEO PLASMS ;= 7OODCHUCKS THAT ORIGINATED IN .EW 9ORK ;= -ARYLAND ;= AND 0ENNSYLVANIA ; = AND MAINTAINED IN A LABORATORY ENVIRONMENT LATER WERE REPORTED WITH PRIMARY HEPATIC NEOPLASMS 4HE WOODCHUCKS FROM 0ENNSYLVANIA WERE THE HARBINGERS FOR DISCOVERY OF 7(6 ; = .EOPLASMS OF THE LIVER ASSOCIATED WITH NATURALLY ACQUIRED 7(6 INFEC TION WERE WELL DIFFERENTIATED TRABECULAR (##S ;n= #HRONIC HEPATITIS WAS PRESENT AND CHARACTERIZED BY ABUNDANT MONONUCLEAR CELL INFILTRATION OF PORTAL TRACTS SOMETIMES WITH EXTENSION BEYOND THE LIMITING PLATE 3CATTERED HEPATOCELLULAR NECROSIS OF PARENCHYMAL HEPATOCYTES AND MODEST BILE DUCT PROLIFERATION OFTEN WERE OBSERVED AND IN SOME THERE WAS EVIDENCE OF EARLY FIBROSIS ;n= (EPATIC CIRRHOSIS HOWEVER WAS NOT CHARACTERISTIC AND IS A NOTABLE DIFFERENCE BETWEEN THE LIVERS OF ("6 INFECTED HUMANS AND 7(6 INFECTED WOODCHUCKS WITH ADVANCED LIVER DISEASE 3OME (##S CONTAINED
"UD # 4ENNANT ET AL
SIGNIFICANT NUMBERS OF INFILTRATING HEMATOPOIETIC CELLS AND PROGRESSION OF NEOPLASIA FROM FOCI OF ALTERED HEPATOCYTES TO SMALL NEOPLASTIC NODULES AND TO FRANK (## WAS RECOGNIZED ;= -ETASTASIS OF (## OUTSIDE THE LIVER WHICH OCCURS IN HUMANS AND OTHER EXPERIMENTAL ANIMAL MODELS WITH SOME FREQUENCY HAS NOT BEEN OBSERVED IN WOODCHUCKS WITH (## BY MOST INVES TIGATORS ALTHOUGH PULMONARY METASTASES HAVE BEEN REPORTED ;=
/THER NATURALLY OCCURRING HEPADNAVIRUS INFECTIONS (EPADNAVIRUSES CLOSELY RELATED TO ("6 AND 7(6 HAVE BEEN REPORTED IN OTHER MAMMALIAN AND AVIAN SPECIES 4AB AND THE MORPHOLOGY AND GENETIC ORGANIZATION OF THESE HEPADNAVIRUSES ARE SIMILAR ;n= #ALIFORNIA GROUND SQUIRRELS 3PERMOPHILUS BEECHEYI ARE THE HOST SPECIES OF THE GROUND SQUIRREL HEPATITIS VIRUS '3(6 ;n= #HRONIC '3(6 INFECTION IS ASSOCI ATED WITH CHRONIC HEPATITIS AND WITH (## ALTHOUGH THE FREQUENCY OF (## IS REMARKABLY LESS THAN THAT ASSOCIATED WITH CHRONIC 7(6 INFECTION AND DEVELOPS IN MUCH OLDER ANIMALS ; n= 4HE ARCTIC GROUND SQUIRREL HEPATITIS VIRUS !'3(6 HAS BEEN REPORTED IN THE ARCTIC GROUND SQUIRREL 3PERMOPHILUS PARRYI AND INFECTION ALSO WAS ASSOCIATED WITH (## ;= )NFECTION WITH A PUTATIVE HEPADNAVIRUS WAS DESCRIBED IN %ASTERN GRAY SQUIRRELS 3PERMOPHILUS CAROLINENSIS FROM THE 3TATE OF 0ENNSYLVANIA ;= IN WHICH LESIONS OF HEPATITIS WERE OBSERVED BUT HEPATIC TUMORS WERE NOT REPORTED (EPADNAVIRUS INFECTION IN 2ICHARDSONS GROUND SQUIRRELS 3PERMOPHILUS RICHARDSONII ORIGINATING IN THE 0ROVINCE OF !LBERTA HAS BEEN REPORTED ; = 4HE HEPATIC LESIONS INCLUDING (## IN 2ICHARDSONS GROUND SQUIRRELS WERE SIMILAR TO THOSE DESCRIBED IN WOODCHUCKS #ALIFORNIA GROUND SQUIRRELS AND !RCTIC GROUND SQUIRRELS ;= $UCK HEPATITIS " VIRUS $("6 HAS BEEN REPORTED IN DOMESTIC 0EKIN DUCKS !NAS DOMESTICUS AND HAS A WORLDWIDE DISTRIBUTION ;n= 3IMILAR AVIAN HEPADNAVIRUSES ALSO HAVE BEEN DESCRIBED IN GREY HERONS !RDEA CINE REA HERON HEPATITIS " VIRUS ;= AND IN SNOW GEESE !NSER CAERULESCENS ;= -UCH OF THE CURRENT UNDERSTANDING OF HEPADNAVIRUS REPLICATION IS BASED ON RESEARCH USING $("6 IN VIVO AND IN VITRO ; = (## HAS BEEN INFREQUENTLY ASSOCIATED WITH $("6 INFECTION ;= AND THE HEPATOCARCINO GENICITY OF $("6 IN DUCKS REMAINS QUESTIONABLE (EPATIC NEOPLASMS HAVE NOT BEEN ASSOCIATED WITH HERON HEPATITIS " VIRUS INFECTION ;=
%XPERIMENTAL WOODCHUCK HEPATITIS VIRUS INFECTION 7OODCHUCKS WITH NATURALLY ACQUIRED 7(6 INFECTION WERE VALUABLE SOURCES OF VIRUS AND HEPATIC TISSUE FOR HISTOLOGICAL AND MOLECULAR ANALYSES 4HEIR USE EXPERIMENTALLY HOWEVER WAS LIMITED BECAUSE IT WAS IMPOSSIBLE TO KNOW
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
WHEN AND FOR HOW LONG TRAPPED WOODCHUCKS HAD BEEN INFECTED WITH 7(6 OR TO KNOW THE NUTRITIONAL HISTORY OR THEIR EXPOSURE TO OTHER ENVIRONMENTAL FACTORS THAT MIGHT INFLUENCE THE OUTCOME OF 7(6 INFECTION )MPORTANTLY HEPATIC LESIONS CAUSED BY NEMATODES SUCH AS !CKERTIA MARMOTAE AND #APILLARIA SP WERE COMMON IN WILD WOODCHUCKS ;= AND COULD COMPLICATE THE INTERPRETATION OF EXPERIMENTAL RESULTS 3UMMERS AND COLLEAGUES ;= DESCRIBED THE EXPERIMENTAL INFECTION OF TO MONTH OLD WOODCHUCKS WITH SERUM FROM CHRONIC 7(6 CARRIERS 4HEY DESCRIBED PRODUCTIVE SELF LIMITED INFECTION BUT NO WOODCHUCKS BECAME CHRONIC 7(6 CARRIERS !TTEMPTS BY OTHERS TO EXPERIMENTALLY INFECT JUVENILE OR ADULT WOODCHUCKS ALSO RESULTED IN ACUTE 7(6 INFECTION ; = BUT WITH ONE EXCEPTION DID NOT CAUSE CHRONIC INFECTION -ORPHOLOGIC AND MOLECULAR VIROLOGICAL STUDIES OF THE LIVER OF WOOD CHUCKS EXPERIMENTALLY INFECTED WITH 7(6 HAVE SHOWN THAT VIRTUALLY OF HEPATOCYTES BECOME INFECTED FOLLOWING EXPERIMENTAL 7(6 INFECTION ;= !LTHOUGH REPLICATIVE FORMS WERE CLEARED RAPIDLY DURING RECOVERY COVA LENTLY CLOSED CIRCULAR 7(6 $.! PERSISTED IN THREE OF WOODCHUCKS AFTER EVIDENCE OF 7(6 REPLICATION HAD CEASED ;= #LEARANCE OF EXPERIMENTAL 7(6 INFECTION IN ADULT WOODCHUCKS WAS ASSOCIATED WITH ROBUST HUMORAL AND CELL MEDIATED IMMUNE RESPONSES ;n= 4REATMENT WITH IMMUNE SUP PRESSIVE DOSES OF CYCLOSPORINE ! SIGNIFICANTLY INCREASED THE RATE OF CHRONIC ITY FOLLOWING EXPERIMENTAL 7(6 INFECTION OF ADULT WOODCHUCKS ; = 7HEN ADULT HUMANS ARE INFECTED WITH ("6 LESS THAN BECOME CHRON IC CARRIERS ; = ("6 INFECTION EARLY IN LIFE HOWEVER RESULTS IN CHARACTER ISTICALLY HIGH RATES OF CHRONIC INFECTION ; = (IGH RATES OF CHRONIC 7(6 INFECTION HAVE BEEN OBSERVED IN WOODCHUCKS FROM HYPERENDEMIC AREAS ; = AND SUGGESTED THAT AS IN HUMANS INFECTION OF WOODCHUCKS EARLY IN LIFE OR POSSIBLY VERTICAL TRANSMISSION MUST BE NECESSARY TO ACCOUNT FOR THE HIGH RATES OF PERSISTENT 7(6 INFECTION OBSERVED 4O FULLY UTILIZE THE WOODCHUCK AS AN EXPERIMENTAL ANIMAL MODEL IT WAS CONSIDERED ESSENTIAL TO BREED AND TO REAR WOODCHUCKS IN A LABORATORY ANI MAL FACILITY 4HIS WOULD PROVIDE WOODCHUCKS OF KNOWN GENETIC BACKGROUND A DEFINED ENVIRONMENTAL AND NUTRITIONAL HISTORY AND IN WHICH THE DISEASES OF WILD WOODCHUCKS INCLUDING 7(6 INFECTION COULD BE CONTROLLED AND PREVENTED ! BREEDING COLONY OF WOODCHUCKS THAT WERE NEGATIVE FOR SERO LOGIC MARKERS OF 7(6 INFECTION WAS ESTABLISHED AT #ORNELL 5NIVERSITY IN 4HE COLONY HAS SERVED AS THE SOURCE OF WOODCHUCKS FOR EXPERIMENTAL STUDIES OF THE PATHOGENESIS OF 7(6 INFECTION AND HEPATOCARCINOGENESIS AND MORE RECENTLY FOR THE PRECLINICAL DEVELOPMENT OF ANTIVIRAL DRUGS AND IMMUNOTHERAPEUTIC STRATEGIES FOR ("6 INFECTION 7OODCHUCKS BORN IN THE LABORATORY ARE INOCULATED AT BIRTH WITH DILUTED SERUM FROM STANDARD IZED INFECTIOUS POOLS OBTAINED FROM CHRONIC 7(6 CARRIERS ;n= !FTER INOCULATION WOODCHUCKS ARE MONITORED USING SPECIFIC SEROLOGICAL MARKERS OF 7(6 INFECTION 7(6 $.! 7(S!G ANTI 7( CORE ANTIBODY AND ANTI 7( SURFACE ANTIBODY ; =
"UD # 4ENNANT ET AL
4HE RATE OF CHRONIC 7(6 INFECTION AFTER NEONATAL INOCULATION IS OR GREATER ;n= 3URVIVAL OF EXPERIMENTALLY INFECTED CHRONIC 7(6 CARRIERS WAS COMPARED TO THAT OF WOODCHUCKS THAT RECOVERED FROM NEONATAL 7(6 INFECTION BY CLEARING 7( VIREMIA AND DEVELOPING ANTI 7(S ANTIBODY AND OF CONTROL WOODCHUCKS NOT INFECTED WITH 7(6 BUT THAT WERE BORN AND REARED IN A SIMILARLY CONTROLLED LABORATORY ENVIRONMENT !LL 7(6 CARRIERS WERE DEAD BY MONTHS OF AGE AND THE LIFETIME RISK OF (## WAS ; = 4HE MEDIAN TIME TO DEATH FROM (## IN 7(6 CARRIERS WAS APPROXI MATELY MONTHS )N CONTRAST OF THE WOODCHUCKS WITH RESOLVED 7(6 INFECTION AND OF UNINFECTED CONTROLS WERE ALIVE AT MONTHS OF AGE !LTHOUGH THE RATE OF (## IN 7(6 CARRIERS WAS SIGNIFICANTLY HIGHER OF WOODCHUCKS THAT RECOVERED FROM NEONATAL 7(6 INFECTION DEVELOPED (## ; = (## WAS NOT OBSERVED IN UNINFECTED LABORATORY REARED CONTROL WOODCHUCKS (## ASSOCIATED WITH EXPERIMENTAL 7(6 INFECTION WAS COMPARABLE TO THAT OF WOODCHUCKS WITH NATURALLY ACQUIRED CHRONIC 7(6 INFECTION ; = 4HE PRESENCE OF PRENEOPLASTIC FOCI OF ALTERED HEPATOCYTES ; = AND PROGRESSIVE ANEUPLOID CHANGE ; = ALSO WAS SIMILAR 4HESE RESULTS PROVIDE DIRECT EXPERIMENTAL EVIDENCE FOR THE CARCINOGENICITY OF 7(6 AND BY ANALOGY FOR THAT OF OTHER MAMMALIAN HEPADNAVIRUSES ("6 '3(6 AND !'3(6 IN WHICH NATURALLY ACQUIRED INFECTION HAS BEEN ASSOCIATED WITH (## 4HE PREVALENCE OF (## IN HUMANS IS HIGHER IN MEN THAN IN WOMEN )N !SIA WHERE ("6 INFECTION IS HYPERENDEMIC THE RATIO MAY BE AS HIGH AS OR 4HE EXPLANATION FOR THE DIFFERENCE IS NOT FULLY UNDERSTOOD BUT MEN HAVE HIGHER RATES OF ("6 INFECTION AND ARE KNOWN TO HAVE GREATER USE OF ALCOHOL AND TOBACCO THAN WOMEN ; = )N EXPERIMENTAL RODENT MODELS HIGHER RATES OF (## ALSO ARE CONSISTENTLY OBSERVED IN MALES (ORMONAL FACTORS ARE CRITICAL IN DETERMINING THE MALE PREDILECTION TO DIETHYLNITROSAMINE $%. INDUCED (## BECAUSE CASTRATION OR ADMINISTRATION OF ESTROGEN TO MALE MICE DIMINISHES THE DEVELOPMENT OF (## SIGNIFICANTLY ;= 2ECENT STUDIES OF +ARIN AND HIS ASSOCIATES HAVE EXTENDED OUR UNDERSTANDING OF THE GENETIC AND HORMONAL FACTORS THAT ARE IMPORTANT IN HEPATOCARCINOGENESIS AND HAVE DELINEATED THE MOLECULAR MECHANISM RESPONSIBLE FOR THE PROPHYLACTIC BEN EFIT OF ESTROGEN ;= 4HEY OBSERVED THAT $%. ADMINISTRATION CAUSED GREATER INCREASES IN THE SERUM CONCENTRATION OF INTERLEUKIN ), IN MALES THAN IN FEMALES AND ABLATION OF THE ), GENE ELIMINATED THE DIFFERENCES BETWEEN GENDERS IN HEPATOCARCINOGENESIS $%. EXPOSURE PROMOTED PRODUCTION OF ), IN +UPFFER CELLS VIA THE 4OLL LIKE RECEPTOR ADAPTOR PROTEIN -Y$ AND ABLATION OF -Y$ PROTECTED MALE MICE AGAINST $%. INDUCED (## %STROGEN REDUCED PLASMA ), IN $%. TREATED MALE MICE AND INHIBITED PRODUCTION OF ), BY +UPFFER CELLS SUGGESTING THAT REDUCED ), PRODUCTION BY +UPFFER CELLS WAS CRITICAL IN REDUCING THE RISK OF (## IN FEMALES 4HESE
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
AUTHORS SUGGESTED THEIR FINDINGS MIGHT BE TRANSLATED FOR USE IN THE PREVEN TION OF (## IN HIGH RISK INDIVIDUALS PRESUMABLY IN COMBINATION WITH OTHER STRATEGIES SUCH AS ANTIVIRAL DRUG THERAPY TO INHIBIT VIRAL REPLICATION PREVENT CHRONIC HEPATITIS AND DECREASE THE RISK OF CIRRHOSIS )N WOODCHUCKS GENDER DOES NOT INFLUENCE EITHER THE RATE OF CHRONIC 7(6 INFECTION OR THE OCCURRENCE OF (## IN CHRONIC 7(6 CARRIERS 4HIS RESULT WAS UNEXPECTED BECAUSE OF THE EXPERIENCE IN HUMANS INFECTED WITH ("6 AND IN LABORATORY RODENTS JUST DESCRIBED 4HE EXPLANATION MAY RELATE TO THE UNUSUAL CIRCANNUAL REPRODUCTIVE CYCLE OF THE WOODCHUCK &OR AT LEAST MONTHS OF THE YEAR THE TESTICLES OF MALE WOODCHUCKS ARE ABDOMINAL AND PRODUCE LITTLE OR NO TESTOSTERONE RESULTING IN FUNCTIONAL CASTRATION ;= )MMUNE MEDIATED GLOMERULONEPHRITIS HAS BEEN REPORTED IN WOODCHUCKS WITH EXPERIMENTALLY INDUCED CHRONIC 7(6 INFECTION !FFECTED WOODCHUCKS MAY DEVELOP SEVERE PROTEIN LOSING NEPHROPATHY AND SIGNS SIMILAR TO THE NEPHROTIC SYNDROME OF HUMANS 3UCH WOODCHUCKS DEVELOP HYPOALBUMIN EMIA AND GENERALITIC PERIPHERAL EDEMA 4HIS IS THE ONLY DISEASE OF WOOD CHUCKS CAUSED BY 7(6 THAT OCCURS OUTSIDE THE LIVER ;= &ULL LENGTH CLONES OF THE GENOMES OF ("6 ;= 7(6 ;= $("6 ;= AND '3(6 ;= HAVE BEEN SHOWN TO PRODUCE PRODUCTIVE INFECTION BY DIRECT INJECTION OF PLASMID $.! INTO THE HEPATIC PARENCHYMA OF THE RESPECTIVE HOST SPECIES $URING TRANSFECTION EXPERIMENTS WITH CHIMERAS OF '3(67(6 GENOMES TO DETERMINE THE VIRAL GENE OR GENES RESPONSIBLE FOR RESTRICTION OF HOST RANGE IT WAS DISCOVERED THAT WOODCHUCKS WERE FULLY SUSCEPTIBLE TO INFECTION WITH '3(6 ;= '3(6 HAD BEEN SHOWN EARLIER TO INFECT THE CHIPMUNK %UTAMIAS SPECIES ;= !S DESCRIBED ABOVE #ALIFORNIA GROUND SQUIRRELS THAT ARE CHRONICALLY INFECTED WITH '3(6 DEVELOP (## LESS FREQUENTLY THAN WOODCHUCKS CHRONICALLY INFECTED WITH 7(6 ; n= AND (## DEVELOPS IN #ALIFORNIA GROUND SQUIRRELS AT AN OLDER AGE ;= "ECAUSE WOODCHUCKS COULD BE INFECTED WITH BOTH 7(6 AND '3(6 IT WAS POSSIBLE TO DETERMINE IF THE APPARENT DIFFERENCE IN ONCOGENICITY OF '3(6 AND 7(6 IN THEIR RESPECTIVE NATURAL HOSTS WAS THE RESULT OF DIFFERENCES IN HOST RESPONSE OR WERE RELATED TO DIFFERENCES IN VIRAL GENETICS 7HEN NEONATAL WOODCHUCKS WERE EXPERIMENTALLY INFECTED EITHER WITH 7(6 OR '3(6 THE RATES OF CHRONIC INFECTION WERE SIMILAR ;= "Y YEARS OF AGE HOWEVER HEPATIC NEOPLASMS OF VARIOUS SIZES WERE OBSERVED AT LAPAROTOMY IN OF CHRONIC 7(6 CARRIERS !T THE SAME AGE ONLY ONE OF CHRONIC '3(6 CARRIERS HAD DEVELOPED A GROSSLY IDENTIFIABLE HEPATIC NEOPLASM A MM DIAMETER NODULE CLASSIFIED HISTOLOGICALLY AS A HEPATIC ADENOMA )T WAS CONCLUDED BASED ON THESE OBSERVATIONS THAT THE DIFFER ENCES IN ONCOGENIC CAPACITY OF '3(6 AND 7(6 THAT WERE RECOGNIZED IN THEIR RESPECTIVE NATURAL HOST SPECIES WERE ATTRIBUTABLE TO VIRAL GENETIC DIF FERENCES BETWEEN THE VIRUSES ALTHOUGH DIFFERENCES IN HOST RESPONSES COULD NOT BE EXCLUDED
"UD # 4ENNANT ET AL
(EPATOCARCINOGENESIS ASSOCIATED WITH HEPADNAVIRUS INFECTION 4HREE CATEGORIES OF EVIDENCE INDICATE THAT ("6 IS AN ETIOLOGIC FACTOR IN HEPATOCARCINOGENESIS &IRST SEROEPIDEMIOLOGIC EVIDENCE HAS DEMONSTRATED A CLOSE RELATION BETWEEN THE PREVALENCE OF INFECTION WITH ("6 AND THE OCCURRENCE OF (## ; = 3IGNIFICANTLY HIGHER RATES OF (## ARE OBSERVED IN INDIVIDUALS WITH CHRONIC ("6 INFECTION THAN IN CASE CONTROLS IN THE HYPER ENDEMIC REGIONS OF !FRICA ;n= AND !SIA ;n= )N THE 5NITED 3TATES AND 'REAT "RITAIN WHERE THE RATES OF ("6 INFECTION AND (## ARE RELATIVELY LOW A SIMILAR RELATIONSHIP BETWEEN ("6 INFECTION AND (## WAS OBSERVED ;n= #OMPELLING EPIDEMIOLOGIC EVIDENCE FOR THE ROLE OF ("6 IN HEPA TOCARCINOGENESIS COMES FROM THE EPIDEMIOLOGICAL STUDIES OF "EASLEY AND COLLEAGUES IN 4AIWAN WHO PROSPECTIVELY DEMONSTRATED THAT CHRONIC ("6 CARRIERS HAD EXTRAORDINARILY HIGH RELATIVE RISK OF DEVELOPING (## COMPARED TO NON CARRIERS ;n= ! SIMILAR HIGH RELATIVE RISK OF (## IN ("6 CARRIERS IS OBSERVED IN THE 5NITED 3TATES ;= 4HE SECOND FORM OF EVIDENCE SUGGESTING AN ETIOLOGIC ROLE OF HEPADNA VIRUSES IN HEPATOCARCINOGENESIS IS MOLECULAR #OVALENT INTEGRATION OF TRUN CATED ("6 $.! SEQUENCES IN THE CELLULAR $.! OF HEPATIC TUMORS OF MOST ("6 CARRIERS ;n= SUGGESTS THAT ("6 HAS A DIRECT ROLE IN HEPATOCARCINO GENESIS SIMILAR TO THAT OF OTHER TUMOR PRODUCING VIRUSES IN WHICH INTEGRATED VIRAL $.! OR PROVIRAL $.! IN THE CASE OF RETROVIRUSES CAUSES NEOPLASTIC CELL TRANSFORMATION BY INSERTIONAL MUTAGENESIS ; = &INALLY AT LEAST FOUR MEMBERS OF THE FAMILY 3CIURIDAE HAVE BEEN DESCRIBED IN WHICH PERSISTENT HEPADNAVIRUS INFECTION IS CLOSELY ASSOCIATED WITH THE DEVELOPMENT OF (## ;= AND THIS OBSERVATION COMBINED WITH THE EXPERIMENTAL INDUCTION OF (## IN LABORATORY WOODCHUCKS INFECTED AT BIRTH WITH 7(6 ;= PROVIDES CREDIBLE COMPARATIVE MEDICAL EVIDENCE FOR THE ETIOLOGIC ROLE OF HEPADNAVI RUSES IN HEPATOCARCINOGENESIS ;=
-OLECULAR MECHANISMS OF HEPATOCARCINOGENESIS ASSOCIATED WITH HEPADNAVIRUS INFECTION 4HE SPECIFIC MECHANISMS BY WHICH HEPADNAVIRUSES CAUSE (## ARE NOT COMPLETELY UNDERSTOOD BUT TWO GENERAL MECHANISMS HAVE BEEN PROPOSED )N THE DIRECT MOLECULAR MODEL ;n= INTEGRATION OF HEPADNAVIRAL $.! INTO HOST CELL $.! RESULTS IN INSERTIONAL MUTATIONS AND ALTERED EXPRESSION OF A GENE OR GENES THAT REGULATE THE CELL CYCLE PROTOONCOGENES AND TUMOR SUPPRESSOR GENES )N THIS MODEL NEOPLASTIC TRANSFORMATION OF HEPATOCYTES IS INITIATED BY INTEGRATION OF HEPADNAVIRAL $.! IN A MANNER ANALOGOUS TO THAT OF CHEMICAL HEPATOCARCINOGENS ; = 4HE MOLECULAR HYPOTHESIS IS BASED ON DETECTION OF HEPADNAVIRAL INTEGRA TIONS IN THE CELLULAR $.! OF MOST (##S FROM PATIENTS INFECTED WITH ("6 ;n= #HARACTERISTICALLY ONLY PORTIONS OF THE VIRAL GENOME ARE INTEGRATED
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
AND SEQUENCES OFTEN ARE REARRANGED ; = )N STUDIES OF THE FLANKING SEQUENCES ("6 INTEGRANTS HAVE BEEN DETECTED INFREQUENTLY NEAR A KNOWN PROTOONCOGENE OR TUMOR SUPPRESSOR GENE AND AS A CONSEQUENCE INTEGRA TIONS WERE CONSIDERED TO HAVE BEEN RANDOM WITHIN THE GENOME -ORE RECENT STUDIES OF HUMAN (##S HAVE DEMONSTRATED RECURRENT PATTERNS OF ("6 INTEGRATION INVOLVING MULTIPLE GENE FAMILIES AND THE TELOMERASE REVERSE TRANSCRIPTASE ; = )N THE STUDY OF HUMAN (##S BY 0ATERLINI "RECHOT AND HER COLLEAGUES INTEGRANTS WERE FOUND IN ALL CHROMOSOMES WITH THE EXCEP TION OF 8 AND 9 ;= )N THE (##S OF MOST 7(6 CARRIERS INTEGRATED 7(6 $.! SEQUENCES HAVE BEEN DEMONSTRATED ;n= -OLECULAR CLONING AND ANALYSES OF INTE GRATED 7(6 $.! AND OF FLANKING CELLULAR $.! SEQUENCES INDICATED THAT INTEGRATIONS OCCURRED AT MULTIPLE SITES WITHIN THE WOODCHUCK GENOME ; = -ULTIPLE INTEGRATIONS IN A SINGLE TUMOR COULD BE EXPLAINED IN DIF FERENT WAYS 4HE ACCUMULATION OF MULTIPLE INTEGRATIONS IN A SINGLE HEPATO CYTE COULD OCCUR PRIOR TO CLONAL PROPAGATION OF THE TRANSFORMED HEPATOCYTE OR AN INITIAL SINGLE INTEGRATION OF HEPADNAVIRAL $.! COULD BE FOLLOWED BY SECONDARY REARRANGEMENTS OF INTEGRATED VIRAL SEQUENCES DURING TUMOR GROWTH ;= ! THIRD ALTERNATIVE COULD BE THAT TWO OR MORE TUMORS COULD DEVELOP INDEPENDENTLY FUSE DURING GROWTH AND THEN BE REMOVED AND ANA LYZED AS A SINGLE TUMOR 6IRAL INTEGRATIONS IN THE NON TUMOROUS HEPATIC TISSUE OF ("6 CARRIERS INDICATES THAT INTEGRATION PRECEDES THE DEVELOPMENT OF HEPATIC NEOPLASMS 5SING 3OUTHERN BLOT ANALYSIS "RECHOT ET AL STUDIED THE STATE OF ("6 $.! IN THE NON NEOPLASTIC LIVER OF GROUPS OF PATIENTS WITH (## WITH CHRONIC HEPATITIS AND WITH ACUTE HEPATITIS ;= )NTEGRATION OF ("6 $.! WAS DETECTED BOTH IN THE CELLULAR $.! OF (##S AND IN NON NEOPLASTIC HEPATIC TISSUE AND THE INTEGRATION PATTERNS WERE DIFFERENT )NTEGRATION OF ("6 $.! ALSO WAS DEMONSTRATED IN SOME PATIENTS WITH CHRONIC HEPATITIS BUT WITHOUT TUMOR INDICATING THAT INTEGRATION MAY BE REQUIRED FOR HEPATOCYTE TRANSFOR MATION BUT IS NOT THE ONLY FACTOR RESPONSIBLE FOR THE DEVELOPMENT OF (## )N THE LIVERS OF TWO PATIENTS WITH ACUTE ("6 INFECTION RESTRICTION ANALYSIS SUGGESTED THE PRESENCE OF INTEGRATED ("6 $.! INDICATING THAT VIRAL $.! INTEGRATION OCCURS VERY EARLY IN ("6 INFECTION )NTEGRATIONS OF 7(6 $.! SEQUENCES HAVE BEEN REPORTED IN THE NON NEOPLASTIC LIVER OF 7(6 INFECTED WOODCHUCKS ; = SUPPORTING THE VIEW THAT INTEGRATIONS OF VIRAL $.! OCCUR EARLY IN HEPATOCARCINOGENESIS 7(6 $.! INTEGRATIONS ALSO HAVE BEEN DESCRIBED IN SMALL NEOPLASTIC NOD ULES BEFORE DEVELOPMENT OF FRANK (## ;n= 3UMMERS -ASON AND THEIR COLLEAGUES HAVE ELEGANTLY DETERMINED THE FREQUENCY OF HEPADNAVIRAL $.! INTEGRATIONS IN INDIVIDUAL HEPATOCYTES IN EXPERIMENTAL ACUTE AND CHRONIC 7(6 INFECTION AND IN CHRONIC 7(6 CARRIERS AFTER SUSTAINED ANTIVI RAL DRUG THERAPY ;n= )N EXPERIMENTAL $("6 INFECTION THE LIVER WAS FOUND TO CONTAIN ONE $("6 $.! INTEGRANT PER TO LIVER CELLS AND SEQUENCE ANALYSIS SUGGESTED THAT LINEAR $("! WAS THE PREDOMINANT
"UD # 4ENNANT ET AL
SUBSTRATE FOR INTEGRATION ;= ! SIMILAR ASSAY SYSTEM AND SIMILAR RESULTS WERE OBTAINED IN INVESTIGATIONS OF EXPERIMENTAL 7(6 INFECTION &OLLOWING RESOLUTION OF ACUTE INFECTION ONE 7(6 $.! INTEGRANT WAS FOUND PER TO LIVER CELLS ;= )N CHRONIC 7(6 INFECTION IT WAS ESTIMATED THAT n OF THE TOTAL NON NEOPLASTIC LIVER CELLS CONTAINED SEQUENCES OF INTEGRATED 7(6 $.! ;= 4HE FREQUENCY OF INTEGRATED VIRAL $.! IN CHRONIC 7(6 CARRIERS WAS FOUND TO BE TO ORDERS OF MAGNITUDE GREATER THAN THAT OBSERVED IN TRANSIENT 7(6 INFECTION SUGGESTING THAT INTEGRATIONS AND OTHER GENOMIC ALTERATIONS WERE ACCUMULATED OVER THE DURATION OF INFEC TION ;= 7HEN CHRONIC 7(6 CARRIERS RECEIVED SUSTAINED TREATMENT WITH THE POTENT NUCLEOSIDE ANALOG CLEVUDINE , &-!5 7(6 CCC$.! WAS DECREASED BY TO FOLD BUT NO DETECTABLE DECREASE IN THE FREQUENCY OF 7(6 INTEGRANTS WAS OBSERVED 4HIS SUGGESTS THE INTEGRATED 7(6 $.! SEQUENCES PERSISTED FOLLOWING SUBSTANTIAL CLEARANCE OF VIRUS AN OBSERVATION THE AUTHORS BELIEVED ARGUED FOR EARLY THERAPEUTIC INTERVENTION IN CHRONIC ("6 INFECTION ;= (EPADNAVIRUSES DO NOT CONTAIN ONCOGENES SIMILAR TO THOSE FOUND IN TRANSFORMING RETROVIRUSES ; = 5PREGULATION OF MANY OF THE WELL CHARAC TERIZED PROTOONCOGENES HAS NOT BEEN DEMONSTRATED ;= )NCREASED EXPRES SION TO FOLD OF C MYC HOWEVER WAS OBSERVED IN THREE OF NINE WOOD CHUCK (##S ;n= AND TRUNCATION AND REARRANGEMENT OF THE GENE WERE DEMONSTRATED )N ONE TUMOR THERE WAS NO DIRECT LINKAGE BETWEEN 7(6 $.! INTEGRATION AND C MYC ACTIVATION !CTIVATION OF C MYC APPEARED TO BE COMPARABLE TO THAT IN "URKITTS LYMPHOMA AND IN ACUTE " AND 4 CELL LEUKE MIAS THAT ARE ASSOCIATED WITH CHROMOSOMAL TRANSLOCATIONS ;= !CTIVATION IN THE OTHER TWO TUMORS WAS RELATED TO INSERTIONAL MUTATIONS ;= WITH 7(6 $.! INSERTIONS INTERRUPTING THE C MYC LOCUS 4HE POSITION AND ORI ENTATION OF THE 7(6 INTEGRANTS IN RELATION TO C MYC EXCLUDED INVOLVEMENT OF THE HEPADNAVIRAL PROMOTER IN C MYC ACTIVATION IE PROMOTER INSERTION 7(6 SEQUENCES ANALOGOUS TO ONE OF THE ("6 ENHANCERS WERE PRESENT IN THE VIRAL INTEGRANTS SUGGESTING THE POSSIBILITY OF ENHANCER INSERTION ;= )N A LARGE SERIES OF WOODCHUCK (##S ACTIVATION OF C MYC WAS OBSERVED IN OF THE TUMORS ;= 4HE EXPRESSION OF . MYC HAS BEEN SHOWN TO BE INCREASED IN OF WOODCHUCK (##S AND THIS TRANSCRIPT IS NOT DETECTED IN NORMAL WOODCHUCK LIVER 4WO . MYC LOCI HAVE BEEN IDENTIFIED IN WOODCHUCKS /NE IS HOMOLO GOUS TO THE . MYC GENE OF OTHER MAMMALIAN SPECIES 4HE OTHER IDENTIFIED AS . MYC IS AN INTRONLESS GENE WITH THE CHARACTERISTIC STRUCTURE OF A RET ROTRANSPOSON ;= AND . MYC HAS BEEN MAPPED TO THE 8 CHROMOSOME %XPRESSION OF . MYC IS HIGHLY RESTRICTED AND THE BRAIN IS THE ONLY NORMAL TISSUE OF THE WOODCHUCK IN WHICH . MYC 2.! WAS DETECTED ;= 4HE PHYSIOLOGICAL FUNCTION OF . MYC IF ANY REMAINS UNKNOWN ;= (EPATOCARCINOGENESIS IN WOODCHUCKS WITH CHRONIC 7(6 INFECTION APPEARS TO BE PREFERENTIALLY ASSOCIATED WITH ALTERATION IN EXPRESSION OF THE . MYC LOCUS ; = )NSERTION OF 7(6 ENHANCER SEQUENCES UPSTREAM OR DOWN
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
STREAM OF . MYC WAS ASSOCIATED WITH INCREASED TRANSCRIPTION OF NORMAL . MYC 2.! OR OF A HYBRID . MYC7(6 TRANSCRIPT INITIATED AT THE . MYC START SITE %NHANCER INSERTION APPEARS TO BE A COMMON MECHANISM ;= FOR INCREASED . MYC EXPRESSION ! LIVER SPECIFIC REGULATORY ELEMENT IN THE 7(6 GENOME HAS BEEN IDENTIFIED THAT APPEARS TO CONTROL CIS ACTIVATION OF . MYC ;= $OWNSTREAM INTEGRATION OF 7(6 $.! ALSO HAS BEEN ASSOCI ATED WITH ACTIVATION OF . MYC ;= 2APICETTA AND HER COLLEAGUES HAVE ANALYZED THE (##S OF WOODCHUCKS TRAPPED IN THEIR NATIVE HABITAT WITH NATURALLY ACQUIRED CHRONIC 7(6 INFEC TION ;= #OMPARISON OF THEIR RESULTS WITH DATA FROM PREVIOUS STUDIES OF WOODCHUCKS WITH EXPERIMENTAL 7(6 DEMONSTRATED THAT TUMORS FROM NATURALLY INFECTED WOODCHUCKS HAD 7(6 INTEGRATIONS NEAR . MYC LESS FREQUENTLY THAN TUMORS FROM EXPERIMENTALLY INFECTED CHRONIC 7(6 CAR RIERS AND . MYC ACTIVATION ASSOCIATED WITH 7(6 INTEGRATIONS NEAR THE . MYC GENE ALSO OCCURRED LESS FREQUENTLY VERSUS 0 4HEIR FINDINGS WERE BELIEVED TO BE RELATED TO THE LESS UNIFORM INFECTING VIRUS AND HOST GENETIC BACKGROUND OF THE NATURALLY INFECTED WOOD CHUCKS AND SUGGESTED THAT VIRAL ANDOR HOST FACTORS COULD INFLUENCE THE SITE OF VIRAL INSERTION THAT WAS DETECTED FINALLY IN HEPATIC TUMORS -ORE THAN ONE THIRD OF THE TUMORS THEY EXAMINED WITH INCREASED . MYC EXPRESSION SHOWED NO EVIDENCE OF REARRANGEMENT EITHER NEAR . MYC OR DOWNSTREAM IN EITHER THE WIN OR BN LOCI 4HESE FINDINGS INDICATED THAT NOT ALL TUMORS WITH INCREASED . MYC EXPRESSION WERE RELATED TO BN OR WIN INTEGRATIONS AND THE AUTHORS SUGGESTED THAT ACTIVATION OF . MYC IN SUCH CASES WAS THE RESULT OF CHROMOSOMAL INTEGRATION OF 7(6 $.! FURTHER DOWN STREAM OR TO MECHANISMS UNRELATED TO VIRAL INSERTION ;= *ACOB ET AL EXAMINED THE FREQUENCY OF $.! INTEGRATIONS AND REARRANGE MENTS OF THE . MYC GENE IN HEPATIC TUMORS FROM WOODCHUCKS WITH (## AND COMPARED THE RESULTS OF THE MOLECULAR CHANGES TO THE SIZE AND HISTOLOGICAL CHARACTERISTICS OF THE HEPATIC TUMORS ;= &OUR SMALL TUMOR NODULES WERE CLASSIFIED HISTOLOGICALLY AS ADENOMAS AND INTEGRATED SEQUENC ES OF 7(6 $.! WERE DETECTED IN TWO OF THE FOUR TUMOR NODULES AND IN ONE OF THE TWO THERE WAS EVIDENCE OF . MYC REARRANGEMENT NEOPLASMS WERE CLASSIFIED AS (## 3EVEN WERE CLASSIFIED WELL DIFFERENTIATED GRADE (##S 7(6 $.! INTEGRATIONS WERE DEMONSTRATED IN BUT NONE HAD DETECTABLE . MYC REARRANGEMENTS GRADE MODERATELY WELL DIFFERENTI ATED (##S WERE ANALYZED AND 7(6 $.! INTEGRATIONS WERE DETECTED IN AND . MYC REARRANGEMENTS WERE PRESENT IN POORLY DIFFERENTI ATED GRADE (##S HAD 7(6 INTEGRATIONS IN AND . MYC REARRANGE MENTS WERE DETECTED IN )N TWO OTHER GRADE (##S REARRANGEMENTS OF . MYC WERE DETECTED IN THE ABSENCE OF 7(6 $.! INTEGRATIONS 4HE LARGEST TUMORS IN THE SERIES WERE CLASSIFIED AS EITHER GRADE OR GRADE (##S AND IN OF THE LARGEST TUMORS BOTH 7(6 $.! INTEGRATIONS AND . MYC REARRANGEMENTS WERE DEMONSTRABLE ! SERIES OF GENETIC ALTERATIONS
"UD # 4ENNANT ET AL
WERE DEMONSTRATED IN WOODCHUCK (##S THAT WERE DIRECTLY RELATED TO TUMOR SIZE AND THE DEGREE OF HISTOLOGICAL DIFFERENTIATION AND APPEARED TO PROVIDE PROGRESSIVE PROLIFERATIVE STIMULUS ANDOR GROWTH ADVANTAGE ;= "UENDIA AND HER COLLEAGUES HAVE REPORTED THAT TRANSGENIC MICE CARRY ING THE . MYC GENE UNDER THE CONTROL OF 7(6 REGULATORY SEQUENCES ARE HIGHLY PREDISPOSED TO CANCER OF THE LIVER ;= DEVELOPED EITHER (## OR HEPATOCELLULAR ADENOMAS ! TRANSGENIC FOUNDER THAT CARRIED THE UNMETH YLATED 7(6. MYC TRANSGENE SEQUENCE DIED AT THE AGE OF MONTHS WITH A LARGE LIVER TUMOR DEMONSTRATING THE HIGH ONCOGENIC CAPACITY OF THE WOODCHUCK . MYC RETROPOSON -UTATIONS OR DELETIONS OF THE ` CATENIN GENE SIMILAR TO THOSE OF (##S FROM HUMANS AND MICE ;= WERE PRESENT IN OF THE HEPATIC TUMORS OF THE . MYC TRANSGENIC ANIMALS AND TUMOR LATENCY TIME TO TUMOR WAS SIGNIFICANTLY REDUCED ;= 7HEN . MYC TRANSGENIC MICE WERE CROSSED WITH P NULL MICE THE ABSENCE OF ONE P ALLELE MARK EDLY ACCELERATED THE ONSET OF LIVER CANCER PROVIDING DIRECT EXPERIMENTAL EVIDENCE FOR SYNERGY IN MULTISTAGE HEPATOCARCINOGENESIS BETWEEN ACTIVATION OF . MYC AND DIMINISHED EXPRESSION OF P ;= ,IKE THE WOODCHUCK THE #ALIFORNIA GROUND SQUIRREL POSSESSES A FUNC TIONAL TRANSCRIPTIONALLY ACTIVE . MYC LOCUS IN THE BRAIN ;= (OWEVER INCREASED . MYC EXPRESSION IS UNUSUAL IN (##S FROM #ALIFORNIA GROUND SQUIRRELS INFECTED WITH '3(6 !MPLIFICATION OF # MYC EXPRESSION HOWEVER IS MORE FREQUENT IN GROUND SQUIRREL HEPATIC NEOPLASMS THAN IN THOSE OF WOODCHUCKS ;= (##S FROM WOODCHUCKS EXPERIMENTALLY INFECTED EITHER WITH 7(6 OR WITH '3(6 HAVE BEEN ANALYZED ;= 4HE PROPENSITY FOR 7(6 GENOMIC $.! TO INTEGRATE IN OR NEAR THE . MYC LOCUS IN (##S FROM CHRONIC 7(6 CARRIERS WAS CONFIRMED WHEREAS IN WOODCHUCK (##S ASSOCI ATED WITH '3(6 INFECTION SUCH INTEGRATIONS WERE EXCEPTIONAL 3EVEN OF 7(6 INDUCED TUMORS HAD REARRANGEMENTS OF THE . MYC ALLELE /NLY ONE OF '3(6 ASSOCIATED TUMORS HOWEVER HAD SUCH . MYC REARRANGEMENTS "ASED ON THE OBSERVATIONS IN '3(6 INDUCED (##S FROM GROUND SQUIRRELS AND FROM WOODCHUCKS IT WAS CONCLUDED THAT THE DIFFERENC ES IN HEPADNAVIRUS INSERTION AND IN . MYC ACTIVATION BETWEEN WOODCHUCKS AND GROUND SQUIRRELS WERE DUE PRIMARILY TO VIRAL GENETIC DIFFERENCES AND NOT TO DIFFERENCES IN THE RESPECTIVE HOST SPECIES ;= ! SIMILAR CONCLUSION WAS REACHED BY "UENDIA AND HER COLLEAGUES ;= 4RANSFECTION OF A NONMALIGNANT 36 4 ANTIGEN TRANSFORMED MOUSE HEPATIC CELL LINE WITH ("6 $.! PRODUCED CELLS WITH A MALIGNANT PHENOTYPE THAT GREW IN SOFT AGAR AND WERE TUMORIGENIC IN NUDE MICE ("8 TRANSCRIPT WAS EXPRESSED AT A MUCH HIGHER LEVEL THAN THAT OBSERVED IN VIVO ;= )N SUBSEQUENT STUDIES IT WAS CONCLUDED THAT OVER EXPRESSION OF THE ("8 WAS REQUIRED FOR MALIGNANT TRANSFORMATION OF THE CELL LINE ;= ("8 IS KNOWN TO PROMOTE HEPATOCARCINOGENESIS IN C MYC TRANSGENIC MICE ;= AND MAY PROMOTE HEPADNAVIRUS INDUCED HEPATOCARCINOGENESIS ;= 4HE 8 GENE APPEARS TO BE ESSENTIAL FOR NORMAL REPLICATION OF HEPADNA VIRUSES IN VIVO 4HE 7(8 PROTEIN IS COEXPRESSED WITH 7(C!G IN THE LIVER
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
OF CHRONIC 7(6 CARRIER WOODCHUCKS ; = &EITELSON DEMONSTRATED THAT WHEN 7(8 WAS CO TRANSLATED IN VITRO WITH P 7(8P COMPLEXES DEVELOPED AND SIMILAR 7(8P COMPLEXES WERE DEMONSTRATED IN THE LIV ERS OF CHRONIC 7(6 CARRIERS ;= #OMBINED WITH OBSERVATIONS IN ("6 TRANSGENIC MICE ; = THE OBSERVATIONS OF &EITELSON ET AL SUGGEST THAT BINDING OF 7(8 TO P MAY PREVENT ENTRY OF P INTO THE NUCLEUS DIMIN ISH TUMOR SUPPRESSOR ACTIVITY AND REPRESENT AN IMPORTANT MECHANISM BY WHICH THE HEPADNAVIRUS 8 GENE PRODUCT COULD PROMOTE HEPATOCARCINOGEN ESIS ;= -UTATIONS OF P ALSO MAY ALTER ITS TUMOR SUPPRESSOR ACTIVITY BUT SUCH MUTATIONS WERE FOUND PRIMARILY IN THE LESS DIFFERENTIATED HEPATIC TUMORS SUGGESTING THE MUTATIONS ALTERED TUMOR PROGRESSION AT A LATER STAGE OF DEVELOPMENT ; =
)NFLAMMATION AND HEPATOCYTE REGENERATION IN HEPADNAVIRUS ASSOCIATED HEPATOCARCINOGENESIS )NFLAMMATION ASSOCIATED INFECTIONS ARE RECOGNIZED AS IMPORTANT RISK FAC TORS FOR CANCER (EPATITIS ASSOCIATED WITH CHRONIC ("6 INFECTION IS A WELL RECOGNIZED EXAMPLE BUT HOW INFLAMMATION OF THE LIVER INFLUENCES HEPATO CARCINOGENESIS IS NOT FULLY UNDERSTOOD .& g" CAN PROMOTE OR INHIBIT CARCI NOGENESIS .& g" PRODUCED BY INFLAMMATORY CELLS IN RESPONSE TO INFECTIOUS AGENTS TO NECROTIC CELLS OR TO CYTOKINES RESULTS IN THE PRODUCTION OF SOLUBLE FACTORS THAT ENHANCE CELL GROWTH SURVIVIAL AND VASCULARIZATION OF CARCINOMA CELLS .& g" PRODUCED BY CARCINOMA CELLS INCREASES THE PRODUCTION OF INHIBI TORS OF APOPTOSIS AND OF PROTEASES THAT FACILITATE CELL INVASION 2EVIEWED ; = (## DEVELOPS REGULARLY IN A SETTING OF CHRONIC HEPATITIS AND EVIDENCE IS ACCUMULATING THAT CHRONIC LIVER INFLAMMATION HAS AN IMPORTANT ROLE IN HEPATOCARCINOGENESIS ; = 3UPPORT FOR A MODEL IN WHICH INFLAM MATION IS A KEY FACTOR IN HEPATOCARCINOGENESIS COMES FROM THE OBSERVA TION THAT CHRONIC LIVER INJURY ASSOCIATED WITH CIRRHOSIS FREQUENTLY PRECEDES THE DEVELOPMENT OF (## IN ("6 INFECTED INDIVIDUALS ; = #HRONIC HEPATITIS # VIRUS INFECTION RESULTS IN SEVERE CHRONIC HEPATITIS AND CIRRHOSIS THAT FREQUENTLY LEADS TO (## BUT IN THIS FORM OF (## THERE IS NO EVIDENCE OF VIRAL NUCLEIC ACID INTEGRATION INTO CELLULAR $.! )NCREASED RATES OF (## IN HUMANS ARE OBSERVED IN INHERITED FORMS OF CHRONIC LIVER DISEASE INCLUD ING HEMOCHROMATOSIS ALPHA ANTITRYPSIN DEFICIENCY AND 7ILSONS DISEASE ;= 4HESE DISEASES ALSO ARE ASSOCIATED WITH DEVELOPMENT OF PROGRESSIVELY SEVERE HEPATOCELLULAR INJURY HEPATOCELLULAR REGENERATION AND CIRRHOSIS THAT PRECEDE DEVELOPMENT OF (## ;= %XPERIMENTAL SUPPORT FOR THE ROLE OF HEPATIC INFLAMMATION AND HEPA TOCELLULAR INJURY IN HEPATOCARCINOGENESIS COMES FROM STUDIES REPORTED BY #HISARI AND HIS COLLEAGUES USING TRANSGENIC MICE ;n= ! DIRECT RELATION WAS FOUND BETWEEN THE EXPRESSION AND RETENTION OF ("S!G IN HEPATOCYTES
"UD # 4ENNANT ET AL
AND THE SEVERITY OF HEPATITIS AND THE SEVERITY OF HEPATITIS WAS CORRELATED WITH THE DEVELOPMENT OF (## ; = )NCREASED FREE RADICAL PRODUCTION WITHIN THE LIVER WAS ASSOCIATED WITH OXIDATIVE $.! DAMAGE IN WOODCHUCKS ;= A FINDING ALSO REPORTED PREVIOUSLY IN MICE ;= (EPATIC INJURY ASSOCIATED WITH 7(6 INFECTION INCREASES THE RATE OF HEPA TOCYTE DEATH AND REGENERATION AND PROVIDES AN ENVIRONMENT THAT ENHANCES FIXATION OF SPONTANEOUS MUTATIONS REARRANGEMENTS OR CHROMOSOMAL TRANS LOCATIONS THAT MAY BE RESPONSIBLE FOR MALIGNANT TRANSFORMATION OF HEPA TOCYTES 3UCH A ROLE FOR HEPADNAVIRUSES IN HEPATOCARCINOGENESIS WOULD BE COMPARABLE TO THE PROCESSES OF PROMOTION ANDOR PROGRESSION RECOGNIZED IN MULTISTAGE CHEMICAL HEPATOCARCINOGENESIS ; = !NOTHER POSSIBLE HEPATOCARCINOGENIC MECHANISM RELATED DIRECTLY TO HEPATIC INFLAMMATION HAS BEEN SUGGESTED BY STUDIES OF NITRIC OXIDE ./ PRODUCTION IN CHRONIC VIRAL HEPATITIS )N THE LIVER ./ BIOSYNTHESIS FROM ARGININE IS CATALYZED BY INDUCIBLE ./ SYNTHETASE %NDOTOXIN a INTERFERON AND OTHER CYTOKINES ;n= CAN INCREASE THE ACTIVITY OF THIS ENZYME SIG NIFICANTLY 5NDER SOME CIRCUMSTANCES ./ MAY BE PROTECTIVE AGAINST EXPERI MENTAL HEPATIC INJURY ;= 5NDER OTHER CONDITIONS HEPATIC PRODUCTION OF ./ MAY CONTRIBUTE TO DEVELOPMENT OF HYPOTENSION IN SEPTIC SHOCK ;= 7OODCHUCKS CHRONICALLY INFECTED WITH 7(6 EXCRETE MORE NITRATE IN THE URINE AND MORE .$-! THAN UNINFECTED CONTROL WOODCHUCKS ;= 3IMILAR INCREASED ./ PRODUCTION HAS BEEN OBSERVED IN ("6 TRANSGENIC MICE ;= .ITRATE AND .$-! ARE DERIVED FROM ./ PRODUCED FROM , ARGININE 5RINARY NITRATE EXCRETION ALSO IS INCREASED IN A HUMAN PATIENT WITH CHRONIC ("6 INFECTION ;= )N PRIMARY HEPATOCYTE CULTURES FROM NORMAL WOODCHUCKS ./ SYNTHESIS CAN BE INDUCED BY ENDOTOXIN AND HEPATOCYTES CULTURED FROM CHRONIC 7(6 CARRIERS PRODUCE SIGNIFICANTLY MORE ./ AND NITROSAMINE THAN HEPATOCYTES FROM UNINFECTED CONTROLS ;= 36 4 ANTIGEN TRANSFORMED WOODCHUCK HEPATOCYTE CELL LINES HAVE THE CAPACITY TO PRODUCE ./ IN RESPONSE TO ENDO TOXIN ;= UTILIZING THE , ARGININE ./ PATHWAY AND TO PRODUCE .$-! 7(S!G PURIFIED FROM WOODCHUCK SERUM CAN INDUCE ./ PRODUCTION IN WOODCHUCK HEPATOCYTE CULTURES ;= ./ REACTS WITH / TO PRODUCE ./ WHICH EXISTS IN EQUILIBRIUM WITH ./ AND ./ ./ OR ./ ARE POTENT NITROSATING AGENTS CAPABLE OF REACTING WITH WATER TO FORM NITRITE AND NITRATE ;= OR IN NEUTRAL SOLUTION OF NITROSATING DIALKYLAMINES TO FORM NITROSA MINES ./ COULD ACT AS A CARCINOGEN INDIRECTLY BY CAUSING FORMATION OF HEPATOCARCINOGENIC NITROSAMINES SUCH AS .$-! WHICH IS A STRONG ALKYLAT ING AGENT 0OINT MUTATIONS CAN BE INDUCED BY .$-! BY METHYLATION OF GUANINE TO METHYL AND TO METHYLGUANINE OR BY METHYLATION OF ADENINE TO METHYLADENINE ; = ./ ALSO HAS THE CAPACITY TO ACT AS A DIRECT MUTAGEN ;= )N VITRO ./ CAN DEAMINATE DEOXYNUCLEOSIDES DEOXYNUCLEOTIDES OR INTACT $.! AND CONTRIBUTE TO DEAMINATION RELATED MUTATIONS )T HAS BEEN PREDICTED BASED ON STUDIES OF THE RATE OF DEAMINATION OF GUANINE TO XANTHINE IN VITRO THAT
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
GUANINECYTOSINE a ADENINETHYMINE TRANSITIONS COULD BE A FREQUENT FORM OF MUTATION INDUCED BY ./ !DENOSINE DEAMINATION TO HYPOXANTHINE WOULD BE EXPECTED TO RESULT IN ADENINETHYMINE TO GUANINECYTOSINE TRANSITIONS AND REMOVAL OF THE XANTHINE FORMED BY GUANINE DEAMINATION WOULD RESULT IN DEPURINATION AND GUANINECYTOSINE TO THYMINEADENINE TRANSVERSIONS ;= 4HE DEMONSTRATION OF INCREASED ./ FORMATION IN THE HEPADNAVIRUS INFECTED LIVER SUGGESTS THAT ./ COULD HAVE AN IMPORTANT ROLE IN HEPATOCAR CINOGENESIS
)NTERACTION OF HEPADNAVIRUS AND OTHER HEPATOCARCINOGENS !FLATOXIN IS AMONG THE MOST POTENT HEPATOCARCINOGENS KNOWN AND IS A FRE QUENT CONTAMINANT OF THE DIETS OF POPULATIONS WITH HIGH INCIDENCE RATES OF ("6 INFECTION AND (## 4HE POSSIBLE INTERACTION BETWEEN HEPADNAVIRUS INFECTION AND AFLATOXIN HAS BEEN INVESTIGATED USING THE WOODCHUCK MODEL ; = 7HEN ADMINISTERED EARLY IN LIFE TO WOODCHUCKS EXPERIMEN TALLY INFECTED AT BIRTH WITH 7(6 AFLATOXIN " DID NOT APPEAR TO INCREASE THE RATE OF CHRONIC 7(6 INFECTION OR THE RATE OF DEVELOPMENT OF (## ;= 7HEN ADMINISTERED TO ESTABLISHED CHRONIC 7(6 CARRIERS AT ONE YEAR OF AGE AFLATOXIN " APPEARED TO PROMOTE (## AND THE TIME TO TUMOR WAS MODER ATELY REDUCED ;= ! SIMILARLY SYNERGISTIC INTERACTION BETWEEN ("6 AND AFLATOXIN HAS BEEN REPORTED IN THE TREE SHREW ;= 7HEN TRANSGENIC MICE THAT EXPRESSED ("S!G WERE EXPOSED TO $%. OR AFLATOXIN THEY DEVELOPED HEPATIC ADENOMAS AND (## MORE RAPIDLY AND MORE EXTENSIVELY THAN UNEXPOSED TRANSGENIC CONTROLS OR NORMAL MICE RECEIVING EITHER HEPATOCARCINOGENS 4HESE RESULTS DEMONSTRATED A SYNERGY BETWEEN THE CHEMICAL HEPATOCARCINOGENS AND THE CHRONIC HEPATOCELLULAR INJURY CAUSED BY OVEREXPRESSION OF ("S!G IN TRANSGENIC MICE ;= ! SIMILAR SYNERGISTIC EFFECT OF ("8 EXPRESSION IN TRANSGENIC MICE AND $%. ON HEPATOCARCINOGENESIS HAS ALSO BEEN REPORTED ;=
4HE WOODCHUCK MODEL AND ANTIVIRAL DRUG DEVELOPMENT #HRONIC 7(6 CARRIER WOODCHUCKS FREQUENTLY HAVE BEEN USED IN THE PRE CLINICAL EVALUATION OF ANTIVIRAL DRUGS DURING DEVELOPMENT FOR THE TREATMENT OF CHRONIC ("6 INFECTION 4HESE STUDIES HAVE UTILIZED BOTH NUCLEOSIDE ANALOGS AND IMMUNE RESPONSE MODIFIERS ;n= 4HE DRUGS ARE SCREENED FOR ANTIVIRAL ACTIVITY AGAINST ("6 IN THE CELL SYSTEM BEFORE TESTING IN WOODCHUCKS ;= !CYCLOVIR AND !:4 WHICH HAD NO SELECTIVITY AGAINST ("6 IN CELLS HAD NO ANTIVIRAL EFFECT IN THE WOODCHUCK MODEL OF ("6 INFECTION !RA !-0 WHICH HAD MODERATE ANTIVIRAL ACTIVITY IN VITRO HAD SIGNIFICANT ANTIVIRAL ACTIVITY IN WOODCHUCKS AND ACTIVITY WAS INCREASED BY SPECIFIC LIVER TARGETING ;= -OST NUCLEOSIDE ANALOGS WITH INTERMEDIATE
"UD # 4ENNANT ET AL
ANTIVIRAL ACTIVITY IN VITRO AGAINST ("6 HAD INTERMEDIATE ANTIVIRAL ACTIVITY IN WOODCHUCKS !N EXCEPTION WAS FIALURIDINE $ &)!5 WHICH HAD ONLY MODEST TISSUE CULTURE ACTIVITY IN CELLS BUT IN WOODCHUCKS HAD POTENT ANTIVIRAL ACTIVITY DURING A MONTH PERIOD OF TREATMENT $URING A WEEK TEST HOWEVER FIALURIDINE WAS HIGHLY TOXIC AND THE CLINICAL SYNDROME IN WOODCHUCKS WAS SIMILAR TO THAT OBSERVED IN HUMANS TREATED WITH FIALURI DINE ;= !NOTHER FLUORINATED PYRIMIDINE CLEVUDINE , &-!5 ALSO HAD MODERATE TISSUE CULTURE ACTIVITY BUT IS AMONG THE MOST POTENT NUCLEOSIDES IN 7(6 CARRIER WOODCHUCKS ; = ,AMIVUDINE WHICH HAD A VERY HIGH SELECTIVE INDEX AGAINST ("6 IN VITRO WAS A POTENT ANTIVIRAL DRUG IN WOODCHUCKS WITH FAVORABLE PHARMACOKINET ICS ;= AND WAS WITHOUT TOXICITY AT DOSES OF OR MGKGDAY FOR DAYS ;= 4HE ABSENCE OF EFFECT OF LAMIVUDINE ON HEPATIC CCC$.! WAS POSTU LATED TO BE DUE TO THE ABSENCE OF CELL DIVISION ;= ,AMIVUDINE HAS BEEN SHOWN IN THE WOODCHUCK MODEL TO ACT SYNERGISTI CALLY BOTH WITH ALPHA INTERFERON ;= AND WITH FAMCICLOVIR ;= !NTIVIRAL POTENCY SIMILAR TO LAMIVUDINE HAS BEEN DEMONSTRATED IN 7(6 CARRIERS WITH THE CLOSELY RELATED EMTRICITABINE ;= %XTENDED LAMIVUDINE TREATMENT OF WOODCHUCKS WITH CHRONIC 7(6 INFECTIONS WAS ASSOCIATED WITH DEVELOPMENT OF VIRAL POLYMERASE MUTATIONS ;n= 4HE ANTIVIRAL ACTIVITY OF THE NUCLEOTIDE ANALOG ADEFOVIR HAS BEEN EVALU ATED IN THE WOODCHUCK ;= AND ADEFOVIR HAS BEEN SHOWN TO HAVE POTENT ANTIVIRAL ACTIVITY IN WOODCHUCKS WITH CIRCULATING LAMIVUDINE RESISTANT 7(6 ;= 4ENOFOVIR ANOTHER NUCLEOTIDE ANALOG ;= AND THE PURINE NUCLEOSIDE BETA $ AMINOPURINE DIOXOLANE !$0 ;= ALSO HAVE BEEN SHOWN TO HAVE SIGNIFICANT ANTIVIRAL ACTIVITY IN THE WOODCHUCK MODEL 4HE GUANOSINE NUCLEOSIDE ENTECAVIR WAS USED IN 7(6 CARRIER WOOD CHUCKS TO DETERMINE THE EFFECT OF SUSTAINED SUPPRESSION OF VIRAL REPLICATION ON HEPATOCARCINOGENESIS ;= !T MONTHS OF AGE LABORATORY BORN AND REARED 7(6 CARRIERS WERE GIVEN ENTECAVIR ORALLY AT MGKG PER DAY FOR WEEKS AND THEN GIVEN A DOSE OF AT MGKG PER WEEK 4REATMENT WAS STOPPED AFTER A TOTAL OF MONTHS IN SIX WOODCHUCKS AND TREATMENT WAS CONTINUED IN FIVE OTHERS FOR MONTHS 4REATMENT RESULTED IN SIGNIFICANT REDUCTIONS IN HEPATIC EXPRESSION OF VIRAL ANTIGENS AND OF COVALENTLY CLOSED CIRCULAR 7(6 $.! 4HREE OF THE SIX WOODCHUCKS TREATED WITH ENTECAVIR FOR MONTHS HAD SUSTAINED ANTIVIRAL RESPONSES FOLLOWING DRUG WITHDRAWALS AND WHEN KILLED AT YEARS OF AGE HAD NO EVIDENCE OF (## 4HE WOODCHUCKS TREATED FOR MONTHS WERE ALSO KILLED AT YEARS OF AGE AND IN FOUR OF FIVE THERE WAS NO EVIDENCE OF (## %NTECAVIR TREATMENT SIGNIFICANTLY DELAYED DEVELOPMENT OF (## AND PROLONGED SURVIVAL COMPARED TO HISTORICAL 7(6 CARRIER CONTROLS WHICH HAD A YEAR SURVIVAL OF 0 -ENNE ET AL ;= TREATED 7(6 CARRIER WOODCHUCKS BEGINNING AT OR YEARS OF AGE FOR WEEKS WITH THE ORALLY ADMINISTERED PYRIMIDINE NUCLEO SIDE CLEVUDINE MGKG PER DAY ;= #ONTROLS RECEIVED THE SALINE VEHICLE AS PLACEBO #LEVUDINE TREATED AND CONTROL WOODCHUCKS EACH WERE SUBDI
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
VIDED INTO TWO GROUPS /NE SUBGROUP OF THE CLEVUDINE TREATED WOODCHUCKS RECEIVED FOUR DOSES OF ALUM ADSORBED 7(S!G VACCINE DURING THE NEXT WEEKS AND A SUBGROUP OF THE PLACEBO CONTROLS RECEIVED IDENTICAL VACCINA TIONS 3UBGROUPS OF THE CLEVUDINE AND OF THE PLACEBO RECIPIENTS SERVED AS UNVACCINATED CONTROLS 6ACCINATION RESULTED IN DETECTABLE ANTI 7(S RESPONSES IN MOST 7(6 CARRIERS BUT HAD NO EFFECT ON SERUM 7(6 $.! ON SERUM 7(S!G OR ON THE SERUM ACTIVITIES OF LIVER ENZYMES #LEVUDINE TREATED CARRIERS HAD MARKED REDUCTIONS IN SERUM 7(6 $.! AND 7(S!G AND WHEN VACCI NATED DEVELOPED A SIGNIFICANTLY MORE ROBUST ANTI 7(S RESPONSE THAN DID WOODCHUCKS NOT RECEIVING ANTIVIRAL THERAPY 7(S!G SPECIFIC CELL MEDIATED IMMUNE RESPONSES DEVELOPED IN BOTH CLEVUDINE AND PLACEBO RECIPIENTS THAT WERE VACCINATED BUT THE IMMUNE RESPONSES WERE SIGNIFICANTLY AUGMENTED IN 7(6 CARRIERS TREATED WITH CLEVUDINE 7(S!G VACCINATION OF CLEVUDINE TREATED WOODCHUCKS DISRUPTED VIRUS SPECIFIC IMMUNE TOLERANCE AND INDUCED ENHANCED IMMUNE RESPONSES COMPARED TO WOODCHUCKS THAT RECEIVED EITHER CLEVUDINE OR VACCINE ALONE 4HERAPY WITH THE CLEVUDINE VACCINE COMBINA TION RESULTED IN IMMUNE RESPONSE PROFILES THAT RESEMBLED THOSE OBSERVED DURING RESOLUTION OF EXPERIMENTAL 7(6 INFECTION ;= )N OF THE 7(6 CARRIER WOODCHUCKS TREATED WITH CLEVUDINE WITH OR WITHOUT VACCINATION TREATMENT WAS INITIATED AT YEAR OF AGE 3USTAINED REDUCTIONS IN SERUM 7(6 $.! AND 7(S ANTIGENEMIA WERE OBSERVED DUR ING TREATMENT AND FOR A PERIOD OF MONTHS FOLLOWING WITHDRAWAL OF CLEVU DINE TREATMENT ,IVER BIOPSIES WERE OBTAINED AT THE TIME TREATMENT WAS INITIATED AT THE END OF TREATMENT MONTHS OF AGE AND AT AND MONTHS FOLLOWING DRUG WITHDRAWAL AND MONTHS OF AGE (EPATIC 7(6 NUCLEIC ACIDS AND 7(C!G EXPRESSION WERE REDUCED SIGNIFICANTLY COMPARED TO PLA CEBO TREATED CONTROLS THROUGHOUT THE PERIOD OF TREATMENT WITH CLEVUDINE 4HE PERCENTAGE OF HEPATIC BIOPSIES WITH FOCI OF ALTERED HEPATOCYTES WAS SIGNIFICANTLY DECREASED IN THE CLEVUDINE TREATED WOODCHUCKS COMPARED TO CONTROLS AND DEVELOPMENT OF (## WAS MARKEDLY DELAYED )N THE 7(6 CARRIERS IN WHICH CLEVUDINE TREATMENT WAS INITIATED AT YEAR OF AGE THREE YEAR SURVIVAL WAS AND YEARS SURVIVAL WAS )N CONTROLS YEAR SURVIVAL WAS AND YEAR SURVIVAL 0 )N A LONG TERM CHEMOPREVENTION STUDY MONTH OLD 7(6 CARRIERS WERE TREATED FOR LIFE WITH LAMIVUDINE INITIAL DOSE OF MGKGDAY FOLLOWED BY MGKG PER DAY AND CONTROLS RECEIVED VEHICLE AS PLACEBO ;= 3ERUM 7(6 $.! DECREASED GRADUALLY OVER THE FIRST FEW MONTHS BY n LOGS IN LAMIVUDINE TREATED WOODCHUCKS 4HE ANTIVIRAL EFFECT WAS SUSTAINED FOR MORE THAN YEAR WHEN RECRUDESCENCE OF VIREMIA WAS DETECTED 2ECRUDESCENCE WAS ASSOCIATED WITH " DOMAIN MUTATIONS OF THE 7(6 POLYMERASE GENE ;= 4HE DEVELOPMENT OF (## IN LAMIVUDINE TREATED WOODCHUCKS WAS SIG NIFICANTLY DELAYED AND THERE WAS AN EQUIVALENT INCREASE IN SURVIVAL TIME 4HE MEDIAN TIME TO CANCER DEATH IN CONTROLS WAS MONTHS AND IN LAMIVUDINE TREATED WOODCHUCKS MONTHS 0 )N PLACEBO CONTROLLED CLINICAL
"UD # 4ENNANT ET AL
TRIAL OF ("6 CARRIER PATIENTS A COMPARABLE BENEFICIAL EFFECT OF LAMIVUDINE TREATMENT ON THE OCCURRENCE OF (## AND LONG TERM SURVIVAL $URING A MEDIAN DRUG TREATMENT PERIOD OF MONTHS (## DEVELOPED IN OF PLACEBO TREATED CONTROL PATIENTS AND IN OF PATIENTS THAT RECEIVED LAMIVUDINE 0 ;= )N ANOTHER STUDY WOODCHUCKS WERE TREATED FOR PERIODS OF TO MONTHS WITH LAMIVUDINE )N THIS STUDY NO LONG TERM BENEFIT OF LAMIVUDINE TREATMENT ON HEPATOCARCINOGENESIS OR SURVIVAL WAS OBSERVED 4REATMENT IN THIS STUDY WAS INITIATED AT AN OLDER AGE THAN THE LIFE TIME STUDY DESCRIBED ABOVE THE DURATION OF TREATMENT WAS FOR A LIMITED TIME AND THE EFFECT OF TREATMENT ON VIRAL LOAD WAS NOT AS GREAT ;= (IGH RATES OF POLYMERASE GENE MUTATIONS WERE DETECTED IN WOODCHUCK AFTER LONG TERM LAMIVUDINE THERAPY OBSERVA TIONS SIMILAR TO THOSE DETECTED IN ("6 INFECTED HUMANS ; =
2EFERENCES
3UMMERS * 3MOLEC *- 3NYDER 2 ! VIRUS SIMILAR TO HUMAN HEPATITIS " VIRUS ASSOCIATED WITH HEPATITIS AND HEPATOMA IN WOODCHUCKS 0ROC .ATL !CAD 3CI 53! n 4YLER '6 3UMMERS * 3NYDER 2 7OODCHUCK HEPATITIS VIRUS IN NATURAL WOODCHUCK POPULATION * 7ILDLIFE $IS n 7ONG $# 3HIH *7+ 0URCELL 2( 'ERIN *, ,ONDON 74 .ATURAL AND EXPERIMENTAL INFECTION OF WOODCHUCKS WITH WOODCHUCK HEPATITIS VIRUS AS MEASURED BY NEW SPECIFIC ASSAYS FOR WOODCHUCK SURFACE ANTIGEN AND ANTIBODY -ARMOTA MONAX * #LIN -ICROBIOL n ,UTWICK ,) (EBERT -" 3YWASSINK *- #ROSS REACTIONS BETWEEN THE HEPATITIS " AND WOODCHUCK HEPATITIS VIRUSES )N 7 3ZMUNESS (* !LTER *% -AYNARD EDS )N 6IRAL HEPATITIS &RANKLIN )NSTITUTE 0RESS 0HILADELPHIA 3UMMERS * 4HREE RECENTLY DESCRIBED ANIMAL VIRUS MODELS FOR HUMAN HEPATITIS " VIRUS (EPATOLOGY n 9OUNG 2! 3IMS %!( 4HE WOODCHUCK -ARMOTA MONAX AS A LABORA TORY ANIMAL ,AB !NIM 3CI n &OX ( /BSERVATIONS UPON NEOPLASMS IN WILD ANIMALS IN THE 0HILADELPHIA :OOLOGICAL 'ARDEN * 0ATHOL "ACTERIOL n 2ATCLIFFE (, )NCIDENCE AND NATURE OF TUMORS IN CAPTIVE MAMMALS AND BIRDS !M * #ANCER n (ABERMANN 24 7ILLIAMS &0 %YESTONE 7( 3PONTANEOUS HEPATOMAS IN TWO WOODCHUCKS AND A CARCINOMA OF THE TESTIS IN A BADGER * !M 6ET -ED !SSOC "OND % (EPATOMA AND ARTERIOSCLEROSIS IN A WOODCHUCK * 7ILDLIFE $IS n ,ONG '' 4ERRELL 4' 3TOCKEY *, (EPATOMAS IN A GROUP OF CAPTURED WOODCHUCKS * !M 6ET -ED !SSOC 3NYDER 2, (EPATOMAS OF CAPTIVE WOODCHUCKS !M * 0ATH 3NYDER 2, 2ATCLIFFE (, -ARMOTA MONAX ! MODEL FOR STUDIES OF CAR
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
DIOVASCULAR CEREBROVASCULAR AND NEOPLASTIC DISEASE !CTA :OOL 0ATHOL !NTVERP n 3NYDER 2, 3UMMERS * 7OODCHUCK HEPATITIS VIRUS AND HEPATOCEL LULAR CARCINOMA )N - %SSEX ' 4ODARO ( ZUR (AUSEN EDS )N 6IRUSES IN NATURALLY OCCURRING CANCERS "OOK ! #OLD 3PRING (ARBOR #ONFERENCES ON #ELL 0ROLIFERATION #OLD 3PRING (ARBOR ,ABORATORY n 3NYDER 2, 4YLER ' 3UMMERS * #HRONIC HEPATITIS AND HEPATOCELLULAR CARCINOMA ASSOCIATED WITH WOODCHUCK HEPATITIS VIRUS !M * 0ATHOL n 0OPPER ( 3HIH *7+ 'ERIN *, 7ONG $# (OYER "( ,ONDON 74 3LY $, 0URCELL 2( 7OODCHUCK HEPATITIS AND HEPATOCELLULAR CARCINOMA #ORRELATION OF HISTOLOGIC WITH VIROLOGIC OBSERVATIONS (EPATOLOGY n 2OTH , +ING *- (ORNBUCKLE 7% (ARVEY (* 4ENNANT "# #HRONIC HEPATITIS AND HEPATOCELLULAR CARCINOMA ASSOCIATED WITH PERSISTENT WOODCHUCK HEPATITIS VIRUS INFECTION 6ET 0ATHOL n 'ANEM $ 6ARMUS (% 4HE MOLECULAR BIOLOGY OF THE HEPATITIS " VIRUSES !NNU 2EV "IOCHEM n 3UMMERS * 3MOLEC *- 7ERNER "' +ELLY 4* 4YLER '6 3NYDER 2, (EPATITIS " VIRUS AND WOODCHUCK HEPATITIS VIRUS ARE MEMBERS OF A NOVEL CLASS OF $.! VIRUSES )N - %SSEX ' 4ODARO ( ZUR (AUSEN EDS )N 6IRUSES IN NATURALLY OCCURRING CANCERS "OOK ! #OLD 3PRING (ARBOR #ONFERENCES ON #ELL 0ROLIFERATION #OLD 3PRING (ARBOR ,ABORATORY n 4IOLLAIS 0 0OURCEL # $EJEAN ! 4HE HEPATITIS " VIRUS .ATURE n -ARION 0, /SHIRO ,3 2EGNERY $# 3CULLARD '( 2OBINSON 73 ! VIRUS IN "EECHEY GROUND SQUIRRELS THAT IS RELATED TO HEPATITIS " VIRUS OF HUMANS 0ROC .ATL !CAD 3CI 53! n 7EISER " 'ANEM $ 3EEGER # 6ARMUS (% #LOSED CIRCULAR VIRAL $.! AND ASYMMETRICAL HETEROGENEOUS FORMS IN LIVERS FROM ANIMALS INFECTED WITH GROUND SQUIRREL HEPATITIS VIRUS WOODCHUCKS DUCKS -ICROBIOLOGY n +ODAMA + /GASAWARA . 9OSHIKAWA ( -URAKAMI 3 .UCLEOTIDE SEQUENCE OF A CLONED WOODCHUCK HEPATITIS VIRUS GENOME %VOLUTIONAL RELATION SHIP BETWEEN HEPADNAVIRUSES * 6IROL n -ARION 0, +NIGHT 33 3ALAZAR &( 0OPPER ( 2OBINSON 73 'ROUND SQUIRREL HEPATITIS VIRUS INFECTION (EPATOLOGY n -ARION 0, 6AN $AVELAAR -* +NIGHT 33 3ALAZAR &( 'ARCIA ' 0OPPER ( 2OBINSON 73 (EPATOCELLULAR CARCINOMA IN GROUND SQUIRRELS PERSIS TENTLY INFECTED WITH GROUND SQUIRREL HEPATITIS VIRUS 0ROC .ATL !CAD 3CI 53! n #ULLEN *- -ARION 0, .ON NEOPLASTIC LIVER DISEASE ASSOCIATED WITH CHRONIC GROUND SQUIRREL HEPATITIS VIRUS INFECTION (EPATOLOGY n 4ESTUT 0 2ENARD #! 4ERRADILLOS / 6ITVITSKI 4, 4EKAIA & $EGOTT # "LAKE * "OYER " "UENDIA -! ! NEW HEPADNAVIRUS ENDEMIC IN ARCTIC GROUND SQUIRRELS IN !LASKA * 6IROL n &EITELSON -! -ILLMAN ) "LUMBERG "3 4REE SQUIRREL HEPATITIS " VIRUS ANTIGENIC AND STRUCTURAL CHARACTERIZATION 0ROC .ATL !CAD 3CI 53! n
"UD # 4ENNANT ET AL
-INUK '9 3HAFFER %! (OAR $) +ELLY * 'ROUND SQUIRREL HEPATITIS VIRUS '3(6 INFECTION AND HEPATOCELLULAR CARCINOMA IN THE #ANADIAN 2ICHARDSON GROUND SQUIRREL 3PERMOPHILUS RICHARDSONII ,IVER n 4ENNANT "# -ROSOVSKY . -C,EAN + #OTE 0* +ORBA "% %NGLE 2% 'ERIN *, 7RIGHT * -ICHENER '2 5HL % ET AL (EPATOCELLULAR CARCINOMA IN 2ICHARDSONS GROUND SQUIRRELS 3PERMOPHILUS RICHARDSONII %VIDENCE FOR ASSO CIATION WITH HEPATITIS " LIKE VIRUS INFECTION (EPATOLOGY n -ASON 73 3EAL ' 3UMMERS * 6IRUS OF 0EKIN DUCKS WITH STRUCTURAL AND BIOLOGICAL RELATEDNESS TO HUMAN HEPATITIS " VIRUS * 6IROL n /MATA - 5CHIUMI + )TO 9 9OKOSUKA / -ORI * 4ERAO + 7EI &A 9 /#ONNELL !0 ,ONDON 74 /KUDA + $UCK HEPATITIS " VIRUS AND LIVER DISEASES 'ASTROENTEROLOGY n -ARION 0, #ULLEN *- !ZCARRAGA 22 VAN$AVELAAR -* 2OBINSON 73 %XPERIMENTAL TRANSMISSION OF DUCK HEPATITIS " VIRUS TO 0EKIN DUCKS AND TO DOMESTIC GEESE (EPATOLOGY n 3PRENGEL 2 +ALETA %& 7ILL ( )SOLATION AND CHARACTERIZATION OF A HEPA TITIS " VIRUS ENDEMIC IN HERONS * 6IROL n #HANG 3 & .ETTER (* "RUNS - 3CHNEIDER 2 &RÚLICH + 7ILL ( ! NEW AVIAN HEPADNAVIRUS INFECTING SNOW GEESE !NSER CAERULESCENS PRODUCES A SIGNIFICANT FRACTION OF VIRIONS CONTAINING SINGLE STRANDED $.! 6IROLOGY n 3UMMERS * -ASON 73 2EPLICATION OF THE GENOME OF A HEPATITIS " LIKE VIRUS BY REVERSE TRANSCRIPTION OF AN 2.! INTERMEDIATE #ELL n #OHN $, %RB (. 'EORGI *2 4ENNANT "# 0ARASITES OF THE LABORATORY WOODCHUCK -ARMOTA MONAX ,AB !NIM 3CI n -ILLMAN ) 3OUTHAM , (ALBHERR 4 3IMMONS ( +ANG #- 7OODCHUCK HEPATITIS VIRUS %XPERIMENTAL INFECTION AND NATURAL OCCURRENCE (EPATOLOGY n 4YLER '6 3NYDER 2, 3UMMERS * %XPERIMENTAL INFECTION OF THE WOOD CHUCK -ARMOTA MONAX MONAX WITH WOODCHUCK HEPATITIS VIRUS ,AB )NVEST n +AJINO + *ILBERT !2 3APUTELLI * !LDRICH #% #ULLEN * -ASON 73 7OODCHUCK HEPATITIS VIRUS INFECTIONS 6ERY RAPID RECOVERY FOLLOWING A PRO LONGED VIREMIA AND INFECTION OF VIRTUALLY EVERY HEPATOCYTE * 6IROL n 'UO *4 :HOU ( ,IU # !LDRICH # 3APUTELLI * 7HITAKER 4 "ARRASA -) -ASON 73 3EEGER # !POPTOSIS AND REGENERATION OF HEPATOCYTES DURING RECOV ERY FROM TRANSIENT HEPADNAVIRUS INFECTIONS * 6IROL n -ENNE 3 -ASCHKE * 4OLLE 4+ ,U - 2OGGENDORF - #HARACTERIZATION OF 4 CELL RESPONSE TO WOODCHUCK HEPATITIS VIRUS CORE PROTEIN AND PROTECTION OF WOODCHUCKS FROM INFECTION BY IMMUNIZATION WITH PEPTIDES CONTAINING A 4 CELL EPITOPE * 6IROL n 3HANMUGANATHAN 3 7ATERS *! +ARAYIANNIS 0 4HURSZ - 4HOMAS (# -APPING OF THE CELLULAR IMMUNE RESPONSES TO WOODCHUCK HEPATITIS CORE ANTIGEN EPITOPES IN CHRONICALLY INFECTED WOODCHUCKS * -ED 6IROL n #OTE 0* +ORBA "% 3TEINBERG ( 2AMIREZ -EJIA # "ALDWIN " (ORNBUCKLE 7% 4ENNANT "# 'ERIN *, #YCLOSPORIN ! MODULATES THE COURSE OF
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
WOODCHUCK HEPATITIS VIRUS INFECTION AND INDUCES CHRONICITY * )MMUNOL n #OTE 0* +ORBA "% "ALDWIN " (ORNBUCKLE 7% 4ENNANT "# 'ERIN *, )MMUNOSUPPRESSION WITH CYCLOSPORINE DURING THE INCUBATION PERIOD OF EXPERI MENTAL WOODCHUCK HEPATITIS VIRUS INFECTION INCREASES THE FREQUENCY OF CHRONIC INFECTION IN ADULT WOODCHUCKS * )NFECT $IS n 3EEFF ," "EEBE '7 (OOFNAGLE *( .ORMAN *% "USKELL "ALES : 7AGGONER *' +APLOWITZ . +OFF 23 0ETRINI *, *R 3CHIFF %2 ET AL ! SEROLOGIC FOL LOW UP OF THE EPIDEMIC OF POST VACCINATION HEPATITIS IN THE 5NITED 3TATES !RMY .EW %NGL * -ED n 4ASSOPOULOS .# 0APAEVANGELOU '* 3JOGREN -( 2OUMELIOTOU +ARAYANNIS ! 'ERIN *, 0URCELL 2( .ATURAL HISTORY OF ACUTE HEPATITIS " SURFACE ANTIGEN POSITIVE HEPATITIS IN 'REEK ADULTS 'ASTROENTEROLOGY n "LUMBERG "3 ,ONDON 74 (EPATITIS " VIRUS 0ATHOGENESIS AND PREVEN TION OF PRIMARY CANCER OF THE LIVER #ANCER n #OTE 0* +ORBA "% -ILLER 2( *ACOB *2 "ALDWIN "( (ORNBUCKLE 7% 0URCELL 2( 4ENNANT "# 'ERIN *, %FFECTS OF AGE AND VIRAL DETERMINANTS ON CHRONICITY AS AN OUTCOME OF EXPERIMENTAL WOODCHUCK HEPATITIS VIRUS INFEC TION (EPATOLOGY n #OTE 0* 4OSHKOV ) "ELLEZZA # !SCENZI - 2ONEKER # 'RAHAM ,! "ALDWIN "( 'AYE + .AKAMURA ) +ORBA "% ET AL 4EMPORAL PATHOGENESIS OF EXPERIMENTAL NEONATAL WOODCHUCK HEPATITIS VIRUS INFECTION )NCREASED INITIAL VIRAL LOAD AND DECREASED SEVERITY OF ACUTE HEPATITIS DURING THE DEVELOPMENT OF CHRONIC VIRAL INFECTION (EPATOLOGY n 'ERIN *, #OTE 0* +ORBA "% 4ENNANT "# (EPADNAVIRUS INDUCED LIVER CANCER IN WOODCHUCKS #ANCER $ETECT 0REV n 0OPPER ( 2OTH , 0URCELL 2( 4ENNANT "# 'ERIN *, (EPATOCARCINOGENICITY OF THE WOODCHUCK HEPATITIS VIRUS 0ROC .ATL !CAD 3CI 53! n #OTE 0* 2ONEKER # #ASS + 3CHÚDEL & 0ETERSON $ 4ENNANT " DE.ORONHA & 'ERIN * .EW ENZYME IMMUNOASSAYS FOR THE SEROLOGIC DETECTION OF WOOD CHUCK HEPATITIS VIRUS INFECTION 6IRAL )MMUNOL n 4ENNANT "# 4OSHKOV )! 0EEK 3& *ACOB *2 -ENNE 3 (ORNBUCKLE 7% 3CHINAZI 2$ +ORBA "% #OTE 0* 'ERIN *, (EPATOCELLULAR CARCINOMA IN THE WOODCHUCK MODEL OF HEPATITIS " VIRUS INFECTION 'ASTROENTEROLOGY 3n 2EVIEW !BE + +URATA 4 3HIKATA 4 4ENNANT "# %NZYME ALTERED LIVER CELL FOCI IN WOODCHUCKS INFECTED WITH WOODCHUCK HEPATITIS VIRUS *PN * #ANCER 2ES n 4OSHKOV ) (ACKER (* 2OGGENDORF - "ANNASCH 0 0HENOTYPIC PATTERNS OF PRENEOPLASTIC AND NEOPLASTIC HEPATIC LESIONS IN WOODCHUCKS INFECTED WITH WOODCHUCK HEPATITIS VIRUS * #ANCER 2ES #LIN /NCOL n -I , * 0ATIL * (ORNBUCKLE 7% #OTE 0* 'ERIN *, 4ENNANT "# 0ARONETTO & $.! PLOIDY ANALYSIS OF HEPATIC PRENEOPLASTIC AND NEOPLASTIC LESIONS IN WOODCHUCKS EXPERIMENTALLY INFECTED WITH WOODCHUCK HEPATITIS VIRUS (EPATOLOGY n #ULLEN *- ,INZEY $7 'EBHARD $( .UCLEAR PLOIDY OF NORMAL AND
"UD # 4ENNANT ET AL
NEOPLASTIC HEPATOCYTES FROM WOODCHUCK HEPATITIS VIRUS INFECTED AND UNINFECTED WOODCHUCKS (EPATOLOGY n 7ANDS * (EPATOCELLULAR CARCINOMA AND SEX . %NGL * -ED n 0RIETO * )NFLAMMATION (## AND SEX ), IN THE CENTRE OF THE TRIANGLE * (EPATOL n .AKATANI 4 2OY ' &UJIMOTO . !SAHARA 4 )TO ! 3EX HORMONE DEPEN DENCY OF DIETHYLNITROSAMINE INDUCED LIVER TUMORS IN MICE AND CHEMOPREVEN TION BY LEUPRORELIN *PN * #ANCER 2ES n .AUGLER 7% 3AKURAI 4 +IM 3 -AEDA 3 +IM + %LSHARKAWY !- +ARIN - 'ENDER DISPARITY IN LIVER CANCER DUE TO SEX DIFFERENCES IN -Y$ DEPEN DENT ), PRODUCTION 3CIENCE n "ALDWIN "( 4ENNANT "# 2EIMERS 4* #OWAN 2' #ONCANNON 07 #IRCANNUAL CHANGES IN SERUM TESTOSTERONE CONCENTRATIONS OF ADULT AND YEARLING WOODCHUCKS -ARMOTA MONAX "IOL 2EPROD n 0ETERS $. 3TEINBERG ( !NDERSON 7) (ORNBUCKLE 7% #OTE 0* 'ERIN *, ,EWIS 2- 4ENNANT "# )MMUNOPATHOLOGY OF GLOMERULONEPHRITIS ASSO CIATED WITH CHRONIC WOODCHUCK HEPATITIS INFECTION IN WOODCHUCKS -ARMOTA MONAX !M * 0ATHOL n 7ILL ( #ATTANEO 2 +OCH (' $ARAI ' 3CHALLER ( 3CHELLEKENS ( VAN%RD 0- $EINHARDT & #LONED ("6 $.! CAUSES HEPATITIS IN CHIMPANZEES .ATURE -ILLER 2( 'IRONES 2 #OTE 0* (ORNBUCKLE 7% #HESTNUT 4 "ALDWIN "( +ORBA "% 4ENNANT "# 'ERIN *, 0URCELL 2( %VIDENCE AGAINST A REQ UISITE ROLE FOR DEFECTIVE VIRUS IN THE ESTABLISHMENT OF PERSISTENT HEPADNAVIRUS INFECTIONS 0ROC .ATL !CAD 3CI 53! n 3PRENGEL 2 +UHN # -ANSO # 7ILL ( #LONED DUCK HEPATITIS " VIRUS $.! IS INFECTIOUS IN 0EKIN DUCKS * 6IROL n 3EEGER # 'ANEM $ 6ARMUS (% .UCLEOTIDE SEQUENCE OF AN INFEC TIOUS MOLECULARLY CLONED GENOME OF GROUND SQUIRREL HEPATITIS VIRUS * 6IROL n 3EEGER # "ALDWIN " (ORNBUCKLE 7% 9EAGER !% 4ENNANT "# #OTE 0 &ERRELL , 'ANEM $ 6ARMUS (% 7OODCHUCK HEPATITIS VIRUS IS A MORE EFFICIENT ONCOGENIC AGENT THAN GROUND SQUIRREL HEPATITIS VIRUS IN A COMMON HOST * 6IROL n 4RUEBA $ 0HELAN - .ELSON * "ECK & 0ECHA "3 "ROWN 2* 6ARMUS (% 'ANEM $ 4RANSMISSION OF GROUND SQUIRREL HEPATITIS VIRUS TO HOMOLOGOUS AND HETEROLOGOUS HOSTS (EPATOLOGY n 3EEGER # "ALDWIN " (ORNBUCKLE 7% 9EAGER !% 4ENNANT "# #OTE 0 &ERRELL , 'ANEM $ 6ARMUS (% 7OODCHUCK HEPATITIS VIRUS IS A MORE EFFICIENT ONCOGENIC AGENT THAN GROUP HEPATITIS VIRUS IN A COMMON HOST * 6IROL n 3ZMUNESS 7 (EPATOCELLULAR CARCINOMA AND THE HEPATITIS " VIRUS %VIDENCE FOR A CAUSAL ASSOCIATION 0ROG -ED 6IROL n -AUPAS 0 7ERNER " ,AROUZE " -ILLMAN ) ,ONDON 74 /#ONNELL ! "LUMBERG "3 !NTIBODY TO HEPATITIS " CORE ANTIGEN IN PATIENTS WITH PRIMARY HEPATIC CARCINOMA ,ANCET n
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
"LUMBERG "3 ,AROUZE " ,ONDON 74 7ERNER " (ESSER *% -ILLMAN ) 3AIMOT ' 0AYET - 4HE RELATION OF INFECTION WITH HEPATITIS " AGENT TO PRIMARY HEPATIC CARCINOMA !M * 0ATH n 0RINCE !- 3ZMUNESS 7 -ICHON * $EMAILLE * $IEBOLT ' ,INHARD * 1UENUM # 3ANKALE - ! CASECONTROL STUDY OF THE ASSOCIATION BETWEEN PRIMARY LIVER CANCER AND HEPATITIS " INFECTION IN 3ENEGAL )NT * #ANCER n !SANO - +ATO ( 9OSHIMOTO + 3EYAMA 3 )TAKURA ( (AMADA 4 )IJIMA 3 0RIMARY LIVER CARCINOMA AND LIVER CIRRHOSIS IN ATOMIC BOMB SURVIVORS (IROSHIMA AND .AGASAKI n WITH SPECIAL REFERENCE TO HEPATITIS " SURFACE ANTIGEN * .ATL #ANCER )NST n #HIEN -# 4ONG -* ,O +* ,EE *+ -ILICH $2 6YAS '. -URPHY ", (EPATITIS " VIRAL MARKERS IN PATIENTS WITH PRIMARY HEPATOCELLULAR CARCINOMA IN 4AIWAN * .ATL #ANCER )NST n (ANN (7 +IM #9 ,ONDON 74 7HITFORD 0 "LUMBERG "3 (EPATITIS " VIRUS AND PRIMARY HEPATOCELLULAR CARCINOMA &AMILY STUDIES IN +OREA )NT * #ANCER n /KUDA + .AKASHIMA 4 3AKAMOTO + )KARI 4 (IDAKA ( +UBO 9 3AKUMA + -OTOIKE 9 /KUDA ( /BATA ( (EPATOCELLULAR CARCINOMA ARISING IN NONCIRRHOTIC AND HIGHLY CIRRHOTIC LIVERS ! COMPARATIVE STUDY OF HISTOPATHOLOGY AND FREQUENCY OF HEPATITIS " MARKERS #ANCER n /MATA - !SHCAVAI - ,IEW #4 0ETERS 2, (EPATOCELLULAR CARCINOMA IN THE 53! ETIOLOGIC CONSIDERATIONS ,OCALIZATION OF HEPATITIS " ANTIGENS 'ASTROENTEROLOGY n 4ABOR % 'ERETY 23 6OGEL #, "YLEY !# !NTHONY 00 #HAN #( "ARKER ,& (EPATITIS " VIRUS INFECTION AND PRIMARY HEPATOCELLULAR CARCINOMA * .ATL #ANCER )NST n 6IOLA ,! "ARRISON )' #OLEMAN *# 0ARADINAS &* &LUKER *, %VANS "! -URRAY ,YON )- .ATURAL HISTORY OF LIVER DISEASE IN CHRONIC HEPATITIS " SURFACE ANTIGEN CARRIERS 3URVEY OF PATIENTS FROM 'REAT "RITAIN ,ANCET n "EASLEY 20 ,IN ## (EPATOMA RISK AMONG HEPATITIS " SURFACE ANTIGEN CARRIERS !M * %PIDEMIOL "EASLEY 20 (WANG ,9 ,IN ## #HIEN #3 (EPATOCELLULAR CARCINOMA AND HEPATITIS " VIRUS ! PROSPECTIVE STUDY OF MEN IN 4AIWAN ,ANCET n "EASLEY 20 (EPATITIS " VIRUS AS THE ETIOLOGIC AGENT IN HEPATOCELLULAR CARCINOMA n %PIDEMIOLOGIC CONSIDERATIONS (EPATOLOGY 3n3 "EASLEY 20 (EPATITIS " VIRUS 4HE MAJOR ETIOLOGY OF HEPATOCELLULAR CAR CINOMA #ANCER n 0RINCE !- !LCABES 0 4HE RISK OF DEVELOPMENT OF HEPATOCELLULAR CARCI NOMA IN HEPATITIS " VIRUS CARRIERS IN .EW 9ORK ! PRELIMINARY ESTIMATE USING DEATH RECORDS MATCHING (EPATOLOGY 3n3 "RECHOT # (ADCHOUEL - 3COTTO * &ONCK - 0OTET & 6YAS '. 4IOLLAIS 0 3TATE OF HEPATITIS " VIRUS $.! IN HEPATOCYTES OF PATIENTS WITH HEPATITIS " SUR FACE ANTIGEN POSITIVE AND NEGATIVE LIVER DISEASE 0ROC .ATL !CAD 3CI 53! n #HEN $3 (OYER "( .ELSON * 0URCELL 2( 'ERIN *, $ETECTION AND
"UD # 4ENNANT ET AL
PROPERTIES OF HEPATITIS " VIRAL $.! IN LIVER TISSUES FROM PATIENTS WITH HEPATO CELLULAR CARCINOMA (EPATOLOGY 3n3 3HAFRITZ $! (EPATITIS " VIRUS $.! MOLECULES IN THE LIVER OF HEPATITIS " SURFACE ANTIGEN CARRIERS -ECHANISTIC CONSIDERATIONS IN THE PATHOGENESIS OF HEPATOCELLULAR CARCINOMA (EPATOLOGY 3n3 +REMSDORF $ 3OUSSAN 0 0ATERLINI "RECHOT 0 "RÏCHOT # (EPATITIS " VIRUS RELATED HEPATOCELLULAR CARCINOMA PARADIGMS FOR VIRAL RELATED HUMAN CAR CINOGENESIS /NCOGENE n -URAKAMI 9 3AIGO + 4AKASHIMA ( -INAMI - /KANOUE 4 "RÏCHOT # 0ATERLINI "RÏCHOT 0 ,ARGE SCALED ANALYSIS OF HEPATITIS " VIRUS ("6 $.! INTEGRATION IN ("6 RELATED HEPATOCELLULAR CARCINOMAS 'UT n "UENDIA -! !NIMAL MODELS FOR HEPATITIS " VIRUS AND LIVER CANCER )N # "RÏCHOT ED )N 0RIMARY LIVER CANCER %TIOLOGICAL AND PROGRESSION FACTORS #2# 0RESS "OCA 2ATON &LORIDA n "UENDIA -! 0INEU 0 4HE COMPLEX ROLE OF HEPATITIS " VIRUS IN HUMAN HEPATOCARCINOGENESIS )N ' "ARBANTI "RODANO - "ENDINELLI ( &RIEDMAN EDS )N $.! TUMOR VIRUSES /NCOGENIC MECHANISMS 0LENUM 0RESS .EW 9ORK n &ARBER % 3ARMA $3 (EPATOCARCINOGENESIS ! DYNAMIC CELLULAR PERSPEC TIVE ,AB )NVEST n 0ITOT (# $RAGAN 90 &ACTS AND THEORIES CONCERNING THE MECHANISMS OF CARCINOGENESIS &!3%" * n +ORBA "% 7ELLS &6 "ALDWIN " #OTE 0* 4ENNANT "# 0OPPER ( 'ERIN *, (EPATOCELLULAR CARCINOMA IN WOODCHUCK HEPATITIS VIRUS INFECTED WOOD CHUCKS 0RESENCE OF VIRAL $.! IN TUMOR TISSUE FROM CHRONIC CARRIERS AND ANI MALS SEROLOGICALLY RECOVERED FROM ACUTE INFECTIONS (EPATOLOGY n &UCHS + (EBERGER # 7EIMER 4 2OGGENDORF - #HARACTERIZATION OF WOODCHUCK HEPATITIS VIRUS $.! AND 2.! IN THE HEPATOCELLULAR CARCINOMAS OF WOODCHUCKS (EPATOLOGY n +ANEKO 3 /SHIMA 4 +ODAMA + !OYAMA 3 9OSHIKAWA ( 5NOURA - &UKUOKA + -ATSUSHITA & -ORIMOTO ( +OBAYASHI + ET AL 3TABLE INTEGRATION OF WOODCHUCK HEPATITIS VIRUS $.! IN TRANSPLANTED TUMORS AND ESTABLISHED TISSUE CULTURE CELLS DERIVED FROM A WOODCHUCK PRIMARY HEPATOCELLULAR CARCINOMA #ANCER 2ES n /GSTON #7 *ONAK '* 2OGLER #% !STRIN 3- 3UMMERS * #LONING AND STRUCTURAL ANALYSIS OF INTEGRATED WOODCHUCK HEPATITIS VIRUS SEQUENCES FROM HEPATOCELLULAR CARCINOMAS OF WOODCHUCKS #ELL n 2OGLER #% 3UMMERS * #LONING AND STRUCTURAL ANALYSIS OF INTEGRATED WOODCHUCK HEPATITIS VIRUS SEQUENCES FROM A CHRONICALLY INFECTED LIVER * 6IROL n 2OGLER #% (INO / 3U #9 -OLECULAR ASPECTS OF PERSISTENT WOODCHUCK HEPATITIS VIRUS AND HEPATITIS " VIRUS INFECTION AND HEPATOCELLULAR CARCINOMA (EPATOLOGY 3n3 2OGLER #% #ELLULAR AND MOLECULAR MECHANISM OF HEPATOCARCINOGEN ESIS ASSOCIATED WITH HEPADNAVIRUS INFECTION )N 73 -ASON # 3EEGER EDS
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
)N (EPADNA VIRUSES -OLECULAR BIOLOGY AND PATHOGENESIS #URRENT 4OPICS IN -ICROBIOLOGY AND )MMUNOLOGY 6OL 3PRINGER 6ERLAG .EW 9ORK n 9ANG $ !LT % 2OGLER #% #OORDINATE EXPRESSION OF . MYC AND INSU LIN LIKE GROWTH FACTOR )) IN PRE CANCEROUS ALTERED HEPATIC FOCI IN WOODCHUCK HEPATITIS VIRUS CARRIERS #ANCER 2ES n 9ANG $ &ARIS 2 !FFIGNE 3 2OGLER #% )NSULIN LIKE GROWTH FACTOR )) BLOCKS APOPTOSIS OF . MYC EXPRESSING WOODCHUCK LIVER EPITHELIAL CELLS * 6IROL n 9ANG 7 3UMMERS * )NTEGRATION OF HEPADNAVIRUS $.! IN INFECTED LIVER %VIDENCE FOR A LINEAR PRECURSOR * 6IROL n 3UMMERS * *ILBERT !2 9ANG 7 !LDRICH #% 3APUTELLI * ,ITWIN 3 4OLL % -ASON 73 (EPATOCYTE TURNOVER DURING RESOLUTION OF A TRANSIENT HEPADNAVIRAL INFECTION 0ROC .ATL !CAD 3CI 53! n -ASON 37 *ILBERT !2 3UMMERS * #LONAL EXPANSION OF HEPATOCYTES DUR ING CHRONIC WOODCHUCK HEPATITIS VIRUS INFECTION 0ROC .ATL !CAD 3CI 53! n 3UMMERS * -ASON 73 2ESIDUAL INTEGRATED VIRAL $.! AFTER HEPADNAVI RUS CLEARANCE BY NUCLEOSIDE ANALOG THERAPY .ATL !CAD 3CI 53! n -OROY 4 -ARCHIO ! %TIEMBLE * 4REPO # 4IOLLAIS 0 "UENDIA -! 2EARRANGEMENT AND ENHANCED EXPRESSION OF C MYC IN HEPATOCELLULAR CARCINOMA OF HEPATITIS VIRUS INFECTED WOODCHUCKS .ATURE n -OROY 4 %TIEMBLE * "OUGUELERET , (ADCHOUEL - 4IOLLAIS 0 "UENDIA -! 3TRUCTURE AND EXPRESSION OF HER A LOCUS REARRANGED WITH C MYC IN A WOODCHUCK HEPATOCELLULAR CARCINOMA /NCOGENE n (SU 49 -OROY 4 %TIEMBLE * ,OUISE ! 4REPO # 4IOLLAIS 0 "UENDIA -! !CTIVATION OF C MYC BY WOODCHUCK HEPATITIS VIRUS INSERTION IN HEPATOCELLULAR CARCINOMA #ELL n $EJEAN ! DE4HE ( (EPATITIS " VIRUS AS AN INSERTIONAL MUTAGENE IN A HUMAN HEPATOCELLULAR CARCINOMA -OL "IOL -ED n &OUREL ' 4REPO # "OUGUELERET , (ENGLEIN " 0ONZETTO ! 4IOLLAIS 0 "UENDIA -! &REQUENT ACTIVATION OF . MYC GENES BY HEPADNAVIRUS INSERTION IN WOODCHUCK LIVER TUMOURS .ATURE n &OUREL ' 4RANSY # 4ENNANT "# "UENDIA -! %XPRESSION OF THE WOOD CHUCK . MYC RETROPOSON IN BRAIN AND IN LIVER TUMORS IS DRIVEN BY A CRYPTIC . MYC PROMOTER -OL #ELL "IOCHEM n &LAJOLET - 'EGONNE ! 'HYSDAEL * 4IOLLAIS 0 "UENDIA -! &OUREL ' #ELLULAR AND VIRAL TRANS ACTING FACTORS MODULATE . MYC PROMOTER ACTIVITY IN WOODCHUCK LIVER TUMORS /NCOGENE n 7EI 9 4ENNANT " 'ANEM $ )N VIVO EFFECTS OF MUTATIONS IN WOODCHUCK HEPATITIS VIRUS ENHANCER )) * 6IROL n 7EI 9 &OUREL ' 0ONZETTO ! 3ILVESTRO - 4IOLLAIS 0 "UENDIA -! (EPADNAVIRUS INTEGRATION MECHANISMS OF ACTIVATION OF THE . MYC RETROTRANS POSON IN WOODCHUCK LIVER TUMORS * 6IROL n &OUREL ' 2INGEISEN & &LAJOLET - 4RONCHE & 0ONTOGLIO - 4IOLLAIS 0 "UENDIA -! 4HE (.&(.& DEPENDENT 7E ELEMENT OF WOODCHUCK HEPATITIS VIRUS CONTROLS VIRAL REPLICATION AND CAN ACTIVATE THE . MYC PROMOTER * 6IROL n
"UD # 4ENNANT ET AL
&OUREL ' #OUTURIER * 7EI 9 !PIOU & 4IOLLAIS 0 "UENDIA -! %VIDENCE FOR LONG RANGE ONCOGENE ACTIVATION BY HEPADNAVIRUS INSERTION %-"/ * n "RUNI 2 #ONTI ) 6ILLANO 5 'IUSEPPETTI 2 0ALMIERI ' 2APICETTA - ,ACK OF 7(6 INTEGRATION NEARBY . MYC AND IN THE DOWNSTREAM BN AND WIN LOCI IN A CONSIDERABLE FRACTION OF LIVER TUMORS WITH ACTIVATED . MYC FROM NATURALLY INFECTED WILD WOODCHUCKS 6IROLOGY n *ACOB *2 3TERCZER ! 4OSHKOV )! 9EAGER !% +ORBA "% #OTE 0* "UENDIA -! 'ERIN *, 4ENNANT "# )NTEGRATION OF WOODCHUCK HEPATITIS AND . MYC REARRANGEMENT DETERMINE SIZE AND HISTOLOGIC GRADE OF HEPATIC TUMORS (EPATOLOGY n 2ENARD # ! &OUREL ' "RALET - 0 $EGOTT # DE LA #OSTE ! 0ERRET # 4IOLLAIS 0 "UENDIA -! (EPATOCELLULAR CARCINOMA IN 7(6. MYC TRANS GENIC MICE /NCOGENIC MUTATIONS OF ã CATENIN AND SYNERGISTIC EFFECT OF P NULL ALLELES /NCOGENE n $E ,A #OSTE ! 2OMAGNOLO " "ILLUART 0 2ENARD # ! "UENDIA -! 3OUBRANE / &ABRE - *AMEL # "ELDJORD # +AHN : ET AL 3OMATIC MUTATIONS OF THE BETA CATENIN GENE ARE FREQUENT IN MOUSE AND HUMAN HEPATOCELLULAR CARCINOMAS 0ROC .ATL !CAD 3CI 53! n 1UIGNON & 2ENARD #! 4IOLLAIS 0 "UENDIA -! 4RANSY # ! FUNCTIONAL . MYC RETROPOSON IN GROUND SQUIRRELS )MPLICATIONS FOR HEPADNAVIRUS ASSOCI ATED CARCINOGENESIS /NCOGENE n 4RANSY # &OUREL ' 2OBINSON 73 4IOLLAIS 0 -ARION 0, "UENDIA -! &REQUENT AMPLIFICATION OF C MYC IN GROUND SQUIRREL LIVER TUMORS ASSOCIATED WITH PAST OR ONGOING INFECTION WITH A HEPADNAVIRUS 0ROC .ATL !CAD 3CI 53! n (ANSEN ,* 4ENNANT "# 3EEGER # 'ANEM $ $IFFERENTIAL ACTIVATION OF MYC GENE FAMILY MEMBERS IN HEPATIC CARCINOGENESIS BY CLOSELY RELATED HEPATITIS " VIRUSES -OL #ELL "IOCHEM n (OHNE - 3CHAEFER 3 3EIFER - &EITELSON -! 0AUL $ 'ERLICH 7( -ALIGNANT TRANSFORMATION OF IMMORTALIZED TRANSGENIC HEPATOCYTES FOLLOWING TRANSFECTION WITH HEPATITIS " VIRUS $.! %-"/ * n 3EIFER - (OHNE - 3CHAEFER 3 'ERLICH 7( )N VITRO TUMORIGENICITY OF HEPATITIS " VIRUS $.! AND ("X PROTEIN * (EPATOL 3n3 4ERRADILLOS / "ILLET / 2ENARD #! ,EVY 2 -OLINA 4 "RIAND 0 "UENDIA -! 4HE HEPATITIS " VIRUS 8 GENE POTENTIATES C MYC INDUCED LIVER ONCOGEN ESIS IN TRANSGENIC MICE /NCOGENE n 3EEGER # -ASON 73 (EPATITIS " VIRUS BIOLOGY -ICROBIOL -OL "IOL 2EV n &EITELSON -! ,EGA , $UAN ,8 #LAYTON - #HARACTERISTICS OF WOOD CHUCK HEPATITIS 8 ANTIGEN IN THE LIVERS AND SERA FROM INFECTED ANIMALS * (EPATOL 3n3 *ACOB *2 !SCENZI -! 2ONEKER #! 4OSHKOV )! #OTE 0* 'ERIN *, 4ENNANT "# (EPATIC EXPRESSION OF THE WOODCHUCK HEPATITIS VIRUS 8 ANTIGEN DUR ING ACUTE AND CHRONIC INFECTION AND DETECTION OF A WOODCHUCK HEPATITIS VIRUS 8 ANTIGEN ANTIBODY RESPONSE (EPATOLOGY n &EITELSON -! 2ANGANATHAN 0. #LAYTON -- :HANG 3- 0ARTIAL CHAR
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
ACTERIZATION OF THE WOODCHUCK TUMOR SUPPRESSOR P AND ITS INTERACTION WITH WOODCHUCK HEPATITIS VIRUS 8 ANTIGEN IN HEPATOCARCINOGENESIS /NCOGENE n 'HEBRANIOUS . 3ELL 3 4HE MOUSE EQUIVALENT OF THE HUMAN PSER MUTATION PSER ENHANCES AFLATOXIN HEPATOCARCINOGENESIS IN HEPATITIS " SURFACE ANTIGEN TRANSGENIC AND P HETEROZYGOUS NULL MICE (EPATOLOGY n 5EDA ( 5LLRICH 3* 'ANGEMI *$ +APPEL #! .GO , &EITELSON -! *AY ' &UNCTIONAL INACTIVATION BUT NOT STRUCTURAL MUTATION OF P CAUSES LIVER CANCER .AT 'ENET n (SIA ## .AKASHIMA 9 4HORGEIRSSON 33 (ARRIS ## -INEMURA - -OMOSAKE 3 7ANG .* 4ABOR % #ORRELATION OF IMMUNOHISTOCHEMICAL STAINING AND MUTATIONS OF P IN HUMAN HEPATOCELLULAR CARCINOMA /NCOL 2EPORTS n +ARIN - .UCLEAR FACTOR KAPPA" IN CANCER DEVELOPMENT AND PROGRESSION .ATURE n (ANAHAN $ 7EINBERG 2! 4HE HALLMARKS OF CANCER #ELL n +ALAYCI # *OHNSON 0* $AVIES 3% 7ILLIAMS 2 (EPATITIS " VIRUS RELATED HEPATOCELLULAR CARCINOMA IN THE NON CIRRHOTIC LIVER * (EPATOL n %L 3ERAG (" 2UDOLPH +, (EPATOCELLULAR CARCINOMA EPIDEMIOLOGY AND MOLECULAR CARCINOGENESIS 'ASTROENTEROLOGY n 3CHAFER $& 3ORRELL -& (EPATOCELLULAR CARCINOMA ,ANCET n *OHNSON 0* 7ILLIAMS 2 #IRRHOSIS AND THE AETIOLOGY OF HEPATOCELLULAR CARCINOMA * (EPATOLOGY n #HISARI &6 6IRUSES IMMUNITY AND CANCER LESSONS FROM HEPATITIS " !M * 0ATHOL n #HISARI &6 +LOPCHIN + -ORIYAMA 4 0ASQUINELLI # $UNSFORD (! 3ELL 3 0INKERT #! "RINSTER 2, 0ALMITER 2$ -OLECULAR PATHOGENESIS OF HEPA TOCELLULAR CARCINOMA IN HEPATITIS " VIRUS TRANSGENIC MICE #ELL n $UNSFORD (! 3ELL 3 #HISARI &6 (EPATOCARCINOGENESIS DUE TO CHRONIC LIVER CELL INJURY IN HEPATITIS " VIRUS TRANSGENIC MICE #ANCER 2ES n -ORIYAMA 4 'UILHOT 3 +LOPCHIN + -OSS " 0INKERT #! 0ALMITER 2$ "RINSTER 2, +ANAGAWA / #HISARI &6 )MMUNOBIOLOGY AND PATHOGENESIS OF HEPATOCELLULAR INJURY IN HEPATITIS " VIRUS TRANSGENIC MICE 3CIENCE n 3ELL 3 (UNT *- $UNSFORD (! #HISARI &6 3YNERGY BETWEEN HEPATITIS " VIRUS EXPRESSION AND CHEMICAL HEPATOCARCINOGENS IN TRANSGENIC MICE #ANCER 2ES n "ANNASCH 0 +HOSHKOU .) (ACKER (* 2ADAEVA 3 -ROZEK - :ILLMANN 5 +OPP 3CHNEIDER ! (ABERKORN 5 %LGAS - 4OLLE 4 ET AL 3YNERGISTIC HEPATOCARCINOGENIC EFFECT OF HEPADNAVIRAL INFECTION AND DIETARY AFLATOXIN " IN WOODCHUCKS #ANCER 2ES n &AUX 30 &RANCIS *% 3MITH !' #HIPMAN *+ )NDUCTION OF HYDROXY DEOXYGUANOSINE IN !H RESPONSIVE MOUSE LIVER BY IRON AND !ROCLOR #ARCINOGENESIS n "ILLIAR 42 #URRAN 2$ (ARBRECHT "# 3TADLER * 7ILLIAMS $, /CHOA *" $I3ILVIO - 3IMMONS 2, -URRAY 3! !SSOCIATION BETWEEN SYNTHESIS
"UD # 4ENNANT ET AL
AND RELEASE OF C'-0 AND NITRIC OXIDE BIOSYNTHESIS BY HEPATOCYTES !M * 0HYSIOL #n# "ILLIAR 42 (OFFMAN 2! #URRAN 2$ ,ANGREHR *- 3IMMONS 2, ! ROLE FOR INDUCIBLE NITRIC OXIDE BIOSYNTHESIS IN THE LIVER IN INFLAMMATION AND IN THE ALLOGENEIC IMMUNE RESPONSE * ,AB #LIN -ED n #URRAN 2$ "ILLIAR 42 3TEUHR $* /CHOA *" (ARBRECHT "' &LINT 3' 3IMMONS 2, -ULTIPLE CYTOKINES ARE REQUIRED TO INDUCE HEPATOCYTE NITRIC OXIDE PRODUCTION AND INHIBIT TOTAL PROTEIN SYNTHESIS !NN 3URG n $ISCUSSION n #URRAN 2$ &ERRARI &+ +ISPERT 0( 3TADLER * 3TEUHR $* 3IMMONS 2, "ILLIAR 42 .ITRIC OXIDE AND NITRIC OXIDE GENERATING COMPOUNDS INHIBIT HEPATO CYTE PROTEIN SYNTHESIS &!3%" * n 'ELLER $! .USSLER !+ $I 3ILVIO - ,OENSTEIN #* 3HAPIRO 2! 7ANG 3# 3IMMONS 2, "ILLIAR 42 #YTOKINES ENDOTOXIN AND GLUCOCORTICOIDS REGULATE THE EXPRESSION OF INDUCIBLE NITRIC OXIDE SYNTHASE IN HEPATOCYTES 0ROC .ATL !CAD 3CI 53! n (ORTELLANO 3 'ENARO !- "OSCA , 0HORBOL ESTERS INDUCE NITRIC OXIDE SYNTHASE ACTIVITY IN RAT HEPATOCYTES * "IOL #HEM n +NOWLES 2' -ERRETT - 3ALTER - -ONCADA 3 $IFFERENTIAL INDUCTION OF BRAIN LUNG AND LIVER NITRIC OXIDE SYNTHASE BY ENDOTOXINS IN THE RAT "IOCHEM * n 7OOD %2 "ERGER ( 3HERMAN 0! ,APETINA %' (EPATOCYTES AND MAC ROPHAGES EXPRESS AN IDENTICAL CYTOKINE INDUCIBLE NITRIC OXIDE SYNTHASE GENE "IOCHEM "IOPHYS 2ES #OMM n +ILBOURN 2' 'ROSS 33 *UBRAN ! !DAMS * 'RIFFITH /7 ,EVI 2 ,ODATO 2& .' METHYL , ARGININE INHIBITS TUMOR NECROSIS FACTOR INDUCED HYPOTEN SION )MPLICATIONS FOR THE INVOLVEMENT OF NITRIC OXIDE 0ROC .ATL !CAD 3CI 53! n ,IU 2( "ALDWIN " 4ENNANT "# (OTCHKISS *( %LEVATED FORMATION OF NITRATE AND . NITROSODIMETHYLAMINE IN WOODCHUCKS -ARMOTA MONAX ASSOCIATED WITH CHRONIC WOODCHUCK HEPATITIS VIRUS INFECTION #ANCER 2ES n .GUYEN 4 "RUNSON $ #RESPI #, 0ENMAN "7 7ISHNOK *3 4ANNENBAUM 32 $.! DAMAGE AND MUTATION IN HUMAN CELLS EXPOSED TO NITRIC OXIDE IN VITRO 0ROC .ATL !CAD 3CI 53! n ,IU 2( *ACOB *2 4ENNANT "# (OTCHKISS *( .ITRITE AND NITROSAMINE SYNTHESIS BY HEPATOCYTES ISOLATED FROM NORMAL WOODCHUCKS -ARMOTA MONAX AND WOODCHUCKS CHRONICALLY INFECTED WITH WOODCHUCK HEPATITIS VIRUS #ANCER 2ES n ,IU 2( *ACOB *2 (OTCHKISS *( 4ENNANT "# 3YNTHESIS OF NITRIC OXIDE AND NITROSAMINE BY IMMORTALIZED WOODCHUCK HEPATOCYTES #ARCINOGENESIS n ,IU 2( *ACOB *2 (OTCHKISS *( #OTE 0* 'ERIN *, 4ENNANT "# 7OODCHUCK HEPATITIS VIRUS SURFACE ANTIGEN INDUCES NITRIC OXIDE SYNTHESIS IN HEPATOCYTES 0OSSIBLE ROLE IN HEPATOCARCINOGENESIS #ARCINOGENESIS n -ARLETTA - 9OON 03 )YENGAR 2 ,EAF #$ 7ISHNOK *3 -ACROPHAGE
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
OXIDATION OF , ARGININE TO NITRITE AND NITRATE .ITRIC OXIDE IS AN INTERMEDIATE "IOCHEM n !RCHER -# -ECHANISMS OF ACTION OF . NITROSO COMPOUNDS #ANCER 3URV n -AGEE 0. 4HE EXPERIMENTAL BASIS FOR THE ROLE OF NITROSO COMPOUNDS IN HUMAN CANCER #ANCER 3URV n 7INK $! +ASPRZAK +3 -ARAGOS #- %LESPURU 2+ -ISRA - "UNAMS 4- #EBULA 4! +OCH 7( !NDREWS !7 !LLEN *3 ET AL $.! DEAMINAT ING ABILITY AND GENOTOXICITY OF NITRIC OXIDE AND ITS PROGENITORS 3CIENCE n 2IVKINA - #OTE 0* 2OBINSON 73 4ENNANT "# -ARION 0, !BSENCE OF MUTATIONS IN THE P TUMOR SUPPRESSOR GENE IN WOODCHUCK HEPATOCELLULAR CARCINOMAS ASSOCIATED WITH HEPADNAVIRUS INFECTION AND INTAKE OF AFLATOXIN " #ARCINOGENSIS n 4ENNANT "# (ORNBUCKLE 7% 9EAGER !% "ALDWIN "( 3HERMAN 7+ !NDERSON 7) 3TEINBER ( #OTE 0( +ORBA "% 'ERIN *, %FFECTS OF AFLATOXIN " ON EXPERIMENTAL WOODCHUCK HEPATITIS VIRUS INFECTION AND HEPA TOCELLULAR CARCINOMA )N &" (OLLINGER 3- ,EMON ( -ARGOLIS EDS )N 6IRAL HEPATITIS AND LIVER DISEASE 7ILLIAMS 7ILKINS "ALTIMORE n 9AN 21 3U ** (UANG $2 'AN 9# 9ANG # (UANG '( (UMAN HEPA TITIS " VIRUS AND HEPATOCELLULAR CARCINOMA )) %XPERIMENTAL INDUCTION OF HEPA TOCELLULAR CARCINOMA IN TREE SHREWS EXPOSED TO HEPATITIS " VIRUS AND AFLATOXIN " * #ANCER 2ES #LIN /NCOL n 3LAGLE ", ,EE 4( -EDINA $ &INEGOLD -* "UTEL *3 )NCREASED SENSITIV ITY TO THE HEPATOCARCINOGEN DIETHYLNITROSAMINE IN TRANSGENIC MICE CARRYING THE HEPATITIS " VIRUS 8 GENE -OL #ARCINOG n #HU #+ "OUDINOT &$ 0EEK 3& (ONG *( #HOI 9 +ORBA "% 'ERIN *, #OTE 0* 4ENNANT "# #HENG 9# 0RECLINICAL INVESTIGATION OF , &-!5 AS AN ANTI HEPATITIS " VIRUS AGENT !NTIVIRAL 4HER n (OSTETLER +9 "EADLE *2 (ORNBUCKLE 7% "ELLEZZA #! 4OCHKOV )! #OTE 0* 'ERIN *, +ORBA "% 4ENNANT "# !NTIVIRAL ACTIVITIES OF ORAL / HEXADECYL PROPANEDIOL PHOSPHO ACYCLOVIR AND ACYCLOVIR IN WOODCHUCKS WITH CHRONIC WOODCHUCK HEPATITIS VIRUS INFECTION !NTIMICROB !GENTS #HEMOTHER n +ORBA "% #OTE 0 (ORNBUCKLE 7 3CHINAZI 2 'ANGEMI *$ 4ENNANT "# 'ERIN *, %NHANCED ANTIVIRAL BENEFIT OF COMBINATION THERAPY WITH LAMIVUDINE AND ALPHA INTERFERON AGAINST 7(6 REPLICATION IN CHRONIC CARRIER WOODCHUCKS !NTIVIR 4HER n +ORBA "% #OTE 0 (ORNBUCKLE 7 3CHINAZI 2 'ERIN *, 4ENNANT "# %NHANCED ANTIVIRAL BENEFIT OF COMBINATION THERAPY WITH LAMIVUDINE AND FAMCI CLOVIR AGAINST 7(6 REPLICATION IN CHRONIC 7(6 CARRIER WOODCHUCKS !NTIVIRAL 2ES n +ORBA "% #OTE 0 (ORNBUCKLE 7 4ENNANT "# 'ERIN *, 4REATMENT OF CHRONIC WOODCHUCK HEPATITIS VIRUS INFECTION IN THE %ASTERN WOODCHUCK -ARMOTA MONAX WITH NUCLEOSIDE ANALOGUES IS PREDICTIVE OF THERAPY FOR CHRONIC HEPATITIS " VIRUS INFECTION IN HUMANS (EPATOLOGY n 'ANGEMI *$ +ORBA " 4ENNANT " 5EDA ( *AY ' !NTIVIRAL AND ANTI PRO
"UD # 4ENNANT ET AL
LIFERATIVE ACTIVITIES OF a INTERFERONS IN EXPERIMENTAL HEPATITIS " VIRUS INFECTIONS !NTIVIRAL 4HERAPY n 4ENNANT "# "ALDWIN "( (ORNBUCKLE 7% +ORBA "% #OTE 0* 'ERIN *, !NIMAL MODELS IN THE PRECLINICAL ASSESSMENT OF THERAPY FOR VIRAL HEPATI TIS !NTIVIR 4HER n +ORBA "% 'ERIN *, 5SE OF A STANDARDIZED CELL CULTURE ASSAY TO ASSESS ACTIVITIES OF NUCLEOSIDE ANALOGS AGAINST HEPATITIS " VIRUS REPLICATION !NTIVIR 2ES n %NRIQUEZ 0- *UNG # *OSEPHSON , 4ENNANT "# #ONJUGATION OF ADENINE ARABINOSIDE MONOPHOSPHATE TO ARABINOGALACTAN 3YNTHESIS CHARACTERIZATION AND ANTIVIRAL ACTIVITY "IOCONJUGATE #HEM n 4ENNANT "# "ALDWIN "( 'RAHAM ,! !SCENZI -! (ORNBUCKLE 7% 2OWLAND 0( 4OCHKOV )! 9EAGER !% %RB (. #OLACINO *- ET AL !NTIVIRAL ACTIVITY AND TOXICITY OF FIALURIDINE IN THE WOODCHUCK MODEL OF HEPATI TIS " VIRUS INFECTION (EPATOLOGY n 0EEK 3& #OTE 0* *ACOB *2 4OSHKOV )! (ORNBUCKLE 7% "ALDWIN "( 7ELLS &6 #HU #+ 'ERIN *, 4ENNANT "# ET AL !NTIVIRAL ACTIVITY OF , &-!5 FLUORO METHYL a , ARABINOFURANOSYL URACIL AGAINST 7(6 REP LICATION AND GENE EXPRESSION IN CHRONICALLY INFECTED WOODCHUCKS - MONAX (EPATOLOGY n 2AJAGOPALAN 0 "OUDINOT &$ #HU #+ 4ENNANT "# "ALDWIN "( 3CHINAZI 2& 0HARMACOKINETICS OF n DIDEOXY THIACYTIDINE IN WOODCHUCKS !NTIMICROB !GENTS #HEMOTHER n -ORALEDA ' 3APUTELLI * !LDRICH #% !VERETT $ #ONDREAY , -ASON 73 ,ACK OF EFFECT OF ANTIVIRAL THERAPY IN NONDIVIDING HEPATOCYTE CULTURES ON THE CLOSED CIRCULAR $.! OF WOODCHUCK HEPATITIS VIRUS * 6IROL n +ORBA "% 3CHINAZI 2& #OTE 0 4ENNANT "# 'ERIN *, %FFECT OF ORAL ADMINISTRATION OF EMTRICITABINE ON WOODCHUCK HEPATITIS VIRUS REPLICATION IN CHRONICALLY INFECTED WOODCHUCKS !NTIMICROB !GENTS #HEMOTHER n 0EEK 3& 4OSHKOV )! %RB (. 3CHINAZI 2& +ORBA "% #OTE 0* 'ERIN *, 4ENNANT "# 4HIACYTIDINE 4# DELAYS DEVELOPMENT OF HEPATOCEL LULAR CARCINOMA (## IN WOODCHUCKS WITH EXPERIMENTALLY INDUCED CHRONIC WOODCHUCK HEPATITIS VIRUS 7(6 INFECTION 0RELIMINARY RESULTS OF A LIFETIME STUDY (EPATOLOGY -ASON 73 #ULLEN * -ORALEDA ' 3APUTELLI * !LDRICH #% -ILLER $3 4ENNANT " &RICK , !VERETT $ #ONDREAY ,$ ET AL ,AMIVUDINE THERAPY OF 7(6 INFECTED WOODCHUCKS 6IROLOGY n :HOU 4 3APUTELLI * !LDRICH #% $ESLAURIERS - #ONDREAY ,$ -ASON 73 %MERGENCE OF DRUG RESISTANT POPULATIONS OF WOODCHUCK HEPATITIS VIRUS IN WOODCHUCKS TREATED WITH THE ANTIVIRAL NUCLEOSIDE LAMIVUDINE !NTIMICROB !GENTS #HEMOTHER n 4ATTI +- +ORBA "% 3TANG (, 0EEK 3 'ERIN *, 4ENNANT "# 3CHINAZI 2& -UTATIONS IN THE CONSERVED WOODCHUCK HEPATITIS VIRUS POLYMERASE &,,! AND 9-$$ REGIONS CONFERRING RESISTANCE TO LAMIVUDINE !NTIVIRAL 2ES n #ULLEN *- ,I $( "ROWN # %ISENBERG %* #UNDY +# 7OLFE * 4OOLE * 'IBBS # !NTIVIRAL EFFICACY AND PHARMACOKINETICS OF ORAL ADEFOVIR DIPIVOXIL IN
4HE WOODCHUCK MODEL OF HEPADNAVIRUS INFECTION
CHRONICALLY WOODCHUCK HEPATITIS VIRUS INFECTED WOODCHUCKS !NTIMICROB !GENTS #HEMOTHER n *ACOB *2 +ORBA "% #OTE 0* 4OSHKOV ) $ELANEY 7% TH 'ERIN *, 4ENNANT "# 3UPPRESSION OF LAMIVUDINE RESISTANT " DOMAIN MUTANTS BY ADEFOVIR DIPIVOXIL IN THE WOODCHUCK HEPATITIS VIRUS MODEL !NTIVIRAL 2ES n -ENNE 3 #OTE 0* +ORBA "% "UTLER 3$ 'EORGE !, 4OCHKOV )! $ELANEY 7% TH 8IONG 3 'ERIN *, 4ENNANT "# !NTIVIRAL EFFECT OF ORAL ADMINISTRA TION OF TENOFOVIR DISOPROXIL FUMARATE IN WOODCHUCKS WITH CHRONIC WOODCHUCK HEPATITIS VIRUS INFECTION !NTIMICROB !GENTS #HEMOTHER n -ENNE 3 !SIF ' .ARAYANASAMY * "UTLER 3$ 'EORGE !, (URWITZ 3* 3CHINAZI 2& #HU #+ #OTE 0* 'ERIN *, ET AL !NTIVIRAL EFFECT OF ORALLY ADMINIS TERED n BETA $ AMINOPURINE DIOXOLANE IN WOODCHUCKS WITH CHRONIC WOOD CHUCK HEPATITIS VIRUS INFECTION !NTIMICROB !GENTS #HEMOTHER n #OLONO 2* 'ENOVESI %6 -EDINA ) ,AMB , $URHAM 3+ (UANG -, #OREY , ,ITTLEJOHN - ,OCAMINI 3 4ENNANT "# ET AL ,ONG TERM ENTECAVIR TREATMENT RESULTS IN SUSTAINED ANTIVIRAL EFFICACY AND PROLONGED LIFE SPAN IN THE WOODCHUCK MODEL OF CHRONIC HEPATITIS INFECTION * )NFECT $IS n -ENNE 3 2ONEKER #! +ORBA "% 'ERIN *, 4ENNANT "# #OTE 0* )MMUNIZATION WITH SURFACE ANTIGEN VACCINE ALONE AND AFTER TREATMENT WITH FLUORO METHYL BETA , ARABINOFURANOSYL URACIL , &-!5 BREAKS HUMORAL AND CELL MEDIATED IMMUNE TOLERANCE IN CHRONIC WOODCHUCK HEPATITIS VIRUS INFECTION * 6IROL n ,IAW 9 & 3UNG ** #HOW 7# &ARRELL ' ,EE #: 9UEN ( 4ANWANDEE 4 4AO 1- 3HUE + +EENE /. ET AL ,AMIVUDINE FOR PATIENTS WITH CHRONIC HEPATITIS " AND ADVANCE LIVER DISEASE . %NGL * -ED n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
(EPADNAVIRUSES HAVE A NARROW HOST RANGE n DO THEY +AI $ALLMEIER AND -ICHAEL .ASSAL 5NIVERSITY (OSPITAL &REIBURG )NTERNAL -EDICINE )) -OLECULAR "IOLOGY (UGSTETTER 3TR &REIBURG 'ERMANY
!BSTRACT (OST RANGE DESCRIBES THE RANGE OF SPECIES THAT A VIRUS CAN INFECT TO PRODUCTIVELY PROPAGATE ITSELF 0RODUCTIVE INFECTION REQUIRES COMPATIBILITY BETWEEN VIRUS AND HOST MOLECULES 4HUS HOST RANGE MAY BE RESTRICTED BY LACK OF APPROPRIATE PERMISSIVITY FACTORS ALTERNATIVELY HOSTS MAY ACTIVELY COUNTERACT INFECTION USING RESTRICTION FACTORS )NCOMPATIBILITY BETWEEN VIRUS AND HOST CAN MANIFEST ON THE LEVEL OF INDIVIDUAL CELLS OF TISSUES OR ORGANS AND OF THE ENTIRE ORGANISM !LL HEPATITIS " VIRUSES ARE HEPATOTROPIC BUT INDIVIDUAL VIRUSES INFECT THE LIVERS OF ONLY SELECTED MAMMALIAN ORTHOHEPADNAVIRUSES AND AVIAN AVIHEPADNAVIRUSES HOSTS (ENCE A NARROW HOST RANGE IS THOUGHT TO BE A SALIENT FEATURE OF HEPADNAVIRUSES (ERE WE BRIEFLY REVIEW GENERAL MECHANISMS OF HOST RANGE RESTRICTION AND SUMMARISE OLDER AS WELL AS RECENT DATA PERTAINING TO HEPADNAVIRAL HOST RANGE #LEARLY THE TERM SPE CIES SPECIFIC IS INADEQUATE FOR MANY HEPADNAVIRUSES BECAUSE THEY CAN INFECT DIFFERENT SPECIES FROM ONE GENUS AND EVEN SPECIES FROM DIFFERENT GENERA &OR A FEW OTHERS ONLY A SINGLE SPECIES OR GENUS HAS BEEN IDENTIFIED THAT SUPPORTS EFFICIENT INFECTION HOWEVER THIS COULD AS WELL RELATE TO THE RESTRICTED NUMBER OF EXPERIMENTALLY ADDRESSABLE TEST SPECIES 4OGETHER WITH THE UNCERTAINTY ABOUT QUANTITATIVE PHYLOGENETIC RELATIONSHIPS BETWEEN SPECIES STILL LARGELY BASED ON MORPHOLOGICAL RATHER THAN MOLECULAR CRITERIA THIS LEAVES THE TERM NARROW OPEN TO INTERPRETATION &INALLY FEW IF ANY OF THE HOST MOLECULES ENABLING PRODUCTIVE INFECTION BY A HEPADNAVIRUS HAVE UNAMBIGUOUSLY BEEN IDENTIFIED THE ROLE OF RESTRICTION FACTORS HAS NOT YET BEEN ASSESSED AND EVEN ON THE VIRUS SIDE THE SO CALLED HOST DETERMINING REGIONS IN THE 0RE3 DOMAINS OF THE LARGE ENVELOPE PROTEINS APPEAR TO BE RELEVANT ONLY UNDER SPECIALISED EXPERIMENTAL CONDITIONS (ENCE THIS IMPORTANT ASPECT OF HEPADNAVIRUS BIOLOGY IS STILL FAR FROM BEING UNDERSTOOD
)NTRODUCTION 7HILE VIRUSES CAN INFECT ALL FORMS OF LIFE AN INDIVIDUAL ORGANISM CANNOT BE INFECTED BY ALL TYPES OF VIRUSES 4HOUGH NOT SURPRISING GIVEN THE DIVERSITY BETWEEN PROKARYOTIC PLANT AND ANIMAL HOSTS EVEN WITHIN ONE KINGDOM MANY VIRUSES ARE SELECTIVE WITH RESPECT TO WHAT FOR THEM CONSTITUTES A SUITABLE SUSCEPTIBLE AND A NON SUITED NON PERMISSIVE HOST OR HOST CELL 7ITHIN METAZOAN HOSTS THREE TYPES OF SPECIFICITY TROPISM CAN BE DISTIN
+AI $ALLMEIER AND -ICHAEL .ASSAL
GUISHED THAT FOR SPECIFIC CELLS CELL TROPISM THAT FOR SPECIFIC ORGANS OR TIS SUES TISSUE TROPISM AND THAT FOR MEMBERS OF ONE BUT NOT ANOTHER SPECIES GENUS FAMILY ORDER AND SO ON HOST TROPISM (OST SPECIFICITY OF HEPATITIS " VIRUSES IS THE TOPIC OF THIS REVIEW HOWEVER ALL THREE ARE CLOSELY INTERTWINED SUCH THAT HOST RANGE CANNOT BE DISCUSSED IN ISOLATION 4HE COMMON NOTION IS THAT A NARROW CELL AND TISSUE SPECIFICITY NAMELY FOR HEPATOCYTES AND HEPATOCYTE DERIVED CELLS AND A NARROW HOST RANGE ARE SALIENT FEATURES OF HEPATITIS " VIRUSES "ELOW WE SUMMARISE THE EVIDENCE FAVOURING AND AT LEAST IN PART QUESTIONING THIS CONCEPT WE BRIEFLY DISCUSS THE VIRAL AND HOST FACTORS THAT IN GENERAL DETERMINE HOST RANGE IN BET TER UNDERSTOOD SYSTEMS AND RELATE THEM TO WHAT IS KNOWN FOR HEPATITIS " VIRUSES "ECAUSE SEVERAL COMPREHENSIVE REVIEWS PERTAINING TO HEPADNAVIRUS BIOLOGY HAVE RECENTLY BEEN PUBLISHED ;n= WE WILL EMPHASISE UNRESOLVED ISSUES FROM BOTH EARLY AND VERY RECENT INVESTIGATIONS 4HEY REVEAL THAT EXPERIMENTAL DEFINITION OF HEPADNAVIRAL HOST RANGE IS OBSCURED BY INSUF FICIENT KNOWLEDGE ON THE INVOLVED VIRAL AND HOST FACTORS AS WELL AS HOST PHY LOGENETIC RELATIONS IS STRONGLY AFFECTED BY THE TEST SYSTEMS USED AND THUS IS MUCH LESS UNDERSTOOD THAN IMPLICATED BY PREVAILING MODELS
'ENERAL IMPORTANCE OF HOST RANGE 7E ARE CONSTANTLY EXPOSED TO AN ENORMOUS VARIETY OF VIRUSES OF WHICH FORTUNATELY ONLY FEW ARE ABLE TO ESTABLISH A PRODUCTIVE INFECTION IN HUMANS BECAUSE OF HOST RANGE RESTRICTIONS (ENCE THIS SPECIES BARRIER PROTECTS US FROM PERMANENTLY BEING INFECTED 4HE IMPORTANCE OF THIS PHENOMENON IS DRAMATICALLY HIGHLIGHTED BY THE OCCASIONAL CROSSING OF THIS BARRIER BY A VIRUS AND ITS POTENTIALLY DEVASTATING CONSEQUENCES ;= NOTORIOUS EXAMPLES INCLUDE HUMAN IMMUNODEFICIENCY VIRUSES ()6S ;= SEVERE ACUTE RESPIRATORY SYN DROME 3!23 CORONAVIRUS ;= OR THE IMMINENT THREAT OF AN INFLUENZA PAN DEMIC ORIGINATING FROM THUS FAR AVIAN (. INFLUENZA VIRUSES ;= )T SHOULD BE NOTED THAT NOT EVERY SPECIES CROSSING LEADS TO DISEASE 3IMIAN VIRUS 36 POSSIBLY INTRODUCED INTO THE HUMAN POPULATION BY THE POLIOVIRUS VACCINE MAY OR MAY NOT BE ASSOCIATED WITH CANCER ;= AND NO INDICATION FOR DISEASE INDUCTION EXISTS FOR SIMIAN FOAMYVIRUS INFECTIONS OF HUMANS ;= ! DIFFERENT CONSEQUENCE OF RELEVANCE FOR VIROLOGICAL AND MEDICAL RESEARCH IS THAT HOST RANGE RESTRICTIONS CAN PREVENT THE ESTABLISHMENT OF ANIMAL MODELS FOR INFECTION WITH A HUMAN VIRAL PATHOGEN FOR WHICH ("6 REPRESENTS AN EMINENT EXAMPLE
-OLECULAR DETERMINANTS OF VIRAL HOST RANGE 6IRAL INFECTION AND DEFENSE AGAINST INFECTION DEPEND ON INTERACTIONS BETWEEN VIRAL AND HOST COMPONENTS WHICH THEREFORE MUST BE MATCHING
(EPADNAVIRUS HOST RANGE
4WO FUNDAMENTALLY DISTINCT MECHANISMS RESTRICT INFECTABILITY %ITHER A LACK OF FACTORS REQUIRED FOR THE VIRUS TO COMPLETE ITS INFECTIOUS CYCLE @PERMIS SIVITY FACTORS OR THE PRESENCE OF HOST FACTORS THAT ACTIVELY BLOCK THAT CYCLE @RESTRICTION FACTORS THE LATTER MAY BE DIVIDED INTO FACTORS THAT ARE CONSTANTLY PRESENT INNATE AND THOSE THAT ARE INDUCED IN RESPONSE TO THE ENCOUNTER WITH A SPECIFIC VIRUS ADAPTIVE %VIDENTLY CELLS FROM DIFFERENT HOSTS AND FROM DIFFERENT TISSUES WITHIN ONE HOST DIFFER IN THEIR EXPRES SION PROFILES ADDITIONAL DIVERSIFICATION COMES IN BY CHANGES RELATED TO THE CELL CYCLE AND DIFFERENTIATION STATUS (ENCE PERMISSIVITY FACTORS MAY EITHER COMPLETELY OR TEMPORARILY BE ABSENT OR DIFFER BETWEEN HOST SPECIES IN THEIR EXACT COMPOSITION SUCH THAT THEY CANNOT PRODUCTIVELY INTERACT WITH THE CORRESPONDING VIRAL COMPONENT THE SAME HOLDS CONVERSELY FOR RESTRICTION FACTORS
(OST RANGE RESTRICTIONS BY LACK OF HOST FACTORS REQUIRED BY THE VIRUS &AILURE TO COMPLETE ANY ONE OF THE INDIVIDUAL INFECTIOUS CYCLE STEPS FOR PHYSICAL LACK OF OR LACK OF COMPATIBILITY WITH A CELLULAR FACTOR INVOLVED WILL EXCLUDE A CELL OR ORGANISM FROM BEING A HOST FOR THAT VIRUS 2ELATED SPE CIES HAVE A RELATED GENETIC OUTFIT AND THE CLOSER THE RELATION THE HIGHER THE SIMILARITY BETWEEN INDIVIDUAL GENES AND GENE PRODUCTS (ENCE SUSCEPTIBIL ITY TO A CERTAIN VIRUS IN ONE HOST SPECIES WILL MOST EASILY BE EXTENDABLE TO CLOSELY RELATED HOSTS 4HE IMPORTANCE OF MATCH BETWEEN VIRAL AND CELLULAR FACTORS IS ALSO HIGHLIGHTED BY THE IMPACT ON INFECTABILITY OF INDIVIDUAL POLY MORPHISMS IN SOME CELLULAR GENES A FAMOUS EXAMPLE ARE HUMANS CARRYING A NON FUNCTIONAL ALLELE OF THE ()6 CORECEPTOR ##2 GENE ##26 ; = )NTERESTINGLY THIS ALLELE ALSO DECREASES THE LIKELIHOOD FOR HEPATITIS " TO BECOME CHRONIC THOUGH PROBABLY BY AN IMMUNOMODULATORY RATHER THAN A DIRECT MECHANISM ;= IN CONTRAST AN INTACT ##2 GENE PROTECTS AGAINST 7EST .ILE VIRUS INFECTION ;= .ONETHELESS VIRUSES DIFFER GREATLY IN THEIR HOST SPECIFICITIES 6ESICULAR STOMATITIS VIRUS 636 INFECTS CELLS FROM A VERY WIDE RANGE OF SPECIES INCLUD ING VERTEBRATES INVERTEBRATES AND EVEN INSECTS SOME MURINE RETROVIRUSES IN CONTRAST ARE SO MUCH RESTRICTED THAT THEY INFECT ONE BUT NOT ANOTHER STRAIN OF MICE !S OUTLINED BELOW HEPADNAVIRUS HOST SPECIFICITY SEEMS TO BE INTER MEDIATE BETWEEN THESE EXTREMES &OR ANY VIRUS INCLUDING ("6 THE EVENTS DURING PRODUCTIVE INFECTION CAN BROADLY BE CATEGORISED INTO ATTACHMENT ENTRY UNCOATING OF THE VIRAL GENOME GENOME REPLICATION AND EXPRESSION OF GENE PRODUCTS AND ASSEM BLY AND EGRESS OF PROGENY VIRIONS -OST OCCUR AT DIFFERENT SITES IN THE CELL HENCE THE IMPORTANCE OF INTRACELLULAR TRAFFICKING IN VIRUS REPLICATION AND CONSEQUENTLY THE DEPENDENCE ON THE INVOLVED CELL FACTORS IS INCREASINGLY RECOGNISED ;=
+AI $ALLMEIER AND -ICHAEL .ASSAL
!TTACHMENT AND ENTRY %ACH VIRUS MUST BIND TO A SUITABLE HOST CELL AND THEN MUST GET ACCESS TO THE CYTOPLASM BY CROSSING EITHER THE HOST CELL PLASMA MEMBRANE OR AN INTER NAL n USUALLY ENDOSOMAL n MEMBRANE FOR ENVELOPED VIRUSES THIS GENERALLY INVOLVES MEMBRANE FUSION EVENTS "INDING AND FUSION ACTIVITIES MAY RESIDE IN A SINGLE PROTEIN AS WITH 636 ' PROTEIN OR ON SEPARATE POLYPEPTIDES /BVIOUSLY THE INITIAL BINDING REQUIRES INTERACTIONS BETWEEN MOLECULES THAT ARE EXPOSED ON THE SURFACES OF THE VIRUS AND OF THE CELL COMMONLY NAMED VIRAL ATTACHMENT PROTEINS OR VIRAL RECEPTORS AND CELLULAR RECEPTORS 4HESE CAN BE DIFFERENT CLASSES OF MOLECULES INCLUDING PROTEINS LIPIDS AND SUGARS &OR MANY VIRUSES THOUGH NOT THE HEPADNAVIRUSES THE HOST INTERAC TION PARTNERS OF THEIR ATTACHMENT AND FUSION PROTEINS ARE KNOWN ;= IN SEVERAL CASES EVEN IN ATOMIC DETAIL ;= %XAMPLES INCLUDE ()6 GP AND #$ INFLUENZA VIRUS HAEMAGGLUTININ (! AND SIALIC ACID RESIDUES &OR PROTEIN RECEPTORS IT IS OBVIOUS THAT THEIR AMINO ACID SEQUENCES WILL VARY BETWEEN HOST SPECIES AND HENCE MAY ACT AS IMPORTANT HOST RANGE RESTRICTION ELEMENTS .OTABLY EVEN LESS COMPLEX BIOLOGICAL STRUCTURES CAN EXERT SUCH A RESTRICTIVE FUNCTION AS SHOWN BY THE DIFFERENTIAL RECOGNI TION OF _ VERSUS _ LINKAGES TO GALACTOSE IN THE SIALIC ACID RECEPTORS USED BY AVIAN VERSUS HUMAN INFLUENZA VIRUSES ;= ! SECOND INCREASINGLY APPRECIATED FEATURE IS THAT OFTEN PERHAPS ALWAYS MORE THAN ONE HOST SURFACE MOLECULE IS INVOLVED 3UCH SECONDARY MOLECULES FOR INSTANCE EXTRACELLULAR MATRIX COMPONENTS SUCH AS GLYCOSAMINOGLYCANS '!'S MAY GENERALLY HELP CONCENTRATING THE VIRUS ON THE CELL SURFACE OR BE MORE SPECIFIC OFTEN SEQUENTIALLY ACTING CO RECEPTORS THAT ARE ESSENTIAL FOR PRO DUCTIVE ENTRY 7ELL KNOWN EXAMPLES INCLUDE FOR NON ENVELOPED VIRUSES THE INITIAL BINDING OF THE ADENOVIRUS FIBER PROTEIN TO THE #OXSACKIE 6IRUS !DENOVIRUS RECEPTOR #!2 AND THE SUBSEQUENT INTERACTION OF THE PEN TON BASE PROTEIN WITH CELLULAR INTEGRINS ;= AND FOR ENVELOPED VIRUSES THE ()6 RECEPTORS AND CO RECEPTORS #$ AND #8#2 AND ##2 ;= /F NOTE RELATIVELY SMALL ALTERATIONS IN A VIRAL PROTEIN CAN LEAD TO THE USE OF ALTERNATIVE HOST RECEPTORS ;= AND THEREFORE CONTRIBUTE TO EXTEND THE VIRUS HOST RANGE &INALLY VIRUS HOST CELL RECEPTOR INTERACTIONS MAY BE MODULATED INDIRECTLY BY AUXILIARY PROTEINS &OR MANY VIRUSES FUSION ACTIV ITY DEPENDS ON A BALANCED PROTEOLYTIC ACTIVATION OF THE FUSION PROTEIN 4HE PERTINENT EXAMPLE IS THE HAEMAGGLUTININ (! OF INFLUENZA VIRUSES AND ITS DEPENDENCE ON PROPERLY TIMED CLEAVAGE INTO (! AND (! ;= (ENCE AVAILABILITY OF SUITABLE PROTEASES AT THE RIGHT CONCENTRATION AND LOCATION CAN WELL AFFECT HOST RANGE
(EPADNAVIRUS HOST RANGE
5NCOATING OF THE VIRAL GENOME REPLICATION AND FORMATION OF PROGENY VIRIONS 4HE STEPS FOLLOWING ENTRY CAN AS WELL PROFOUNDLY AFFECT VIRAL HOST RANGE 0OXVIRUSES FOR INSTANCE USING UBIQUITOUSLY PRESENT MOLECULES POSSIBLY '!'S AS RECEPTORS CAN ENTER MANY DIFFERENT CELLS 4HEIR NARROW HOST RANGE 6ARIOLA VIRUS INFECTS EXCLUSIVELY HUMANS MUST THEREFORE RELATE MOSTLY TO DOWNSTREAM INTRACELLULAR EVENTS ;= 3OME OF THE BASIC CELLULAR MACHINERY FOR TRANSCRIPTION TRANSLATION AND PROTEIN FOLDING ; = IS PROBABLY UNI VERSAL HOWEVER THE ONGOING SEARCH FOR A MOUSE MODEL OF ()6 INFECTION ;= IS REVEALING AN EVER INCREASING NUMBER OF HOST SPECIFIC FACTORS ;= THAT LACK COMPATIBILITY WITH COMPONENTS OF THE HUMAN VIRUS %XAMPLES INCLUDE PREINTEGRATION COMPLEX NUCLEAR IMPORT ;= AND THE 4AT PROTEIN WHICH TOGETHER WITH THE HOST FACTORS CYCLIN 4 AND A CYCLIN KINASE #DK BINDS TO THE 4!2 ELEMENT ON NASCENT VIRAL 2.! ENHANCING THE RATE OF VIRAL 2.! TRANSCRIPTION BY 2.! POLYMERASE )) ()6 4AT INTERACTS PRODUCTIVELY WITH HUMAN BUT NOT MURINE CYCLIN 4 ;= !LSO ()6 ASSEMBLES AND BUDS POORLY IN MOUSE CELLS SUGGESTING THAT COMPONENTS OF OR ASSOCIATED WITH THE ENDOSOMAL SORTING COMPLEX REQUIRED FOR TRANSPORT %3#24 CONTRIBUTE TO SPECIES TROPISM ;= 4HIS MACHINERY IS PROBABLY ALSO INVOLVED IN ("6 MORPHOGENESIS ;n= HOWEVER THE SINGLE MOST IMPORTANT SPECIES SPECIFIC BLOCKS TO HEPADNAVIRUS INFECTION APPEAR TO OPERATE DURING THE INITIAL STEPS OF INFECTION SEE BELOW
0RESENCE OF HOST RESTRICTION FACTORS #ELLS MAY ACTIVELY COUNTERACT VIRAL INFECTION BY INNATE RESTRICTION FACTORS ADAPTIVE RESPONSES THOUGH CRUCIAL ARE NOT CONSIDERED HERE )NNATE RESTRIC TION FACTORS TYPICALLY ACT IN A DOMINANT SATURABLE FASHION IE INHIBITION CAN BE OVERCOME BY HIGH DOSES OF VIRUS @ABROGATION AND THEY CAN TARGET DIVERSE STEPS OF VIRAL REPLICATION AS IS BEST KNOWN FOR RETROVIRUSES ;n= #LASSIC EXAMPLES ARE THE ENDOGENOUS RETROVIRAL GENE PRODUCTS &V WHICH RESTRICTS &RIEND MURINE LEUKAEMIA VIRUS BY RECEPTOR BLOCKADE AND &V A 'AG LIKE PROTEIN THAT TARGETS THE CAPSID PROTEINS OF SOME RETROVIRUSES AND INTERFERES WITH PROPER FUNCTIONING OF THE PREINTEGRATION COMPLEX !NOTHER WIDELY PRESENT RESTRICTION SYSTEM IS BASED ON THE FAMILY OF TRIPARTITE SEQUENCE MOTIF 42)- PROTEINS ;= WHICH TYPICALLY CONTAIN A 2).' DOMAIN FOUND IN MANY % UBIQUITIN LIGASES ONE OR TWO " BOXES AND A COILED COIL REGION PLUS DIFFERENT # TERMINAL DOMAINS 4HE MOST FAMOUS OF THE ABOUT 42)- FAMILY MEMBERS ;= IS 42)-_ A SPECIES SPECIFIC RESTRICTION FACTOR FOR VARIOUS IMMUNODEFICIENCY VIRUSES AND ALSO SIMPLE RETROVIRUSES ;= FOR INSTANCE RHESUS MONKEY BUT NOT HUMAN 42)-_ RESTRICTS ()6 AND ()6 42)-_ ALSO TARGETS THE CAPSID PROTEIN AND PREVENTS PROPER REVERSE TRANSCRIPTION PROBABLY BY PREMATURE UNCOATING AND POSSIBLY ALSO THROUGH
+AI $ALLMEIER AND -ICHAEL .ASSAL
DEGRADATION OF 'AG POLYPROTEIN PRECURSORS ;= 4HIS MECHANISM MAY BE ANTAGONISED BY THE HOST PROLINE ISOMERASE CYCLOPHILIN ! #YP! WHICH AUGMENTS ()6 INFECTION IN HUMAN CELLS BUT INHIBITS REPLICATION IN MONKEY CELLS ;= /THER 42)- FAMILY MEMBERS ARE ALSO INVOLVED IN ANTIVIRAL RESIS TANCE ;= !NOTHER RESTRICTION SYSTEM IS BASED ON THE !0/"%# FAMILY OF CYTIDINE DEAMINASES ;= NAMED AFTER THE FOUNDING MEMBER !0/"%# WHICH EDITS THE M2.! FOR APOLIPOPROTEIN " !0/"%#' TARGETS INSTEAD SINGLE STRAND ED $.! FOR INSTANCE RETROVIRUS MINUS STRAND $.! AND INTRODUCES VARI OUS # 5 MUTATIONS RESULTING IN ' ! HYPERMUTATION IN THE PLUS STRAND 4HE 5 RESIDUES RENDER THE $.! UNSTABLE AND HYPERMUTATION CAN PREVENT FORMATION OF FUNCTIONAL GENE PRODUCTS 4HE LENTIVIRAL 6IF GENE PRODUCTS PRO TECT THE VIRUSES BY INDUCING !0/"%#' DEGRADATION SPECIES SPECIFICITY RESULTS MAINLY FROM THE ABILITY OR INABILITY OF A GIVEN !0/"%# PROTEIN TO INTERACT WITH THE RESPECTIVE 6IF PROTEIN ;= !0/"%#' AND OTHER FAMILY MEMBERS IF OVEREXPRESSED IN HEPATIC CELL LINES ALSO RESTRICT ("6 THOUGH THE DEAMINASE ACTIVITY IS NOT REQUIRED ; = (EPADNAVIRUSES DO NOT SEEM TO ENCODE A 6IF LIKE ANTI !0/"%# ACTIVITY HENCE POTENTIAL HOST RANGE RESTRIC TION WOULD HAVE TO ACT DIRECTLY VIA CAPSID !0/"%# INTERACTIONS ! ROLE FOR !0/"%# IN AVIHEPADNAVIRUS INFECTIONS IS UNLIKELY BECAUSE !0/"%# PROTEINS LIKE !0/"%# APPEAR TO BE MAMMAL SPECIFIC ;= 9ET ANOTHER INNATE FACTOR RESTRICTION FACTOR IS THE ZINC FINGER ANTIVIRAL PROTEIN :!0 WHICH TARGETS VIRAL 2.! FOR DESTRUCTION BY THE EXOSOME 2.! DEGRADATION MACHINERY AS SHOWN FOR RETROVIRUSES AND 3INDBIS VIRUS ; = AND RECENTLY MADE LIKELY FOR FILOVIRUSES ;= 7HETHER :!0 CAN AFFECT HOST RANGE IS CURRENTLY NOT KNOWN ! FURTHER COMPLEX INNATE DEFENSE SYSTEM AGAINST VIRUSES AND OTHER PATHOGENS CONSISTS OF THE VARIOUS 4OLL LIKE RECEPTORS 4,2S 2ECOGNITION OF NON SELF @PATHOGEN ASSOCIATED MOLECULAR PATTERNS 0!-0S BY THESE PRO TEINS LOCATED IN THE PLASMA MEMBRANE 4,2 OR IN ENDOSOMAL MEMBRANES MOST OTHER 4,2S INDUCES ANTIVIRAL SIGNALING PATHWAYS THAT ACTIVATE EG .&K" OR INTERFERON REGULATORY FACTOR )2& LEADING TO EXPRESSION OF ANTIVIRAL CYTOKINES AND INTERFERONS ;= 4HE VIRAL 0!-03 MAY BE PROTEINS 4,2 4,2 OR NUCLEIC ACIDS SUCH AS DS2.! 4,2 SS2.! 4,2 4,2 OR DS$.! 4,2 2ECENTLY DISCOVERED CYTOPLASMIC SENSING SYSTEMS INCLUDE THE 2.! HELICASES RETINOIC ACID INDUCED GENE ) 2)' ) WHICH APPEARS TO RECOGNISE UNCAPPED DOUBLE STRANDED VIRAL 2.! BEARING TRIPHOSPHATES EG FROM INFLUENZA 3ENDAI OR FLAVIVIRUSES INCLUDING (#6 ;= AND MELANOMA DIFFERENTIATION ASSOCIATED GENE -$! WHICH SENSES PROTECTED 2.! EG FROM PICORNAVIRUSES ;= "OTH ACTIVATE THROUGH THEIR CASPASE RECRUITMENT DOMAINS #!2$ A MITOCHONDRIA BOUND PROTEIN VARIOUSLY KNOWN AS #!2$ ADAPTOR INDUCING )&. ` #!2$)& INTERFERON ` PROMOTER STIMULATOR )03 VIRUS INDUCED SIGNALING ADAPTOR 6)3! OR MITOCHONDRIAL ANTIVIRAL SIGNALING -!63 ALSO LEADING TO .& g" AND )2& )2& MEDIATED INTERFERON INDUCTION (OW MUCH THESE ANTIVIRAL FAC
(EPADNAVIRUS HOST RANGE
TORS CONTRIBUTE TO SPECIES TROPISM IS NOT YET CLEAR HOWEVER THE ANTIVIRAL ACTIVITY 2)' ) IS EMPHASISED FOR INSTANCE BY THE MUCH BETTER REPLICATION OF HEPATITIS # VIRUS (#6 IN A HEPATOMA CELL LINE CLONE LACKING A FUNCTIONAL 2)' ) PROTEIN AND IN THAT (#6 TRIES TO ESCAPE FROM THIS MECHANISM BY CLEAVING #!2$)& AS WELL AS THE 4,2 ADAPTOR 42)& USING ITS .3 ! SERINE PROTEASE ;= 7HILE ("6 CAN COUNTERACT THE DOWNSTREAM INTERFERON EFFECTS ;= IT IS CURRENTLY NOT KNOWN WHETHER THESE OR SIMILAR DEFENCE SYS TEMS AFFECT HEPADNAVIRAL HOST RANGE &INALLY 2.! INTERFERENCE MAY CONTRIBUTE TO PERMISSIVENESS OF CELLS TO VIRAL INFECTION WHILE THIS IS PROVEN FOR INVERTEBRATES AND PLANTS A ROLE IN MAMMALS IS STILL UNDER DEBATE ;= (ENCE CELLS ARE EQUIPPED WITH A LARGE VARIETY OF DEFENCE SYSTEMS THAT COULD ALSO AFFECT HEPADNAVIRUS INFECTION AND HOST RANGE HOWEVER CURRENTLY FEW IF ANY DATA ARE AVAILABLE
#OMMON FEATURES OF HEPADNAVIRUSES AND THEIR INFECTIOUS CYCLES !S OUTLINED ABOVE EACH STEP OF THE VIRAL INFECTIOUS CYCLE MAY BE SUBJECT TO NEGATIVE REGULATION BY LACK OF POSITIVE OR PRESENCE OF NEGATIVE FACTORS IN A SPECIFIC HOST CELL THIS CERTAINLY HOLDS ALSO FOR HEPADNAVIRUSES 7E NEXT BRIEFLY CONSIDER THE HEPADNAVIRAL INFECTIOUS CYCLE IN TOTO &IG ! HOWEVER BASED ON CURRENT KNOWLEDGE MOST OF THE LATER STEPS ARE CONTROLLED ON THE TISSUE RATHER THAN HOST SPECIES LEVEL LEAVING THE EARLY STEPS OF ATTACHMENT AND ENTRY AS THE MOST LIKELY CANDIDATES FOR DETERMINING HOST TROPISM /NE LINE OF EVIDENCE SUPPORTING THIS VIEW IS THAT ARTIFICIAL INTRODUCTION OF A TRAN SCRIPTIONAL TEMPLATE EQUIVALENT TO HUMAN ("6 COVALENTLY CLOSED CIRCULAR $.! CCC$.! INTO MOUSE LIVER AS A TRANSGENE OR BY HYDRODYNAMIC INJEC TION ;= YIELDS VIRIONS THAT ARE INFECTIOUS IN AN AUTHENTIC HOST BUT DO NOT INFECT THE MOUSE !LL HEPADNAVIRUSES ARE SMALL ENVELOPED HEPATOTROPIC $.! CONTAINING VIRUSES THAT SHARE A COMMON GENETIC ORGANISATION AND REPLICATION STRATEGY ;= 4HEIR GENOMES &IG " ARE ALL BETWEEN n KB IN LENGTH ARE PRODUCED BY REVERSE TRANSCRIPTION OF THE PREGENOMIC 2.! PG2.! INTERMEDIATE AND ARE PRESENT IN VIRIONS AS PARTIALLY DOUBLE STRANDED CIRCULAR BUT NOT COVA LENTLY CLOSED IE RELAXED CIRCULAR 2# $.! WITH THE REVERSE TRANSCRIPTASE 0 PROTEIN COVALENTLY LINKED TO THE TERMINAL NUCLEOTIDE OF THE n STRAND $.! !LL ENCODE BESIDES 0 PROTEIN A SINGLE CAPSID OR CORE PROTEIN WHICH FORMS THE ICOSAHEDRAL PROTEIN SHELL OF THE NUCLEOCAPSID AND TWO AVIAN ("6S OR THREE MAMMALIAN ("6S CARBOXY TERMINALLY COLINEAR SURFACE PROTEINS WHICH ARE EMBEDDED INTO THE LIPID OF THE ENVELOPE 4HE SURFACE PROTEINS CAN FORM EMPTY ENVELOPES TERMED SUBVIRAL OR 3 PARTICLES 360S WHICH ARE SECRETED IN LARGE EXCESS OVER INTACT VIRIONS ;= -OST ABUNDANT IS THE SMALL 3 PROTEIN ABOUT AMINO ACIDS IN ORTHO AND ABOUT AMINO ACIDS IN AVIHEPADNAVIRUSES CONSTITUTING THE MAJORITY OF ("S!G IN HUMAN
+AI $ALLMEIER AND -ICHAEL .ASSAL
&IGURE #OMMON ASPECTS OF HEPADNAVIRUSES ! )NFECTIOUS CYCLE %NVELOPED VIRIONS ENTER THEIR HOST CELLS PRIMARILY HEPATOCYTES VIA INTERACTION WITH LARGELY UNKNOWN RECEPTORS LEADING TO CYTOPLASMIC RELEASE OF THE NUCLEOCAPSID IMPORT OF THE RELAXED CIRCULAR 2# $.! GENOME INTO THE NUCLEUS AND CONVERSION INTO COVALENTLY CLOSED CIRCULAR CCC $.! &ROM THIS TEMPLATE SUB GENOMIC NOT SHOWN AND PREGENOMIC PG 2.!S ARE TRANSCRIBED BY CELLULAR 2.! POLYMERASE )) EXPORTED FROM THE NUCLEUS AND TRANSLATED 0G2.! ACTS AS M2.! FOR THE CAPSID AND 0 PRO TEIN AND VIA THE ENCAPSIDATION SIGNAL E IS COPACKAGED WITH 0 INTO NEW IMMATURE NUCLEOCAPSIDS 2EVERSE TRANSCRIPTION INTO THE 2# $.! FORM OCCURS INSIDE THE NUCLEOCAPSID -ATURE PROGENY CAPSID CAN REPEAT THE INTRACELLULAR AMPLIFICATION CYCLE INCREASING THE COPY NUMBER OF CCC$.! MOLECULES OR INTERACT AT COMPARTMENTS OF THE SECRETORY PATHWAY LOWER LEFT CORNER OF THE CELL WITH THE ENVELOPE PROTEINS AND BE SECRETED %MPTY ENVELOPES SUBVIRAL PARTICLES 360S ARE SECRETED IN LARGE EXCESS OVER VIRIONS PROBABLY BY A DISTINCT MECHANISM ; = " 'ENOME ORGANISATION !LL HEPADNAVIRUS GENOMES AS PRESENT IN VIRIONS ARE ABOUT KB IN LENGTH WITH THE n STRAND $.! COVALENTLY LINKED TO 0 PROTEIN AND THE STRAND BEING INCOMPLETE !LL ENCODE ONE CAPSID PROTEIN # THE REVERSE TRANSCRIPTASE 0 AND COMPLETELY OVERLAPPING WITH 0 A SHORT 3 PLUS ONE AVIAN OR TWO MAMMALIAN LONGER FORMS 0RE33 OF ENVELOPE PROTEINS )NTACT GENES FOR 8 ARE PRESENT IN ALL MAMMALIAN BUT ONLY IN CRYPTIC FORM IN THE AVIAN VIRUSES
("6 INFECTION THE MIDDLE - PROTEIN OF MAMMALIAN ("6S CONTAINS AN . TERMINAL EXTENSION OF AMINO ACIDS ENCODED BY THE PRE3 REGION AND THE , PROTEIN AN ADDITIONAL EXTENSION OF AROUND n AMINO ACIDS ENCODED BY THE PRE3 REGION !VIAN ("6S LACK A PRE3 INITIATION CODON THEIR PRE3 REGIONS COMPRISE ABOUT CODONS )N ALL HEPADNAVIRUSES THE 0RE3 REGIONS OF THE , PROTEIN ARE INVOLVED IN TWO ESSENTIAL FUNCTIONS NAMELY NUCLEO CAPSID ENVELOPMENT AND ATTACHMENT TO AND ENTRY INTO THE HOST CELL 4HIS IS ACCOUNTED FOR BY AN UNUSUAL DUAL TOPOLOGY WITH ABOUT ONE HALF OF THE 0RE3 DOMAINS DIRECTED TOWARDS THE INNER AND THE OTHER HALF TO THE OUTER FACE OF THE VIRIONS !N . TERMINAL EXTENSION ON THE CORE PROTEIN ENCODED BY THE PRE# REGION GIVES RISE TO THE SECRETORY NON ASSEMBLING PRECORE PROTEIN WHICH AFTER . AND # TERMINAL PROCESSING EVENTS IS FOUND IN THE CIRCULATION AS ("E!G &INALLY MAMMALIAN BUT MOST LIKELY NOT AVIAN ("6S PRODUCE A REGULATORY PROTEIN ("X WHOSE FUNCTION IS ONLY POORLY UNDERSTOOD
(EPADNAVIRUS HOST RANGE
4HE HEPADNAVIRAL INFECTIOUS CYCLE &IG ! IS INITIATED BY BINDING OF THE VIRION TO AS YET UNKNOWN CELL SURFACE RECEPTORS INTERNALISATION RELEASE OF THE NUCLEOCAPSIDS INTO THE CYTOPLASM AND TRANSPORT OF THE 2# $.! GENOME INTO THE NUCLEUS WHERE CONVERSION INTO CCC$.! OCCURS .ONE OF THESE EVENTS IS WELL UNDERSTOOD 7HETHER FUSION OCCURS AT THE PLASMA OR AT AN INTERNAL MEMBRANE AND WHETHER IT REQUIRES PASSAGE THROUGH AN ACIDIC COMPARTMENT IS CONTROVERSIAL AS IS THE NATURE OF THE FUSION PEPTIDE AND THE REQUIREMENT FOR ITS EXPOSURE OR NOT BY A PROTEOLYTIC PROCESSING EVENT 3OME EVIDENCE SUGGESTS THAT ARTIFICIAL CLEAVAGE CAN FACILITATE ENTRY INTO NON SUSCEPTIBLE CELLS ; = WHICH WOULD BE COMPATIBLE WITH THE PRESENCE OF A FUSOGENIC PEPTIDE WITHIN THE FIRST TRANS MEMBRANE DOMAIN 4- OF THE 3 DOMAIN ;= ! RECENT ALTERNATIVE PROPOSAL WAS THAT TRANSLOCATION MOTIFS 4,-S SHORT _ HELICAL PEPTIDE SEQUENCES PREDICTED TO BE PRESENT IN ORTHO AND AVIHEPADNAVIRUS 0RE3 PROTEINS WOULD MEDIATE DIRECT TRANSLOCATION ;= 4HIS HAS NOT HOWEVER BEEN REPRODUCED FOR ("6 BY OTHERS ; = .UCLEAR TRANSPORT ;= OF THE RELAXED CIRCULAR 2# $.! GENOME OCCURS IN NUCLEOCAPSIDS ALONG CYTOSKELETAL COMPONENTS AND PROBABLY RESULTS VIA INTERACTIONS OF THE CAPSID WITH COMPONENTS OF THE NUCLEAR PORE COMPLEX .0# IN THE RELEASE OF THE $.! INTO THE NUCLEUS .0# COMPONENTS ARE HIGHLY CONSERVED THROUGH EVOLUTION AND 8 LAEVIS OOCYTES APPEAR TO BEHAVE SIMILARLY WITH RESPECT TO HEPADNAVIRAL NUCLEOCAPSIDS AS HUMAN HEPATOCYTE CELL LINES SUGGESTING THE ABSENCE OF SPECIES SPECIFIC EFFECTS CCC$.! FORMA TION INCLUDES COMPLETION OF THE $.! STRAND REMOVAL OF THE COVALENTLY BOUND 0 PROTEIN AND THE SMALL TERMINAL REDUNDANCIES AND RELIGATION 4HE VIRTUAL ABSENCE OF CCC$.! IN ("6 TRANSGENIC MICE SUGGESTED THE INVOLVE MENT OF SPECIES SPECIFIC FACTORS HOWEVER IN MICE WITH A HEPATOCYTE NUCLEAR FACTOR A (.&A NULL BACKGROUND CCC$.! BECOMES DETECTABLE ;= 2ECENTLY INITIATED EFFORTS TO SYSTEMATICALLY RE EVALUATE CCC$.! FORMATION ARE CERTAINLY WORTHWHILE AND MAY UNCOVER AS YET UNKNOWN SPECIES SPECIFIC FACTORS ;= CCC$.! IS THE PIVOTAL INTRACELLULAR INTERMEDIATE OF HEPADNAVIRUS REP LICATION AS IT SERVES AS TEMPLATE FOR ALL VIRAL TRANSCRIPTS 4RANSCRIPTION OF CCC$.! BY 2.! POLYMERASE )) APPEARS MOSTLY CONTROLLED ON THE TISSUE n RATHER THAN SPECIES n SPECIFICITY LEVEL IN THAT THE CORE PROMOTER DRIVING PREGENOMIC 2.! TRANSCRIPTION AND THE PRE3 PROMOTER RESPONSIBLE FOR THE PRE3 M2.! REQUIRE LIVER ENRICHED FACTORS FOR HIGH LEVEL ACTIVITY FOR INSTANCE ("6 AND $("6 REPLICATION IN MOUSE CELLS OF NONHEPATIC ORIGIN CAN BE RESCUED BY LIVER ENRICHED FACTORS SUCH AS HEPATOCYTE NUCLEAR FACTOR (.& ;= (OWEVER 7(6 REPLICATION IS NOT SUPPORTED IN THAT SYSTEM AND THE 7(6 ENHANCER ) DOES NOT WORK PROPERLY IN HUMAN HEPATOMA CELLS THAT FULLY SUPPORT ("6 TRANSCRIPTION ;= !TTEMPTS TO PROVE SPECIES SPE CIFIC CONTRIBUTIONS FOR 7(6 ARE HAMPERED BY THE LACK OF SUITABLE WOOD CHUCK HEPATOMA CELL LINES AND CLONED TRANSCRIPTION FACTORS PG2.! ENCAPSIDATION AND REVERSE TRANSCRIPTION DEPEND ON THE SPECIFIC INTERACTION BETWEEN THE HEPADNAVIRAL 24 AND A STEM LOOP STRUCTURE ¡ ON
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THE PREGENOMIC 2.! 4HIS INTERACTION IS STRICTLY DEPENDENT ON CELLULAR CHAPERONES ;= HOWEVER THERE IS NO KNOWN REQUIREMENT FOR SPECIES SPECIFIC CHAPERONES WHICH IS NOT THAT SURPRISING GIVEN THEIR EXTREME CONSERVATION THROUGHOUT ALL KINGDOMS .EWLY FORMED MATURE 2# $.! CONTAINING NUCLEOCAPSIDS CAN EITHER RECYCLE THE GENOME TO THE NUCLEUS FOR CCC$.! AMPLIFICATION OR INTERACT WITH THE ENVELOPE PROTEINS BUD INTO THE %2 OR A LATER COMPARTMENT OF THE SECRETORY PATHWAY AND BE SECRETED AS ENVELOPED VIRIONS .EW DATA SUGGEST THE INVOLVEMENT OF THE MACHINERY INCLUDING %3#24 THAT GENERATES MULTIVE SICULAR BODIES -6"S UNEXPECTEDLY IN A DISTINCT FASHION REGARDING VIRIONS VERSUS SUBVIRAL PARTICLES ; = !GAIN A ROLE FOR SPECIES SPECIFIC FACTORS IS UNLIKELY BECAUSE $("6 PRODUCED IN TRANSFECTED HUMAN HEPATOMA CELL LINES IS INFECTIOUS IN DUCKS ;n= HOWEVER IN VIVO INFECTION WITH $("6 IS HIGHLY EFFICIENT ;= HENCE EVEN A DRASTIC REDUCTION IN THE EFFICIENCY OF VIRION PRODUCTION BETWEEN AVIAN AND MAMMALIAN CELLS COULD HAVE GONE UNDETECTED
%XPERIMENTALLY ASSESSING VIRAL HOST RANGE 4HERE ARE SEVERAL APPROACHES FOR EXPLORING VIRAL HOST RANGE EACH WITH ITS OWN BENEFITS AND LIMITATIONS /NE IS TO SCREEN DIFFERENT ANIMAL SPECIES FOR THE PRESENCE OF A COMMON OR RELATED VIRUS CHANCES FOR SUCCESS ARE SOME TIMES INCREASED IF THE VIRUS CAUSES A TYPICAL PATHOLOGY AS IS THE CASE FOR SOME ; = THOUGH NOT ALL HEPADNAVIRUSES (OWEVER GIVEN THE LIMITED RANGE OF KNOWN HEPADNAVIRUS HOSTS SPECIMEN COLLECTION IS NOT TRIVIAL AND CERTAINLY CANNOT BE COMPREHENSIVE HENCE SOME OR MANY POTENTIAL HOST SPECIES MAY BE MISSED ! SECOND APPROACH IS EXPERIMENTAL TRANSMISSION OF A NATURAL VIRUS INTO A NEW HOST THIS MAY BE EXTENDED TO VIRUSES THAT HAVE GENETICALLY BEEN MODIFIED IN A DEFINED WAY YET AGAIN ETHICAL AND OTHER CONSTRAINTS APPLY FOR SPECIES THAT ARE NOT COMMONLY USED AS EXPERIMENTAL ANIMALS &URTHERMORE EVEN IF A SPECIES IS PRINCIPALLY SUSCEPTIBLE INFECTION MAY BE DIFFICULT TO DETECT IF INNATE AND ADAPTIVE IMMUNE RESPONSES LIMIT REPLICATION TO LOW LEVELS OR SHORT PERIODS OF TIME &OR INSTANCE INFECTION OF WEEK OLD VERSUS DAY OLD DUCKLINGS WITH $("6 LEADS TO THE EXTREMELY RAPID WITHIN n DAYS INDUC TION OF NEUTRALISING ANTIBODIES WHICH DRASTICALLY REDUCE VIRAL SPREAD IN THE LIVER AND PREVENT PERSISTENT INFECTION ;= !DAPTIVE IMMUNE RESTRICTIONS CAN BE OVERCOME BY USING CULTURED CELLS OR CELL LINES AS TARGETS &OR HEPADNAVIRUSES HOWEVER ONLY A SINGLE HUMAN HEPATOMA CELL LINE (EPA2' HAS BEEN IDENTIFIED THAT UNDER SPECIALISED CONDITIONS CAN BE INFECTED BY ("6 ; = HENCE THE NEARLY ONLY SOURCE FOR INFECTABLE CULTURED CELLS ARE PRIMARY HEPATOCYTES .OTABLY HOWEVER WE HAVE RECENTLY IDENTIFIED A CHIMERIC $("6 WHICH IS CLEARLY RESTRICTED IN
(EPADNAVIRUS HOST RANGE
CULTURED HEPATOCYTES YET IN VIVO REPLICATES AS WELL AS WILD TYPE $("6 + $ALLMEIER AND - .ASSAL SEE BELOW (ENCE IN VITRO AND IN VIVO INFECTION MAY LEAD TO DIFFERENT CONCLUSIONS ON VIRAL HOST RANGE
.ATURAL HEPADNAVIRUS HOSTS 3HORTLY AFTER HUMAN ("6 GENETICALLY RELATED YET DISTINCT VIRUSES HAVE BEEN FOUND IN SEVERAL MAMMALS ORTHOHEPADNAVIRUSES AND IN SELECTED BIRD SPECIES AVIHEPADNAVIRUSES 4HOUGH A SINGLE CLONED VIRUS GENOME MAY NOT ALWAYS REPRESENT AN INFECTIOUS CLONE ;= A WILD CAUGHT ANIMAL FROM WHICH THE CORRESPONDING VIRUS HAS BEEN ISOLATED IS A STRONG CANDIDATE FOR BEING A GENUINE HOST THIS IS LESS CERTAIN FOR VIRUSES FROM CAPTIVE INDI VIDUALS ;= YET IT INDICATES AT ANY RATE THAT THE VIRUS CAN USE THAT SPECIES AS A HOST "ASED ON THIS CRITERION CURRENTLY RECOGNISED NATURAL ORTHOHEPADNAVIRUS HOSTS ARE HUMANS AND HOMINOID PRIMATES CHIMP0AN TROGLODYTES GORILLA 'ORILLA GORILLA ORANGUTAN0ONGO PYGMAEUS GIBBONS(YLOBATIDAE ;= ONE .EW 7ORLD MONKEY WOOLLY MONKEY,AGOTHRIX LAGOTRICHA ; = AND SOME RODENTS NAMELY WOODCHUCK -ARMOTA MONAX ;= #ALIFORNIA GROUND SQUIRREL 3PERMOPHILUS BEECHEYI ;= 2ICHARDSONS GROUND SQUIRREL 3PERMOPHILUS RICHARDSONI ;= AND ARCTIC GROUND SQUIRREL 3PERMOPHILUS PARRYI ;= n BUT NOT MICE OR RATS ! LARGE GROUP OF NATURAL HOSTS FOR AVIAN HEPADNAVIRUSES HAVE BEEN FOUND IN THE ORDER !NSERIFORMES WATERFOWL BUT NOT 'ALLIFORMES LAND FOWL IE 0EKIN DUCKS !NAS PLATYRHYNCHOS VAR DOMESTICA ;= AND THEIR WILD MALLARD ANCESTORS OTHER !NATINAE DUCK RELATED BIRDS ;= FROM THE GENUS !NAS 0UNA TEAL! PUNA #HILOE WIGEON! SIBILATRIX AS WELL AS OTHER GENERA SUCH !IX -ANDARIN DUCK!IX GALERICULATA .EOCHEN /RINOCO GOOSE. JUBATA #HLOEPHAGA !SHY HEADED SHELDGOOSE# POLIOCEPHALA AND !NSERINAE GOOSE RELATED BIRDS INCLUDING SNOW GEESE !NSER CAE RULESCENS ;= AND 2OSS GEESE !NSER ROSSII 'EN"ANK !CCESSION NO - $ISTINCT HEPADNAVIRUSES HAVE BEEN FOUND IN TWO FAMILIES OF THE ORDER #ICONIIFORMES NAMELY STORKS #ICONIIDAE SPECIFICALLY THE WHITE STORK#ICONIA CICONIA ;= AND HERONS !RDEIDAE SPECIFICALLY THE GREY HERON!RDEA CINEREA ;= GREAT WHITE HERON!RDEA ALBA GREAT BLUE HERON !RDEA HERODIAS AND 7UERDEMANNS HERON A HYBRID BETWEEN ! ALBA AND ! HERODIAS ;= AND FINALLY IN CRANES ;= ORDER 'RUIFORMES SPECIFICALLY THE CROWNED CRANE"ALEARICA PAVONIA AND DEMOISELLE CRANE'RUS VIRGO SYN ONYM !NTHROPOIDES VIRGO "ECAUSE NEGATIVE RESULTS ARE USUALLY NOT PUBLISHED IT IS UNKNOWN HOW MANY OTHER SPECIES HAVE BEEN TESTED 'IVEN THE LIMITED CHOICES OF ESTAB LISHED HOSTS ONLY THE 0EKIN DUCK ;= AND TO SOME EXTENT THE WOODCHUCK ;= HAVE BEEN DEVELOPED INTO FEASIBLE ANIMAL MODELS FOR HEPADNAVIRUS INFECTION
+AI $ALLMEIER AND -ICHAEL .ASSAL
&IGURE 0HYLOGENY OF ORTHOHEPADNAVIRUSES ! 5NROOTED FULL LENGTH GENOME BASED TREE &OR THE ANIMAL VIRUSES THE HOST SPECIES FROM WHICH THE VIRUSES WERE ISOLATED ARE INDICATED (UMAN ISOLATES ARE DESIGNATED ("6 PLUS THE CORRESPONDING GENOTYPE WHERE APPLICABLE SEQUENCES FROM TWO DISTINCT SUBGENOTYPES WERE USED .ODES INDICATE COMMON ANCESTORS THE LENGTHS OF THE CONNECTIONS ARE PROPORTIONAL TO SEQUENCE DISTANCES .OTE THAT DIVERGENCE AMONG INDIVIDUAL HUMAN ISOLATES IS LARGER THAN BETWEEN HUMAN AND APE VIRUSES " 'ENOME AND 0RE3 DOMAIN AMINO ACID IDENTITIES BETWEEN ORTHOHEPADNAVIRUSES .UMBERS INDICATE PERCENT IDENTITIES FOR THE NUCLEOTIDE SEQUENCES OF THE GENOMES COLUMNS LABELED GEN AND PROTEIN SEQUENCES OF ONLY THE 0RE30RE3 REGIONS PR3 .OTE THE MUCH LOWER IDENTITY SCORES FOR THE 0RE3 PROTEINS VERSUS THE GENOMES DEMONSTRATING THE HIGH DIVERSITY OF 0RE3 BETWEEN DIFFERENT VIRUSES
0HYLOGENETIC RELATIONSHIPS BETWEEN HEPADNAVIRUSES AND BETWEEN THEIR RECOGNISED NATURAL HOST SPECIES 0HYLOGENETIC DISTANCES BETWEEN DIFFERENT HOSTS ARE LIKELY REFLECTED IN COR RESPONDING SEQUENCE DIFFERENCES BETWEEN THEIR RESPECTIVE VIRUSES 4HE SMALL GENOME SIZE OF HEPADNAVIRUSES MAKES DERIVATION OF SEQUENCE BASED PHYLO GENIES RATHER STRAIGHTFORWARD HOWEVER THIS IS NOT THE CASE FOR DETERMINING QUANTITATIVE DISTANCES BETWEEN HOSTS $UE TO THE MEDICAL IMPORTANCE OF ("6 THOUSANDS OF GENOME SEQUENCES HAVE MEANWHILE BEEN DETERMINED THEY CAN BE CLASSIFIED INTO EIGHT DISTINCT GENOTYPES ! TO ( ! GENOTYPE BY DEFINITION MUST DIFFER IN SEQUENCE FROM ANOTHER BY AT LEAST SUBGENOTYPES WITH ONE GENOTYPE BY AT LEAST ;= )N THE UNROOTED PHYLOGENETIC TREE SHOWN IN &IGURE ! TWO REPRESENTATIVES OF EACH OF THE EIGHT ("6 GENOTYPES ONE FROM EACH SUBGENOTYPE IF APPLI CABLE HAVE BEEN COMBINED WITH THE FULL GENOME SEQUENCES OF THE KNOWN ANIMAL ORTHOHEPDNAVIRUSES &IGURE ! SHOWS A CORRESPONDING ANALYSIS FOR THE AVIHEPADNAVIRUSES HOWEVER BASED ON THE PROTEIN SEQUENCES OF ONLY THE 0RE3 REGIONS WITH THREE REPRESENTATIVES OF THE %ASTERN AND THREE OF THE 7ESTERN CLADE OF $("6 INCLUDING THE COMMONLY USED LABORATORY STRAIN $("6 !NOTHER PARAMETER THAT ILLUSTRATES RELATEDNESS IS @PERCENT IDENTI
(EPADNAVIRUS HOST RANGE
&IGURE 0HYLOGENY OF AVIHEPADNAVIRUSES ! 5NROOTED TREE BASED ON 0RE3 DOMAIN PROTEIN SEQUENCES 'ENERA ARE GIVEN IN ITALICS EXAMPLES FOR SPECIFIC SPECIES FROM WHICH THE VIRUSES WERE ISOLATED ARE INDICATED BELOW &OR THE CRANES THE FAMILY DESIGNATION 'RUIDAE IS USED TO AVOID CONFUSION WITH SPECIES DESIGNATION "ALEARICA FOR THE CROWNED CRANE !NAS .EOCHEN #HLOEPHAGA AND ALSO !IX ALL BELONG TO THE FAMILY !NATIDAE .OTE THE NEAR IDENTITY OF THE VIRUSES FROM THE -ANDARIN DUCK AND 2OSSS GOOSE AND THE CLOSE RELATION OF THESE VIRUSES WITH THE CRANE VIRUSES " 'ENOME AND 0RE3 DOMAIN AMINO ACID IDENTITIES BETWEEN AVIHEPADNAVI RUSES $IVERGENCE BETWEEN ISOLATES FROM DIFFERENT GENERA OF THE !NATINAE AND EVEN FROM THE SNOW GOOSE IS NOT LARGER THAN THAT AMONG ISOLATES FROM WITHIN THE GENUS !NAS BY CONTRAST THE -ANDARIN DUCK2OSSS GOOSE ISOLATES ARE EVEN LESS RELATED TO THE DUCK ISOLATES THAN THE CRANE VIRUSES AND THEIR DIVERGENCE FROM THE OTHER DUCK ISOLATES IS HIGHER THAN THAT BETWEEN HERON VERSUS THE STORK ISOLATES
TY WHICH AFTER ALIGNMENT INDICATES THE PROPORTION OF IDENTICAL NUCLEOTIDES OR AMINO ACIDS AT A GIVEN POSITION &IGS " AND " 4HE ORTHOHEPADNAVIRUSES CLUSTER IN THREE GROUPS HOMINOID IE HOMI NID PLUS GIBBON PRIMATE ("6S 7-("6 IE .EW 7ORLD MONKEY VIRUS AND GROUND SQUIRREL '3(6 PLUS WOODCHUCK 7(6 IE RODENT VIRUSES &OR THE AVIHEPADNAVIRUSES THREE MAJOR CLADES ARE SEEN ONE ENCOMPASSING THE DUCK AND MOST GOOSE VIRUSES ONE FOR THE 2OSSS GOOSE-ANDARIN DUCK VIRUSES WHICH CLUSTERS WITH THE CRANE VIRUSES AND ONE COMPRISING STORK AND HERON VIRUSES #OMPARISON OF THE GENOME SEQUENCES GIVES SIMILAR RESULTS EXCEPT THAT THE 2OSSS GOOSE-ANDARIN DUCK AND CRANE ("6S ARE NOT PRE DICTED TO HAVE A COMMON ANCESTOR HOWEVER THEY REMAIN ABOUT EQUIDISTANT FROM THE DUCK ISOLATES NOT SHOWN 4HESE DISTANCES ARE REFLECTED IN THE PERCENT IDENTITY VALUES &IGS " AND " WHICH FOR THE ENTIRE GENOMES ARE MINIMALLY ABOUT WITHIN THE HOMINOID GROUP ABOUT FOR HOMINOID VERSUS 7-("6 FOR HOMINOID VERSUS RODENT AND ABOUT FOR HOMI NOID VERSUS AVIAN MINIMAL IDENTITIES AMONG THE RODENT VIRUSES ARE AMONG THE AVIAN VIRUSES n FOR DUCK GOOSE AND CRANE VIRUSES ABOUT FOR THESE VERSUS STORK AND HERON AND ABOUT BETWEEN STORK AND HERON VIRUSES 0ERCENTAGE VALUES ARE SIMILAR FOR THE 3 PROTEINS BUT SIGNIFI CANTLY LOWER FOR THE 0RE3 REGIONS THIS MUCH HIGHER THAN AVERAGE DIVERSITY
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IN 0RE3 IS ONE OF THE ARGUMENTS FOR ITS ROLE IN DETERMINING HOST RANGE SEE BELOW 0RE3 IDENTITY SCORES DROP TO WITHIN THE HOMINOID GROUP TO ABOUT FOR HOMINOID VERSUS 7-("6 AND TO BELOW FOR HOMINOID VERSUS RODENT VIRUSES AMONG THE RODENT VIRUSES MINIMAL IDENTITIES ARE AROUND )DENTITY BETWEEN ORTHO AND AVIHEPADNAVIRUS 0RE3 REGIONS IS ONLY AROUND &OR THE AVIAN VIRUSES 0RE3 PERCENT IDENTITY SCORES ARE AROUND WITHIN THE DUCK AND GOOSE VIRUS GROUP AGAIN A HIGHER VALUE IS OBSERVED FOR THESE VERSUS CRANE VIRUSES n BUT A SIGNIFICANTLY LOWER FOR ALL FORMER VIRUSES VERSUS HERON AND STORK VIRUSES n 4HERE ARE SEVERAL NOTEWORTHY POINTS !LL HOMINOID APE VIRUSES CLUSTER IN BETWEEN THE HUMAN ISOLATES IE EVEN THE GIBBON VIRUSES ARE AS CLOSE TO THE HUMAN VIRUSES AS THESE ARE AMONG EACH OTHER 7-("6 IS THE ONLY TRUE OUTLIER 7HILE AN INITIAL CAVEAT WAS THAT THOSE ANIMALS MIGHT HAVE ACQUIRED THEIR VIRUSES FROM HUMANS NEWER SEQUENCES WERE DERIVED FROM WILD CAUGHT ANIMALS THAT BONA FIDE HAD NOT BEEN IN CLOSE CONTACT WITH HUMANS (ENCE THESE VIRUSES APPEAR TO BE TRUE APE VIRUSES ;= 4HERE IS ALSO EVIDENCE FOR RECOMBINATION BETWEEN CHIMP AND NOTABLY GIBBON AND HUMAN ("6S ;= SUGGESTING THAT PRIMATE AND HUMAN ("6S CAN SHARE HOSTS (ENCE ("6 IS CERTAINLY NOT A SPECIES SPECIFIC VIRUS ! SIMILAR TREND IS SEEN AMONG THE AVIHEPADNAVIRUSES WHERE %ASTERN AND 7ESTERN $("6 ISOLATES ARE AS DIFFERENT FROM EACH OTHER AS THEY ARE FROM VARIOUS OTHER DUCK AND GOOSE VIRUSES EXCEPT FOR THE 2OSSS GOOSE-ANDARIN DUCK ISOLATES .OTABLY THE CRANE VIRUS IS NOT FURTHER APART FROM THE DUCK VIRUS CLADE THAN THE 2OSSS GOOSE-ANDARIN DUCK VIRUSES 4HUS #("6 IS MUCH MORE A @$("6 LIKE VIRUS THAN THE HERON AND STORK VIRUSES
(OST PHYLOGENIES %STABLISHING PHYLOGENETIC RELATIONSHIPS BETWEEN HOST SPECIES IS MUCH MORE COMPLEX AND TRADITIONAL MORPHOLOGY BASED VERSUS PARTIAL SEQUENCE BASED ANALYSES FREQUENTLY GIVE DISCORDANT RESULTS 1UANTITATIVE MOLECULAR RELATIONS BETWEEN NATURAL HEPADNAVIRUS HOSTS ARE FIRMLY ESTABLISHED ONLY FOR HUMANS AND CHIMPS ABOUT OVERALL DIVERSITY ON THE GENOME LEVEL ;= THE ABOUT DIVERSITY BETWEEN THE HUMAN AND THE 2HESUS MACAQUE GENOME ;= GIVE AT LEAST AN INDICATION OF THE GENETIC DISTANCES BETWEEN PRIMATES THOUGH THESE MONKEYS ARE NOT HEPADNAVIRUS HOSTS &OR ALL OTHER HEPADNAVIRUS HOSTS CLASSIFICATION STILL HAS TO RELY ON A COMBI NATION OF MORPHOLOGICAL TRAITS THE SEQUENCES OF MITOCHONDRIAL AND SELECTED NUCLEAR GENES PLUS FOR A TIME SCALE FOSSILE RECORDS (ENCE THE PHYLOGENETIC TREES SHOWN IN &IGURES AND SHOULD BE REGARDED AS AN ONLY APPROXIMATE INDICATOR OF RELATIVE KINSHIP BETWEEN SPECIES 4HIS IS PARTICULARLY TRUE FOR BIRD PHYLOGENY 7HILE TRADITIONAL APPROACHES ARE STILL CONTINUED ;= CROSS HYBRIDISATION STUDIES REVOLUTIONISED THE PREVAILING GENEALOGIES ;= BUT NOW
(EPADNAVIRUS HOST RANGE
&IGURE 0HYLOGENETIC TREE OF MAMMALS WITH RESPECT TO RECOGNISED ORTHOHEPADNAVIRUS HOST SPECIES 4HE TREE IS BASED ON THE CLASSIFICATION USED BY THE .#") TAXONOMY DATA BASE HTTP WWWNCBINLMNIHGOV4AXONOMY"ROWSER /NLY THOSE BRANCHES LEADING TO HEPADNAVIRUS INFECTABLE HOST GENERA BOLD FACE ARE EXPLICITLY INDICATED THE LENGTHS OF THE BRANCHES ARE NOT PROPORTIONAL TO A SPECIFIC TIME SCALE .OTE THAT ALL KNOWN RODENT HEPADNAVIRUS HOSTS BELONG TO THE TRIBE 8ERINI
ARE CONSIDERED MORE CAUTIOUSLY AS MORE DIRECT SEQUENCING DATA COME IN EVEN THEN THE CHOICE OF $.! MITOCHONDRIAL VERSUS NUCLEAR AND OF REPRE SENTATIVE SPECIES CAN AFFECT THE RESULTS 4HERE IS NO DOUBT ABOUT A CLOSE RELATION AMONG THE (OMINIDAE 'REAT !PES HOWEVER THE (YLOBATIDAE ,ESSER !PES GIBBONS ARE CLEARLY DIS TINCT YET THE ("6S ISOLATED FROM GIBBONS CLUSTER WITHIN THE HUMAN ISOLATES ABOVE AND ;= "Y CONTRAST BABOONS BELONGING TO THE /LD 7ORLD MON KEYS ARE NOT ;= OR EXTREMELY INEFFICIENTLY ;= SUSCEPTIBLE TO ("6 INFEC TION (ENCE HUMAN ("6 CAN NOT INFECT ALL PRIMATES YET ALL HOMINOID APES 7-("6 REPLICATING TO HIGH LEVELS VGEML IN WOOLLY MONKEYS LED TO ONLY INEFFICIENT INFECTION OF THE SUPPOSEDLY CLOSELY RELATED BLACK HANDED SPIDER MONKEY !TELES GEOFFREYI ;= (ENCE IN THIS SENSE 7-("6 APPEARS TO HAVE A TRULY NARROW HOST RANGE (OWEVER THE PICTURE IS DIFFERENT WITH PRIMARY HEPATOCYTES IN CULTURE SEE BELOW !LL OTHER KNOWN MAMMALIAN ("6 HOSTS BELONG TO THE RODENTS COM PRISING ABOUT SPECIES WITH THE LAGOMORPHS RABBITS AND HARES AS THEIR APPARENTLY CLOSEST RELATIVES 4HE RODENTIA FORM THREE MAJOR CLADES MOUSE RELATED GUINEAPIG GUNDI RELATED AND SQUIRREL DORMOUSE RELATED 3CIURIDAE 7ITHIN THE SUBFAMILY 8ERINAE BOTH THE GENERA -ARMOTA MAR MOTS INCLUDING WOODCHUCKS AND 3PERMOPHILUS GROUNDSQUIRRELS ROCK SQUIRRELS BELONG TO THE SAME TRIBE -ARMOTINI /THER GENERA FROM THIS TRIBE ARE CHIPMUNKS #HINESE ROCK SQUIRRELS ANTELOPE SQUIRRELS AND PRAIRIE DOGS ; = /NE SPECIAL CASE ARE TUPAIAS COMMONLY KNOWN AS TREE SHREWS 4HERE IS NO EVIDENCE THAT THEY ARE A NATURAL HOST FOR A HEPADNAVIRUS YET THEY
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&IGURE 0HYLOGENETIC TREE OF BIRDS WITH RESPECT TO RECOGNISED AVIHEPADNAVIRUS HOST SPECIES 4HE TREE IS A COMPOSITE BASED ON THE GENERAL !VES CLASSIFICATION BY #RACRAFT ;= FOR THE .EOAVES AND A MITOCHONDRIAL $.! BASED PHYLOGENY ;= FOR THE !NSERIFORMES .OTE THE CLOSE RELATION BETWEEN THE GENERA !IX AND #AIRINA !S IN &IGURE THE LENGTHS OF THE BRANCHES DO NOT IMPLY A SPECIFIC TIME SCALE
MAY BE INFECTABLE AT A VERY LOW LEVEL BY HUMAN ("6 IN VIVO ;= AND ISO LATED TUPAIA HEPATOCYTES ARE DEFINITELY INFECTABLE WITH ("6 AND 7-("6 ; = BUT NOT 7(6 4HE EVOLUTIONARY ASPECTS OF THIS REMAIN OBSCURE BECAUSE TUPAIAS ARE NO MORE CONSIDERED PRIMATES &IG BUT AS A DISTINCT SISTER TAXON 3CANDENTIA TO THE PRIMATES FLYING LEMURS $ERMOPTERA AND THE RODENTS PLUS LAGOMORPHS 'LIRES ;= !VIAN PHYLOGENY IS HIGHLY CONTROVERSIAL BUT SOME BASIC CONCEPTS APPEAR TO BE GENERALLY ACCEPTED EG ;= FOR ADDITIONAL INFORMATION SEE HTTP ANIMALDIVERSITYUMMZUMICHEDU !CCORDINGLY THERE ARE TWO SUBCLASSES PALEOGNATHS OSTRICHES EMUS KIWIS AND NEOGNATHS &IG THESE ARE DIVIDED INTO TWO LARGE INFRACLASSES 'ALLOANSERAE CHICKEN PLUS GOOSE DUCK RELATED AND .EOAVES WHICH COMPRISE ALL OTHER BIRDS INCLUDING HEPAD NAVIRUS HOSTS SUCH AS HERONS STORKS AND CRANES FOR A RECENT PHYLOGENETIC ANALYSIS OF CRANE RELATED BIRDS SEE ;= 'ALLOANSERAE ARE DIVIDED INTO THE ORDERS 'ALLIFORMES LANDFOWL AND !NSERIFORMES WATERFOWL WHICH COM PRISE THE FAMILIES !NHIMIDAE SCREAMERS !NSERANATIDAE WITH THE MAGPIE GOOSE AS THEIR ONLY REPRESENTATIVE AND !NATIDAE THESE ARE DIVIDED INTO THE SUBCLASSES !NATINAE DUCKS AND !NSERINAE GEESE AND SWANS 4HE PHY LOGENY OF THE INDIVIDUAL GENERA WITHIN THE !NATIDAE AS SHOWN IN &IGURE IS BASED ON MITOCHONDRIAL $.! ANALYSES ;= THAT OF THE .EOAVES BRANCH SEE ALSO HTTPTOLWEBORG.EORNITHES ON REFERENCE ;=
(EPADNAVIRUS HOST RANGE
.ONE OF THE KNOWN AVIHEPADNAVIRUS HOSTS BELONG TO THE 'ALLIFORMES BUT MANY TO THE !NSERIFORMES 0ERHAPS MOST STRIKING IS THE WIDE DISTRIBUTION OF INFECTABLE GENERA AMONG THE !NATIDAE RANGING FROM !NAS EG 0EKIN DUCK ! PLATYRHYNCHOS V DOMESTICA PUNA TEAL! PUNA #HILOE WIGEON! SIBILA TRIX AND !IX EG -ANDARIN DUCK! GALERICULATA TO THE APPARENTLY DISTANT #HLOEPHAGA EG !SHY HEADED SHELDGOOSE# POLIOCEPHALA AND BEYOND TO THE !NSERINAE EG SNOW GOOSE! CAERULESCENS 2OSSS GOOSE! ROSSII -OST SURPRISINGLY THE GENUS CLOSEST TO !IX IS #AIRINA YET #AIRINA MOSCHATA THE -USCOVY DUCK IS NOT INFECTABLE IN VIVO BY $("6 ; = 2EGARDING THE OTHER BIRD ("6 HOSTS CLASSICAL AND MOLECULAR PHYLOG ENIES AGREE THAT STORKS AND HERONS BOTH #ICONIIFORMES ARE RELATIVELY CLOSE TO EACH OTHER ; = BUT NOT TO CRANES ;= 'RUIFORMES 4HIS IS CONSIS TENT WITH THE CLOSER RELATION BETWEEN THE HERON AND STORK VERSUS THE CRANE VIRUSES )T SHOULD BE NOTED THOUGH THAT EVEN STORKS AND HERONS HAVE VERY LONG INDEPENDENT HISTORIES ESTIMATED SEPARATION TIME ABOUT -YR AGO ;= SPANNING ALMOST THE SAME PERIOD OF TIME AS THAT LEADING TO CHICKEN AND DUCKS AFTER SEPARATION FROM THEIR LAST COMMON ANCESTORS ABOUT -YR ;n= FOR COMPARISON DUCKS AND GEESE ARE THOUGHT TO HAVE SEPA RATED ABOUT -YR RATS AND MICE ABOUT -YR AGO ;= $UE TO ITS ORIGIN FROM CRANES AND ABILITY TO INFECT HEPATOCYTES FROM THE UNDOUBTEDLY DISTANT 0EKIN DUCK CRANE ("6 HAS BEEN PROPOSED TO BE THE FIRST AND UNEXPECTED EXAMPLE OF A HEPADNAVIRUS WITH A RATHER BROAD HOST RANGE ;= (OWEVER GIVEN THE CLOSE RELATION OF THE CRANE VIRUS ISOLATES TO THE 2OSS GOOSE-ANDARIN ISOLATES AND THE ABILITY OF THE LATTER TO EVEN INFECT 0EKIN DUCKS IN VIVO SEE BELOW THIS RESULT IS MUCH LESS SURPRISING 2ATHER THE QUESTION IS WHY THE CRANE AND 2OSSS GOOSE-ANDARIN DUCK VIRUSES ARE SO CLOSELY RELATED &IG -ORE GENERALLY THERE IS NO EVIDENCE THAT THE 2OSSS GOOSE-ANDARIN DUCK VIRUS OR $("6 HAVE A LESS BROAD HOST RANGE THAN CRANE ("6 AS LONG NO EXPERIMENTS PERTAINING TO THIS QUESTION HAVE BEEN PERFORMED
#ROSS SPECIES TRANSMISSION OF @NATURAL ("6S IN VIVO /NE MAIN BENEFIT OF EXPERIMENTAL TRANSMISSION IS THE ABILITY TO USE A PRE CHARACTERISED AND POSSIBLY CLONAL VIRUS INOCULUM WHEN SCREENING FOR NATU RAL INFECTIONS THE ORIGINAL SOURCE OF VIRUS IS UNCERTAIN PARTICULARLY FOR CAP TIVE ANIMALS THAT ARE KEPT IN CLOSE TO OTHER SPECIES (ENCE THE NEAR IDENTITY BETWEEN THE -ANDARIN DUCK VIRUS ISOLATES AND THE 2OSSS GOOSE ISOLATE MAY BE DUE TO THAT 2OSSS GOOSE HAVING CONTRACTED A HEPADNAVIRUS FROM OTHER BIRDS HELD IN THE SAME FACILITY ;= THIS LIMITATION PROBABLY HOLDS FOR MOST SPECIMENS FROM CAPTIVE ANIMALS #ROSS SPECIES TRANSMISSION OF NATURAL HEPADNAVIRUSES IF SUCCESSFUL GIVES CLEAR HINTS ON HOST RANGE NEGATIVE RESULTS HOWEVER CANNOT BE CONSIDERED ABSOLUTE %SSENTIALLY NONE OF THE NATURAL HOSTS AND THEIR RELATIVES IS AVAIL
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ABLE IN INBRED FORM AND FEW CAN BE KEPT UNDER STANDARDISED CONDITIONS (ENCE DIFFERENCES BETWEEN STRAINS OR INDIVIDUALS COULD CONTRIBUTE TO FAILURE OF TRANSMISSION 3IMILARLY NEWBORN ANIMALS WHICH DUE TO THEIR IMMATURE IMMUNE SYSTEM ARE MORE LIKELY TO BE INFECTABLE THAN ADULTS ARE FREQUENTLY NOT AVAILABLE 4HIS HOLDS PARTICULARLY FOR PRIMATES MANY OF WHICH INCLUDING WOOLLY MONKEYS ARE ENDANGERED %VEN FOR THE AVIHEPADNAVIRUSES FEW OTHER SPECIES THAN 0EKIN DUCKS ARE AVAILABLE FOR ROUTINE EXPERIMENTS (ENCE WHILE DIFFERENT AVIHEPADNAVIRUSES HAVE BEEN TESTED IN 0EKIN DUCKS THE HOST RANGE OF $("6 ITSELF HAS NOT EXTENSIVELY BEEN EXPLORED 4HE FIRST CROSS SPECIES TRANSMISSIONS OF A CLONAL ("6 ISOLATE BY INTRA HEPATIC INJECTION WITH CLONED VIRUS $.! RATHER THAN INFECTION WERE PERFORMED IN CHIMPANZEES AND PROVED THAT THIS MOLECULAR CLONE OF ("6 WAS PRINCIPALLY INFECTIOUS AND COULD USE CHIMPS AS HOST ; = SIMILAR EXPERIMENTS WERE PERFORMED WITH ANIMAL ("6S ; = 0ROBABLY THIS IS THE ONLY TECHNIQUE ALLOWING ESTABLISHMENT OF INFECTION BY A SINGLE MOLECULAR CLONE HOWEVER TRANSMISSION IS AS WELL ACHIEVABLE BY INTRAPERITONEAL IP OR INTRAVENEOUS IV INJECTION OF VIRIONS CONTAINED IN SERUM FROM INFECTED ANIMALS OR SUPERNATANTS FROM TRANSFECTED CELLS !N ALTERNATIVE TEST SYSTEM ARE PRIMARY HEPATOCYTES FROM DUCKS ;= HUMANS ; = TUPAIAS ;= AND AT SELECTED FACILITIES FROM SOME PRIMATES ;= AND RECENTLY THE HUMAN HEPATOMA CELL LINE (EPA2' ; = (OWEVER IN VIVO AND IN VITRO ASSAYS CAN GIVE CONTRADICTORY RESULTS SEE BELOW !N ADDITIONAL SYSTEM LIKELY TO REPRODUCE MANY THOUGH POSSIBLY NOT ALL FEATURES OF ORTHOHEPADNAVIRUS INFECTION IS THE USE OF HEPATITIS DELTA VIRUS ($6 ($6 IS AN 2.! VIRUS THAT REPLICATES AUTONOMOUSLY BUT FOR INFECTION AND SPREAD DEPENDS ON THE ("6 ENVELOPE PROTEINS ;= 4HOUGH IN CONTRAST TO ("6 0RE3 IS NOT REQUIRED FOR ENVELOPMENT OF ($6 RIBONUCLEOPROTEIN COMPLEXES IT IS ESSENTIAL FOR INFECTIVITY "ECAUSE ($6 REPLICATES TO VERY HIGH COPY NUMBERS IN THE RANGE OF GENOMES CELL INFECTION CAN VERY SENSITIVELY BE MONITORED 4HIS SYSTEM WAS THE FIRST TO RAISE DOUBTS ON AN ESSENTIAL ROLE FOR THE 4,- MOTIFS ;= AND SIMILAR NEGATIVE DATA HAVE BEEN FORWARDED FOR ("6 INFECTION OF HUMAN HEPATO CYTES ;= AND (EPA2' CELLS ;= )MPORTANTLY ($6 CAN BE ENVELOPED WITH SURFACE PROTEINS FROM DIFFERENT ORTHOHEPADNAVIRUSES ALLOWING TO ASSESS THEIR IMPACT ON INFECTION OF PRIMARY HEPATOCYTES FROM DIFFERENT HOSTS IN PARTICULAR PRIMATES ; = 4ABLES TO SUMMARISE PUBLISHED DATA ON CROSS SPECIES TRANSMISSION EXPERIMENTS WITH PRIMATE RODENT AND BIRD ("6S INDICATING THE INOCULUM VIRUS THE RECIPIENT SPECIES AND THE OUTCOME OF THE EXPERIMENTS IN VIVO OR WITH CULTURED HEPATOCYTES !N ANECDOTAL REPORT ON ("6 TRANSMISSION INTO TURTLES ;= IS NOT INCORPORATED .EITHER FOR THE MAMMALIAN NOR FOR THE BIRD ("6S DOES A UNIFORM PIC TURE EMERGE FROM THESE DATA ("6 LIKE VIRUSES CAN CERTAINLY INFECT CHIM PANZEES AND THE NATURAL OCCURRENCE OF HIGHLY SIMILAR VIRUSES IN HOMINID PRIMATES INDICATES THAT THEY CAN INFECT A SPECTRUM OF RELATED SPECIES 4AB
(EPADNAVIRUS HOST RANGE
4ABLE )N VIVO AND IN VITRO INFECTIVITY OF ("6 AND 7OOLLY MONKEY ("6 7-("6 FOR OTHER PRIMATES TUPAIAS AND THEIR ISOLATED HEPATOCYTES
A3YSTEMATIC NAMES ARE GIVEN ONLY AT FIRST OCCURRENCE OF THE COMMON NAME B)NFECTIVITY SCORES ARE AS FOLLOWS EASILY DETECTABLE VIREMIA AND ANTIGENEMIA VIREMIA AND ANTIGENEMIA CLEARLY DEMONSTRATED THOUGH AT LOW LEVELS n SOME INDIRECT EVIDENCE FOR INFECTION INFEC TION DETECTABLE ONLY IN THE PRESENCE OF POLYETHYLENGLYKOL 0%' AS FACILITATOR n NO DETECTABLE INFECTION C#OMMENTS ON SPECIFIC EXPERIMENTAL SET UP
7-("6 BY CONTRAST APPEARS SPECIALISED FOR WOOLLY MONKEYS BECAUSE TRANSMISSION TO EVEN SPIDER MONKEYS THEIR PRESUMED CLOSEST RELATIVES WAS VERY INEFFICIENT ;= 3IMILARLY '3(6 4AB DID NOT INFECT MICE GUINEA
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4ABLE )N VIVO INFECTIVITY OF GROUND SQUIRREL '3(6 AND 7OODCHUCK HEPATITIS VIRUS 7(6 FOR DIFFERENT RODENT SPECIES
PIGS AND HAMSTERS ;= AND MORE SURPRISINGLY NOT TWO OTHER SQUIRREL SPE CIES GOLDEN MANTLED GROUND SQUIRREL3PERMOPHILUS LATERALIS THIRTEEN LINED GROUND SQUIRREL3PERMOPHILUS TRIDECEMLINEATUS BUT COULD ESTABLISH INFEC TION IN THE MORE DISTANT CHIPMUNK %UTAMIAS SP ;= AND WOODCHUCK ;= CONVERSELY 7(6 WAS NOT INFECTIOUS FOR "EECHEY GROUND SQUIRRELS ;= 4HUS '3(6 APPEARS TO HAVE A BROADER HOST RANGE THAN 7(6 BUT THERE IS CURRENTLY NO RATIONAL EXPLANATION /NE PROBLEM IS CERTAINLY THAT THE TRUE PHYLOGENETIC RELATIONSHIPS BETWEEN THESE SPECIES ARE INSUFFICIENTLY ESTABLISHED .EARLY ALL OF THE AVIHEPADNAVIRUSES ISOLATED FROM !NATIDAE &IG ARE INFECTIOUS 4AB FOR 0EKIN DUCKS IN VIVO AND $("6 IS TRANSMITTABLE TO DOMESTIC GEESE THOUGH NOT CHICKEN ;= AND -USCOVY DUCKS #AIRINA MOSCATA ; = 4HE /RINOCO SHELDGOOSE GENUS .EOCHEN ISOLATE WAS INFECTIOUS FOR 0ARADISE SHELDUCK GENUS 4ADORNA AND 0EKIN DUCK GENUS !NAS AND EVEN THE 2OSS GOOSE VIRUS LIKE -ANDARIN DUCK ISOLATE EFFICIENTLY INFECTED 0EKIN DUCKS ;= CLEARLY DEMONSTRATING CROSS GENERA TRANSMISSION 4HUS MANY OF THESE VIRUSES HAVE AN EXPANDED HOST RANGE (OWEVER THERE IS ALSO AN EXCEPTION IN THAT THE ASHY HEADED SHELDGOOSE ISOLATE THOUGH CLOSELY RELATED TO $("6 &IG DID NOT INFECT 0EKIN DUCKLINGS SIX OUT OF SIX INOCULATED ANIMALS REMAINED NEGATIVE ;= WHETHER THIS RELATES TO A CLONE SPECIFIC PROBLEM THE FULL LENGTH GENOME HAD TO BE RESTORED USING A SEPARATELY AMPLIFIED CORE GENE OR A GENUINE RESTRICTION IS UNCLEAR ,ESS SURPRISINGLY THE HERON VIRUS WAS NOT DETECTABLY INFECTIOUS FOR 0EKIN DUCKS ; = 4HE IN VITRO INFECTION EXPERIMENTS WITH CULTURED HEPATOCYTES GAVE OFTEN THOUGH NOT ALWAYS CONSISTENT RESULTS IN GENERAL IN VITRO INFECTION WAS LESS
(EPADNAVIRUS HOST RANGE
4ABLE )N VIVO AND IN VITRO INFECTIVITY OF NATURAL AVIHEPADNAVIRUSES FOR OTHER BIRD SPECIES AND THEIR HEPATOCYTES
3EE FOOTNOTES TO 4ABLE FOR EXPLANATIONS ND NOT DETERMINED
RESTRICTIVE %XAMPLES INCLUDE THE ABILITY OF BOTH ("6 AND 7-("6 TO INFECT PRIMARY TUPAIA HEPATOCYTES ; = OR THE INFECTIVITY THOUGH AT LOW EFFICIENCY OF THE ASHY HEADED SHELDGOOSE ISOLATE TO INFECT DUCK HEPATOCYTES ;= 4HEY ALSO REVEALED IN SEVERAL CASES THAT THE APPARENT BLOCK TO IN VIVO INFECTION WAS NOT ABSOLUTE -USCOVY DUCK HEPATOCYTES WERE SUSCEPTIBLE TO $("6 INFECTION ;= AND 0EKIN DUCK HEPATOCYTES TO HERON ;= AND STORK VIRUS ;= INFECTION THOUGH ALL AT TO FOLD REDUCED EFFICIENCY 4HE CRANE VIRUS INFECTED 0EKIN DUCK HEPATOCYTES WITH $("6 LIKE EFFICIENCY ;= HOWEVER ITS SEQUENCE IS AS MENTIONED HIGHLY SIMILAR TO THE 2OSSS GOOSE -ANDARIN DUCK ISOLATES THAT ARE ABLE TO INFECT 0EKIN DUCK HEPATOCYTES ;= AND + $ALLMEIER UNPUBLISHED RESULTS AND 0EKIN DUCKS IN VIVO ;= 4HERE ARE HOWEVER ALSO EXAMPLES WHICH ARE NOT EASILY RECONCILED WITH THE IN VIVO DATA ($6 WITH AN ("6 ENVELOPE EFFICIENTLY INFECTED IN THE ABSENCE OF THE FACILITATING AGENT POLYETHYLENGLYKOL 0%' HEPATOCYTES FROM HUMANS
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AND CHIMPS BUT ALSO FROM SPIDER MONKEY YET NOT BABOONS ($6 WITH A 7-("6 ENVELOPE WAS AS EXPECTED POORLY INFECTIOUS FOR HEPATOCYTES FROM HUMANS CHIMPS AND BABOONS BUT THE EFFICIENCY OF SPIDER MONKEY HEPATO CYTE INFECTION WAS NOT HIGHER ;= (ENCE NO SIMPLE UNIFYING CONCEPT ON HEPADNAVIRAL HOST RANGE CAN BE INFERRED FROM THESE DATA
-OLECULAR BASIS OF HEPADNAVIRAL HOST RANGE 4HE GENOME WIDE DISTRIBUTION OF NUCLEOTIDE EXCHANGES BETWEEN ISOLATES IN CROSS SPECIES TRANSMISSION OF NATURAL HEPADNAVIRUSES PREVENTS AN ACCURATE ASSIGNMENT OF INFECTIVITY PHENOTYPES TO SPECIFIC GENES OR GENE PRODUCTS 4HIS PROBLEM CAN BE OVERCOME BY USING ONE CHARACTERISED VIRUS WITH DEFINED MUTATIONS !TTACHMENT AND ENTRY REPRESENT MAJOR BARRIERS FOR SUCCESSFUL HEPAD NAVIRUS INFECTION SEE ABOVE YET THE RESPONSIBLE CELLULAR FACTORS ARE ONLY PARTIALLY KNOWN FOR THE AVIAN ("6S AND NOT AT ALL FOR THE MAMMALIAN ("6S HENCE IDENTIFYING THE HOST RECEPTORS REMAINS ONE OF THE HOLY GRAILS IN HEPATITIS " VIROLOGY &OR THE HUMAN VIRUS MANY DIFFERENT CANDIDATE RECEP TORS HAVE BEEN PROPOSED ;= INCLUDING ANNEXIN 6 )G! RECEPTOR SQUAMOUS CELL CARCINOMA ANTIGEN DIFFERENT FORMS OF THE ASIALOGLYCOPROTEIN RECEP TOR TRANSFERRIN RECEPTOR APOLIPOPROTEIN ( FIBRONECTIN OR MOST RECENTLY LIPOPROTEIN LIPASE AS ONE OF SEVERAL PROTEINS CONTAINING A PEPTIDE MOTIF THAT BINDS TO ("6 0RE3 ;= .ONE HOWEVER CONFERS SUSCEPTIBILITY TO ("6 INFECTION OF CELLS THAT LIKE (UH OR (EP' SUPPORT DOWNSTREAM EVENTS IN THE ("6 REPLICATION CYCLE &OR $("6 A K$A GLYCOPROTEIN GP NOW KNOWN AS CARBOXYPEPTIDASE $ ; = AND P A SUBUNIT OF MITOCHONDRIAL GLYCINE DECARBOXYLASE ; = HAVE BEEN IMPLICATED IN THE EARLY STEPS OF INFECTION YET AGAIN NEITHER OF THE TWO FULFILS ALL CRITERIA FOR A FUNCTIONAL VIRUS RECEPTOR ALSO CARBOXYPEPTIDASE $ IS HIGHLY CONSERVED BETWEEN DIFFERENT BIRD SPECIES AND NOT LIVER SPECIFICALLY EXPRESSED HENCE THE 0RE3nCARBOXYPEPTIDASE $ INTERACTION CAN EXPLAIN NEITHER HOST NOR TISSUE TROPISM OF AVIHEPADNAVIRUSES ;= )N CONTRAST THERE IS NO DOUBT THAT THE 0RE3 DOMAINS OF THE HEPADNAVIRAL LARGE ENVELOPE PROTEINS &IG ARE CRUCIAL FOR BINDING AND PROBABLY ENTRY INTO HOST CELLS ;= AND THUS ARE PRIME CANDIDATES FOR BEING INVOLVED IN HOST SPECIFICITY 4HIS VIEW IS SUPPORTED BY THE MUCH HIGHER SEQUENCE DIVERGENCE OF THE 0RE3 REGIONS COMPARED TO OTHER PARTS OF THE GENOME &IGS " AND " (ENCE MOST EFFORTS ON UNDERSTANDING THE MOLECULAR BASIS OF HEPADNA VIRAL HOST RANGE HAVE CONCENTRATED ON MUTATING 0RE3 AND MONITORING THE CONSEQUENCES IN ONE OF THE INFECTION SYSTEMS 7HILE SUCH DATA LED TO A SEEM INGLY PRECISE DEFINITION OF RATHER SIMPLE @HOST RANGE DETERMINING REGIONS WITHIN 0RE3 &IG THE OUTCOME OF THESE EXPERIMENTS CAN DRASTICALLY BE AFFECTED BY THE SPECIFIC TEST SYSTEM USED SEE BELOW
(EPADNAVIRUS HOST RANGE
&IGURE ! (EPADNAVIRAL LARGE ENVELOPE PROTEINS AND SUPPOSED FUNCTIONS OF INDIVIDUAL 0RE3 REGIONS .UMBERS REPRESENT AMINO ACID POSITIONS NUMBERS INSIDE THE BARS INDICATE THE LENGTHS OF THE INDIVIDUAL DOMAINS MYR REFERS TO THE MYRISTOYLATION AT THE 'LY RESIDUES OF ALL , PROTEINS &UNCTIONAL SUBREGIONS ARE INDICATED SIMILARLY AS DESCRIBED IN REFERENCE ;= EXCEPT THAT QUESTION MARKS HAVE BEEN ADDED TO THE TRANSLOCATION MOTIFS 4,- AND THE SO CALLED HOST RANGE DETERMINING REGIONS TO INDICATE THAT THEIR ROLES ARE AT THE LEAST DEBATABLE &OR THE $("6 , PROTEIN THE CARBOXYPEPTIDASE $ #0$ BINDING REGION ESSENTIAL AMINO ACIDS STABILISING AMINO ACIDS AND THE POSITIONS OF THE SHORT 0RE3 AMINO ACIDS AND LONG AMINO ACIDS FORMS OF THE PROPOSED HOST DETERMINING REGION ; = ARE INDICATED " )NFECTIVITIES OF CHIMERIC $("6 AND (("6 VIRUSES FOR PRIMARY DUCK HEPATOCYTES 0$( AND DUCKLINGS IN VIVO $UCK ("6 REFERS TO $("6 GENOMES CARRYING IN CIS THE INDICATED REGIONS OF THE HERON ("6 PRE3 GENE AND (("6 TO HERON ("6 GENOMES CARRYING THE CORRESPONDING REGIONS OF THE $("6 PRE3 GENE )NFECTIVITIES ARE SCORED AS FOLLOWS WILD TYPE $("6 LIKE AT LEAST FOLD REDUCED AT LEAST FOLD REDUCED n NO DETECTABLE INFECTION
)NFECTION EXPERIMENTS WITH HEPADNAVIRUSES CARRYING DEFINED ENVELOPE PROTEIN MUTATIONS 4HE TWO MAJOR EXPERIMENTAL APPROACHES TO STUDY THE EFFECTS OF 0RE3 MUTA TIONS ON INFECTIVITY AND HOST RANGE IN USE ARE PSEUDOTYPING ; = AND THE CREATION OF CHIMERIC VIRUSES ;= A THIRD ALTERNATIVE NOT DISCUSSED HERE IN
+AI $ALLMEIER AND -ICHAEL .ASSAL
DETAIL IS INFECTION INHIBITION BY 0RE3 DERIVED PEPTIDES ;= 0SEUDOTYPES ARE VIRUSES THAT CARRY AN ENVELOPE WHICH THEY DO NOT ENCODE THEMSELVES USUALLY PROVIDED IN TRANS FROM A SUITABLE EXPRESSION VECTOR PSEUDOTYPED AS WELL AS CHIMERIC VIRIONS CAN BE GENERATED BY TRANSFECTION OF SUITABLE CELL LINES SUCH AS (UH OR (EP' FOR THE PRIMATE AND ,-( FOR THE BIRD ("6S !N ADVAN TAGE IS THAT ONLY MINIMAL CHANGES IN THE GENOME ARE REQUIRED TO KNOCKOUT THE OPEN READING FRAMES FOR THE LARGE AND IF DESIRED ALSO SMALL ENVELOPE PROTEINS THIS PREVENTS PROBLEMS POTENTIALLY ARISING FROM MORE COMPLEX MANIPULATIONS THAT MIGHT HAVE UNFORESEEN CONSEQUENCES ON THE OVERLAP PING 0 GENE &IG " AND THE NUMEROUS CIS ELEMENTS DISTRIBUTED OVER THE HEPADNAVIRAL GENOME ;= (OWEVER BECAUSE PSEUDOTYPED VIRUSES DO NOT ENCODE THEIR ENVELOPE PROTEINS INFECTION IS RESTRICTED TO A SINGLE ROUND AND THEREFORE CAN ONLY BE MONITORED IN CULTURED CELLS NOT IN VIVO 4HE REVERSE IS TRUE FOR CHIMERIC VIRUSES HOWEVER PRINCIPAL REPLICATION COMPETENCE AND PROPER ENVELOPMENT ;= CAN BE TESTED BEFOREHAND BY TRANSFECTION "ECAUSE OF THE LACK OF SUITABLE HOST ANIMALS FOR THE PRIMATE ("6S ALL STUDIES SO FAR HAVE USED THE PSEUDOTYPING APPROACH SOMETIMES WITH ($6 INSTEAD ("6 ; n= AND PRIMARY HUMAN OR PRIMATE HEPATOCYTES OR RECENTLY THE (EPA2' CELL LINE ;= -UTATIONS IN THE ENVELOPE PROTEINS INCLUDED SYSTEMATIC DELETIONS IN 0RE3 OR IN 3 ; = OR THE REPLACEMENT OF SEGMENTS WITH THE HOMOLOGOUS SEGMENTS FROM ANOTHER HEPADNAVIRUS USU ALLY 7-("6 ; = #OLLECTIVELY THE MOST RECENT COMPREHENSIVE DATA INDICATE THAT ALL INFECTIVITY DETERMINANTS WITHIN ("6 0RE3 ARE CONFINED TO THE FIRST AMINO ACIDS ;= WITH A POSSIBLE ROLE FOR THE ANTIGENIC LOOP IN 3 ;= BUT NOT THE 4,- MOTIF IN 0RE3 ("6 PSEUDOTYPED WITH A 7-("6 DERIVED ENVELOPE DISPLAYED REDUCED INFECTIVITY FOR PRIMARY HUMAN HEPATO CYTES YET INFECTIVITY WAS RESTORED WHEN THE . TERMINAL AMINO ACIDS WERE DERIVED FROM ("6 0RE3 ;= CONVERSELY REPLACEMENT OF THIS SEGMENT BY THAT OF 7-("6 IN THE CONTEXT OF THE ("6 , PROTEIN REDUCED INFECTIVITY 0ARTLY CONGRUENT DATA HAVE BEEN OBTAINED USING THE ($6 PSEUDOTYPE SYS TEM ;= IN THAT THE FIRST 7-("6 0RE3 AMINO ACIDS IMPLANTED INTO THE ("6 , PROTEIN REDUCED INFECTIVITY FOR HUMAN HEPATOCYTES HOWEVER IN THE REVERSE SETTING THE FIRST ("6 0RE3 AMINO ACIDS IN 7-("6 , ONLY PART LY INCREASED INFECTIVITY FOR THE HUMAN CELLS MOST SURPRISINGLY HOWEVER THIS CHIMERIC , PROTEIN HAD A STRONGLY ENHANCED INFECTIVITY FOR SPIDER MONKEY HEPATOCYTES TO A LEVEL HIGHER THAN THAT PROVIDED BY A COMPLETE 7-("6 , PROTEIN /THER THAN SUGGESTING THAT 0RE3 CONTAINS SEPARATE DOMAINS THAT INTERACT WITH DISTINCT CELL RECEPTORS INTERPRETATION OF THESE RESULTS REMAINS ENIGMATIC AND FARTHER REACHING IN VIVO EXPERIMENTS ARE CURRENTLY NOT FEA SIBLE WITH THE PRIMATE ("6S !LSO THE RODENT ("6S ARE NOT IDEAL FOR SUCH STUDIES BECAUSE NO CELL LINES EXIST THAT UPON TRANSFECTION SUPPORT EFFICIENT PRODUCTION OF RECOMBINANT VIRUSES OR PSEUDOTYPES (ENCE THERE IS ONLY ONE EARLY STUDY ON CHIMERIC '3(6S IN WHICH ABOUT OR ABOUT OF THE 3 GENE WERE REPLACED BY 7(6 SEQUENCE THESE VIRUSES WERE INFECTIOUS FOR GROUND SQUIRRELS UPON
(EPADNAVIRUS HOST RANGE
INTRAHEPATIC $.! INOCULATION ;= SUGGESTING THAT 3 DOES NOT DETERMINE HOST RANGE $UE TO THESE LIMITATIONS MOST STUDIES ON HEPADNAVIRAL HOST RANGE HAVE BEEN PERFORMED WITH AVIHEPADNAVIRUSES ALTHOUGH UNTIL RECENTLY SEE BELOW THE POTENTIAL OF THIS SYSTEM FOR TRUE IN VIVO STUDIES HAS NOT BEEN EXPLOITED -OST INFLUENTIAL FOR THE ENTIRE FIELD HAS BEEN A PSEUDOTYPE STUDY BY )SHIKAWA AND 'ANEM ;= "ASED ON THE HIGH INFECTIVITY OF $("6 BUT ABOUT FOLD LOWER INFECTIVITY OF HERON ("6 (("6 FOR PRIMARY 0EKIN DUCK HEPATOCYTES A (("6 GENOME DEFICIENT FOR SURFACE PROTEIN PRODUCTION WAS PSEUDOTYPED WITH CHIMERIC (("6 ENVELOPE PROTEINS IN WHICH VARIOUS PARTS OF THE 0RE3 REGION WERE REPLACED BY THE CORRESPONDING $("6 0RE3 SEQUENCES !LL CONSTRUCTS YIELDED ENVELOPED VIRIONS AFTER TRANSFECTION INTO ,-( CELLS WHICH WERE THEN USED TO INOCULATE PRIMARY DUCK HEPATOCYTES FORMATION OF INTRACELLULAR REPLICATIVE INTERMEDIATES INDICATED THAT THE ENTIRE $("6 0RE3 SEQUENCE AND SEGMENTS n n n BUT NOT n RESCUED INFECTIVITY FROM THIS IT WAS CONCLUDED THAT RESIDUES TO DETERMINE THE HOST RANGE OF AVIAN ("6S !N ADDITIONAL CHIMERA BEAR ING ONLY $("6 AMINO ACIDS n WAS APPARENTLY ALSO INFECTIOUS FOR DUCK HEPATOCYTES 4 )SHIKAWA PERS COMMUNICATION AND 0RE3 DERIVED PEPTIDES SPANNING SLIGHTLY MORE THAN THIS REGION $("6 0RE3 PARTICULARLY IF MYRISTOYLATED LIKE NATURAL 0RE3 INHIBITED $("6 INFECTION OF DUCK HEPATO CYTES ;= 4HEREFORE THE PREVAILING VIEW IS THAT 0RE3 AMINO ACIDS n OR POSSIBLY n CONSTITUTE THE HOST DETERMINING REGION OF THE AVIAN ("6S ; = .OTABLY THIS REGION IS NOT INVOLVED IN CARBOXYPEPTIDASE $ BINDING &IG AND A MYRISTOYLATED PEPTIDE CORRESPONDING TO THE HERON ("6 0RE3 SEQUENCE n BLOCKED $("6 INFECTION OF DUCK HEPATOCYTES AS EFFICIENTLY AS THE AUTOLOGOUS $("6 0RE3 PEPTIDE ;= %VIDENTLY THIS IS NOT EASILY RECON CILED WITH A SPECIFIC ROLE OF THIS 0RE3 SEGMENT IN DETERMINING HOST RANGE )N ORDER TO SHED MORE LIGHT ON THE RELEVANCE OF THESE DATA FOR A TRUE IN VIVO INFECTION WE GENERATED TWO SERIES OF CHIMERIC DUCK AND HERON ("6S BEARING IN CIS THE SHORT AND LONG FORMS OF THE PROPOSED HOST DETERMINING 0RE3 REGIONS FROM THE OTHER VIRUS &IG BOTTOM BEING ABLE TO INHERIT THE CHIMERIC ENVELOPE PROTEINS TO THEIR PROGENY THESE VIRUSES ARE SUITABLE FOR IN VIVO STUDIES ;= AND $ALLMEIER AND .ASSAL SUBMITTED "ASED ON THE PUBLISHED PSEUDOTYPE DATA WE EXPECTED THAT IMPLANTATION OF THE HERON SEQUENCE INTO $("6 WOULD REDUCE AND CONVERSELY IMPLANTATION OF THE SUPPOSED $("6 0RE3 HOST DETERMINING REGION INTO HERON ("6 WOULD INCREASE INFECTIVITY FOR DUCK HEPATOCYTES AND DUCKLINGS !LL THE CHIMERIC VIRUSES UPON TRANSFECTION WERE FULLY REPLICATION COMPETENT AND FORMED COMPARABLE AMOUNTS OF ENVELOPED VIRIONS AS WILD TYPE $("6 (OWEVER NONE OF THE HERON ("6 CHIMERAS CONTAINING $("6 0RE3 SEGMENTS n n n AND n AND OR EVEN THE ENTIRE 0RE3 REGION DISPLAYED SIGNIFICANTLY INCREASED INFECTIVITY FOR PRIMARY DUCK HEPATOCYTES OVER WILD TYPE HERON ("6 OR WAS ABLE TO ESTABLISH IN VIVO INFECTIONS IN DUCKLINGS 2EPEATING THE ORIGINAL PSEUDOTYPE EXPERIMENTS THE COMPLETE $("6 0RE3
+AI $ALLMEIER AND -ICHAEL .ASSAL
REGION AS WELL AS SEGMENTS n AND n THOUGH NOT n AS REPORTED AND n AS INFERRED CLEARLY INCREASED INFECTIVITY FOR HEPATOCYTES 4HUS IN OUR HANDS SUBSTANTIAL PARTS OF THOUGH NOT ALL THE PREVIOUSLY PUBLISHED DATA WERE REPRODUCED WITH THE PSEUDOTYPE SYSTEM n BUT NOT WITH THE CHIMERIC VIRUSES 4HERE IS CURRENTLY NO TRIVIAL EXPLANATION FOR THIS DIFFERENCE %VEN MORE DISTURBING ARE THE DATA OBTAINED WITH $("6 GENOMES CAR RYING THE CORRESPONDING HERON ("6 0RE3 SEQUENCES IN THEIR , PROTEINS !S ANTICIPATED A REDUCTION IN INFECTIVITY FOR DUCK HEPATOCYTES WAS SEEN WITH CHIMERAS IN WHICH THE $("6 0RE3 SEGMENTS n AND ALSO ITS SUBSEGMENT n WERE REPLACED BY HERON ("6 SEQUENCE HOWEVER REPLACEMENT OF RESIDUES n HAD NO NEGATIVE IMPACT ON INFECTIVITY FOR DUCK HEPATOCYTES (ENCE IN THIS SETTING THE SHORT FORM OF THE SUPPOSED HOST DETERMINING REGION DID NOT AFFECT HOST RANGE -OST SURPRISING HOWEVER WERE THE IN VIVO INFECTION DATA !LL THREE VIRUSES INCLUDING THOSE WITH THE LARGE HETEROLOGOUS 0RE3 SEGMENTS AND POOR INFECTIVITY FOR CULTURED HEPATOCYTES WERE ABLE TO INFECT DUCKLINGS IN VIVO 4HE CHIMERA WITH THE ENTIRE ORIGINALLY PROPOSED DUCK SPECIFICITY DETERMINING REGION n REPLACED BY HERON VIRUS SEQUENCE WAS FURTHER CHARACTERISED AND SHOWN TO ESTABLISH HIGH TITERED CHRONIC INFEC TIONS IN DUCKLINGS AND TO BE BOTH HORIZONTALLY AND VERTICALLY TRANSMITTABLE 1UANTITATIVE MONITORING DURING THE EARLY INFECTION PHASE ALSO SHOWED KINET ICS OF VIRAL SPREAD THAT WERE EQUAL TO OR EVEN FASTER THAN THOSE FOR WILD TYPE $("6 4HUS ALTHOUGH SERIOUSLY HANDICAPPED IN CELL CULTURE THIS VIRUS WITHOUT THE PROPER HOST DETERMINING REGION FOR DUCKS WAS AS INFECTIOUS IN VIVO AS ITS AUTHENTIC $("6 PARENT 4HIS DEFIES THE VIEW THAT CULTURED CELLS ARE LESS RESTRICTIVE THAN AN INTACT HOST ORGANISMS AND IT SERIOUSLY QUESTIONS THE CURRENT CONCEPT OF A SHORT AMINO ACID SEQUENCE IN 0RE3 AS THE CRUCIAL FACTOR IN HOST RANGE DETERMINATION OF AVIAN AND POSSIBLY ALSO MAMMALIAN ("6S 5NLESS THE CHIMERIC VIRUS HAS SWITCHED TO A DIFFERENT RECEPTOR THE DATA STRONGLY SUGGEST THAT IN VIVO THE HERON ("6 0RE3 SEQUENCE INTERACTS AS WELL WITH THE DUCK RECEPTORS AS THE AUTHENTIC $("6 0RE3 SEQUENCE .OTABLY THIS IS IN ACCORD WITH THE LACK OF SPECIES SPECIFIC RESTRICTIONS SUG GESTED BY THE COMPARABLY EFFICIENT INHIBITION OF $("6 INFECTION BY BOTH DUCK ("6 AND HERON ("6 0RE3 PEPTIDES ;= AND THE STRONG BINDING OF THE DOWNSTREAM 0RE3 REGIONS FROM BOTH VIRUSES TO DUCK CARBOXYPEPTIDASE $ ;= %VIDENTLY CULTURED HEPATOCYTES ARE NOT THE ULTIMATE SYSTEM FOR DEFI NITE STATEMENTS ON WHAT DETERMINES HEPADNAVIRAL HOST RANGE MOREOVER THE ENTIRE CURRENT CONCEPT OF A SHORT 0RE3 SEGMENT AS HOST DETERMINING REGION MAY NEED REEVALUATION
#ELLULAR RESTRICTION FACTORS AS DETERMINANTS FOR HEPADNAVIRAL HOST RANGE !NOTHER UNRESOLVED QUESTION IS THE SUSPICIOUS NON SUSCEPTIBILITY OF -USCOVY DUCKS FOR IN VIVO $("6 INFECTION ; = IN CELL CULTURE INFECTION IS
(EPADNAVIRUS HOST RANGE
NOT COMPLETELY BLOCKED AS IS IT WITH CHICKEN HEPATOCYTES BUT IS SIMILARLY INEFFICIENT AS INFECTION OF 0EKIN DUCK HEPATOCYTES WITH HERON ("6 ;= 0HYLOGENY PROVIDES NO CLUE AS TO WHY THE GENUS #AIRINA SHOULD NOT BE INFECTABLE WHILE -ANDARIN DUCKS CAN HOST A $("6 LIKE VIRUS SEE ABOVE (ENCE -USCOVY DUCKS MAY FORTUITOUSLY LACK A FUNCTIONAL PERMISSIVITY FAC TOR OR POSSESS A RESTRICTION FACTORS THAT ISARE ABSENT FROM 0EKIN AND OTHER $("6 INFECTABLE DUCK SPECIES 4HAT NON PERMISSIVENESS CAN AT LEAST IN CULTURED HEPATOCYTES BE PARTIALLY OVERCOME BY HIGH DOSES OF VIRUS WOULD BE COMPATIBLE WITH OUT TITRATION ABROGATION OF SUCH A NEGATIVE FACTOR BUT ALSO WITH THE ABSENCE OF OR INCOMPATIBILITY WITH HOST PERMISSIVITY FACTORS !S A FIRST STEP TOWARDS DISTINGUISHING BETWEEN THESE POSSIBILITIES WE RESORT ED TO A CLASSIC GENETIC APPROACH -USCOVY AND 0EKIN DUCKS CAN INTERBREED ATTESTING TO THEIR CLOSE PHYLOGENETIC RELATION SUCH MULE DUCKS ARE PRODUCED IN LARGE NUMBERS IN THE FOOD INDUSTRY ! -USCOVY DRAKE WAS CROSSED WITH CHRONICALLY $("6 INFECTED 0EKIN DUCK FEMALES AND THE OFFSPRING EMBRYOS WERE ANALYSED FOR $("6 INFECTION + $ALLMEIER 5 3CHULTZ - .ASSAL UNPUBLISHED DATA &OUR OF FOUR EMBRYOS TESTED SHOWED CLEARLY DETECTABLE THOUGH SLIGHTLY VARYING LEVELS OF TYPICAL $("6 REPLICATIVE INTERMEDIATES IN THEIR LIVERS !S & HYBRIDS THESE EMBRYOS CARRIED ONE COPY EACH OF THE PATERNAL AND OF THE MATERNAL ALLELES (ENCE THEIR GAIN OF SUSCEPTIBILITY FOR INFECTION IS INCOMPATIBLE WITH THE PRESENCE OF A DOMINANTLY ACTING PATERNALLY INHERITED RESTRICTION FACTOR YET COMPATIBLE WITH THE PRESENCE OF A FUNCTIONAL PERMISSIVITY FACTOR ENCODED BY A MATERNAL GENE 4HE NATURE OF THIS FACTOR IS CURRENTLY UNCLEAR BUT DIFFERENTIAL CLONING OR SIMILAR TECHNIQUES MIGHT BE SUITED FOR ITS IDENTIFICATION !LSO THESE RESULTS DO NOT RULE OUT THAT RESTRICTION FACTORS PLAY AN IMPORTANT ROLE IN OTHER HEPADNAVIRUS HOST SYSTEMS
#ONCLUSIONS AND OUTLOOK -ANY ASPECTS OF HEPADNAVIRAL REPLICATION HAVE BEEN ELUCIDATED IN CONSID ERABLE DETAIL HOWEVER OUR UNDERSTANDING OF HEPADNAVIRUS HOST RANGE AND ITS MOLECULAR BASIS LAGS FAR BEHIND #ERTAINLY HEPADNAVIRUSES DO NOT HAVE A BROAD HOST RANGE YET WHETHER THEIR HOST RANGE IS TRULY NARROW REMAINS A MATTER OF INTERPRETATION AS LONG AS THE PHYLOGENETIC RELATIONS BETWEEN THE PROVEN HEPADNAVIRUS HOST SPECIES ARE NOT RIGIDLY DEFINED 5NFORTUNATELY HEPADNAVIRAL HOST RANGE IS SUFFICIENTLY RESTRICTED SO AS TO LIMIT IN VIVO STUDIES TO FEW EXPERIMENTALLY ACCESSIBLE SPECIES EVEN FOR $("6 THE FULL SPECTRUM OF INFECTABLE HOSTS IS UNKNOWN )N VITRO INFECTION ASSAYS ALLOW ACCESS TO CELLS FROM A WIDER RANGE OF HOSTS YET RECENT DATA BOTH FOR ORTHOHEPADNAVIRUSES USING HUMAN AND 7OOLLY MONKEY ("6 AND FOR AVIHEPADNAVIRUSES USING DUCK AND HERON ("6 CAST DOUBTS ON THE TRANSFERABILITY OF IN VITRO DATA ON STATEMENTS ON IN VIVO HOST RANGE /NE OF THE MAJOR CHALLENGES AS MENTIONED YEARS AGO ;= REMAINS THE UNAMBIGUOUS IDENTIFICATION OF THE CELLULAR RECEPTORS MEDIATING PRODUCTIVE HEPADNAVIRUS INFECTION CARBOXYPEPTIDASE
+AI $ALLMEIER AND -ICHAEL .ASSAL
$ THOUGH LIKELY INVOLVED IN $("6 INFECTION DOES NOT EXPLAIN TISSUE AND HOST TROPISM AND DOES NOT AT ALL SEEM TO PLAY A ROLE FOR HUMAN ("6 INFEC TION 'IVEN THE LIMITED SUCCESS OF CONVENTIONAL APPROACHES IT IS HOPED THAT APPLICATION OF NEW TECHNIQUES SUCH AS EXPRESSION PROFILING AND GENE KNOCK DOWN BY 2.! INTERFERENCE TO PERMISSIVE VERSUS NON PERMISSIVE CELLS WILL HELP ANSWERING THIS QUESTION HOWEVER THE POTENTIALLY CRUCIAL ROLES OF NON PROTEINACEOUS MOLECULES AS WELL AS OF HOST RESTRICTION FACTORS MUST NOT BE DISREGARDED AND SIMILARLY VIRAL FACTORS OTHER THAN 0RE3 COULD IMPOR TANTLY CONTRIBUTE TO HEPADNAVIRAL HOST RANGE (ENCE BOTH SYSTEMATIC WORK AND IMAGINATIVE THINKING WILL BE REQUIRED TO SOLVE THIS ENIGMATIC ASPECT OF HEPADNAVIRUS BIOLOGY AND REALISE THE MEDICALLY HIGHLY RELEVANT ISSUE OF A SMALL ANIMAL MODEL FOR HUMAN ("6 INFECTION
!CKNOWLEDGEMENTS 7ORK IN OUR OWN LABORATORY RELATING TO THE TOPIC OF THIS REVIEW WAS SUP PORTED BY A GRANT FROM THE ,ANDESSTIFTUNG "ADEN 7àRTTEMBERG 7E THANK 5LLA 3CHULTZ FOR INVALUABLE HELP WITH DUCK EXPERIMENTS AND $ANIEL ,OEB "ILL -ASON AND PARTICULARLY *ESSE 3UMMERS AND (EINZ 3CHALLER FOR VIVID DIS CUSSIONS AND NUMEROUS SUGGESTIONS FOR ADDITIONAL CONTROLS IN THE CHIMERIC AVIHEPADNAVIRUS INFECTION EXPERIMENTS
2EFERENCES
"ECK * .ASSAL - (EPATITIS " VIRUS REPLICATION 7ORLD * 'ASTROENTEROL n &UNK ! -HAMDI - 7ILL ( 3IRMA ( !VIAN HEPATITIS " VIRUSES MOLECU LAR AND CELLULAR BIOLOGY PHYLOGENESIS AND HOST TROPISM 7ORLD * 'ASTROENTEROL n 'LEBE $ 5RBAN 3 6IRAL AND CELLULAR DETERMINANTS INVOLVED IN HEPADNA VIRAL ENTRY 7ORLD * 'ASTROENTEROL n ,OUZ $ "ERGMANS (% ,OOS "0 (OEBEN 2# #ROSS SPECIES TRANSFER OF VIRUSES IMPLICATIONS FOR THE USE OF VIRAL VECTORS IN BIOMEDICAL RESEARCH GENE THERAPY AND AS LIVE VIRUS VACCINES * 'ENE -ED n (EENEY *, $ALGLEISH !' 7EISS 2! /RIGINS OF ()6 AND THE EVOLUTION OF RESISTANCE TO !)$3 3CIENCE n :HAO '0 3!23 EPIDEMIOLOGY n &ROM DESCRIPTIVE TO MECHANISTIC ANALY SES 6IRUS 2ES DOI JVIRUSRES 0EIRIS *3 DE *ONG -$ 'UAN 9 !VIAN INFLUENZA VIRUS (. A THREAT TO HUMAN HEALTH #LIN -ICROBIOL 2EV n 6ILCHEZ 2! +USNE 3 -OLECULAR AND CLINICAL PERSPECTIVES OF POLYOMAVI RUSES EMERGING EVIDENCE OF IMPORTANCE IN NON KIDNEY TRANSPLANT POPULATIONS ,IVER 4RANSPL n &ALCONE 6 3CHWEIZER - .EUMANN (AEFELIN $ 2EPLICATION OF PRIMATE
(EPADNAVIRUS HOST RANGE
FOAMY VIRUSES IN NATURAL AND EXPERIMENTAL HOSTS #URR 4OP -ICROBIOL )MMUNOL n "RUMME :, (ARRIGAN 02 4HE IMPACT OF HUMAN GENETIC VARIATION ON ()6 DISEASE IN THE ERA OF (!!24 !)$3 2EV n 2EICHE %- "ONAMETTI !- 6OLTARELLI *# -ORIMOTO (+ 7ATANABE -! 'ENETIC POLYMORPHISMS IN THE CHEMOKINE AND CHEMOKINE RECEPTORS IMPACT ON CLINICAL COURSE AND THERAPY OF THE HUMAN IMMUNODEFICIENCY VIRUS TYPE INFECTION ()6 #URR -ED #HEM n 4HIO #, !STEMBORSKI * "ASHIROVA ! -OSBRUGER 4 'REER 3 7ITT -$ 'OEDERT ** (ILGARTNER - -AJESKE ! /"RIEN 3* ET AL 'ENETIC PROTECTION AGAINST HEPATITIS " VIRUS CONFERRED BY ##2$ELTA %VIDENCE THAT ##2 CONTRIBUTES TO VIRAL PERSISTENCE * 6IROL n ,IM *+ 'LASS 7' -C$ERMOTT $( -URPHY 0- ##2 NO LONGER A tGOOD FOR NOTHING GENEnCHEMOKINE CONTROL OF 7EST .ILE VIRUS INFECTION 4RENDS )MMUNOL n -ARSH - (ELENIUS ! 6IRUS ENTRY OPEN SESAME #ELL n "ARANOWSKI % 2UIZ *ARABO #- $OMINGO % %VOLUTION OF CELL RECOGNI TION BY VIRUSES 3CIENCE n 7EISSENHORN 7 (INZ ! 'AUDIN 9 6IRUS MEMBRANE FUSION &%"3 ,ETT n .EUMANN ' +AWAOKA 9 (OST RANGE RESTRICTION AND PATHOGENICITY IN THE CONTEXT OF INFLUENZA PANDEMIC %MERG )NFECT $IS n ,AW ,+ $AVIDSON ", 7HAT DOES IT TAKE TO BIND #!2 -OL 4HER n "RIZ 6 0OVEDA % 3ORIANO 6 ()6 ENTRY INHIBITORS MECHANISMS OF ACTION AND RESISTANCE PATHWAYS * !NTIMICROB #HEMOTHER n -C&ADDEN ' 0OXVIRUS TROPISM .AT 2EV -ICROBIOL n -AYER -0 2ECRUITMENT OF (SP CHAPERONES A CRUCIAL PART OF VIRAL SURVIVAL STRATEGIES 2EV 0HYSIOL "IOCHEM 0HARMACOL n -AYER -0 "UKAU " (SP CHAPERONES CELLULAR FUNCTIONS AND MOLECU LAR MECHANISM #ELL -OL ,IFE 3CI n !MBROSE : +EWALRAMANI 6. "IENIASZ 0$ (ATZIIOANNOU 4 ()6!)$3 IN SEARCH OF AN ANIMAL MODEL 4RENDS "IOTECHNOL n 'OFF 30 (OST FACTORS EXPLOITED BY RETROVIRUSES .AT 2EV -ICROBIOL n 4SURUTANI . 9ASUDA * 9AMAMOTO . #HOI ") +ADOKI - )WAKURA 9 .UCLEAR IMPORT OF THE PREINTEGRATION COMPLEX IS BLOCKED UPON INFECTION BY HUMAN IMMUNODEFICIENCY VIRUS TYPE IN MOUSE CELLS * 6IROL n 3UN * 3OOS 4 +EWALRAMANI 6. /SIECKI + :HENG *( &ALKIN , 3ANTAMBROGIO , ,ITTMAN $2 'OLDSTEIN ( #$ SPECIFIC TRANSGENIC EXPRESSION OF HUMAN CYCLIN 4 MARKEDLY INCREASES HUMAN IMMUNODEFICIENCY VIRUS TYPE ()6 PRODUCTION BY #$ 4 LYMPHOCYTES AND MYELOID CELLS IN MICE TRANS GENIC FOR A PROVIRUS ENCODING A MONOCYTE TROPIC ()6 ISOLATE * 6IROL n ,AMBERT # $ORING 4 0RANGE 2 (EPATITIS " 6IRUS -ATURATION IS 3ENSITIVE TO &UNCTIONAL )NHIBITION OF %3#24 ))) 6PS AND [GAMMA] !DAPTIN * 6IROL n
+AI $ALLMEIER AND -ICHAEL .ASSAL
7ATANABE 4 3ORENSEN %- .AITO ! 3CHOTT - +IM 3 !HLQUIST 0 )NVOLVEMENT OF HOST CELLULAR MULTIVESICULAR BODY FUNCTIONS IN HEPATITIS " VIRUS BUDDING 0ROC .ATL !CAD 3CI 53! n -HAMDI - &UNK ! (OHENBERG ( 7ILL ( 3IRMA ( !SSEMBLY AND BUD DING OF A HEPATITIS " VIRUS IS MEDIATED BY A NOVEL TYPE OF INTRACELLULAR VESICLES (EPATOLOGY n 'OFF 30 2ETROVIRUS RESTRICTION FACTORS -OL #ELL n 'OFF 30 'ENETIC CONTROL OF RETROVIRUS SUSCEPTIBILITY IN MAMMALIAN CELLS !NNU 2EV 'ENET n 0EREZ / (OPE 4* #ELLULAR RESTRICTION FACTORS AFFECTING THE EARLY STAGES OF ()6 REPLICATION #URR ()6!)$3 2EP n .ISOLE 3 3TOYE *0 3AIB ! 42)- FAMILY PROTEINS RETROVIRAL RESTRICTION AND ANTIVIRAL DEFENCE .AT 2EV -ICROBIOL n *AMES ,# +EEBLE !( +HAN : 2HODES $! 4ROWSDALE * 3TRUCTURAL BASIS FOR 0293029 MEDIATED TRIPARTITE MOTIF 42)- PROTEIN FUNCTION 0ROC .ATL !CAD 3CI 53! n 3EBASTIAN 3 ,UBAN * 4HE 2ETROVIRAL 2ESTRICTION &ACTOR 42)-ALPHA #URR )NFECT $IS 2EP n 3AKUMA 2 .OSER *! /HMINE 3 )KEDA 9 2HESUS MONKEY 42)-ALPHA RESTRICTS ()6 PRODUCTION THROUGH RAPID DEGRADATION OF VIRAL 'AG POLYPROT EINS .AT -ED n 4OWERS '* (ATZIIOANNOU 4 #OWAN 3 'OFF 30 ,UBAN * "IENIASZ 0$ #YCLOPHILIN ! MODULATES THE SENSITIVITY OF ()6 TO HOST RESTRICTION FACTORS .AT -ED n 'ACK -5 3HIN 9# *OO #( 5RANO 4 ,IANG # 3UN , 4AKEUCHI / !KIRA 3 #HEN : )NOUE 3 ET AL 42)- 2).' FINGER % UBIQUITIN LIGASE IS ESSEN TIAL FOR 2)' ) MEDIATED ANTIVIRAL ACTIVITY .ATURE n #ULLEN "2 2OLE AND MECHANISM OF ACTION OF THE !0/"%# FAMILY OF ANTIRETROVIRAL RESISTANCE FACTORS * 6IROL n -ARIANI 2 #HEN $ 3CHROFELBAUER " .AVARRO & +ONIG 2 "OLLMAN " -UNK # .YMARK -C-AHON ( ,ANDAU .2 3PECIES SPECIFIC EXCLUSION OF !0/"%#' FROM ()6 VIRIONS BY 6IF #ELL n .GUYEN $( 'UMMULURU 3 (U * $EAMINATION INDEPENDENT INHIBITION OF HEPATITIS " VIRUS REVERSE TRANSCRIPTION BY !0/"%#' * 6IROL n 2ÚSLER # +ÚCK * +ANN - -ALIM -( "LUM (% "AUMERT 4& VON 7EIZSËCKER & !0/"%# MEDIATED INTERFERENCE WITH HEPADNAVIRUS PRODUCTION (EPATOLOGY n #ONTICELLO 3' 4HOMAS #* 0ETERSEN -AHRT 3+ .EUBERGER -3 %VOLUTION OF THE !)$!0/"%# FAMILY OF POLYNUCLEOTIDE DEOXY CYTIDINE DEAMINASES -OL "IOL %VOL n 'AO ' 'UO 8 'OFF 30 )NHIBITION OF RETROVIRAL 2.! PRODUCTION BY :!0 A ###( TYPE ZINC FINGER PROTEIN 3CIENCE n 'UO 8 -A * 3UN * 'AO ' 4HE ZINC FINGER ANTIVIRAL PROTEIN RECRUITS THE 2.! PROCESSING EXOSOME TO DEGRADE THE TARGET M2.! 0ROC .ATL !CAD 3CI 53! n -àLLER 3 -ÚLLER 0 "ICK -* 7URR 3 "ECKER 3 'àNTHER 3 +àMMERER "-
(EPADNAVIRUS HOST RANGE
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4HE LIVER AS IMMUNE ESCAPE SITE FOR PATHOGENS 0ERCY ! +NOLLE AND $IRK 3TABENOW )NSTITUTE OF -OLECULAR -EDICINE AND %XPERIMENTAL )MMUNOLOGY 5NIVERSITY (OSPITAL "ONN &RIEDRICH 7ILHELM 5NIVERSITY "ONN 3IGMUND &REUD 3TR "ONN 'ERMANY
!BSTRACT "ESIDES ITS IMPORTANT FUNCTION FOR PROTEIN LIPID AND GLUCOSE METABOLISM THE LIVER EXERTS SCAVENGER FUNCTION IN ORDER TO CLEAR THE BLOOD FROM DEGRADATION PRODUCTS )T IS BECOM ING INCREASINGLY CLEAR THAT THIS SCAVENGER FUNCTION IS CLOSELY LINKED TO THE LIVERS IMMUNE FUNCTION WHICH FAVOURS INDUCTION OF IMMUNE TOLERANCE RATHER THAN IMMUNITY 4HE CELL POPULATION MOST ACTIVELY INVOLVED IN SCAVENGING OF BLOOD BORNE MACROMOLECULES IS AN ORGAN RESIDENT CELL POPULATION THE LIVER SINUSOIDAL ENDOTHELIAL CELLS ,3%# ,3%# ALSO HAVE PROMINENT IMMUNE REGULATORY FUNCTION AS THEY BEAR THE CAPACITY TO PRIME NAIVE #$ AND #$ 4 CELLS AFTER PRESENTATION OF EXOGENOUS ANTIGENS ON -(# #LASS )) OR -(# #LASS ) MOLECULES RESPECTIVELY 4HE OUTCOME OF SUCH 4 CELL PRIMING BY ANTIGEN PRESENT ING ,3%# IS INDUCTION OF 4 CELL TOLERANCE (ERE WE ALSO DISCUSS THE OTHER MECHANISMS AND CELL POPULATIONS INVOLVED IN MEDIATION OF HEPATIC IMMUNE TOLERANCE 7E DESCRIBE THE MECHANISMS OF HOW A VIRUS MAY GET ACROSS CELL BARRIERS IN PARTICULAR THE ENDOTHELIAL CELL BARRIER )MPORTANTLY BLOOD BORNE VIRUS IS SCAVENGED BY ,3%# (ERE WE DISCUSS THE EXPERIMENTAL EVIDENCE IN THE LITERATURE THAT VIRUS UPTAKE BY ,3%# DOES NOT NECESSARILY LEAD TO LYSOSOMAL DESTRUCTION BUT RATHER RESULTS IN TRANSCYTOTIC TRANSPORT OF THE VIRUS TO HEPATOCYTES 4HUS ,3%# MAY PLAY A PIVOTAL ROLE IN HEPATOCELLULAR INFECTION BY BLOOD BORNE VIRUS I RETRIEVAL FROM THE BLOODSTREAM AND TRANSCYTOTIC TRANSPORT FOR INFECTION OF THE TARGET CELL THE HEPATOCYTE AND II PREVENTION OF VIRUS SPECIFIC #$ 4 CELL IMMUNITY BY SKEWING ANTIGEN SPECIFIC 4 CELL RESPONSES BY PRESENTATION OF VIRAL ANTIGENS AT THE VERY EARLY STAGE OF INFECTION
)NTRODUCTION 4HE LIVER AS AN ORGAN FULFILS MANY DIFFERENT TASKS THAT INCLUDE PROTEIN AND LIPID METABOLISM CLEARANCE FUNCTION FOR REMOVAL OF TOXIC WASTE PRODUCTS FROM THE BLOOD CIRCULATION AND A PROMINENT IMMUNE REGULATORY FUNCTION 4HESE DIVERSE FUNCTIONS ARE PERFORMED BY COOPERATIVE ACTION OF DIFFERENT CELL POPULATIONS IN THE LIVER THAT ARE EITHER ORGAN RESIDENT OR ARE DERIVED FROM THE BONE MARROW FOLLOWED BY FUNCTIONAL ADAPTATION THROUGH INTER ACTION WITH THE UNIQUE HEPATIC MICROENVIRONMENT -OREOVER THE UNIQUE MICROANATOMY ALSO CONTRIBUTES TO THESE HEPATIC FUNCTIONS
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4HE HEPATIC MICROANATOMY AND CELL POPULATIONS (EPATOCYTES FORM THE MOST PROMINENT HEPATIC CELL POPULATION WHICH CONSTI TUTES APPROXIMATELY n OF LIVER CELLS ;= (EPATOCYTES HAVE EXTRAORDI NARY METABOLIC FUNCTION FOR PROTEINLIPID METABOLISM AND FOR DEGRADATION DISPOSAL OF TOXIC MATERIAL VIA THE BILE 4HUS HEPATOCYTES ARE OFTEN REGARDED AS THE CELL POPULATION THAT DETERMINES LIVER FUNCTION 4HIS ASSUMPTION IS SUPPORTED BY THE CLINICAL OBSERVATIONS THAT LOSS OF MORE THAN OF HEPA TOCYTES EITHER DURING ACUTE DISEASE SUCH AS TOXIC LIVER DAMAGE OR FULMINANT VIRAL HEPATITIS OR AS A CONSEQUENCE OF CHRONIC INFLAMMATORY DISEASE LEADING TO CIRRHOSIS IS FOLLOWED BY THE DEVELOPMENT OF LIVER FAILURE (OWEVER FROM THESE OBSERVATIONS IT CANNOT BE CONCLUDED THAT OTHER CELL POPULATIONS DO NOT CONTRIBUTE TO THE FUNCTIONAL REPERTOIRE OF THE LIVER (EPATOCYTES TIGHTLY INTERACT WITH NEIGHBOURING HEPATOCYTES VIA THEIR APICAL SURFACE WHICH ENCLOSES THE BILE CANALICULI 4HE CELLS ARE ARRANGED IN A SANDWICH FORMAT WITH THEIR BASOLATERAL SIDE FACING THE SINUSOIDAL ENDOTHE LIUM -ICROVILLI PROTRUDE FROM THE BASOLATERAL SURFACE OF THE HEPATOCYTES TO INCREASE THE SURFACE AND ALLOW FOR EFFICIENT UPTAKE AND RELEASE OF MATERIALS BETWEEN HEPATOCYTE AND BLOOD "ECAUSE OF THE METABOLIC FUNCTION MORE THAN OF CARDIAC BLOOD OUTPUT PASSES THROUGH THE LIVER IN A UNIQUE MIXED ARTERIO VENOUS CIRCULATION .UTRIENT RICH BLOOD FROM THE INTESTINAL TRACT REACHES THE LIVER VIA THE PORTAL VEIN THAT BRANCHES INTO SMALL VENULES ENTERING THE PARENCHYMAL AREA IN THE PORTAL TRACT TOGETHER WITH A BRANCH OF THE HEPATIC ARTERY !RTERIAL AND VENOUS VESSELS MERGE IN THE HEPATIC SINU SOIDS THAT ARE LINED BY THE SPECIALISED SINUSOIDAL ENDOTHELIAL CELLS OF THE LIVER "LOOD FLOW IN THE LIVER IS SLOW n +MS AS A RESULT OF THE ENOR MOUS CUMULATIVE SINUSOIDAL VESSEL DIAMETER AND THE MIXED ARTERIOVENOUS CIRCULATION THAT RESULTS IN A LOW PRESSURE PERFUSION PROFILE ;= "LOOD PERCO LATES THROUGH THE HEPATIC SINUSOIDS TO REACH THE CENTRAL VEIN THAT DRAINS INTO THE INFERIOR VENA CAVA +UPFFER CELLS CONSTITUTE THE HEPATIC MACROPHAGE POPULATION 4HEY ARE DERIVED FROM THE BONE MARROW AND SHOW CONSIDERABLE HALF LIFE IN THE TIS SUE +UPFFER CELLS ARE A RICH SOURCE OF SOLUBLE MEDIATORS SUCH AS PROSTANOIDS CYTOKINES AND CHEMOKINES ;= THAT ARE NOT ONLY OPERATIVE IN LOCAL IMMUNE REGULATION DISCUSSED BELOW BUT ALSO ENHANCE HEPATOCELLULAR EXPRESSION OF ACUTE PHASE PROTEINS THROUGH RELEASE OF ), AND ), ; = -OREOVER +UPFFER CELLS HAVE POTENT PHAGOCYTIC ACTIVITY AND ELIMINATE OPSONISED MICROORGANISMS AS WELL AS CELLULAR DEBRIS ;= 4HE MACROPHAGES PATROL THROUGH HEPATIC SINUSOIDS EVEN AGAINST THE BLOODSTREAM AND THUS CAUSE TURBULENCE OF BLOOD FLOW &IG ;= (OWEVER MOST +UPFFER CELLS ARE FOUND IN THE PERIPORTAL AREA WHERE THE BLOOD ENTERS THE LIVER ,IVER SINUSOIDAL ENDOTHELIAL CELLS ,3%# LINE THE HEPATIC SINUSOIDS FROM THE PORTAL TRACT TO THE CENTRAL VEIN ;= ,3%# NOT ONLY SERVE AS A PLATFORM FOR MIGRATING +UPFFER CELLS OR LIVER ASSOCIATED LYMPHOCYTES SEE BELOW BUT ALSO MARK THE SPACE OF $ISSÏ THAT IS SITUATED BETWEEN THE HEPATOCYTES
The liver as immune escape site for pathogens
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Figure 1. Schematic demonstration of a hepatic sinusoid. The lumen of the sinusoidal blood vessel is lined by liver sinusoidal endothelial cells. Liver-associated lymphocytes (LAL), a heterogeneous population of NK, NKT and T-cells, as well as bone marrow-derived liver resident macrophages, Kupffer cells, reside within the lumen of the sinusoids. LSEC physically separate cells and molecules circulating with the blood from hepatocytes. The area between hepatocytes and LSEC is called the space of Dissé. Stellate cells are located inside the space of Dissé giving them the possibility to control the diameter of the sinusoid.
and LSEC (Fig. 1). Due to the small sinusoidal diameter (7–10 μm) leukocytes and red blood cells that pass through the vessels cause a sinusoidal ‘massage’ or ‘forced sieving’ that increases fluid exchange between the sinusoidal lumen and the space of Dissé [9]. In contrast to microvascular endothelial cells in most other tissues, LSEC have fenestrations that allow for fluid exchange to occur between the blood and hepatocytes. The size of fenestrae is dynamically regulated and allows for passage of chylomicrons into the space of Dissé [10]. There is no basal membrane and tight junctions between adjacent LSEC are lacking. Although hepatocellular microvilli can protrude through endothelial fenestrae, the cumulative surface of LSEC is
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MUCH LARGER AS COMPARED TO HEPATOCYTE MICROVILLI ,3%# ARE ORGAN RESIDENT CELLS THAT REPOPULATE SIMILAR TO HEPATOCYTES FROM A SO FAR ILL DEFINED HEPATIC PRECURSOR CELL POPULATION ;= 3TELLATE CELLS ARE SITUATED BETWEEN HEPATOCYTES AND ,3%# WITHIN THE SPACE OF $ISSÏ &IG ;= 4HESE CELLS ARE THE MAJOR STORAGE SITE FOR RETI NOIDS INCLUDING VITAMIN ! AND POSSESS LARGE NUMBERS OF MICROTUBULES AND MICROFILAMENTS 3TELLATE CELLS ARE INVOLVED IN REGULATION OF BLOOD FLOW BY ACTIVELY CONTROLLING THE SINUSOIDAL DIAMETER IN RESPONSE TO VASODILATORY OR VASOCONSTRICTORY SIGNALS ;= -OREOVER STELLATE CELLS ARE A RICH SOURCE OF CHEMOKINES AND CYTOKINES 4HEY ARE MOST IMPORTANT DURING DEVELOPMENT OF HEPATIC FIBROSIS BECAUSE INFLAMMATION OR INJURY CAUSES STELLATE CELL ACTIVATION THAT RESULTS IN PREDOMINANT DEPOSITION OF EXTRACELLULAR MATRIX RATHER THAN DEGRADATION ;= 3TELLATE CELLS ARE IN CLOSE INTERACTION WITH HEPATOCYTES AND ,3%# ON EITHER SIDE AND ARE IN CLOSE ASSOCIATION WITH NERVE FIBERS ;= ,IVER ASSOCIATED LYMPHOCYTES HAVE ORIGINALLY BEEN DEFINED BY THEIR CHAR ACTERISTIC MICROSCOPIC APPEARANCE BUT CONSIST OF A RATHER HETEROGENEOUS POPULATION OF .+ CELLS 4 CELLS AND .+4 CELLS ;= 4HESE CELL POPULATIONS ARE ABUNDANT IN THE LIVER WITH MORE THAN LYMPHOCYTES BEING FOUND IN HUMAN LIVER %XPRESSION OF CERTAIN CHEMOKINES AND ADHESION MOLECULES BY ORGAN RESIDENT LIVER CELLS AND EXPRESSION OF APPROPRIATE HOMING RECEPTORS ALLOW THESE CELLS TO ACCUMULATE IN THE LIVER ;= 4HESE CELLS ALSO MIGRATE THROUGH HEPATIC SINUSOIDS ;= 4HE HETEROGENEITY OF HEPATIC LYMPHOCYTES INDICATES THAT THESE CELLS CONTRIBUTE IN A COMPLEX FASHION TO LOCAL IMMUNE REGULATION IN THE LIVER )N THE PORTAL TRACTS FURTHER CELL POPULATIONS ARE FOUND SUCH AS BILE DUCT CELLS PORTAL FIBROBLASTS AND DENDRITIC CELLS 4HE PORTAL TRACT APPEARS TO BE A DISTINCT FUNCTIONAL COMPARTMENT OF THE LIVER SERVING AS ENTRY PORTAL FOR ARTE RIAL AND VENOUS BLOOD AS WELL AS EXIT PORTAL FOR HEPATIC BILE 4HE CELLULAR AND MOLECULAR MECHANISMS SUPPORTING THE VARIOUS REQUIREMENTS TO ALLOW THESE FUNCTIONAL PROPERTIES ARE LARGELY UNKNOWN
4HE LIVER AS TARGET ORGAN FOR PATHOGENS "LOOD BORNE PATHOGENS THAT CIRCULATE WITH THE BLOODSTREAM ARE ELIMINATED MAINLY IN TWO ORGAN SYSTEMS IE THE SPLEEN AND THE LIVER 7HILE MACRO PHAGES IN THE MARGINAL ZONE ARE RESPONSIBLE FOR ELIMINATION OF BACTERIAL PATHOGENS IN THE SPLEEN +UPFFER CELLS AS WELL AS PLATELETS AND NEUTROPHILS WITHIN HEPATIC SINUSOIDS COOPERATE TO ACHIEVE CLEARANCE OF CIRCULATING BAC TERIA IN THE LIVER ; = -ECHANISTICALLY INTRAVASCULAR NEUTROPHIL ACTIVA TION RESULTING FROM BINDING OF PLATELETS ACTIVATED BY BACTERIAL 4,2 LIGANDS LEADS TO FORMATION OF NEUTROPHIL EXTRACELLULAR TRAPS 4HESE TRAPS ENSNARE BACTERIA WITHIN THE VASCULATURE OF THE LIVER BUT ALSO OF THE LUNG AND PROMOTE BACTERIAL TRAPPING AND PHAGOCYTIC ELIMINATION ;= 4HUS THE LIVER SERVES AS A FILTER SYSTEM TO ELIMINATE CIRCULATING BACTERIA FROM THE BLOOD #ENTRAL TO
4HE LIVER AS IMMUNE ESCAPE SITE FOR PATHOGENS
THIS ANTIBACTERIAL ACTIVITY IS THE CONSTITUTIVE EXPRESSION OF INNATE IMMUNE RECEPTORS SUCH AS THE 4OLL LIKE RECEPTORS ON VARIOUS LIVER CELL POPULATIONS THAT ALLOWS SENSING OF BACTERIAL PATHOGENS AND APPROPRIATE CELL ACTIVATION ;= !NTI BACTERIAL DEFENSE IN THE LIVER APPARENTLY WORKS EFFICIENTLY BECAUSE THERE ARE FEW CLINICAL EXAMPLES FOR PERSISTENT BACTERIAL INFECTIONS OF THE LIVER WHICH ARE DEALT WITH ELSEWHERE IN THIS BOOK 6IRAL INFECTION OF THE LIVER HOWEVER REPRESENTS A SIGNIFICANT PROBLEM AND MANY HUNDRED MILLIONS OF PATIENTS PERSISTENTLY INFECTED WITH HEPATITIS " OR HEPATITIS # VIRUS SUFFER FROM THE CONSEQUENCES OF IMMUNE MEDIATED CHRONIC VIRAL HEPATITIS &OR DISTRIBUTION WITHIN A POPULATION HEPATOTROPIC VIRUSES HAVE TO CROSS DIFFERENT BARRIERS IN ORDER TO ACHIEVE INFECTION OF A NEW HOST 4HE FIRST BARRIER ENCOUNTERED IS THE SKIN OR MUCOSAL SURFACES THAT BLOCK ENTRY INTO THE BODY %VEN IF THIS BARRIER IS OVERCOME BLOOD BORNE VIRUS AGAIN HAS TO CROSS BARRIERS SUCH AS ENDOTHELIAL SURFACESCELL LAYERS TO REACH THEIR TARGET CELLS WHICH ARE THE PARENCHYMAL CELLS OF THE LIVER )N PRIN CIPLE FOR A VIRUS TO CROSS A PHYSICAL BARRIER OF EPITHELIAL OR ENDOTHELIAL CELLS REQUIRES EITHER A @4ROJAN HORSE STRATEGY OR UTILISATION OF CELLULAR TRANSPORT MACHINES WITH POLAR ORIENTATION "OTH THE @4ROJAN HORSE STRATEGY AS WELL AS TRANSCYTOSIS HAVE BEEN REPORTED TO BE EMPLOYED BY VIRUSES SUCH AS ()6 TO ACHIEVE INFECTION OF NEW HOSTS ; = (EPATOTROPIC VIRUSES LIKE HEPATITIS ! VIRUS (!6 HEPATITIS " VIRUS ("6 AND HEPATITIS # VIRUS (#6 ALSO HAVE TO CROSS EPITHELIAL BARRIERS AND THE LIVER SINUSOIDAL ENDOTHELIAL CELL LAYER WHICH SEPARATES THE HEPATO CYTES FROM THE BLOOD TO FINALLY INFECT THEIR TARGET CELLS THE HEPATOCYTES 6ERY LITTLE IS KNOWN ON THE MECHANISMS THAT ALLOW THESE VIRUSES TO CROSS EPITHELIAL BARRIERS IN THE GASTROINTESTINAL OR UROGENITAL TRACT ;= !LSO AFTER DISSEMI NATION INTO THE BLOODSTREAM THE MECHANISMS THAT ALLOW EFFICIENT TARGETING OF HEPATOCYTES HAVE NOT BEEN CLEARLY UNRAVELLED &URTHERMORE ,3%# HAVE SOME UNIQUE FEATURES THAT COMPLICATE HEPATOCELLULAR INFECTION FOR A BLOOD BORNE VIRUS 4HE FIRST OBSTACLE IS THE PHYSICAL BARRIER FORMED BY ,3%# ,3%# SEPARATE HEPATOCYTES FROM LEUKOCYTES PASSING WITHIN THE BLOOD THROUGH THE LIVER ;= )T HAS BEEN OBSERVED THAT HEPATOCYTE MICROVILLI PROTRUDE INTO THE SINUSOIDAL LUMEN ALLOWING FOR DIRECT CONTACT WITH BLOOD BORNE CELLS OR PATHOGENS ;= "UT THE OVERALL SURFACE AREA OF ,3%# COMPARED TO PENETRATING HEPATOCYTE MICROVILLI IS MUCH MORE PROMINENT (OWEVER ,3%# HAVE FENESTRAE WHICH ARE ORGANISED INTO SIEVE PLATES AND THE MEAN SIZE OF THESE FENESTRAE RANG ING BETWEEN AND NM IS DYNAMICALLY REGULATED ;= &ENESTRAE WOULD PROVIDE A DIRECT PORTAL OF ENTRY FOR BLOOD BORNE VIRUSES TO THE PARENCHYMA )T HAS BEEN PROPOSED EARLIER FOR 0LASMODIUM BERGHEI THAT SPOROZOITES INFECT HEPATOCYTES DIRECLY THROUGH FENESTRAE ;= BUT THIS HAS NOT BEEN CONFIRMED BY OTHER SCIENTISTS IN THE FIELD RATHER SPOROZOITE TARGETING OF THE LIVER INVOLVES INITIAL INFECTION OF +UPFFER CELLS ;= AND TRANSIENT INFECTION OF MUL TIPLE HEPATOCYTES BY A SINGLE SPOROZOITE BEFORE PRODUCTIVE HEPATOCELLULAR INFECTION IS FINALLY ACHIEVED ;= (EPATOTROPIC VIRUSES COULD ALSO GAIN ACCESS
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TO THE SPACE OF $ISSÏ BY DIFFUSION THROUGH ENDOTHELIAL FENESTRAE "UT AS THE SPACE OF $ISSÏ IS FILLED WITH EXTRACELLULAR MATRIX WHICH IS NOT READILY VISIBLE IN ELECTRON MICROSCOPY PASSIVE DIFFUSION OF PARTICLES LARGER THAN NM INTO THE SPACE OF $ISSÏ AND UPTAKE BY HEPATOCYTES DOES NOT OCCUR WITH HIGH EFFI CIENCY ;= )T IS THEREFORE REASONABLE TO ASSUME THAT HEPATOTROPIC VIRUSES WHICH ALL EXCEED NM IN DIAMETER DO NOT HAVE DIRECT ACCESS TO HEPATOCEL LULAR MICROVILLI IN THE SPACE OF $ISSÏ )T IS ALSO UNLIKELY THAT IN THE CASE OF VIRUS ENTRY THROUGH FENESTRAE PASSIVE DIFFUSION WOULD SUFFICE TO BRIDGE THE DISTANCE TO THE HEPATOCYTE WITHIN THE EXTRACELLULAR MATRIX 4HE SECOND OBSTACLE POSED BY ,3%# IS THEIR ENORMOUS SCAVENGER ACTIVITY ;= "LOOD BORNE MOLECULES ARE SCAVENGED MOST EFFICIENTLY AND ALSO BLOOD BORNE HEPA$.! VIRUS IS FOUND WITHIN MINUTES AFTER INTRAVENOUS APPLICA TION IN THE LIVER WITHIN ,3%# BUT NOT IN OTHER HEPATIC CELL POPULATIONS ;= )NTERESTINGLY +UPFFER CELLS DO NOT CONTRIBUTE TO THE SAME EXTENT AS ,3%# TO SCAVENGING OF SMALL MOLECULES OR PATHOGENS FROM THE BLOOD STREAM ;= 'IVEN THE LOW DOSE INFECTION PARADIGM FOR HEPA$.! VIRUSES WHERE ONE VIRUS IS SUFFICIENT TO ESTABLISH HEPATOCELLULAR INFECTION ;= AND 3 7IEHLAND PERSONAL COMMUNICATION 4HESE EXPERIMENTAL RESULTS RATHER SUPPORT THE NOTION THAT HEPA$.! VIRUSES INITIALLY TAKEN UP BY ,3%# STILL HAVE THE POTENTIAL TO REACH AND INFECT NEIGHBOURING HEPATOCYTES THE ONLY CELL TYPE WHERE REPLICATION OF THIS HEPATOTROPIC VIRUS CAN TAKE PLACE 4HE MOST LIKELY MOLECULAR MECHANISM FOR VIRUSES TO COME ACROSS THIS PHYSICAL AND FUNCTIONAL CELL BARRIER IS TRANSCYTOSIS 4RANSCYTOSIS IS A COMMON MECHANISM FOR MACROMOLECULES TO OVERCOME TIGHT CELL LAYERS )T IS DIVIDED INTO ENDOCYTOSIS TRANSPORT ACROSS THE CELL AND EXOCYTOSIS 4HE BEST STUDIED EXAMPLES ARE TRANSCYTOSIS OF )G! IN POLARISED EPITHELIAL CELLS AND THE TRANS CYTOSIS OF MACROMOLECULES THROUGH ENDOTHELIUM
2ECEPTOR MEDIATED TRANSCYTOSIS )MMUNGLOBULIN ! )G! IS SYNTHESISED BY PLASMA CELLS IN THE LAMINA PROPRIA OF THE DIGESTIVE UROGENITAL AND RESPIRATORY TRACT "UT )G! EXERTS ITS FUNCTION ON THE LUMINAL SIDE OF THE MUCOSA INDICATING THAT TRANSPORT OF )G! THROUGH EPITHELIAL CELLS IS REQUIRED 4HE TRANS CELLULAR TRANSPORT OF DIMERIC )G! D)G! WITH ITS RECEPTOR POLYMERIC IMMUNOGLOBULIN RECEPTOR P)G2 WAS EXTENSIVELY STUDIED IN POLARISED -ADIN $ARBY CANINE KIDNEY CELLS -$#+ RAT LIVER HEPATOCYTES AND HEPATOCYTE CELL LINES D)G! BINDS ON THE BASOLATERAL SURFACE TO ITS RECEPTOR P)G2 AND THE RESULTING COMPLEX BUT ALSO THE EMPTY P)G2 AND IS THEN ENDOCYTOSED VIA CLATHRIN COATED PITS ;= /N THEIR WAY FROM THE BASOLATERAL TO APICAL CELL SURFACE THE P)G2 TRAFFICS THROUGH VARIOUS ENDOSOMAL COMPARTMENTS DEPENDING ON THE MODEL SYSTEM )N -$#+ CELLS THE P)G2 TRAVELS THROUGH A BASOLATERAL EARLY ENDOSOME A COMMON ENDO SOME AND AN APICAL RECYCLING ENDOSOME !2% ;n= )N HEPATOCYTES THERE ARE ONLY TWO COMPARTMENTS THE BASOLATERAL EARLY ENDOSOME AND A
The liver as immune escape site for pathogens
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Figure 2. The different mechanisms of transcytosis. Immunglobulins or immunglobin/antigencomplexes are transported through cells after binding to specific receptors (left). The pIgR transports dIgA molecules, produced in the lamina propria, across the epithelial cell layer in a basolateral to apical direction into the lumen. The reverse mechanism, the transport of IgA-Antigen complexes from the lumen (apical) to the basolateral side of the cell, is also possible, but to a lesser extent. For IgG, the receptor involved in transcytosis is FcRn, which can transport IgGs and IgG-Antigen-complexes in both directions. In the middle, the direct, receptor-independent transport of particles through caveolae is depicted. Furthermore, transport of virus can occur independent of transcytosis through transinfection. Thereby a cell, which is not infected by the virus, transports virus bound to its surface across cell layers. After transmigration the cell mediates infection in trans of the target cells, where the virus then replicates (right).
subapical compartment (SAC) [35, 36]. After exit from the ARE/SAC, pIgR is transported to the apical plasma membrane. During this transport or at the plasma membrane pIgR is cleaved at the extracellular domain and this cleaved part is called the secretory component (SC) [37]. dIgA which has been bound to pIgR and is now in complex with cleaved SC is called secretory IgA (sIgA) (Fig. 2). Binding of luminal IgA to virus and subsequently to pIgR on mucosal surfaces may therefore allow virus to cross the epithelial barrier. As mentioned above pIgR is endocytosed at the basolateral side irrespective if dIgA is bound or not. Transcytosis of ‘empty’ pIgR may thus allow for binding of luminal IgA to occur at the apical plasma membrane. This is possible because, at least in the MDCK model, pIgR molecules are not completely cleaved. IgA bound to pIgR at the apical plasma membrane has been shown to be transcytosed in a retrograde fashion and to be released at the basolateral side [38]. This empty pIgR can also bind HAV-IgA complexes on the apical side and transcytoses it back to the basolateral side where HAV-IgA complexes are released (Fig. 2). Such HAV-IgA complexes are shown to
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BE INFECTIOUS FOR HEPATOCYTES ;= (OWEVER THIS RETROGRADE TRANSCYTOTIC TRANSPORT APPEARS UNLIKELY TO BE EFFICIENT FOR VIRUS TRANSCYTOSIS BECAUSE THE PRESENCE OF VIRUS SPECIFIC )G! LEADS TO INTRACELLULAR VIRUS NEUTRALISATION DUR ING THE PROCESS OF TRANSCYTOSIS ;= ! SECOND RECEPTOR INVOLVED IN TRANSCYTOTIC TRANSPORT IS ALSO SPECIFIC FOR )G IE &C2N &C2N IS EXPRESSED IN VARIOUS TISSUES NAMELY THE PLACENTA WHERE IT ALLOWS SELECTIVE DELIVERY OF )G' FROM THE MATERNAL TO THE FETAL BLOOD CIRCULATION AND ALSO IN THE ENDOTHELIUM OF SMALL BLOOD VESSELS AND BINDS )G'S ;= )N INTESTINAL EPITHELIAL CELLS AS WELL AS CULTURED INTESTINAL 4 CELLS )G'S ARE TRANSCYTOSED IN BOTH DIRECTIONS BY &C2N &IG ; = 4HIS INDICATES A NEW ROLE FOR THE NEONATAL &C2N NAMELY TRANSPORT OF )G' FROM THE BASAL SIDE TO APICAL SIDE OF THE CELL AND SUBSEQUENT SECRETION !FTER ANTI GEN BINDING )G' ANTIGEN COMPLEXES ARE BOUND BY &C2N AND TRANSCYTOSED IN THE OPPOSITE DIRECTION DELIVERING THE COMPLEXES OUT OF THE LUMEN TO THE LAMINA PROPRIA WHERE IMMUNE RESPONSES AGAINST LUMINAL ANTIGENS THEN CAN TAKE PLACE ;= ,3%# ALSO EXPRESS &C2N AND IT IS TEMPTING TO SPECULATE THAT HEPATOTROPIC VIRUSES COMPLEXED BY )G' WOULD BIND TO &C2N WHICH THEN WOULD ALLOW TRANSCELLULAR TRANSPORT TOWARDS THE SPACE OF $ISSÏ 3TILL IT IS UNCLEAR WHETHER )G COMPLEXED VIRUS WOULD BE SUBJECTED TO INTRACELLULAR NEUTRALISATION SIMILAR TO THE OBSERVATION FOR )G! MEDIATED NEUTRALISATION OF ()6 ;= )T HAS ALSO BEEN SHOWN THAT RECEPTOR MEDIATED TRANSCYTOSIS FROM A NON IMMUNGLOBULIN RECEPTOR CAN LEAD TO A TRANSPORT OF MACROMOLECULESPARTICLES ACROSS A CELL LAYER -ANNAN COATED GOLD PARTICLES OF NM SIZE COMPARABLE IN SIZE TO SOME VIRUSES INJECTED INTO THE TAIL VEIN OF RATS ARE RAPIDLY TAKEN UP BY ENDOTHELIAL CELLS IN THE LIVER 4HE MANNAN COATED GOLD PARTICLES ACCU MULATED IN COATED PITS ON THE PLASMA MEMBRANE ON ENDOTHELIAL CELLS n H AFTER INJECTION THE GOLD PARTICLES ARE FOUND NEAR THE BASOLATERAL SIDE OF ,3%# NEXT TO THE SPACE OF $ISSÏ AND LATER ON THEY ARE ALSO FOUND IN THE ADJA CENT HEPATOCYTES ;= INDICATING TRANSCYTOTIC TRANSPORT OF MANNAN COATED PARTICLES AND DELIVERY INTO NEIGHBOURING HEPATOCYTES .OT ONLY GOLD PARTICLES MAY BE SUBJECT TO TRANSCYTOTIC TRANSPORT THROUGH ,3%# )T HAS BEEN SUGGESTED THAT BLOOD BORNE HEPATOTROPIC VIRUSES IN PARTICULAR DUCK HEPATITIS " VIRUS $("6 ARE TRANSCYTOSED THROUGH THE LIVER SINUSOIDAL ENDOTHELIUM "REINER ET AL HAS SHOWN THAT FLUORESCENTLY LABELLED VIRAL PARTICLES AND GOLD LABELLED $("6 PARTICLES ARE RAPIDLY TAKEN UP BY ,3%# ;= #ONFOCAL LASER SCANNING MICROSCOPY ANALYSIS REVEALED THAT FLUORESCENTLY LABELLED VIRAL PARTICLES COLOCALISED WITH THE $("6 RECEPTOR CARBOXYPEPTIDASE $ IN THE TRANS 'OLGI COMPARTMENT THEREBY RESCUING VIRUS PARTICLES FROM LYSOSOMAL DEGRADATION !LTHOUGH RAPID UPTAKE OF $("6 WAS OBSERVED INTO ,3%# THERE WAS NO VIRAL GENE EXPRESSION OR FORMATION OF VIRAL PROGENY ;= 7E ASSUMED THAT $("6 PARTICLES WERE TRANSCYTOSED THROUGH ,3%# FOLLOWING RAPID INITIAL UPTAKE AND THAT ABSENCE OF ,3%# INFECTION WOULD ALLOW TRANSCYTOSED $("6 TO BE AVAILABLE FOR SUBSEQUENT INFECTION OF NEIGHBOURING HEPATOCYTES ;= 3UCH A MODEL WOULD NOT ONLY
4HE LIVER AS IMMUNE ESCAPE SITE FOR PATHOGENS
EXPLAIN THE PARADOX THAT THE VAST MAJORITY OF VIRUS PARTICLES IS TAKEN UP PREFERENTIALLY BY SCAVENGER ,3%# AND NOT BY HEPATOCYTES BUT STILL ALLOWS FOR SMALL NUMBERS OF VIRUSES TO ESTABLISH PRODUCTIVE HEPATOCELLULAR INFECTION )T WOULD ALSO PROVIDE AN EXPLANATION TO THE QUESTION HOW HEPATOTROPIC VIRUSES REACH THE LIVER BECAUSE THE SCAVENGER FUNCTION OF ,3%# WOULD TARGET THE VIRUS TO THE LIVER
2ECEPTOR INDEPENDENT TRANSCYTOSIS 5PTAKEENDOCYTOSIS OF MACROMOLECULES CAN ALSO OCCUR IN A RECEPTOR INDEPENDENT WAY /N ENDOTHELIAL CELLS NEGATIVELY CHARGED MOLECULES ARE MOSTLY REJECTED DUE TO THE NEGATIVE CHARGE OF THE APICAL PLASMA MEMBRANE #LATHRIN COATED PITS ARE ALSO MOSTLY NEGATIVELY CHARGED LEADING TO THE FACT THAT CATIONIC MOLECULES PREFERENTIALLY BIND TO CLATHRIN COATED PITS AND ARE SUBSEQUENTLY DEGRADED IN LYSOSOMES ;= .EGATIVELY CHARGED MOLECULES WHICH ARE NOT ACCESSIBLE TO THIS PATHWAY ARE TAKEN UP BY PINOCYTOSIS AND SHUTTLED TO THE BASOLATERAL SIDE WHERE THEY ARE RELEASED 4HIS TRANSCYTOTIC TRANSPORT IS MOSTLY MEDIATED THROUGH CAVEOLAE BY CAVEOLIN &IG )T HAS BEEN SHOWN RECENTLY THAT CAVEOLIN KNOCKOUT MICE CANNOT TRANS PORT GOLD LABELLED "3! FROM THE LUMINAL SIDE OF THE VESSEL TO THE INTERSTI TIUM WHEREAS WILD TYPE MICE ARE CAPABLE OF TRANSCYTOSING THESE PARTICLES 'IVEN THE SMALL SIZE OF SOME VIRUSES WHICH IS IN SOME CASES COMPARABLE TO GOLD PARTICLES THIS IS ALSO AN ATTRACTIVE MODEL HOW VIRUSES CAN CROSS ENDOTHE LIAL CELLS TO REACH THEIR TARGET CELLS IN THE TISSUE
)NFECTION IN TRANS 4RANSINFECTION IS A COMMON MECHANISM BY WHICH VIRUSES REACH THEIR TARGET CELLS )N CONTRAST TO INFECTION IN CIS WHERE THE VIRUS DIRECTLY INFECTS ITS TARGET CELL INFECTION IN TRANS DESCRIBES A MECHANISM WHERE THE VIRUS ATTACHES FIRST TO A CELL WHICH ITSELF IS NOT INFECTED BUT AT LATER TIME POINTS MEDIATES INFEC TION OF THE TARGET CELL 3UCH A @4ROJAN HORSE STRATEGY HAS BEEN SHOWN TO BE USED BY ()6 WHICH FIRST BINDS TO DENDRITIC CELLS IN SUBMUCOSAL TISSUE AND IS CARRIED BY DENDRITIC CELLS INTO THE DRAINING LYMPH NODE WHERE INFECTION OF THE #$ 4 CELLS OCCURS BY CLOSE INTERACTION OF $# SURFACE BOUND ()6 WITH #$ 4 CELLS ;= )NTERESTINGLY ()6 IS CAPTURED BY A # TYPE )) LECTIN $# 3)'. THAT DOES NOT TARGET ()6 FOR LYSOSOMAL DESTRUCTION UPON RECEP TOR MEDIATED ENDOCYTOSIS BUT ALLOWS FOR RE SHUTTLING OF ()6 $# 3)'. COMPLEXES TO THE CELL SURFACE 4HIS STEP FACILITATES INFECTION OF THE TARGET CELLS IN TRANS ! SIMILAR MECHANISM FOR VIRAL PROPAGATION HAS BEEN REPORTED FOR %"6 ;= 4HIS OPENS UP THE POSSIBILITY THAT HEPATOTROPIC VIRUSES BOUND TO LEUKOCYTES THAT TRANSMIGRATE ACROSS THE ENDOTHELIAL BARRIER MAY ACHIEVE ACCESS TO HEPATOCYTES &IG
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(OWEVER $# 3)'. IS KNOWN TO BIND A BROAD VARIETY OF DIFFERENT VIRUSES ;n= AND $# 3)'. AS WELL AS ITS HOMOLOG $# 3)'.2 , 3)'. ARE FOUND IN THE LIVER ;= 2ECENT PUBLICATIONS SHOW THAT , 3)'. AND ALSO $# 3)'. ARE EXPRESSED ON ,3%# AND THAT THESE LECTINS ARE CAPABLE OF CAPTUR ING (#6 PARTICLES WITH HIGH AFFINITY ; = 4HESE MOLECULES HOWEVER DO NOT PROMOTE ENTRY OF (#6 AND SUBSEQUENT INFECTION OF ,3%# )N CONTRAST IT HAS BEEN SHOWN THAT LIVER SINUSOIDAL ENDOTHELIAL CELLS PROMOTE THE UPTAKE OF (#6 LIKE PARTICLES IN PRIMARY RAT AND HUMAN HEPATOCYTES ;= (IGHLY PURI FIED HEPATOCYTES IN CULTURE DO NOT TAKE UP (#6 LIKE PARTICLES WHEREAS IN CO CULTURE WITH ,3%# UPTAKE OF VIRUS PARTICLES INTO HEPATOCYTES WAS OBSERVED #OLLECTIVELY THESE RESULTS SUGGEST THE NOTION THAT VIRUS INTERNALISED BY ,3%# IS NOT DEGRADED BUT IS AVAILABLE AT LATER TIME POINTS FOR INFECTION OF HEPATO CYTES IN TRANS
4HE LIVER AS AN IMMUNOREGULATORY ORGAN 4HERE IS A CONTINUOUS NEED TO REGULATE ANTIGEN SPECIFIC IMMUNE RESPONSES IN ORDER TO ACHIEVE PROTECTION FROM INFECTION BY MICROORGANISMS AND AT THE SAME TIME TO AVOID AUTOIMMUNE REACTIVITY 4HIS BALANCE IS MAINTAINED BY REGULATING THE ACTIVITY OF ANTIGEN SPECIFIC EFFECTOR 4 CELLS AT VARIOUS LEVELS !UTOREACTIVE 4 CELLS ARE ELIMINATED EARLY ON DURING THEIR DEVELOP MENT IN THE THYMUS BY NEGATIVE SELECTION WHICH ASSURES ABSENCE OF 4 CELLS THAT RECOGNISE SELF ANTIGENS WITH HIGH AFFINITY ;= )N THE PERIPHERY 4 CELL ACTIVITY IS FURTHER CONTROLLED BY SEGREGATION OF ANTIGEN THEREBY AVOIDING ANTIGEN SPECIFIC STIMULATION OF 4 CELLS BY CLONAL DELETION FOLLOWING CONTACT WITH TOLEROGENIC ANTIGEN PRESENTING CELLS OR INCOMPLETE 4 CELL STIMULA TION BY INDUCTION OF ANERGY AGAIN THROUGH TOLEROGENIC ANTIGEN PRESENT ING CELLS OR BY SKEWING IMMUNE RESPONSES EITHER BY MODULATING 4 HELPER CELL RESPONSES 4Hn4H OR BY REGULATING EFFECTOR CELL FUNCTION THROUGH REGULATORY 4 CELLS 0ERIPHERAL IMMUNE TOLERANCE ENTAILS THE CONTROL OF EFFECTOR ACTIVITY OF #$ 4 CELLS BUT EVEN MORE IMPORTANTLY OF EFFECTOR #$ 4 CELLS 3ECONDARY LYMPHATIC TISSUE IS BELIEVED TO BE THE ONLY LOCATION WHERE INDUCTION OF IMMUNE RESPONSES EITHER IN THE DIRECTION OF IMMUNITY OR PERIPHERAL TOLERANCE CAN BE INITIATED "UT NUMEROUS REPORTS HAVE POINTED TO THE FACT THAT THE INITIATION OF IMMUNE RESPONSES IS NOT LIMITED TO SECONDARY LYMPHATIC TISSUE BUT MAY OCCUR AT MANY SITES IN THE BODY ; = %ARLY WORK IN EXPERIMENTAL TRANSPLANTATION SURGERY REVEALED THAT LIVER TRANSPLANTS WERE BETTER TOLERATED BY THE RECIPIENTS IMMUNE SYSTEM AND THAT THIS TOLERANCE WAS ANTIGEN SPECIFIC BECAUSE LIVER TRANSPLANTATION TRANSFERRED PROTECTION FROM IMMUNE REJECTION PROVIDED THE SECOND TRANSPLANTED ORGAN WAS FROM THE SAME DONOR WHEREAS THIRD PARTY GRAFTS WERE INEVITABLY REJECTED ;n= 4HUS CELL POPULATIONS WITHIN THE LIVER CONTRIBUTE TO THE INDUCTION OF PERIPH ERAL IMMUNE TOLERANCE
4HE LIVER AS IMMUNE ESCAPE SITE FOR PATHOGENS
)NVESTIGATING THE IMMUNE REGULATORY FUNCTION OF HEPATIC CELL POPULATIONS ONE HAS TO CONSIDER THAT THE ABILITY TO PRESENT EXOGENOUS ANTIGENS ON -(# #LASS )) OR -(# #LASS ) MOLECULES TO #$ OR #$ 4 CELLS RESPECTIVELY IS RESTRICTED TO PROFESSIONAL ANTIGEN PRESENTING CELLS IE MACROPHAGES " CELLS AND DENDRITIC CELLS /NLY THESE IMMUNE CELL POPULATIONS ARE EQUIPPED WITH CO SIGNALLING MOLECULES THAT DELIVER IN ADDITION TO 4 CELL RECEPTOR SIGNALING FURTHER STIMULI THAT INFLUENCE THE QUALITY IMMUNITY OR TOLERANCE OF THE ENSUING 4 CELL RESPONSE (EPATOCYTES EXPRESS LITTLE -(# #LASS ) AND NO -(# #LASS )) MOLECULES AND BEAR THE ABILITY TO INITIATE #$ 4 CELL RESPONSES (OWEVER PRIMING OF NAIVE #$ 4 CELLS BY HEPATOCYTES LEADS TO INCOMPLETE 4 CELL ACTIVATION AND FOLLOWING INITIAL PROLIFERATION 4 CELLS UNDERGO APOPTOSIS RESULTING IN CLONAL DELETION OF 4 CELLS RECOGNISING THEIR ANTIGEN ON HEPATOCYTES ;= )NTERESTINGLY LOCATION AND TIMING DURING THE INDUCTION OF AN IMMUNE RESPONSE DETERMINES ALSO THE QUALITY OF AN IMMUNE RESPONSE )F ANTIGEN IS FIRST RECOGNISED BY #$ 4 CELLS ON HEPATOCYTES IMMUNE TOLERANCE ENSUES EVEN IF ANTIGEN RECOGNITION OCCURS LATER ON PROFESSIONAL ANTIGEN PRESENTING DENDRITIC CELLS IN LYMPHATIC TISSUE )N CONTRAST IF ANTIGEN IS FIRST SEEN ON ACTI VATED DENDRITIC CELLS IN LYMPHATIC TISSUE IMMUNITY DEVELOPS AND SUBSEQUENT ANTIGEN RECOGNITION ON HEPATOCYTES LEADS TO DEVELOPMENT OF IMMUNE MEDI ATED HEPATITIS ;= 4HESE RESULTS DEMONSTRATE THAT THE INITIAL ANTIGEN SPE CIFIC CONTACT OF NAIVE #$ 4 CELLS DETERMINES THE OUTCOME OF AN IMMUNE RESPONSE !S VIRUS INFECTED HEPATOCYTES WILL PRESENT VIRAL ANTIGENS ON -(# #LASS ) MOLECULES TO #$ 4 CELLS IT IS TEMPTING TO SPECULATE THAT SUCH TOLERIS ING MECHANISMS MAY ALSO BE OPERATIVE DURING VIRAL HEPATITIS 4HERE IS A CONTINUOUS DEBATE AS TO WHETHER THERE IS DIRECT CONTACT OF CIRCULATING #$ 4 CELLS WITH -(# #LASS ) MOLECULES ON HEPATOCYTES ACROSS STELLATE CELLS AND ,3%# 5SING ULTRASTRUCTURAL ANALYSIS IT WAS REPORTED THAT #$ 4 CELLS COULD PENETRATE WITH PODOSOMES THROUGH SINUSOIDAL FENESTRA TIONS AND ESTABLISH DIRECT FOCAL CONTACT SITES WITH HEPATOCYTES ;= 4HE INVA SION OF ENDOTHELIAL CELLS WITH PODOSOMES INITIATES TRANSCELLULAR DIAPEDESIS OF 4 CELLS ;= BUT IT HAS NOT BEEN CONVINCINGLY SHOWN THAT 4 CELLS RECOGNISING THEIR ANTIGEN IN THE LIVER NECESSARILY UNDERGO TRANSMIGRATION INTO THE HEPATIC PARENCHYMA (OWEVER RECOGNITION OF A UBIQUITOUSLY EXPRESSED ANTIGEN LEADS TO PREFERENTIAL ACCUMULATION OF #$ 4 CELLS IN THE LIVER WHICH SUP PORTS THE NOTION MENTIONED ABOVE THAT THE LIVER INITIATES 4 CELL RESPONSES ;= #ONTROVERSIAL RESULTS WERE OBTAINED WHEN USING DIFFERENT MOUSE STRAINS TO DETERMINE WHETHER #$ 4 CELLS CAN RECOGNISE THEIR ANTIGEN ON HEPATO CYTES IN VIVO $EPENDING ON THE MOUSE MODEL USED NAIVE OR ACTIVATED #$ 4 CELLS WERE EITHER SECLUDED FROM RECOGNISING THEIR ANTIGEN ON HEPATOCYTES ; = WHICH INDICATED EFFICIENT BARRIER FUNCTION BY SINUSOIDAL CELL POPU LATIONS OR WERE INCOMPLETELY STIMULATED ; = WHICH SUGGESTED DIRECT 4 CELL HEPATOCYTE CONTACT #OLLECTIVELY THESE RESULTS SUGGEST THAT IN CASE OF INFECTION WITH A HEPATOTROPIC VIRUS PRESENTATION OF VIRAL ANTIGENS BY HEPA TOCYTES WILL TRIGGER THE INDUCTION OF A #$ 4 CELL RESPONSE WHICH HOWEVER
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WILL BE INSUFFICIENT TO CLEAR INFECTION )T IS OF INTEREST TO NOTE THAT INTERACTION WITH RECENTLY PRIMED #$ 4 CELLS LICENSES HEPATOCYTES TO ENGAGE IN FURTHER INTERACTION WITH NAIVE #$ 4 CELLS ;= 4HIS WOULD ALLOW HEPATOCYTES TO ENGAGE IN IMMUNE REGULATION ONCE THE INITIAL TRIGGER FOR INDUCTION OF AN IMMUNE RESPONSE HAS BEEN GIVEN BY A PROFESSIONAL ANTIGEN PRESENTING CELL POPULATION "ONE MARROW DERIVED ANTIGEN PRESENTING CELLS IN THE LIVER SUCH AS +UPFFER CELLS AND DENDRITIC CELLS ALSO CONTRIBUTE TO LOCAL MODULATION OF THE IMMUNE RESPONSE IN THE LIVER +UPFFER CELLS INDUCE TOLERANCE RATHER THAN IMMUNITY ;= 4HIS TOLEROGENIC PHENOTYPE OF +UPFFER CELLS MAY BE RELATED TO THE CONTINUOUS EXPOSURE TO GUT DERIVED ,03 ; = THAT STIMULATES PRO DUCTION OF THE IMMUNOREGULATORY CYTOKINE ), IN +UPFFER CELLS ;= )N THE ABSENCE OF A STRONG PROINFLAMMATORY STIMULUS SUCH CONTINUOUS EXPRES SION OF ), MAY PREVENT THE INITIATION OF 4 CELL RESPONSES BY THIS CELL POPULATION &URTHERMORE +UPFFER CELLS ARE NOT ENDOWED WITH THE MOLECULAR MACHINERY TO PRESENT EXOGENOUS ANTIGENS ON -(# #LASS ) MOLECULES TO #$ 4 CELLS ;= AND THEREFORE CANNOT CONTRIBUTE TO INDUCTION OF VIRUS SPE CIFIC IMMUNITY WHICH REQUIRES CROSS PRESENTATION OF VIRAL ANTIGENS ON -(# #LASS ) MOLECULES TO #$ 4 CELLS ;= (EPATIC DENDRITIC CELLS ARE A HETEROGENEOUS POPULATION CONSISTING OF MYELOID AND PLASMACYTOID DENDRITIC CELLS ;= 7HILE DENDRITIC CELLS ARE CONSIDERED TO BE MOST POTENT IN INDUCING 4 CELL IMMUNITY UPON APPROPRIATE STIMULATION VARIOUS REPORTS HAVE SHOWN THAT HEPATIC DENDRITIC CELLS DO NOT UNDERGO FULL MATURATION UPON CONTACT WITH 4,2 LIGANDS AND SUBSEQUENTLY FAIL TO INDUCE STRONG 4 CELL IMMUNITY ; = )T IS LIKELY THAT CROSS PRESENTA TION OF VIRAL ANTIGENS BY HEPATIC DENDRITIC CELLS ALSO FAILS TO INDUCE VIRUS SPE CIFIC IMMUNITY AND RATHER PROMOTES INDUCTION OF ANTIGEN SPECIFIC IMMUNE TOLERANCE 3TELLATE CELLS HAVE BEEN FOR MANY YEARS IN THE FOCUS OF RESEARCH ON THE MOLECULAR MECHANISMS PROMOTING HEPATIC FIBROSIS ;= !MONG THE SOLUBLE PROFIBROGENIC MEDIATORS RELEASED BY STELLATE CELLS IS THE POTENT IMMUNE REGULATORY CYTOKINE 4'&B "UT STELLATE CELLS DO NOT ONLY CONTRIBUTE AS BYSTANDER CELLS TO HEPATIC IMMUNE REGULATION BUT ALSO HAVE CELL AUTONOMOUS IMMUNE FUNCTIONS 4HEY CONSTITUTIVELY EXPRESS 4,2S AND ARE RESPONSIVE TO STIMULATION WITH ,03 WHICH ENDOWS THEM WITH SENTINEL FUNCTION ;= &URTHERMORE THEY BEAR THE CAPACITY TO PRESENT ANTIGENS ON -(# #LASS ) AND #$ MOLECULES TO #$ OR .+4 CELLS ;= (OWEVER STELLATE CELLS DO NOT HAVE PROMINENT SCAVENGER FUNCTION 3CHURICH AND +NOLLE UNPUBLISHED OBSERVATION AND THEREFORE ARE UNLIKELY TO CONTRIBUTE TO THE CONTROL OF 4 CELL RESPONSES DIRECTED AGAINST SOLUBLE VIRAL ANTIGENS !MONG THE DIFFERENT ANTIGEN PRESENTING CELL POPULATIONS IN THE LIVER ,3%# APPEAR TO HAVE A PROMINENT ROLE BECAUSE THEY COMBINE EXTRAOR DINARY SCAVENGER ACTIVITY WITH ANTIGEN PRESENTING CAPACITY ; = 3CAVENGER FUNCTION OF ,3%# IS RELATED TO MOST EFFICIENT RECEPTOR MEDI ATED ENDOCYTOSIS AND CONSTITUTIVE EXPRESSION OF SCAVENGER RECEPTORS AND
4HE LIVER AS IMMUNE ESCAPE SITE FOR PATHOGENS
VARIOUS PATTERN RECOGNITION RECEPTORS SUCH AS THE MANNOSE RECEPTOR # TYPE LECTINS SUCH AS , 3)'. THE HYALURONIC ACID RECEPTOR ,96% AND THE MEMBERS OF THE STABILIN FAMILY ; = 4HIS HIGH ENDOCYTOTIC ACTIV ITY OF ,3%# IS COMBINED WITH THEIR ABILITY TO PRESENT EXOGENOUS ANTIGENS BOTH ON -(# #LASS )) MOLECULES AS WELL AS ON -(# #LASS ) MOLECULES !NTIGEN PRESENTATION ON CONSTITUTIVELY EXPRESSED -(# #LASS )) MOL ECULES TO #$ 4 CELLS IS NOT VERY EFFICIENT ;= BUT IN COMBINATION WITH CO STIMULATORY SIGNALING THROUGH LOW LEVEL EXPRESSION OF #$ ALLOWS ,3%# TO PRIME NAIVE #$ 4 CELLS ;= )MPORTANTLY #$ 4 CELLS PRIMED BY ANTIGEN PRESENTING ,3%# FAIL TO UNDERGO FUNCTIONAL MATURATION AND DO NOT DEVELOP INTO 4H EFFECTOR CELLS ;= 4HESE CELLS RATHER EXPRESS ), AND ), UPON ANTIGEN SPECIFIC RESTIMULATION AND THEREFORE LIKELY HAVE REGULATORY FUNCTION FOR OTHER IMMUNE RESPONSES -ORE IMPORTANTLY ,3%# HAVE THE CAPACITY TO PRIME NAIVE #$ 4 CELLS TOWARDS SOLUBLE ANTIGENS PRESENTED ON -(# #LASS ) MOLECULES )N CONTRAST TO -(# #LASS )) RESTRICTED ANTIGEN PRESENTATION THE CROSS PRESENTATION OF EXOGENOUS ANTIGENS ON -(# #LASS ) MOLECULES TO #$ 4 CELLS IS VERY EFFICIENT IN ,3%# ;= "UT AGAIN #$ 4 CELLS PRIMED BY ANTIGEN PRESENTING ,3%# FAIL TO UNDERGO FUNCTIONAL DIFFERENTIATION AND RATHER GAIN A STATE OF ANERGY WHERE THEY DO NOT RESPOND TO ANTIGEN SPE CIFIC RESTIMULATION WITH 4 CELL EFFECTOR FUNCTION SUCH AS EXPRESSION OF ), )&. a OR CYTOTOXICITY ;= 4OLERANCE INDUCTION BY ,3%# TOWARDS SOLUBLE ANTIGENS PLAYS A ROLE IN TWO PHYSIOLOGICAL SITUATIONS I ORAL TOLERANCE UPON INGESTION ORAL ANTIGENS RAPIDLY SPREAD IN THE ENTIRE ORGANISM WITHIN MINUTES TO HOURS /RAL ANTIGENS ARE ALSO DISTRIBUTED TO THE LIVER WHERE THEY ARE CROSS PRESENTED BY ,3%# #ROSS PRESENTATION OF ORAL ANTIGENS BY ,3%# LEADS TO INDUCTION OF #$ 4 CELL TOLERANCE TOWARDS ORAL ANTIGENS ;= AND THUS COMPLEMENTS THE INDUCTION OF REGULATORY #$ 4 CELLS BY TOLEROGENIC DENDRITIC CELLS WITHIN MESENTERIC LYMPH NODES ;= II TOLER ANCE TOWARDS APOPTOTIC CELL MATERIAL TOGETHER WITH THE SPLEEN THE LIVER CONTRIBUTES TO REMOVAL OF APOPTOTIC CELLS FROM THE SYSTEMIC CIRCULATION ;n= 7E HAVE REPORTED THAT APOPTOTIC CELL MATERIAL TAKEN UP BY ,3%# IS PROCESSED FOR ANTIGEN PRESENTATION ON -(# #LASS ) MOLECULES AND THAT APOPTOTIC CELL MATERIAL TAKEN UP IN VIVO IS SUFFICIENT TO DRIVE ANTIGEN SPE CIFIC 4 CELL STIMULATION ;= (OWEVER THE OUTCOME OF 4 CELL STIMULATION IS AGAIN TOLERANCE BECAUSE #$ 4 CELLS PRIMED BY ,3%# PRESENTING ANTIGEN FROM APOPTOTIC CELLS FAILED TO SHOW ANTIGEN SPECIFIC EFFECTOR FUNCTIONS ;= -ECHANISTICALLY TOLERANCE INDUCED BY ,3%# REQUIRES THE DELIVERY OF CO INHIBITORY SIGNALS VIA "( 0$ RECEPTOR LIGAND INTERACTION TO 4 CELLS DURING THE PRIMING PROCESS ;= $ESPITE INITIAL STIMULATION AND PROLIF ERATION TOLERANCE EVENTUALLY DEVELOPS IN ,3%# STIMULATED 4 CELLS WHICH EXPRESS ANTIAPOPTOTIC MOLECULES SUCH AS BCL ;= 4HIS DEMONSTRATES THAT TOLERANCE INDUCED BY ,3%# IS AN ACTIVE PROCESS THAT DOES NOT RESULT FROM INSUFFICIENT STIMULATION BUT RATHER RELIES ON DELIVERY OF CO INHIBITORY SIG NALS &URTHERMORE 4 CELLS ARE ANERGISED AND NOT CLONALLY ELIMINATED AFTER
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CONTACT WITH ANTIGEN PRESENTING ,3%# ;= WHICH IS IN CONTRAST TO CLONAL ELIMINATION OF 4 CELLS OBSERVED AFTER 4 CELL PRIMING BY TOLEROGENIC DEN DRITIC CELLS ;= 4HESE RESULTS SUGGEST THAT ,3%# CONTINUOUSLY SKEW #$ 4 CELL RESPONSES TOWARDS CIRCULATING ANTIGENS AND THEREBY CONTRIBUTE TO THE CONTROL OF SELF REACTIVITY BY PREVENTING AUTOIMMUNE REACTION AGAINST APOPTOTIC CELL MATERIAL OR DEVELOPMENT OF IMMUNITY AGAINST INNOCUOUS ANTIGENS SUCH AS FOOD ANTIGENS 4OLERANCE IS NOT ONLY ACHIEVED BY SKEWING THE FUNCTIONAL REPERTOIRE OF NAIVE #$ 4 CELLS BUT ALSO RESULTS FROM ATTENUATION OF EFFECTOR #$ 4 CELL FUNCTION +UPFFER CELLS AND ,3%# CONTRIBUTE TO ANTIGEN SPECIFIC RETEN TION AND ELIMINATION OF ACTIVATED #$ 4 CELLS IN THE LIVER ;n= 4HE CO INHIBITORY MOLECULE "( THAT IS EXPRESSED ON ,3%# AND +UPFFER CELLS ALSO CONTRIBUTES TO ELIMINATION OF ACTIVATED #$ 4 CELLS IN THE LIVER ;= )NTERESTINGLY "( MEDIATED ELIMINATION OF #$ 4 CELLS CONTRIBUTED TO THE DEVELOPMENT OF CHRONICITY OF VIRAL INFECTION IN THE LIVER ;=
4HE LIVER AS AN IMMUNE ESCAPE SITE FOR PATHOGENS 'IVEN THE TOLEROGENIC NATURE OF THE HEPATIC CELL POPULATIONS AND THE HEPATIC MICROENVIRONMENT IT IS NOT SURPRISING THAT THE LIVER FUNCTIONS AS AN IMMUNE ESCAPE SITE FOR PATHOGENS 4HE SEQUENCE OF ANTIGEN ENCOUNTER IN LIVER OR LYMPHATIC TISSUE AND THE NATURE OF THE CELL THAT PRESENTS ANTIGEN FIRST TO #$ 4 CELLS DETERMINE THE OUTCOME OF THE ANTIGEN SPECIFIC IMMUNE RESPONSE 4HIS MEANS THAT INFECTION OF THE LIVER WITH HEPATOTROPIC VIRUSES WHICH ARE RAPIDLY TAKEN UP BY ,3%# AND WHICH INFECT HEPATOCYTES GIVES RISE TO A SITUATION WHERE ANTIGEN IS PRESENTED BY TWO PROMINENT TOLEROGENIC CELL POPULATIONS IN THE LIVER )NITIAL PRESENTATION OF VIRAL ANTIGENS IN THE LIVER COULD SKEW SUBSEQUENT VIRUS SPECIFIC IMMUNE RESPONSES FOR A CERTAIN TIME PERIOD SO THAT ADDITIONAL MECHANISMS OF VIRAL PERSISTENCE SUCH AS WIDE SPREAD HEPATOCELLULAR INFECTION OR OTHER IMMUNE ESCAPE MECHANISMS COULD DEVELOP 4HUS ,3%# MAY CONTRIBUTE AT TWO STAGES TO VIRAL INFECTION OF THE LIVER FIRST IN ACUTE INFECTION WHERE SCAVENGING AND POSSIBLY TRANSCYTOSIS MAY SUPPORT LIVER SPECIFIC TARGETING OF HEPATOTROPIC VIRUSES AND FACILITATE HEPATOCYTE INFECTION AND SECOND DURING THE INITIAL AND LATER PHASES OF ANTIVIRAL IMMUNE RESPONSES WHERE ,3%# MAY CONTRIBUTE TO ATTENUATION OF VIRUS SPECIFIC #$ 4 CELL RESPONSES BY INDUCING VIRUS SPECIFIC #$ 4 CELL TOLERANCE
!CKNOWLEDGMENTS 4HE AUTHORS WISH TO THANK THE $&' AND THE 6OLKSWAGENSTIFTUNG FOR CON TINUOUS FINANCIAL SUPPORT
4HE LIVER AS IMMUNE ESCAPE SITE FOR PATHOGENS
2EFERENCES
"LOUIN ! "OLENDER 20 7EIBEL %2 $ISTRIBUTION OF ORGANELLES AND MEM BRANES BETWEEN HEPATOCYTES AND NONHEPATOCYTES IN THE RAT LIVER PARENCHYMA ! STEREOLOGICAL STUDY * #ELL "IOL n -AC0HEE 0* 3CHMIDT %% 'ROOM !# )NTERMITTENCE OF BLOOD FLOW IN LIVER SINUSOIDS STUDIED BY HIGH RESOLUTION IN VIVO MICROSCOPY !M * 0HYSIOL 'n "ILZER - 2OGGEL & 'ERBES !, 2OLE OF +UPFFER CELLS IN HOST DEFENSE AND LIVER DISEASE ,IVER )NT n &EY '( 'AULDIE * 4HE ACUTE PHASE RESPONSE OF THE LIVER IN INFLAMMA TION 0ROG ,IVER $IS n 7INWOOD 0* !RTHUR -* +UPFFER CELLS THEIR ACTIVATION AND ROLE IN ANIMAL MODELS OF LIVER INJURY AND HUMAN LIVER DISEASE 3EMIN ,IVER $IS n &ALASCA , "ERGAMINI ! 3ERAFINO ! "ALABAUD # $INI , (UMAN +UPFFER CELL RECOGNITION AND PHAGOCYTOSIS OF APOPTOTIC PERIPHERAL BLOOD LYMPHOCYTES %XP #ELL 2ES n -AC0HEE 0* 3CHMIDT %% 'ROOM !# %VIDENCE FOR +UPFFER CELL MIGRA TION ALONG LIVER SINUSOIDS FROM HIGH RESOLUTION IN VIVO MICROSCOPY !M * 0HYSIOL 'n 7ISSE % !N ELECTRON MICROSCOPIC STUDY OF THE FENESTRATED ENDOTHELIAL LINING OF RAT LIVER SINUSOIDS * 5LTRASTRUCT 2ES n 7ISSE % $E :ANGER 2" #HARELS + 6AN $ER 3MISSEN 0 -C#USKEY 23 4HE LIVER SIEVE CONSIDERATIONS CONCERNING THE STRUCTURE AND FUNCTION OF ENDO THELIAL FENESTRAE THE SINUSOIDAL WALL AND THE SPACE OF $ISSE (EPATOLOGY n "RAET & 7ISSE % 3TRUCTURAL AND FUNCTIONAL ASPECTS OF LIVER SINUSOIDAL ENDOTHELIAL CELL FENESTRAE A REVIEW #OMP (EPATOL ,IMMER ! /HL * 7INGENDER ' "ERG - *UNGERKES & 3CHUMAK " $JANDJI $ 3CHOLZ + +LEVENZ ! (EGENBARTH 3 ET AL #ROSS PRESENTATION OF ORAL ANTIGENS BY LIVER SINUSOIDAL ENDOTHELIAL CELLS LEADS TO #$ 4 CELL TOLERANCE %UR * )MMUNOL n 2EYNAERT ( 4HOMPSON -' 4HOMAS 4 'EERTS ! (EPATIC STELLATE CELLS ROLE IN MICROCIRCULATION AND PATHOPHYSIOLOGY OF PORTAL HYPERTENSION 'UT n 3AFADI 2 &RIEDMAN 3, (EPATIC FIBROSIS n ROLE OF HEPATIC STELLATE CELL ACTIVATION -ED'EN-ED n -C#USKEY 23 !NATOMY OF EFFERENT HEPATIC NERVES !NAT 2EC ! $ISCOV -OL #ELL %VOL "IOL n .ORRIS 3 #OLLINS # $OHERTY $' 3MITH & -C%NTEE ' 4RAYNOR / .OLAN . (EGARTY * /&ARRELLY # 2ESIDENT HUMAN HEPATIC LYMPHOCYTES ARE PHE NOTYPICALLY DIFFERENT FROM CIRCULATING LYMPHOCYTES * (EPATOL n (EYDTMANN - !DAMS $( 5NDERSTANDING SELECTIVE TRAFFICKING OF LYM PHOCYTE SUBSETS 'UT n 'EISSMANN & #AMERON 4/ 3IDOBRE 3 -ANLONGAT . +RONENBERG - "RISKIN -* $USTIN -, ,ITTMAN $2 )NTRAVASCULAR IMMUNE SURVEILLANCE BY #8#2 .+4 CELLS PATROLLING LIVER SINUSOIDS 0,O3 "IOL E
0ERCY ! +NOLLE AND $IRK 3TABENOW
'REGORY 3( 7ING %* .EUTROPHIL +UPFFER CELL INTERACTION IN HOST DEFENSES TO SYSTEMIC INFECTIONS )MMUNOL 4ODAY n #LARK 32 -A !# 4AVENER 3! -C$ONALD " 'OODARZI : +ELLY -- 0ATEL +$ #HAKRABARTI 3 -C!VOY % 3INCLAIR '$ ET AL 0LATELET 4,2 ACTIVATES NEUTROPHIL EXTRACELLULAR TRAPS TO ENSNARE BACTERIA IN SEPTIC BLOOD .AT -ED n 3CHWABE 2& 3EKI % "RENNER $! 4OLL LIKE RECEPTOR SIGNALING IN THE LIVER 'ASTROENTEROLOGY n "OMSEL - 4RANSCYTOSIS OF INFECTIOUS HUMAN IMMUNODEFICIENCY VIRUS ACROSS A TIGHT HUMAN EPITHELIAL CELL LINE BARRIER .AT -ED n 'EIJTENBEEK 4" +WON $3 4ORENSMA 2 VAN 6LIET 3* VAN $UIJNHOVEN '# -IDDEL * #ORNELISSEN ), .OTTET (3 +EWAL2AMANI 6. ,ITTMAN $2 ET AL $# 3)'. A DENDRITIC CELL SPECIFIC ()6 BINDING PROTEIN THAT ENHANCES TRANS INFECTION OF 4 CELLS #ELL n $OTZAUER ! "RENNER - 'EBHARDT 5 6ALLBRACHT ! )G! COATED PARTICLES OF (EPATITIS ! VIRUS ARE TRANSLOCALIZED ANTIVECTORIALLY FROM THE APICAL TO THE BASOLATERAL SITE OF POLARIZED EPITHELIAL CELLS VIA THE POLYMERIC IMMUNOGLOBULIN RECEPTOR * 'EN 6IROL n 3HIN 3# 6ANDERBERG *0 4ERZAKIS *! $IRECT INFECTION OF HEPATOCYTES BY SPOROZOITES OF 0LASMODIUM BERGHEI * 0ROTOZOOL n 0RADEL ' &REVERT 5 -ALARIA SPOROZOITES ACTIVELY ENTER AND PASS THROUGH RAT +UPFFER CELLS PRIOR TO HEPATOCYTE INVASION (EPATOLOGY n -OTA -- 0RADEL ' 6ANDERBERG *0 (AFALLA *# &REVERT 5 .USSENZWEIG 23 .USSENZWEIG 6 2ODRIGUEZ ! -IGRATION OF 0LASMODIUM SPOROZOITES THROUGH CELLS BEFORE INFECTION 3CIENCE n 3CHLEPPER 3CHAFER * (ULSMANN $ $JOVKAR ! -EYER (% (ERBERTZ , +OLB ( +OLB "ACHOFEN 6 %NDOCYTOSIS VIA GALACTOSE RECEPTORS IN VIVO ,IGAND SIZE DIRECTS UPTAKE BY HEPATOCYTES ANDOR LIVER MACROPHAGES %XP #ELL 2ES n 3MEDSROD " #LEARANCE FUNCTION OF SCAVENGER ENDOTHELIAL CELLS #OMP (EPATOL 3UPPL 3 "REINER +- 3CHALLER ( +NOLLE 0! %NDOTHELIAL CELL MEDIATED UPTAKE OF A HEPATITIS " VIRUS A NEW CONCEPT OF LIVER TARGETING OF HEPATOTROPIC MICROORGAN ISMS (EPATOLOGY n ,IMMER ! /HL * +URTS # ,JUNGGREN (' 2EISS 9 'ROETTRUP - -OMBURG & !RNOLD " +NOLLE 0! %FFICIENT PRESENTATION OF EXOGENOUS ANTIGEN BY LIVER ENDOTHELIAL CELLS TO #$ 4 CELLS RESULTS IN ANTIGEN SPECIFIC 4 CELL TOLER ANCE .AT -ED n *ILBERT !2 -ILLER $3 3COUGALL #! 4URNBULL ( "URRELL #* +INETICS OF DUCK HEPATITIS " VIRUS INFECTION FOLLOWING LOW DOSE VIRUS INOCULATION ONE VIRUS $.! GENOME IS INFECTIOUS IN NEONATAL DUCKS 6IROLOGY n 'EUZE (* 3LOT *7 3TROUS '* 0EPPARD * VON &IGURA + (ASILIK ! 3CHWARTZ !, )NTRACELLULAR RECEPTOR SORTING DURING ENDOCYTOSIS COMPARATIVE IMMUNO ELECTRON MICROSCOPY OF MULTIPLE RECEPTORS IN RAT LIVER #ELL n 7ANG % "ROWN 03 !ROETI " #HAPIN 3* -OSTOV +% $UNN +7 !PICAL AND BASOLATERAL ENDOCYTIC PATHWAYS OF -$#+ CELLS MEET IN ACIDIC COMMON
4HE LIVER AS IMMUNE ESCAPE SITE FOR PATHOGENS
ENDOSOMES DISTINCT FROM A NEARLY NEUTRAL APICAL RECYCLING ENDOSOME 4RAFFIC n ,EUNG 3- 2UIZ 7' !PODACA ' 3ORTING OF MEMBRANE AND FLUID AT THE APICAL POLE OF POLARIZED -ADIN $ARBY CANINE KIDNEY CELLS -OL "IOL #ELL n 4UMA 0, (UBBARD !, 4RANSCYTOSIS CROSSING CELLULAR BARRIERS 0HYSIOL 2EV n )HRKE ' -ARTIN '6 3HANKS -2 3CHRADER - 3CHROER 4! (UBBARD !, !PICAL PLASMA MEMBRANE PROTEINS AND ENDOLYN TRAVEL THROUGH A SUBAPICAL COMPARTMENT IN POLARIZED 7)& " HEPATOCYTES * #ELL "IOL n 2OJAS 2 !PODACA ' )MMUNOGLOBULIN TRANSPORT ACROSS POLARIZED EPITHE LIAL CELLS .AT 2EV -OL #ELL "IOL n "REITFELD 00 (ARRIS *- -OSTOV +% 0OSTENDOCYTOTIC SORTING OF THE LIGAND FOR THE POLYMERIC IMMUNOGLOBULIN RECEPTOR IN -ADIN $ARBY CANINE KIDNEY CELLS * #ELL "IOL n "OMSEL - (EYMAN - (OCINI ( ,AGAYE 3 "ELEC , $UPONT # $ESGRANGES # )NTRACELLULAR NEUTRALIZATION OF ()6 TRANSCYTOSIS ACROSS TIGHT EPITHELIAL BARRIERS BY ANTI ()6 ENVELOPE PROTEIN D)G! OR )G- )MMUNITY n 'HETIE 6 7ARD %3 -ULTIPLE ROLES FOR THE MAJOR HISTOCOMPATIBILITY COM PLEX CLASS ) RELATED RECEPTOR &C2N !NNU 2EV )MMUNOL n )SRAEL %* 4AYLOR 3 7U : -IZOGUCHI % "LUMBERG 23 "HAN ! 3IMISTER .% %XPRESSION OF THE NEONATAL &C RECEPTOR &C2N ON HUMAN INTESTINAL EPI THELIAL CELLS )MMUNOLOGY n $ICKINSON ", "ADIZADEGAN + 7U : !HOUSE *# :HU 8 3IMISTER .% "LUMBERG 23 ,ENCER 7) "IDIRECTIONAL &C2N DEPENDENT )G' TRANSPORT IN A POLARIZED HUMAN INTESTINAL EPITHELIAL CELL LINE * #LIN )NVEST n +EMPKA ' +OLB "ACHOFEN 6 "INDING UPTAKE AND TRANSCYTOSIS OF LIGANDS FOR MANNOSE SPECIFIC RECEPTORS IN RAT LIVER AN ELECTRON MICROSCOPIC STUDY %XP #ELL 2ES n 3IMIONESCU - 3IMIONESCU . %NDOTHELIAL TRANSPORT OF MACROMOLECULES TRANSCYTOSIS AND ENDOCYTOSIS ! LOOK FROM CELL BIOLOGY #ELL "IOL 2EV n 3HANNON ,OWE #$ .EUHIERL " "ALDWIN ' 2ICKINSON !" $ELECLUSE (* 2ESTING " CELLS AS A TRANSFER VEHICLE FOR %PSTEIN "ARR VIRUS INFECTION OF EPITHELIAL CELLS 0ROC .ATL !CAD 3CI 53! n !LVAREZ #0 ,ASALA & #ARRILLO * -UNIZ / #ORBI !, $ELGADO 2 # TYPE LECTINS $# 3)'. AND , 3)'. MEDIATE CELLULAR ENTRY BY %BOLA VIRUS IN CIS AND IN TRANS * 6IROL n 4ASSANEETRITHEP " "URGESS 4( 'RANELLI 0IPERNO ! 4RUMPFHELLER # &INKE * 3UN 7 %LLER -! 0ATTANAPANYASAT + 3ARASOMBATH 3 "IRX $, ET AL $# 3)'. #$ MEDIATES DENGUE VIRUS INFECTION OF HUMAN DENDRITIC CELLS * %XP -ED n +LIMSTRA 7" .ANGLE %- 3MITH -3 9UROCHKO !$ 2YMAN +$ $# 3)'. AND , 3)'. CAN ACT AS ATTACHMENT RECEPTORS FOR ALPHAVIRUSES AND DISTIN GUISH BETWEEN MOSQUITO CELL AND MAMMALIAN CELL DERIVED VIRUSES * 6IROL n "ASHIROVA !! 'EIJTENBEEK 4" VAN $UIJNHOVEN '# VAN 6LIET 3* %ILERING *" -ARTIN -0 7U , -ARTIN 4$ 6IEBIG . +NOLLE 0! ET AL ! DENDRITIC CELL
0ERCY ! +NOLLE AND $IRK 3TABENOW
SPECIFIC INTERCELLULAR ADHESION MOLECULE GRABBING NONINTEGRIN $# 3)'. RELATED PROTEIN IS HIGHLY EXPRESSED ON HUMAN LIVER SINUSOIDAL ENDOTHELIAL CELLS AND PROMOTES ()6 INFECTION * %XP -ED n ,AI 7+ 3UN 0* :HANG * *ENNINGS ! ,ALOR 0& (UBSCHER 3 -C+EATING *! !DAMS $( %XPRESSION OF $# 3)'. AND $# 3)'.2 ON HUMAN SINU SOIDAL ENDOTHELIUM A ROLE FOR CAPTURING HEPATITIS # VIRUS PARTICLES !M * 0ATHOL n .AHMIAS 9 #ASALI - "ARBE , "ERTHIAUME & 9ARMUSH -, ,IVER ENDO THELIAL CELLS PROMOTE ,$, 2 EXPRESSION AND THE UPTAKE OF (#6 LIKE PARTICLES IN PRIMARY RAT AND HUMAN HEPATOCYTES (EPATOLOGY n +YEWSKI " +LEIN , ! CENTRAL ROLE FOR CENTRAL TOLERANCE !NNU 2EV )MMUNOL n &EUERER - "ECKHOVE 0 'ARBI . -AHNKE 9 ,IMMER ! (OMMEL - (AMMERLING '* +YEWSKI " (AMANN ! 5MANSKY 6 ET AL "ONE MAR ROW AS A PRIMING SITE FOR 4 CELL RESPONSES TO BLOOD BORNE ANTIGEN .AT -ED n #ANTOR ( $UMONT ! (EPATIC SUPPRESSION OF SENSITIZATION TO ANTIGEN ABSORBED INTO THE PORTAL SYSTEM .ATURE n #ALNE 29 )NDUCTION OF IMMUNOLOGICAL TOLERANCE BY PORCINE LIVER ALLOGRAFTS .ATURE n $AHMEN 5 1IAN 3 2AO !3 $EMETRIS !* &U & 3UN ( 'AO , &UNG ** 3TARZL 4% 3PLIT TOLERANCE INDUCED BY ORTHOTOPIC LIVER TRANSPLANTATION IN MICE 4RANSPLANTATION n "ERTOLINO 0 4RESCOL "IEMONT -# 2ABOURDIN #OMBE # (EPATOCYTES INDUCE FUNCTIONAL ACTIVATION OF NAIVE #$ 4 LYMPHOCYTES BUT FAIL TO PROMOTE SURVIVAL %UR * )MMUNOL n "OWEN $' :EN - (OLZ , $AVIS 4 -C#AUGHAN '7 "ERTOLINO 0 4HE SITE OF PRIMARY 4 CELL ACTIVATION IS A DETERMINANT OF THE BALANCE BETWEEN INTRA HEPATIC TOLERANCE AND IMMUNITY * #LIN )NVEST n 7ARREN ! ,E #OUTEUR $' &RASER 2 "OWEN $' -C#AUGHAN '7 "ERTOLINO 0 4 LYMPHOCYTES INTERACT WITH HEPATOCYTES THROUGH FENESTRATIONS IN MURINE LIVER SINUSOIDAL ENDOTHELIAL CELLS (EPATOLOGY n #ARMAN #6 3AGE 04 3CIUTO 4% DE LA &UENTE -! 'EHA 23 /CHS ($ $VORAK (& $VORAK !- 3PRINGER 4! 4RANSCELLULAR DIAPEDESIS IS INITIATED BY INVASIVE PODOSOMES )MMUNITY n "ERTOLINO 0 3CHRAGE ! "OWEN $' +LUGEWITZ + 'HANI 3 %ULENBURG + (OLZ , (OGG . -C#AUGHAN '7 (AMANN ! %ARLY INTRAHEPATIC ANTIGEN SPE CIFIC RETENTION OF NAIVE #$ 4 CELLS IS PREDOMINANTLY )#!- ,&! DEPEN DENT IN MICE (EPATOLOGY n ,IMMER ! 3ACHER 4 !LFERINK * +RETSCHMAR - 3CHONRICH ' .ICHTERLEIN 4 !RNOLD " (AMMERLING '* &AILURE TO INDUCE ORGAN SPECIFIC AUTOIM MUNITY BY BREAKING OF TOLERANCE IMPORTANCE OF THE MICROENVIRONMENT %UR * )MMUNOL n 3ACHER 4 +NOLLE 0 .ICHTERLEIN 4 !RNOLD " (AMMERLING '* ,IMMER ! #P' /$. INDUCED INFLAMMATION IS SUFFICIENT TO CAUSE 4 CELL MEDIATED AUTOAG GRESSION AGAINST HEPATOCYTES %UR * )MMUNOL n $IKOPOULOS . 7EGENKA 5 +ROGER ! (AUSER ( 3CHIRMBECK 2 2EIMANN *
4HE LIVER AS IMMUNE ESCAPE SITE FOR PATHOGENS
2ECENTLY PRIMED #$ 4 CELLS ENTERING THE LIVER INDUCE HEPATOCYTES TO INTERACT WITH NAIVE #$ 4 CELLS IN THE MOUSE (EPATOLOGY n +AMEI 4 #ALLERY -0 &LYE -7 +UPFFER CELL BLOCKADE PREVENTS INDUCTION OF PORTAL VENOUS TOLERANCE IN RAT CARDIAC ALLOGRAFT TRANSPLANTATION * 3URG 2ES n *ACOB !) 'OLDBERG 0+ "LOOM . $EGENSHEIN '! +OZINN 0* %NDOTOXIN AND BACTERIA IN PORTAL BLOOD 'ASTROENTEROLOGY n .OLAN *0 %NDOTOXIN RETICULOENDOTHELIAL FUNCTION AND LIVER INJURY (EPATOLOGY n +NOLLE 0 3CHLAAK * 5HRIG ! +EMPF 0 -EYER ZUM "USCHENFELDE +( 'ERKEN ' (UMAN +UPFFER CELLS SECRETE ), IN RESPONSE TO LIPOPOLYSACCHARIDE ,03 CHALLENGE * (EPATOL n 3IGAL ,* #ROTTY 3 !NDINO 2 2OCK +, #YTOTOXIC 4 CELL IMMUNITY TO VIRUS INFECTED NON HAEMATOPOIETIC CELLS REQUIRES PRESENTATION OF EXOGENOUS ANTIGEN .ATURE n *OMANTAITE ) $IKOPOULOS . +ROGER ! ,EITHAUSER & (AUSER ( 3CHIRMBECK 2 2EIMANN * (EPATIC DENDRITIC CELL SUBSETS IN THE MOUSE %UR * )MMUNOL n $E #REUS ! !BE - ,AU !( (ACKSTEIN ( 2AIMONDI ' 4HOMSON !7 ,OW 4,2 EXPRESSION BY LIVER DENDRITIC CELLS CORRELATES WITH REDUCED CAPAC ITY TO ACTIVATE ALLOGENEIC 4 CELLS IN RESPONSE TO ENDOTOXIN * )MMUNOL n ,AU !( 4HOMSON !7 $ENDRITIC CELLS AND IMMUNE REGULATION IN THE LIVER 'UT n &RIEDMAN 3, 3TELLATE CELLS A MOVING TARGET IN HEPATIC FIBROGENESIS (EPATOLOGY n 0AIK 9( 3CHWABE 2& "ATALLER 2 2USSO -0 *OBIN # "RENNER $! 4OLL LIKE RECEPTOR MEDIATES INFLAMMATORY SIGNALING BY BACTERIAL LIPOPOLYSAC CHARIDE IN HUMAN HEPATIC STELLATE CELLS (EPATOLOGY n 7INAU & (EGASY ' 7EISKIRCHEN 2 7EBER 3 #ASSAN # 3IELING 0! -ODLIN 2, ,IBLAU 23 'RESSNER !- +AUFMANN 3( )TO CELLS ARE LIVER RESIDENT ANTIGEN PRESENTING CELLS FOR ACTIVATING 4 CELL RESPONSES )MMUNITY n +NOLLE 0! 'ERKEN ' ,OCAL CONTROL OF THE IMMUNE RESPONSE IN THE LIVER )MMUNOL 2EV n -AGNUSSON 3 "ERG 4 %XTREMELY RAPID ENDOCYTOSIS MEDIATED BY THE MANNOSE RECEPTOR OF SINUSOIDAL ENDOTHELIAL RAT LIVER CELLS "IOCHEM * n (ANSEN " ,ONGATI 0 %LVEVOLD + .EDREDAL ') 3CHLEDZEWSKI + /LSEN 2 &ALKOWSKI - +ZHYSHKOWSKA * #ARLSSON & *OHANSSON 3 ET AL 3TABILIN AND STABILIN ARE BOTH DIRECTED INTO THE EARLY ENDOCYTIC PATHWAY IN HEPATIC SINUSOIDAL ENDOTHELIUM VIA INTERACTIONS WITH CLATHRIN!0 INDEPENDENT OF LIGAND BINDING %XP #ELL 2ES n ,OHSE !7 +NOLLE 0! "ILO + 5HRIG ! 7ALDMANN # )BE - 3CHMITT % 'ERKEN ' -EYER :UM "USCHENFELDE +( !NTIGEN PRESENTING FUNCTION AND " EXPRESSION OF MURINE SINUSOIDAL ENDOTHELIAL CELLS AND +UPFFER CELLS 'ASTROENTEROLOGY n +NOLLE 0! 3CHMITT % *IN 3 'ERMANN 4 $UCHMANN 2 (EGENBARTH 3 'ERKEN
0ERCY ! +NOLLE AND $IRK 3TABENOW
' ,OHSE !7 )NDUCTION OF CYTOKINE PRODUCTION IN NAIVE #$ 4 CELLS BY ANTIGEN PRESENTING MURINE LIVER SINUSOIDAL ENDOTHELIAL CELLS BUT FAILURE TO INDUCE DIFFERENTIATION TOWARD 4H CELLS 'ASTROENTEROLOGY n -OWAT !- !NATOMICAL BASIS OF TOLERANCE AND IMMUNITY TO INTESTINAL ANTIGENS .AT 2EV )MMUNOL n (UANG , 3OLDEVILA ' ,EEKER - &LAVELL 2 #RISPE ). 4HE LIVER ELIMI NATES 4 CELLS UNDERGOING ANTIGEN TRIGGERED APOPTOSIS IN VIVO )MMUNITY n $INI , 0AGLIARA 0 #ARLA %# 0HAGOCYTOSIS OF APOPTOTIC CELLS BY LIVER A MORPHOLOGICAL STUDY -ICROSC 2ES 4ECH n -ORELLI !% ,ARREGINA !4 3HUFESKY 7* :AHORCHAK !& ,OGAR !* 0APWORTH '$ 7ANG : 7ATKINS 3# &ALO ,$ *R 4HOMSON !7 )NTERNALIZATION OF CIRCULATING APOPTOTIC CELLS BY SPLENIC MARGINAL ZONE DENDRITIC CELLS DEPEN DENCE ON COMPLEMENT RECEPTORS AND EFFECT ON CYTOKINE PRODUCTION "LOOD n "ERG - 7INGENDER ' $JANDJI $ (EGENBARTH 3 -OMBURG & (AMMERLING ' ,IMMER ! +NOLLE 0 #ROSS PRESENTATION OF ANTIGENS FROM APOPTOTIC TUMOR CELLS BY LIVER SINUSOIDAL ENDOTHELIAL CELLS LEADS TO TUMOR SPECIFIC #$ 4 CELL TOLERANCE %UR * )MMUNOL n $IEHL , 3CHURICH ! +ERN - VON /PPEN . 'ROCHTMANN 2 (EGENBARTH 3 #HEN , ,IMMER ! +NOLLE 0! ,IVER SINUSOIDAL ENDOTHELIAL CELL INDUCED #$ 4 CELL TOLERANCE IS MEDIATED BY " ( AND REVERSED BY CO STIMULATION IN THE PRESENCE OF INFECTION (EPATOLOGY n 0ROBST (# -C#OY + /KAZAKI 4 (ONJO 4 VAN DEN "ROEK - 2ESTING DENDRITIC CELLS INDUCE PERIPHERAL #$ 4 CELL TOLERANCE THROUGH 0$ AND #4,! .AT )MMUNOL n -àSCHEN - 7ARSKULAT 5 $OUILLARD 0 'ILBERT % (ËUSSINGER $ 2EGULATION OF #$ !0/ &AS RECEPTOR AND LIGAND EXPRESSION BY LIPOPOLY SACCHARIDE AND DEXAMETHASONE IN PARENCHYMAL AND NONPARENCHYMAL RAT LIVER CELLS (EPATOLOGY n -EHAL 7: *UEDES !% #RISPE ). 3ELECTIVE RETENTION OF ACTIVATED #$ 4 CELLS BY THE NORMAL LIVER * )MMUNOL n -EHAL 7: !ZZAROLI & #RISPE ). !NTIGEN PRESENTATION BY LIVER CELLS CONTROLS INTRAHEPATIC 4 CELL TRAPPING WHEREAS BONE MARROW DERIVED CELLS PREF ERENTIALLY PROMOTE INTRAHEPATIC 4 CELL APOPTOSIS * )MMUNOL n $ONG ( :HU ' 4AMADA + &LIES $" VAN $EURSEN *- #HEN , " ( DETERMINES ACCUMULATION AND DELETION OF INTRAHEPATIC #$ 4 LYMPHOCYTES )MMUNITY n
#OMPARATIVE (EPATITIS ED BY /LAF 7EBER AND 5LRIKE 0ROTZER ¥ "IRKHËUSER 6ERLAG "ASEL3WITZERLAND
$RUG CANDIDATES FOR THE TREATMENT OF VIRAL HEPATITIS /LAF 7EBER "AYER !' ,EVERKUSEN 'ERMANY
!BSTRACT 7HILE PROGRESS HAS BEEN MADE IN TREATING VIRAL HEPATITIS SOME PROBLEMS ARE NOT ADE QUATELY ADDRESSED WITH CURRENT THERAPIES 4HIS INCLUDES THE CHALLENGE OF TREATING BOTH CHRONIC AS WELL AS FULMINANT INFECTIONS 4HIS CHAPTER PROVIDES AN OVERVIEW ABOUT CURRENT ACTIVITIES IN THE DEVELOPMENT OF NOVEL THERAPIES FOR VIRAL HEPATITIS 4HE ACTIVITIES IN THIS AREA ARE VERY COMPETITIVE AND DYNAMIC AND THEREFORE THE LIST OF PROJECTS AND COMPOUNDS MIGHT NOT BE COMPLETE OR REFLECT THE VERY LATEST STATUS OF CERTAIN PROJECTS (OWEVER IT IS CLEAR THAT THE MEDICAL NEED IS BEING ADDRESSED AND THAT NOVEL APPROACHES CAN BE EXPECTED THAT MIGHT HOPEFULLY STRENGTHEN THE ANTIVIRAL ARMAMENTARIUM IN THE FUTURE
$RUG CANDIDATES UNDER DEVELOPMENT FOR THE TREATMENT OF HEPATITIS 4HERE ARE MANY CAUSES OF HEPATITIS IN HUMANS n BOTH INFECTIOUS AGENTS AS WELL AS NON INFECTIOUS ETIOLOGIES ARE OF IMPORTANCE 4HIS CHAPTER PROVIDES A SHORT OVERVIEW ABOUT SOME DRUGS UNDER DEVELOPMENT FOR THE TREATMENT OF HEPATITIS )T IS IMPORTANT TO NOTICE THAT A @ONE FOR ALL TREATMENT OF HEPATITIS DOES NOT EXIST DUE TO THE DIVERSITY OF THE AGENTS CAUSING HEPATITIS AND THE VARIOUS CLINICAL COURSES OF HEPATITIS 4ABLE ILLUSTRATES THIS DIVERSITY THE CAUSES OF HEPATITIS WILL BE DISCUSSED ELSEWHERE IN THIS BOOK 4HIS CHAPTER IS FOCUSING ON RECENT DEVELOPMENTS IN SOME OF THE EPIDE MIOLOGICALLY MOST IMPORTANT FORMS OF VIRAL HEPATITIS 3EVERAL CHAPTERS IN THIS BOOK DESCRIBE VIRAL HEPATITIS IN DETAIL 4ABLE PROVIDES AN OVERVIEW ABOUT TYPES OF HEPATITIS CAUSED BY SPECIFIC HEPATOTROPIC VIRUSES )N ADDITION VIRUSES INCLUDING THE FOLLOWING ONES MAY CAUSE CONCOMITANT HEPATITIS UPON A GENERALISED INFECTION (ANTAVIRUS CERTAIN 0ICORNAVIRIDAE LIKE #OXSACKIE VIRUSES 0ARVOVIRUS " !DENOVIRUSES -UMPS VIRUS %UROPEAN AND 2USSIAN 3PRING 3UMMER ENCEPHALITIS VIRUS HAEMORRHAGIC FEVER VIRUSES LIKE ,ASSAVIRUS +RIM +ONGO VIRUS 2IFT VALLEY FEVER VIRUS -ARBURG VIRUS %BOLA VIRUS
/LAF 7EBER
4ABLE -AJOR CAUSES OF HUMAN HEPATITIS )NFECTIONS THAT CAUSE HEPATITIS 6IRUSES
"ACTERIA
&UNGI 0ARASITES
(EPATITIS 6IRUSES ! " # $ % #ONCOMITANT VIRAL HEPATITIS CAUSED BY (ERPESVIRUSES AND OTHER VIRUSES $ENGUEVIRUS "RUCELLA SPP ,EPTOSPIRA SPP #OXIELLA BURNETII OTHER BACTERIA #ANDIDA SPP &ASCIOLA HEPATICA %CHINOCOCCUS GRANULOSUS 3CHISTOSOMA MANSONI ,EISHMANIA ,EISHMANIA
.ON INFECTIOUS CAUSES OF HEPATITIS 4OXINS
!BNORMAL METABOLISMSTORAGE #HOLANGITIS !UTOIMMUNE DISORDERS
!LCOHOL -YCOTOXINS $RUGS (AEMOCHROMATOSIS -ORBUS 7ILSON ,UPOID HEPATITIS #HRONIC ACTIVE HEPATITIS
)MMUNOMODULATORY AGENTS UNDER DEVELOPMENT 4HIS CHAPTER DOES NOT INCLUDE COMBINATION PRODUCTS AND VERY EARLY PRECLINI CAL APPROACHES 4HE DEVELOPMENT OF IMMUNOMODULATORY AGENTS IS INCREAS INGLY REPORTED 4HIS INCLUDES BOTH THERAPEUTIC AGENTS AND THERAPEUTIC AND PROPHYLACTIC VACCINES
!LBUFERON ALBUMIN INTERFERON ALFA (UMAN 'ENOME 3CIENCES ('3 AND .OVARTIS ARE DEVELOPING ALBINTERFERON ALFA B !LBUFERON !"& !LBUFERON ALPHA FOR THE TREATMENT OF (#6 INFECTION !LBUFERON IS A LONG ACTING INJECTABLE ALBUMINHUMAN )&. ALPHA B FUSION PROTEIN ('3 IS CURRENTLY CONDUCTING TWO PIVOTAL 0HASE ))) CLINICAL TRIALS OF !LBUFERON !#()%6% IN TREATMENT NAÕVE PATIENTS WITH GENOTYPE CHRONIC HEPATITIS # AND !#()%6% IN TREATMENT NAIVE PATIENTS WITH GENOTYPE OR HEPATITIS # ;= #LINICAL DATA SUGGEST THAT !LBUFERON COULD OFFER HEPATITIS # PATIENTS A THERAPEUTIC OPTION REQUIRING LESS FREQUENT INJEC TIONS AND A VIROLOGIC RESPONSE COMPARABLE TO THAT OBTAINED WITH PEGYLATED INTERFERON ALFA A WITH THE POTENTIAL FOR LESS IMPAIRMENT OF HEALTH RELATED QUALITY OF LIFE ;n=
)NFECTION MAY BECOME CHRONIC n OF INFECTIONS SOME AGE DEPENDENCY POST PARTUM )NFECTION MAY BECOME CHRONIC n OF INFECTIONS UP TO OF INFEC TIONS BECOME CHRONIC SOMETIMES FULMINANT HEPATITIS .O CHRONIC INFECTIONS
n
HEPATITIS !
!CUTE AND CHRONIC HEPATITIS "
!CUTE AND CHRONIC HEPATITIS #
CO INFECTION WITH ("6
!CUTE HEPATITIS %
.OT PATHOGENIC
(EPATITIS ! &AMILY VIRUS (!6 0ICORNAVIRIDAE 'ENUS (EPATOVIRUS
(EPATITIS " &AMILY VIRUS ("6 (EPADNAVIRIDAE 'ENUS /RTHOHEPADNA VIRUS
(EPATITIS # &AMILY VIRUS (#6 &LAVIVIRIDAE 'ENUS (EPACIVIRUS
(EPATITIS $ &AMILY VIRUS ($6 NOT CLASSIFIED 'ENUS $ELTAVIRUS
(EPATITIS % &AMILY VIRUS (%6 NOT CLASSIFIED 'ENUS (EPEVIRUS
'" 6IRUS 4YPE # '"6 #
4RANSMISSION
0ROPHYLAXIS 4REATMENT
3YMPTOMATIC TREATMENT OF ("6 CO INFECTION
0ARENTERAL TRANSMISSION BLOOD SEXUAL TRANSMISSION
n
6ERTICAL TRANSMISSION PARENTERAL (YGIENE EDUCATION TRANSMISSION BLOOD SEXUAL TRANSMISSION
ILY @(EPEVIRIDAE IN THE .#") TAXONOMY DATABASE
!CCORDING TO THE )NTERNATIONAL #OMMITTEE ON 4AXONOMY OF 6IRUSES )#46 (%6 IS STILL OFFICIALLY UNASSIGNED 4HE GENUS IS NAMED @(EPEVIRUS AND THE FAM
3YMPTOMATIC
&AECAL ORAL FOOD CONTAMINATION (YGIENE SEAFOOD EDUCATION
(YGIENE EDUCATION
6ARIETY OF AGENTS INCLUDING INTERFERON ALPHA PEGYLATED INTER FERON ALPHA RIBAVIRIN
6ACCINATION 6ARIETY OF AGENTS INCLUDING INTERFERON HYGIENE ALPHA PEGYLATED INTER EDUCATION FERON ALPHA LAMIVUDINE ADEFOVIR DIPIVOXIL
0ARENTERAL TRANSMISSION "LOOD (YGIENE BLOOD PRODUCTS SEXUAL TRANSMIS EDUCATION SION SURGICAL INSTRUMENTS IV DRUG ABUSE
0ARENTERAL TRANSMISSION BLOOD SEXUAL TRANSMISSION
GENERALLY ACUTE APPROX &AECAL ORAL FOOD CONTAMINATION VACCINATION SYMPTOMATIC SEAFOOD HYGIENE OF ADULTS SHOW A EDUCATION DELAYED COURSE OF THE DISEASE
$ISEASE
6IRUS
4ABLE /VERVIEW ABOUT TYPES OF HEPATITIS CAUSED BY SPECIFIC HEPATOTROPIC VIRUSES
$RUG CANDIDATES FOR THE TREATMENT OF VIRAL HEPATITIS
(EPATITIS
(EPATITIS IN UP TO OF ACUTE %"6 INFECTIONS
6ARICELLA ZOSTER VIRUS &AMILY 6:6 (ERPESVIRIDAE 3UBFAMILY !LPHAHERPESVIRINAE 'ENUS 6ARICELLOVIRUS
&AMILY (ERPESVIRIDAE 3UBFAMILY 'AMMAHERPESVIRINAE 'ENUS 6ARICELLOVIRUS
&AMILY (ERPESVIRIDAE 3UBFAMILY "ETAHERPESVIRINAE 'ENUS #YTOMEGALOVIRUS
%PSTEIN "ARR VIRUS %"6
#YTOMEGALOVIRUS #-6
(EPATITIS IN IMMUNO COMPROMISED PATIENTS NEWBORNS
(EPATITIS IN IMMUNO COMPROMISED PATIENTS NEWBORNS
(ERPES SIMPLEX VIRUS &AMILY (36 (ERPESVIRIDAE 3UBFAMILY !LPHAHERPESVIRINAE 'ENUS (ERPES SIMPLEX VIRUS (ERPES SIMPLEX VIRUS TYPE AND
$ISEASE !CUTE HEPATITIS WITH ICTERUS hYELLOW FEVERv FULMINANT HEPATITIS POSSIBLE
&AMILY &LAVIVIRIDAE 'ENUS &LAVIVIRUS $ENGUE TYPE YELLOW FEVER VIRUS
6IRUS
$ENGUEFEVER VIRUS
4ABLE /THER CONCOMITANT VIRAL HEPATITIS
!CUTE
!CUTE
!CUTE
!CUTE
!CUTE
4RANSMISSION
#ONTACT INFECTION
#ONTACT INFECTION
#ONTACT INFECTION CHICKEN POX
#ONTACT INFECTION HERPES
4RANSMISSION BY !EDES AEGYPPTII
0ROPHYLAXIS
4REATMENT
n
n
6ACCINATION
3YMPTOMATIC OR TREATMENT OF HERPESVIRUS INFECTION
3YMPTOMATIC OR TREATMENT OF HERPESVIRUS INFECTION
3YMPTOMATIC OR TREATMENT OF HERPESVIRUS INFECTION
3YMPTOMATIC OR TREATMENT OF HERPESVIRUS INFECTION
3UPPORTIVE 2EDUCTION OF !EDES TREATMENT AEGYPPTII .O VACCINATION AVAILABLE YET UNDER DEVELOPMENT
/LAF 7EBER
$RUG CANDIDATES FOR THE TREATMENT OF VIRAL HEPATITIS
0EGASYS 0EGINTERFERON !LFA A 0EGASYS IS A PEGYLATED INTERFERON ALFA A THAT UTILISES A K$A POLYETH YLENE GLYCOL 0%' STRAND TO ALLOW FOR STABLE AND SUSTAINED THERAPEUTIC SERUM LEVELS OF INTERFERON ALFA A FOR UP TO A WEEK WITH A SINGLE DOSE 2OCHE LAUNCHED 0EGASYS IN FOR THE TREATMENT OF CHRONIC (#6 AND IN FOR THE TREATMENT OF CHRONIC ("6 INFECTION AND IS CURRENTLY INVESTIGATING THE DRUG IN A VARIETY OF CLINICAL SETTINGS INCLUDING PATIENTS WITH VARIOUS (#6 GENOTYPES IN SUBSETS OF ("6 PATIENTS OR IN COMBINATIONS 4HESE COMBINA TIONS INCLUDE RIBAVIRIN #OPEGUS 0EGYLATED INTERFERON IS ALSO CURRENTLY ASSESSED FOR THE TREATMENT OF CHRONIC HEPATITIS $ IN A 0HASE )) TRIAL SPONSORED BY THE .ATIONAL )NSTITUTE OF $IABETES AND $IGESTIVE AND +IDNEY $ISEASES .)$$+ ;= 4HIS STUDY WILL EVALUATE THE EFFECTS OF PEGYLATED INTERFERON ON HEPATITIS $ AND HEPATITIS " )T WILL DETERMINE WHETHER LONG TERM THERAPY WITH THIS DRUG IMPROVES INFLAM MATION AND SCARRING OF THE LIVER THEREBY DELAYING OR REVERSING CIRRHOSIS AND WHETHER THE IMPROVEMENT CAN BE MAINTAINED
(UMAN LEUKOCYTE INTERFERON ALFA (UMAN LEUKOCYTE INTERFERON ALFA A FORMULATION OF NATURAL INTERFERON ALFA WAS LAUNCHED IN BY (EMISPHERX "IOPHARMA FOR THE TREATMENT OF REFRACTORY OR RECURRING EXTERNAL GENITAL AND PERIANAL EXOPHYTIC WARTS CAUSED BY HUMAN PAPILLOMAVIRUS (06 )T IS CURRENTLY INVESTIGATED IN VARIOUS ADDITIONAL INDICATIONS SUCH AS ()6 7EST .ILE VIRUS INFECTION SEVERE ACUTE RESPIRATORY SYNDROME 3!23 AND (#6
(EPATITIS " IMMUNE GLOBULIN ! HIGHLY PURIFIED HUMAN HEPATITIS " IMMUNE GLOBULIN GAMMA GLOBULIN CONTAINING ANTIBODIES TO HEPATITIS " SURFACE ANTIGEN WAS APPROVED IN THE 53 IN FOR USE AFTER ACUTE EXPOSURE TO BLOOD CONTAINING ("S!G INCLUDING PERINATAL EXPOSURES OF INFANTS BORN TO ("S!G POSITIVE MOTHERS AND DISTRIB UTED AS (EPA'AM " BY !POTEX
(EPATITIS # n %$ n (#6 NEUTRALISING MONOCLONAL ANTIBODIES /NE (#6 DISEASE RELATED AREA OF SPECIAL CONCERN IS LIVER TRANSPLANTATION #HRONIC HEPATITIS # IS THE MOST COMMON INDICATION FOR LIVER TRANSPLANTS IN THE 53 AND %UROPE YEAR BUT THERE IS NO SATISFACTORY STRATEGY AT PRESENT TO MANAGE THE POST TRANSPLANTATION RECURRENCE OF (#6 4HE NEED TO PREVENT (#6 RE INFECTION IS GIVEN SINCE MORBIDITY AND MORTALITY IN THESE PATIENTS ARE
/LAF 7EBER
ESPECIALLY HIGH )NNOGENETICS HAS AN ACTIVE PRECLINICAL PROGRAM USING MONO CLONAL ANTIBODIES M!BS TARGETING THE % AND % (#6 ENVELOPE REGIONS 4HESE HUMAN M!BS MAY HAVE POTENTIAL TO CROSS NEUTRALISE (#6 GENOTYPES AS RECENTLY IDENTIFIED IN COLLABORATION WITH THE .)( .)!)$ 53! ;=
#IVACIR (EPATITIS # )MMUNE 'LOBULIN #IVACIR ;(EPATITIS # )MMUNE 'LOBULIN (UMAN = IS AN INVESTIGATIONAL HUMAN POLYCLONAL ANTIBODY PRODUCT THAT CONTAINS ANTIBODIES TO HEPATITIS # VIRUS (#6 0RECLINICAL STUDIES INDICATE THAT #IVACIR CONTAINS ANTIBOD IES THAT ARE NEUTRALISING TO (#6 .ABI "IOPHARMACEUTICALS IS DEVELOPING #IVACIR TO PREVENT RE INFECTION WITH HEPATITIS # DISEASE IN (#6 POSITIVE LIVER TRANSPLANT PATIENTS ;=
)../ %VIDENCE HAS BEEN REPORTED THAT THE HUMORAL AND CELLULAR IMMUNE RESPONS ES TO THE (#6 GENOTYPE B ENVELOPE PROTEIN % ARE LARGELY IMPAIRED IN PATIENTS WITH CHRONIC ACTIVE HEPATITIS # AND MAY BE IMPORTANT FOR CLEAR ANCE OF (#6 ;= ! CANDIDATE THERAPEUTIC VACCINE WAS DEVELOPED BY )NNOGENETICS CONSISTING OF A PROPRIETARY VIRAL % PROTEIN OF (#6 TOGETHER WITH AN ALUM ADJUVANT TO ENHANCE THE IMMUNE RESPONSE )NNOGENETICS IS DEVELOPING )../ )NNO6AC # )NNOVAX # AN INJECTABLE RECOMBINANT PROTEIN AS A THERAPEUTIC VACCINE FOR THE TREATMENT OF CHRONIC HEPATITIS # VIRUS (#6 INFECTION )N *UNE THE COMPANY EXTENDED ITS ONGOING 0HASE ))B TRIAL
)../ )../ IS A POLYEPITOPE RECOMBINANT PLASMID $.! VACCINE CURRENTLY BEING INVESTIGATED IN A 0HASE ) PROGRAM FOR THE PREVENTION OF HEPATITIS " INFECTION
)NTERFERON /MEGA /N -AY )NTARCIA 4HERAPEUTICS ANNOUNCED FINAL RESULTS FROM A 0HASE )) STUDY COMPARING THE COMBINATION OF INJECTABLE OMEGA INTERFERON AND RIB AVIRIN TO OMEGA INTERFERON ALONE IN TREATMENT NAÕVE PATIENTS WITH GENOTYPE CHRONIC HEPATITIS # 4HE RESULTS DEMONSTRATED THAT OMEGA INTERFERON IN COMBINATION WITH RIBAVIRIN WAS WELL TOLERATED AND SHOWED ROBUST ANTIVIRAL ACTIVITY COMPARABLE TO PUBLISHED DATA ON THE USE OF ALPHA INTERFERON PLUS RIBAVIRIN IN SIMILAR PATIENT POPULATIONS ;= (OWEVER OMEGA INTERFERON WAS ADMINISTERED BY DAILY INJECTIONS
$RUG CANDIDATES FOR THE TREATMENT OF VIRAL HEPATITIS
%(4 %NZO4HERAPEUTICS IS DEVELOPING %(4 A FORMULATION OF ("6 VIRAL PRO TEIN DESIGNED TO ELIMINATE THE UNDESIRABLE IMMUNE RESPONSE ELICITED BY THE ("6 INFECTION !CCORDING TO THE COMPANY %(4 ALSO ENHANCES A SECOND ARY IMMUNE RESPONSE TO CLEAR THE VIRAL INFECTION RESULTING IN REDUCTION IN LIVER DAMAGE AND DECREASE IN VIRAL LOAD )N A CLINICAL STUDY A FORMULATION OF %(4 WAS ADMINISTERED ORALLY TO A TOTAL OF PATIENTS WITH CHRONIC ACTIVE HEPA TITIS 0ATIENTS RECEIVED THE MEDICATION THREE TIMES A WEEK FOR n WEEKS AND WERE FOLLOWED FOR AN ADDITIONAL WEEKS 2ESULTS OF THE TRIAL HAVE SHOWN THAT THE DRUG WAS WELL TOLERATED IN ALL SUBJECTS OF SUBJECTS SHOWED A DECREASE IN ("6 VIRAL LOAD AND IMPROVEMENT IN LIVER FUNCTION TESTS AND OF SUB JECTS SHOWED A DECREASE IN INFLAMMATION SEEN ON LIVER BIOPSY ;=
%(# %NZO IS ALSO DEVELOPING %(# AS A THERAPY FOR (#6 4HE 0HASE ) CLINI CAL TRIAL CONDUCTED BY PHYSICIANS AT THE ,IVER 5NIT OF (ADASSAH 5NIVERSITY -EDICAL #ENTER IN *ERUSALEM )SRAEL HAS MET ITS SAFETY ENDPOINTS %NZO IS CURRENTLY LOOKING TO THE NEXT LEVEL OF STUDY ;=
"AVITUXIMAB "AVITUXIMAB IS A CHIMERIC ANTI PHOSPHATIDYLSERINE MONOCLONAL ANTIBODY DEVELOPED BY 0EREGRINE 0HARMACEUTICALS ! 0HASE )B OPEN LABEL ESCALATING REPEAT DOSE TRIAL OF BAVITUXIMAB IN PATIENTS WITH CHRONIC HEPATITIS # HAS COMPLETED ENROLMENT ;=
2 )N COLLABORATION WITH -AXYGEN 2OCHE IS DEVELOPING 2 A NOVEL PEGYLATED INTERFERON ALPHA VARIANT CREATED THROUGH THE USE OF -AXYGENS PROPRIETARY -OLECULAR"REEDING AGAINST (#6 ;=
2ESIQUIMOD 2ESIQUIMOD IS AN IMMUNOMODULATING AGENT BASICALLY A 4OLL LIKE RECEPTOR AND AGONIST THAT INDUCES ENDOGENOUS INTERFERON ALPHA 4HE AGENT IS CURRENTLY BEING DEVELOPED FOR ENHANCING THE PROTECTIVE RESPONSE TO HEPATITIS " VACCINE ! CLINICAL STUDY WAS RECENTLY CONDUCTED TO EXPLORE SAFETY PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL ADMINISTRATION OF RESIQUIMOD IN SUBJECTS WITH
/LAF 7EBER
CHRONIC (#6 INFECTION 4WO RANDOMISED DOUBLE BLIND 0HASE ))A STUDIES OF RESIQUIMOD ADMINISTERED TWO TIMES PER WEEK FOR WEEKS )N A MULTICENTRE STUDY IN THE 53 SUBJECTS RECEIVED RESIQUIMOD MGKG AND FOUR RECEIVED PLACEBO )N ANOTHER SINGLE CENTRE STUDY SIX SUBJECTS RECEIVED RESIQUIMOD MGKG RECEIVED MGKG AND SIX RECEIVED PLACEBO 2ESIQUIMOD MGKG WAS TOLERATED TWO MGKG SUBJECTS DISCONTINUED TREATMENT -ORE SUBJECTS REPORTED SEVERE GRADE ADVERSE EVENTS AT MGKG EVENTS WERE CON SISTENT WITH SYSTEMIC CYTOKINE INDUCTION INCLUDING FEVER HEADACHE SHIVERING AND LYMPHOPENIA -EAN MAXIMUM SERUM RESIQUIMOD CONCENTRATIONS WERE ¢ AND ¢ NGM, FOR MGKG AND MGKG RESPECTIVELY !T MGKG TWO THREE AND ONE SUBJECTS HAD MAXIMAL REDUCTIONS IN VIRAL LEVELS OF AT LEAST AND LOGS RESPECTIVELY REDUCTIONS WERE GENERALLY TRANSIENT )NTERFERON ALPHA LEVELS APPEARED TO CORRELATE WITH DECREASES IN VIRAL TITRE AND LYMPHOCYTE COUNTS AS WELL AS INCREASE IN NEUTROPHIL COUNTS /RAL ADMINISTRATION OF RESIQUIMOD MGKG TRANSIENTLY REDUCED VIRAL LEVELS BUT WAS ASSOCIATED WITH ADVERSE EFFECTS SIMILAR TO INTERFERON ALPHA ;=
3MALL MOLECULES UNDER DEVELOPMENT ! ! IS DEVELOPED BY !RROW 4HERAPEUTICS RECENTLY ACQUIRED BY !STRA:ENECA FOR THE TREATMENT OF HEPATITIS # !RROWS (#6 PROGRAM IS FOCUSED ON .3A WHICH IS ESSENTIAL FOR VIRUS 2.! PRODUCTION .3A LACKS ANY HOMOLOGUE IN THE HUMAN GENOME AND IS WELL CONSERVED ACROSS (#6 GENOTYPES ! HAS SHOWN POTENT ACTIVITY IN THE REPLICON ASSAY 0HASE ) TRIALS ON THE COMPOUND WERE INITIATED IN 1 ;=
!.! !.! ," IS DEVELOPED BY !NADYS AND ,' ,IFE 3CIENCES FOR THE ORAL ONCE DAILY TREATMENT OF CHRONIC AND ACUTE LAMIVUDINE RESISTANT ("6 INFECTION ," IS A PRODRUG OF THE GUANOSINE PHOSPHONATE NUCLEOSIDE ," AND WAS DEVELOPED TO IMPROVE ORAL BIOAVAILABILITY
!6) !6) IS A .EU'ENE ANTISENSE COMPOUND THAT IS CURRENTLY IN 0HASE )) TRIALS AT !6) "IO0HARMA FOR THE TREATMENT OF CHRONIC (#6 INFECTION (OWEVER !6) "IO0HARMA ANNOUNCED ON !UGUST TO DISCONTINUE THEIR CURRENT HEPATITIS # CLINICAL DEVELOPMENT PROGRAM AS A CONSEQUENCE OF A FOCUS EFFORT ;=
$RUG CANDIDATES FOR THE TREATMENT OF VIRAL HEPATITIS
")6. "IOENVISION IS DEVELOPING ")6. METHYLENE BLUE 3UVUS FOR THE TREAT MENT OF CHRONIC (#6 INFECTION 3UVUS ESPECIALLY WHEN PHOTO SENSITISED BY LIGHT ACTS BY PREVENTING REPLICATION OF NUCLEIC ACID $.! AND 2.! IN PATHOGENS )NVESTIGATOR SPONSORED 0HASE )) CLINICAL TRIALS HAVE BEEN CONDUCTED "IOENVISION ANNOUNCED INTERIM RESULTS AT THE 5"3 'LOBAL ,IFE 3CIENCES #ONFERENCE IN .EW 9ORK IN 3EPTEMBER 3UVUS WAS GIVEN TO PATIENTS WITH GENOTYPE HEPATITIS # WHO HAD FAILED A PRIOR TREATMENT INCLUDING INTERFERON IN MANY OF THE PATIENTS 3IXTEEN OF THE PATIENTS HAD CIRRHOSIS 3UVUS WAS GIVEN ORALLY FOR DAYS AND MEASUREMENT OF THE VIRAL LOAD WAS PERFORMED AT DAY !T DAYS PATIENTS HAD SHOWN A REDUCTION IN VIRAL LOAD OF GREATER THAN /F THESE RESPONDERS HAD A CLEARANCE OF GREATER THAN WITH FOUR RESPONDERS HAVING SHOWN COMPLETE VIRAL CLEARANCE 3EVEN OF THE PATIENTS HAD VIRAL LOAD MEASURED AT DAYS 3IX OF THESE PATIENTS SHOW CONTINUED REDUCTION IN VIRAL LOAD AND THE SEVENTH PATIENT WHO HAD BEEN ONE OF THE THREE NON RESPONDERS AT DAYS HAD A GREATER THAN REDUCTION IN VIRAL LOAD .O MAJOR ADVERSE EVENTS WERE NOTED !CCORDING TO THE COMPANYS WEBSITE AN .$! WAS FILED IN %GYPT ;=
#ELGOSIVIR #ELGOSIVIR -8 IS A ALPHA GLUCOSIDASE ) INHIBITOR CURRENTLY IN 0HASE )) CLINICAL TRIALS AT -IGENIX AS A MONOTHERAPY IN FIRST LINE AND INTERFERON INTOLERANT GENOTYPE (#6 PATIENTS IN #ANADA AND IN COMBINATION WITH PEGINTERFERON ALFA B WITH OR WITHOUT RIBAVIRIN FOR THE TREATMENT OF CHRONIC (#6 GENOTYPE ) INFECTIONS IN #ANADA AND THE 53 #ELGOSIVIR ADDED TO PEGINTERFERON ALPHA B AND RIBAVIRIN RESULTS IN IMPROVED VIRAL LOAD REDUC TIONS AND CLINICALLY SIGNIFICANT BENEFIT IN GENOTYPE NON RESPONDERS ;= #ELGOSIVIR IS AN ORAL PRODRUG OF CASTANOSPERMINE A NATURAL PRODUCT DERIVED FROM THE !USTRALIAN BLACK BEAN CHESTNUT TREE #ASTANOSPERMUM AUSTRALE -IGENIX ACQUIRED WORLDWIDE RIGHTS FOR THE DRUG FROM 6IROGEN ;=
#LEVUDINE #LEVUDINE IS AN ORAL ONCE DAILY PYRIMIDINE NUCLEOSIDE ANALOGUE THAT HAS BEEN APPROVED FOR THE TREATMENT OF HEPATITIS " IN 3OUTH +OREA IN )T IS MARKETED BY "UKWANG #LEVUDINE IS CURRENTLY BEING INVESTIGATED IN 0HASE ))) CLINICAL TRIALS IN !SIA BY %ISAI AND IN THE 53 AND IN %UROPE BY 0HARMASSET #LEVUDINE HAS DEMONSTRATED EFFICACY IN BOTH ("E !G NEGA TIVE CHRONIC HEPATITIS " WITH DURABLE OFF THERAPY VIRAL SUPPRESSION AND IN ("E!G POSITIVE CHRONIC HEPATITIS " ; =
/LAF 7EBER
$$" 3 $$" 3 ,EBECEL IN CURRENTLY IN 0HASE )) CLINICAL TRIALS AT $AEWOO 0HARMACEUTICALS FOR THE TREATMENT OF ACUTE AND CHRONIC HEPATITIS
$%")/ $%")/ IS A CYCLOPHILIN INHIBITOR DEVELOPED BY $EBIOPHARM FOR THE TREATMENT OF (#6 INFECTIONS )T IS CURRENTLY IN 0HASE )) CLINICAL TRIALS $%")/ MONOTHERAPY FOR DAYS INDUCED AN ANTIVIRAL EFFECT VERSUS (#6 OF ,OG REDUCTION IN ()6 (#6 CO INFECTED PATIENTS A POPULATION GENERALLY RESPONDING POORLY TO ANTI (#6 TREATMENT 4HE ANTIVIRAL EFFECT WAS CONSISTENT THROUGHOUT TREATMENT ON THE THREE GENOTYPES IDENTIFIED IN THE STUDY $%")/ DID ALSO SHOW SOME ANTI ()6 EFFECT ,OG REDUC TION 2EVERSIBLE AND DOSE DEPENDENT HYPERBILIRUBINAEMIA SEEMED TO BE THE DOSE LIMITING FACTOR FOR $%")/ ;=
'3 '3 IS AN INHIBITOR OF 2.! DIRECTED 2.! POLYMERASE .3" CUR RENTLY UNDER CLINICAL EVALUATION FOR THE TREATMENT OF HEPATITIS # ;=
(#6 (#6 IS A NON NUCLEOSIDIC .3" INHIBITOR IN 0HASE )) CLINICAL DEVELOP MENT AT 6IRO0HARMA AND 7YETH 0HARMACEUTICALS FOR AN INTERFERON COM BINATION TREATMENT OF (#6 INFECTION /N !UGUST THE COMPANY ANNOUNCED DISCONTINUATION OF DOSING IN THIS TRIAL DUE TO POTENTIAL SAFETY ISSUES ;=
)4-. 2 4HE COMPOUND IS AN ORAL (#6 .3! PROTEASE INHIBITOR BEING DEVELOPED BY )NTER-UNE AND 2OCHE 4HE COMPOUND HAS ENTERED 0HASE ) CLINICAL TRIALS ;=
.)- 2 .)- IS .OVARTIS NON IMMUNOSUPPRESSIVE CYCLOSPORIN DERIVATIVE THAT IS CURRENTLY BEING DEVELOPED AGAINST (#6 INFECTIONS !NALYSIS USING CYCLO SPORIN ! #S! AS A BIOPROBE SHOWED THAT CYCLOPHILIN #Y0 " A CELLULAR
$RUG CANDIDATES FOR THE TREATMENT OF VIRAL HEPATITIS
TARGET OF #S! REGULATES THE FUNCTION OF (#6 2.! POLYMERASE .3" WHICH IS ESSENTIAL FOR EFFICIENT VIRAL GENOME REPLICATION "Y TARGETING #Y0 (#6 GENOME REPLICATION WAS DRASTICALLY SUPPRESSED ;= 4HE COMPOUND IS CURRENTLY IN 0HASE ) CLINICAL TRIALS
2 2 IS BEING DEVELOPED BY 0HARMASSET AND 2OCHE FOR THE TREATMENT OF CHRONIC (#6 INFECTIONS 2 IS A PRODRUG OF A MOLECULE NAMED 03) AN ORAL CYTIDINE NUCLEOSIDE ANALOG THAT INHIBITS THE 2.! DIRECTED 2.! POLYMERASE .3" ; = 03) IS THE ACTIVE COMPONENT OF 2 !T LOW CONCENTRATIONS 03) WAS SHOWN TO BE AN INHIBITOR OF (#6 REPLICA TION SPECIFICALLY TARGETING THE (#6 2.! POLYMERASE )N COMBINATION WITH INTERFERON 03) WAS ACTIVE AND ADDITIVE TO THE ACTIVITY OF INTERFERON ALONE IN THESE PRECLINICAL ASSAYS )N /CTOBER A 0HASE CLINICAL TRIAL UNDER AN ).$ WAS INITIATED 4HIS TRIAL IS A MULTI CENTRE OBSERVER BLINDED RANDOMISED AND PLACEBO CONTROLLED STUDY DESIGNED TO ASSESS THE PHARMACO KINETICS PHARMACODYNAMICS SAFETY TOLERABILITY AND FOOD EFFECT OF 2 IN HEALTHY VOLUNTEERS AND IN PATIENTS CHRONICALLY INFECTED WITH (#6 GENOTYPE AS WELL AS PROVIDE ANTIVIRAL POTENCY DATA OVER DAYS IN PATIENTS CHRONI CALLY INFECTED WITH (#6 GENOTYPE ;=
2 2OCHE IS DEVELOPING 2 AN ORAL (#6 .3" POLYMERASE INHIBITOR 4HE COMPOUND IS A PRODRUG OF 2 ! 0HASE )) TRIAL WAS INITIATED IN ;=
4ENOFOVIR DISOPROXIL FUMARATE 'ILEAD IS INVESTIGATING TENOFOVIR DISOPROXIL FUMARATE 6IREAD A PRODRUG OF TENOFOVIR THE NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR AS A TREATMENT AGAINST ("6 INFECTIONS 3TART OF A 0HASE )) CLINICAL STUDY IS IMMINENT EVALU ATING TENOFOVIR DISOPROXIL FUMARATE $& MONOTHERAPY VERSUS THE COMBINA TION OF EMTRICITABINE AND TENOFOVIR $& FOR THE TREATMENT OF CHRONIC ("6 INFECTION ;= )N *UNE 'ILEAD COMPLETED ENROLMENT OF TWO 0HASE ))) CLINICAL TRIALS TO EVALUATE 6IREAD FOR THE TREATMENT OF ("6 ;=
3CH "OCEPREVIR 4HE 3CHERING 0LOUGH COMPOUND BOCEPREVIR IS AN (#6 .3 PROTEASE INHIBI TOR CURRENTLY IN 0HASE )) CLINICAL TRIALS FOR THE TREATMENT OF CHRONIC HEPATITIS
/LAF 7EBER
# GENOTYPE INFECTION IN COMBINATION WITH PEGYLATED INTERFERON WITH AND WITHOUT RIBAVIRIN IN PATIENTS WHO DO NOT RESPOND TO PEGYLATED INTERFERON AND RIBAVIRIN COMBINATION &AST TRACK DESIGNATION WAS GRANTED BY THE &$! ;=
4ARIBAVIRIN HYDROCHLORIDE 4ARIBAVIRIN B $ RIBOFURANOSYL ( TRIAZOLE CARBOXAMIDINE IS A SYNTHETIC NUCLEOSIDE GUANOSINE ANALOGUE UNDER DEVELOPMENT BY 6ALEANT FOR THE TREATMENT OF CHRONIC HEPATITIS # !FTER ORAL ADMINISTRATION TARIBA VIRIN IS RAPIDLY ABSORBED AFTER WHICH IT IS READILY AND EXTENSIVELY TAKEN UP BY THE LIVER AND CONVERTED INTO ITS ACTIVE METABOLITE RIBAVIRIN 6ALEANT HAS BEGUN ENROLLING PATIENTS IN A 0HASE ))B CLINICAL STUDY COMBINING TARIBAVIRIN WITH A PEGYLATED INTERFERON 4HIS STUDY IS SUBSEQUENT TO TWO PIVOTAL 0HASE ))) TRIALS FOR TARIBAVIRIN THAT WERE COMPLETED IN ;=
4ELAPREVIR 4ELAPREVIR 68 IS AN ORAL (#6 PROTEASE INHIBITOR DEVELOPED BY 6ERTEX IN COMBINATION WITH PEGYLATED INTERFERON FOR THE TREATMENT OF HEPATITIS # 4HE COMPOUND IS CURRENTLY IN 0HASE )) CLINICAL TRIALS )N *UNE 6ERTEX AND *ANSSEN 0HARMACEUTICA ENTERED INTO A CO DEVELOPMENT AND CO PROMO TION AGREEMENT 4HE COMPOUND HAS BEEN GRANTED FAST TRACK DESIGNATION BY THE &$! 3TART OF 0HASE ))) STUDIES IS IMMINENT ;=
54 " 54 " IS IN 0HASE )) CLINICAL TRIALS AT 5NITED 4HERAPEUTICS FOR THE TREATMENT OF (#6 4HE WEEK STUDY ASSESSES THE ANTIVIRAL EFFECT OF ORAL 54 " IN NON CIRRHOTIC (#6 PATIENTS WHO HAVE FAILED INTERFERON BASED THERAPY 54 " IS AN IMINOSUGAR ABLE TO ALTER THE ASSEMBLY OF THE VIRUS ;=
6ALOPICITABINE )DENIX ANNOUNCED IN *ULY THAT THE DEVELOPMENT PROGRAM OF VALOPICI TABINE .- FOR THE TREATMENT OF HEPATITIS # HAS BEEN PLACED ON CLINICAL HOLD IN THE 5NITED 3TATES BASED ON THE OVERALL RISKBENEFIT PROFILE OBSERVED TO DATE IN CLINICAL TESTING ;= 6ALOPICITABINE IS AN 2.! POLY MERASE INHIBITOR THAT WAS INVESTIGATED IN A 0HASE )) STUDY TO EVALUATE THE COMBINATION OF PEGYLATED INTERFERON ALFA PLUS VALOPICITABINE IN PATIENTS WITH HEPATITIS #
$RUG CANDIDATES FOR THE TREATMENT OF VIRAL HEPATITIS
6ALTORCITABINE DIHYDROCHLORIDE )DENIX IS CONDUCTING CLINICAL TRIALS OF VALTORCITABINE AN INVESTIGATIONAL DRUG CANDIDATE FOR THE TREATMENT OF CHRONIC HEPATITIS " 6ALTORCITABINE IS BEING DEVELOPED AS A FIXED DOSE COMBINATION WITH TELBIVUDINE FOR THOSE PATIENTS FOR WHOM TREATMENT WITH A SINGLE AGENT MAY NOT BE ADEQUATE )N LABORATORY STUDIES AND ANIMAL MODELS OF THE DISEASE TELBIVUDINE AND VALTORCITABINE EACH DEMONSTRATE HIGHLY SPECIFIC ANTIVIRAL ACTIVITY AGAINST ("6 )N THESE PRECLINICAL STUDIES THE COMBINATION OF THE TWO AGENTS HAS DEMONSTRATED EVEN GREATER ANTIVIRAL ACTIVITY THAN EITHER DRUG ALONE 6ALTORCITABINE IS ONE OF SEVERAL NOVEL AGENTS IN CLINICAL DEVELOPMENT THAT HAVE SHOWN PROMISING CLINICAL PROFILES IN PATIENTS WITH CHRONIC HEPATITIS " ;=
6#( 6IRO#HEM 0HARMA )NC HAS IDENTIFIED SEVERAL LOW MOLECULAR WEIGHT INHIBI TORS OF (#6 POLYMERASE WHICH INHIBITED (#6 REPLICATION IN THE CELLULAR REPLICON MODEL /NE OF THEM COMPLETED 0HASE ) CLINICAL TRIALS AND IS PRO GRESSING IN 0HASE ))A PROOF OF CONCEPT TRIALS ;=
6'8 # -IFEPRISTONE -IFEPRISTONE IS CURRENTLY INVESTIGATED BY 6IRAL 'ENOMIX NOW NAMED 6'8 0HARMACEUTICALS IN A RANDOMISED OPEN LABEL 0HASE )) TRIAL IN (#6 INFECT ED PATIENTS ;=
6ACCINES AND OTHER DRUG CANDIDATES UNDER DEVELOPMENT ') ') IS CURRENTLY DEVELOPED BY 'LOBE)MMUNE IN 0HASE )B CLINICAL TRIALS FOR THE TREATMENT OF (#6 INFECTIONS ') BELONGS TO A GROUP OF TARGETED MOLECULAR IMMUNOTHERAPIES CALLED 4ARMOGENS hTARGETED MOLECULAR IMMU NOGENSv FOR THE TREATMENT OF INFECTIOUS DISEASES AND CANCER 4ARMOGENS ARE WHOLE HEAT KILLED RECOMBINANT 3ACCHAROMYCES CEREVISIAE YEAST PARTICLES GENETICALLY MODIFIED TO EXPRESS ONE OR MORE PROTEIN TARGETS THAT STIMULATE THE IMMUNE SYSTEM AGAINST DISEASED CELLS 4HE WHOLE HEAT KILLED YEAST WITH THE ANTIGEN EXPRESSED INSIDE IS ADMINISTERED TO THE PATIENT #YTOTOXIC 4 CELLS ARE BEING DISCUSSED AS EFFECTOR CELLS )NTERIM RESULTS HAVE SHOWN THAT ') GEN ERATED CELLULAR IMMUNE RESPONSES IN PATIENTS ELICITED A STATISTI CALLY SIGNIFICANT IMPROVEMENT IN ALANINE AMINO TRANSFERASE !,4 LEVELS FROM BASELINE AND CAUSED NEAR LOG VIRAL LOAD REDUCTIONS IN THREE PATIENTS ;=
/LAF 7EBER
(#6 %%-&# 6ACCINE .OVARTIS #HIRON IS DEVELOPING AN (#6 VACCINE IN A 0HASE ) RANDOMISED OBSERVER BLINDED PLACEBO CONTROLLED STUDY TO EVALUATE THE SAFETY TOLERABIL ITY AND IMMUNOGENICITY OF (#6 %%-& 6ACCINE IN HEALTHY (#6 NEGA TIVE ADULTS %NROLMENT HAS BEEN COMPLETED ;=
(EPATITIS " VACCINES 4HIS SECTION DOES NOT INCLUDE COMBINATION PRODUCTS AND VERY EARLY PRECLINI CAL APPROACHES 6ARIOUS EFFORTS TO DEVELOP NOVEL VACCINES AGAINST HEPATITIS " ARE UNDER WAY AND INCLUDE APPROACHES LIKE VIRUS LIKE PARTICLES 6,0 AS BY #ELL$EX 4HERAPEUTICS #$8 #$8 IS A 6,0 COMPRISING MODIFIED ("C!G PROTEIN SUBUNITS WHICH HAVE BEEN ENGINEERED TO IMPROVE STABILITY REMOVE THE $.! BINDING # TERMINUS AND TO INACTIVATE A DOMINANT EPITOPE RECOGNISED BY ("C!G SPECIFIC ANTIBODIES FROM INFECTED INDIVIDUALS #ELLDEX HAS COMPLETED A FULL PRECLINICAL RESEARCH PROGRAM THAT DEMONSTRATES THE EFFECTIVENESS OF #$8 VACCINE IN ANIMAL MODELS #LINICAL STUDIES ARE IMMINENT ACCORDING TO THE COMPANY ;= $YNAVAX IS DEVELOPING ("6 )33 (EPLISAV AN ("6 VACCINE THAT COM BINES AN IMMUNOSTIMULATING SEQUENCE )33 )33 OF ("6 $.! WHICH ACTS AS A TOLL LIKE RECEPTOR 4,2 AGONIST WITH RECOMBINANT ("S!G FOR THE POTENTIAL TREATMENT OF ("6 INFECTION ! PIVOTAL 0HASE ))) TRIAL IS ONGO ING IN 3INGAPORE 4AIWAN +OREA AND THE 0HILIPPINES ;= $YNAVAX IS ALSO DEVELOPING ANOTHER ("6 VACCINE THAT COMBINES SURFACE AND CORE ANTIGENS OF ("6 FOR THE POTENTIAL TREATMENT OF CHRONIC ("6 ! 0HASE ) STUDY WAS INITIATED EARLIER IN (ENOGEN IS DEVELOPING (" !36 AN ADJUVANTED VACCINE FOR THE POTENTIAL PREVENTION OF ("6 INFECTION IN IMMUNOCOMPRO MISED SUBJECTS 0HASE ))) STUDIES WERE INITIATED IN
(EPATITIS # VACCINES !LTHOUGH NUMEROUS CANDIDATE VACCINES ARE BEING INVESTIGATED IN VERY EARLY PRECLINICAL SETTINGS THERE IS CURRENTLY ONLY LIMITED DATA ON CLINICAL PROGRAMS AVAILABLE ! THERAPEUTIC (#6 VACCINE IS DEVELOPED BY 0EVION BY USING ITS 0EVI4%2 AND 0EVI02/ VIROSOMES CONTAINING SYNTHETIC (#6 PEPTIDES 0%6! AND 0%6" ! 0HASE ) TRIAL WAS INITIATED IN ;= )NTERCELL HAS A THERAPEUTIC (#6 VACCINE IN 0HASE )) CLINICAL TRIALS ;= 4HIS PEPTIDE VACCINE )# CONSISTS OF FIVE SYNTHETIC PEPTIDES HARBOURING (#6 4 CELL EPITOPES AND POLY , ARGININE AS SYNTHETIC ADJUVANT )N A RANDOMISED PLACE BO CONTROLLED TRIAL (,! ! POSITIVE HEALTHY VOLUNTEERS RECEIVED FOUR SC VACCINATIONS OF SEVEN DIFFERENT DOSES )# (#6 PEPTIDES ALONE POLY
$RUG CANDIDATES FOR THE TREATMENT OF VIRAL HEPATITIS
, ARGININE ALONE OR SALINE SOLUTION EVERY WEEKS )# INDUCED RESPONSES IN ALL DOSE GROUPS 0OLY , ARGININE WAS REQUIRED FOR THE AIMED FOR 4H4C TYPE IMMUNITY ;=
(EPATITIS % VACCINE 'LAXO3MITH+LINE IS INVESTIGATING A PROPHYLACTIC HEPATITIS % VIRUS VACCINE IN 0HASE )) CLINICAL TRIALS ;=
2EFERENCES
#OMPANY WEBSITE AT HTTPWWWHGSICOMPRODUCTSINDEXHTML RETRIEVED ON !UGUST :EUZEM 3 "ENHAMOU 9 "AIN 6' 3HOUVAL $ 0IANKOS 3 &LISIAK 2 'RIGERESEN - 2EHAK 6 9OSHIDA % +AITA + ET AL !NTIVIRAL RESPONSE AT WEEK FOLLOWING COMPLETION OF TREATMENT WITH ALBINTERFERON ALFA B PLUS RIBAVIRIN IN GENOTYPE )&. NAÕVE CHRONIC HEPATITIS # PATIENTS ND !NNUAL -EETING OF THE %UROPEAN !SSOCIATION FOR THE 3TUDY OF THE ,IVER %!3, /RAL PRESENTA TION !PRIL "AIN 6' -AROTTA 0 +AITA + 9OSHIDA % 3WAIN - "AILEY 2 .EUMANN ! #RAIN 0 -C(UTCHINSON * 0ULKSTENIS % 3UBRAMANIAN - ET AL #OMPARABLE ANTIVIRAL RESPONSE RATES WITH ALBINTERFERON ALFA B DOSED AT 17 OR 17 INTER VALS IN NAÕVE SUBJECTS WITH GENOTYPES OR CHRONIC HEPATITIS # ND !NNUAL -EETING OF THE %UROPEAN !SSOCIATION FOR THE 3TUDY OF THE ,IVER %!3, /RAL PRESENTATION !PRIL &ISCELLA - "ALAN 6 .ELSON $ #OREY ! &AVORABLE PHARMACOKINETIC OF ALBUMIN INTERFERON ALFA B IN SUBJECTS WITH CHRONIC HEPATITIS # TH !NNUAL -EETING OF THE !MERICAN !SSOCIATION FOR THE 3TUDY OF ,IVER $ISEASES /CTOBER 0OSTER PRESENTATION "AIN 6' +AITA +$ 9OSHIDA %- 3WAIN -' (EATHCOTE %* .EUMANN !5 &ISCELLA - 9U 2 /SBORN ", #RONIN 07 ET AL ! 0HASE STUDY TO EVALUATE THE ANTIVIRAL ACTIVITY SAFETY AND PHARMACOKINETICS OF RECOMBINANT HUMAN ALBUMIN INTERFERON ALFA FUSION PROTEIN IN GENOTYPE CHRONIC HEPATITIS # PATIENTS * (EPATOL n "ALAN 6 .ELSON $2 3ULKOWSKI -3 %VERSON '4 ,AMBIASE ,2 7IEGNER 2( $ICKSON 2# 0OST !" 2EDFIELD 22 $AVIS ', .EUMANN !5 ET AL ! 0HASE STUDY EVALUATING ESCALATING DOSES OF RECOMBINANT HUMAN ALBUMIN INTERFERON ALPHA FUSION PROTEIN IN CHRONIC HEPATITIS # PATIENTS WHO HAVE FAILED PREVIOUS INTERFERON ALPHA BASED THERAPY !NTIVIR 4HER n HTTPWWWCLINICALTRIALSGOVCTSHOW.#4 ORDER RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWINNOGENETICSCOMSITETHERAPEUTICSHTML RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWNABICOMPIPELINEPIPELINEPHP ID RETRIEVED ON !UGUST
/LAF 7EBER
$EPRAETERE 3 ,EROUX 2OELS ' (EPATITIS # VIRUS ENVELOPE PROTEINS IMMUNOGENICITY IN HUMANS AND THEIR ROLE IN DIAGNOSIS AND VACCINE DEVELOP MENT 6IRAL (EPAT 2EV n #OMPANY PRESS RELEASE ON -AY #OMPANY WEBSITE AT HTTPWWWENZOCOMTHERAPEUTICSPRODUCT?PIPELINEASP RETRIEVED ON !UGUST HTTPCLINICALTRIALSGOVCTSHOW.#4 RETRIEVED ON !UGUST #OMPANY WEBSITE ATHTTPWWWMAXYGENCOMPRODUCTS HEPPHP RETRIEVED ON !UGUST 0OCKROS 0* 'UYADER $ 0ATTON ( 4ONG -* 7RIGHT 4 -C(UTCHISON *' -ENG 4# /RAL RESIQUIMOD IN CHRONIC (#6 INFECTION 3AFETY AND EFFICACY IN PLACEBO CONTROLLED DOUBLE BLIND PHASE ))A STUDIES * (EPATOL n #OMPANY WEBSITE AT HTTPWWWARROWTCOUKPRODUCT HCVASP RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWAVIBIOCOMPRPRHTML RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWBIOENVISIONCOMPRODUCTS?PIPELINEPHP RETRIEVED ON !UGUST +AITA + 0HASE )) STUDY OF #ELGOSIVIR IN COMBINATION WITH PEGINTERFERON ALFA B AND RIBAVIRIN IN CHRONIC HEPATITIS # GENOTYPE NON RESPONDER PATIENTS PRESENTATION AT THE $IGESTIVE $ISEASE 7EEK n -AY n 7ASHINGTON $# -EALY .% ,UPONE " 4ELL - $RUGS UNDER DEVELOPMENT FOR THE TREAT MENT OF HEPATITIS $RUGS &UT n 9OO "# +IM *( +IM 4( +OH +# 5M 3( +IM 93 ,EE +3 (AN "( #HON #9 (AN *9 ET AL #LEVUDINE IS HIGHLY EFFICACIOUS IN HEPATITIS " E ANTI GEN NEGATIVE CHRONIC HEPATITIS " WITH DURABLE OFF THERAPY VIRAL SUPPRESSION (EPATOLOGY n 9OO "# +IM *( #HUNG 9( ,EE +3 0AIK 37 2YU 3( (AN "( (AN *9 "YUN +3 #HO - ET AL 4WENTY FOUR WEEK CLEVUDINE THERAPY SHOWED POTENT AND SUSTAINED ANTIVIRAL ACTIVITY IN ("E!G POSITIVE CHRONIC HEPATITIS " (EPATOLOGY n &LISIAK 2 (ORBAN ! +IERKUS * 3TANCZAK * #IELNIAK ) 3TANCZAK '0 7IERCINSKA $RAPALO ! 3IWAK % (IGERSBERGER * !ESCHLIMANN # ET AL 4HE CYCLOPHILIN INHIBITOR $%")/ HAS A POTENT DUAL ANTI ()6 AND ANTI (#6 ACTIVITY IN TREATMENT NAÕVE ()6(#6 CO INFECTED SUBJECTS !MERICAN !SSOCIATION FOR THE 3TUDY OF ,IVER $ISEASES !!3,$ "OSTON n /CTOBER #OMPANY WEBSITE AT HTTPWWWGILEADCOMANTIVIRAL RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPPHXCORPORATE IRNETPHOENIXZHTML C P IROL RESEARCH.EWS!RTICLE)$ HIGHLIGHT RETRIEVED ON !UGUST #OMPANY PRESS RELEASE 7ATASHI + 3HIMOTOHNO + #HEMICAL GENETICS APPROACH TO HEPATITIS # VIRUS REPLICATION CYCLOPHILIN AS A TARGET FOR ANTI HEPATITIS # VIRUS STRATEGY 2EV -ED 6IROL n 3TUYVER ,* -C"RAYER 42 4HRANISH 0- #LARK * (OLLECKER , ,OSTIA 3 .ACHMAN 4 'RIER * "ENNETT -! 8IE - 9 ET AL )NHIBITION OF HEPA
$RUG CANDIDATES FOR THE TREATMENT OF VIRAL HEPATITIS
TITIS # REPLICON 2.! SYNTHESIS BY ` $ DEOXY FLUORO METHYLCYTIDINE ! SPECIFIC INHIBITOR OF HEPATITIS # VIRUS REPLICATION !NTIVIRAL #HEMISTRY AND #HEMOTHERAPY n -URAKAMI % "AO ( 2AMESH - -C"RAYER 42 7HITAKER 4 -ICOLOCHICK 3TEUER (- 3CHINAZI 2& 3TUYVER ,* /BIKHOD ! /TTO -* ET AL -ECHANISM OF ACTIVATION OF ["ETA] $ DEOXY FLUORO # METHYLCYTIDINE AND INHIBI TION OF HEPATITIS # VIRUS .3" 2.! POLYMERASE !NTIMICROBIAL !GENTS AND #HEMOTHERAPY n #OMPANY WEBSITE AT HTTPWWWPHARMASSETCOMPIPELINEPSI ASP RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWROCHECOMHOMEINVESTORSINV? PIPELINEINV? PIPELINE?DETHTM TA 6IROLOGY0HASE SUBMIT 3HOW PIPELINE RETRIEVED ON !UGUST HTTPWWWCLINICALTRIALSGOVCTSHOW.#4 ORDER RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWGLOBEIMMUNECOMINDEXPHP LOAD NEWS PAGE INDEX OP NEWS?VIEWNEWS?ID RETRIEVED ON !UGUST HTTPWWWCLINICALTRIALSGOVCTSHOW.#4 ORDER RETRIEVED ON !UGUST 6ERTEX PRESS RELEASE *ANUARY #OMPANY WEBSITE AT HTTPWWWUNITHERCOMPRODUCTS?GLYBOASP RETRIEVED ON !UGUST #OMPANY PRESS RELEASE *ULY +EEFFE %" -ARCELLIN 0 .EW AND EMERGING TREATMENT OF CHRONIC HEPATI TIS " #LIN 'ASTROENTEROL (EPATOL n #OMPANY WEBSITE AT HTTPWWWVIROCHEMPHARMACOMOUR&OCUSHTML RETRIEVED ON !UGUST HTTPWWWCLINICALTRIALSGOVCTSHOW.#4 ORDER RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWSCHERING PLOUGHCOMPDFPRODUCTPIPELINEPDF RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWVALEANTCOMRESEARCH!ND$EVELOPMENTPIPE LINE TARIBAVIRINJSPF RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWCELLDEXTHERAPEUTICSCOMWTPAGECDX? RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWDYNAVAXCOMHEPATITIS?BPREVHTM RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWPEVIONCOMINDEXPHP PAGE RETRIEVED ON !UGUST #OMPANY WEBSITE AT HTTPWWWINTERCELLCOAT3ELECT-ENUWA SE)$- CCCBA FE AC BAA RETRIEVED ON !UGUST &IRBAS #H *ILMA " 4AUBER % "UERGER 6 *ELOVCAN 3 ,INGNAU + "USCHLE - &RISCH * +LADE #H )MMUNOGENICITY AND SAFETY OF A NOVEL THERAPEUTIC HEPATITIS # VIRUS (#6 PEPTIDE VACCINE A RANDOMIZED PLACEBO CONTROLLED TRIAL FOR DOSE OPTIMIZATION IN HEALTHY SUBJECTS 6ACCINE n #OMPANY WEBSITE AT HTTPWWWGSKCOMINVESTORSPP?PIPELINE?STANDARDHTM RETRIEVED ON !UGUST
)NDEX
! ACETAMINOPHEN !CKERTIA MARMOTAE ACUTE PHASE PROTEIN ACYCLOVIR ADAPTIVE IMMUNITY ADEFOVIR ADENOVIRUS AmATOXIN " ALANINE AMINOTRANSFERASE !,!4 ALBUMIN UROKINASE TYPE PLASMINOGEN ACTIVATOR U0! TRANSGENIC MOUSE ALCOHOL INDUCED LIVER CIRRHOSIS ALCOHOLIC STEATOHEPATITIS !3( ALKALINE PHOSPHATASE !0 ALPHA ANTITRYPSIN DElCIENCY ALPHA INTERFERON AMINO ACID SERUM CONCENTRATION AMMONIA DETOXIlCATION !.! ANIMAL MODEL n ANTHROPOZOONOSIS ANTIMICROBIAL DRUG !0/"%# PROTEIN ARA !-0 ARCTIC SQUIRREL HEPATITIS VIRUS !3(6 !RMILLIFER ASCITES ASPARTATE AMINOTRANSFERASE !3!4 ASSOCIATED AUTOIMMUNE DISEASE AUTOIMMUNE HEPATITIS !)( AUTOIMMUNE LIVER DISEASE !6) AVIHEPADNAVIRUS !:4 BACTERIAL ABSCESS BACTERIAL HEPATITIS BACTERIAL HEPATITIS EQUINE
"ARTONELLA HENSELAE BAVITUXIMAB BILE ACID BILIRUBIN UNCONJUGATED ")6. BLOOD COAGULATION BLUE GREEN ALGAE TOXIN "RUCELLA "URKHOLDERIA PSEUDOMALLEI CALICIVIRUS #ANINE !DENOVIRUS #!6 #APILLARIA SP #APILLARIA HEPATICA n CARBOXYPEPTIDASE $ CARCINOMA HEPATOCELLULAR CARPROFEN ` CATENIN CELGOSIVIR CELL CULTURE n CELLULAR IMMUNE RESPONSE CELLULAR RESTRICTION FACTOR CHIMERIC MOUSE MODEL CHIMERIC VIRUS CHIPMUNK CHOLANGIOHEPATITIS CHOLELITHIASIS CHOLESTASIS CHRONIC ACTIVE HEPATITIS #ICAVIR CLEVUDINE #LONORCHIS SINENSIS n C MYC COMBINATION THERAPY #/--$ GENE COMPARATIVE MEDICINE COPPER METABOLISM COPPER STORAGE CORE PROTEIN COVALENTLY CLOSED CIRCULAR $.! CCC $.! CRANE HEPATITIS " VIRUS
CREATININE CYCLOPHOSPHAMIDE CYTOKINE CYTOMEGALOVIRUS #-6 $$" 3 $%")/ DENGUE FEVER VIRUS $ICROCOELIUM DENDRITICUM n DIETHYLNITROSAMINE $%. DIFFERENTIAL DIAGNOSIS DIHYDROARYLPYRIMIDINE CCC $.! RC $.! DRUG INDUCED LIVER DISEASE DUCK HEPATITIS " VIRUS $("6 %CHINOCOCCUS GRANULOSUS n %CHINOCOCCUS MULTILOCULARIS n %$ %(# %(4 ELECTRON MICROSCOPY EMTRICITABINE ENDOCYTOSIS %NTAMOEBA HISTOLYTICA n ENTECAVIR %NTEROBACTERIACEAE %NTEROCOCCUS ENTEROVIRUS ENVELOPE PROTEIN %PSTEIN "ARR VIRUS %"6 EQUINE VIRAL HEPATITIS %UTAMIAS FAMCICLOVIR &ASCIOLA HEPATICA n FATTY LIVER lALURIDINE lBRINOGEN lBROPLASIA lBROSING CHOLESTATIC HEPATITIS &#( &LAVIVIRIDAE FAMILY FOCAL NECROTISING PATTERN &RANCISELLA TULARENSIS GAMMA GLUTAMYLTRANSFERASE a'4 '" VIRUS ! AND " '"6 ! '"6 " GLOMERULONEPHRITIS IMMUNE MEDIATED GLUCOCORTICOID GLUCOSE SERUM CONCENTRATION GLUTAMATE DEHYDROGENASE ',$(
)NDEX
GLYCOPROTEIN GRADING GRANULOMATOUS BACTERIAL HEPATITIS GRANULOMATOUS INmAMMATION GROUND SQUIRREL HEPATITIS VIRUS '3(6 GROUND GLASS HEPATOCYTE '3 HAEMATOLOGY HAEMOCHROMATOSIS HELIOXANTHIN HEPADNAVIRAL HOST RANGE MOLECULAR BA SIS HEPADNAVIRAL INFECTIVITY HEPADNAVIRUS n HEPADNAVIRUS CROSS SPECIES TRANSMISSI ON HEPADNAVIRUS INFECTIOUS CYCLE HEPADNAVIRUS INFECTIVITY TESTING HEPADNAVIRUS PHYLOGENY HEPADNAVIRUS HOST NATURAL HEPADNAVIRUS HOST PHYLOGENY n HEPATIC ENCEPHALOPATHY (% HEPATIC FUNCTION TEST HEPATIC GRANULOMA HEPATIC PROGENITOR CELL HEPATIC STELLATE CELL (3# HEPATITIS ACUTE HEPATITIS ACUTE IN DOGS n HEPATITIS BACTERIAL AND PARASITIC HEPATITIS CHRONIC n HEPATITIS CHRONIC IN DOGS n HEPATITIS COPPER RELATED HEPATITIS FULMINANT HEPATITIS ISCHAEMIC HEPATITIS MONONUCLEOSIS LIKE HEPATITIS TOXIC HEPATITIS VIRAL n HEPATITIS VIRAL DIAGNOSIS n HEPATITIS VIRAL DIAGNOSTIC ALGORITHM HEPATITIS ! n HEPATITIS ! SYMPTOMS HEPATITIS ! VIRUS (!6 n (!6 INTERNATIONAL 6IRUS #ODE (!6 PATHOGENESIS (!6 VIRUS STABILITY (!6 ANTIGEN (!6 HYPERIMMUNOGLOBULIN (!6 TRANSMISSION (!6 VACCINE HEPATITIS " CHRONIC
)NDEX
HEPATITIS " SURFACE ANTIGEN ("S!G ("E!G n HEPATITIS " TREATMENT HEPATITIS " VIRUS ("6 n n ("6 CAPSID n ("6 PRE3 DERIVED PEPTIDE HEPATITIS # TREATMENT n HEPATITIS # VIRUS (#6 (#6 2.! REPLICATION n (#6 TRANSMISSION OF (#6 DIAGNOSIS (#6 GENOME (#6 PARTICLE ANATOMY (#6 PARTICLE ASSEMBLY n (#6 PERSISTENCE (#6 PSEUDOPARTICLE (#6PP (#6 HEPATITIS $ HEPATITIS $ VIRUS ($6 HEPATITIS DRUG n HEPATITIS % n HEPATITIS % INCUBATION HEPATITIS % VIRUS (%6 n (%6 INTERNATIONAL 6IRUS #ODE (%6 REPLICATION HEPATITIS EPIDEMICA HEPATITIS ' VIRUS '"6 #('6 HEPATITIS TREATMENT HORSE n HEPATITIS VACCINE n HEPATOCARCINOGENESIS n HEPATOCELLULAR BURNED OUT PHENOMENON HEPATOCELLULAR CARCINOMA (## n HEPATOTOXIC CHEMICALS (EPATOVIRUS (EPEVIRIDAE HEREDITARY LIVER DISEASE HERON HEPATITIS " VIRUS (("6 HERPES SIMPLEX VIRUS (36 HOST DETERMINING REGION HOST RANGE n HOST RANGE EXPERIMENTAL ASSESSMENT HOST RANGE MOLECULAR DETERMINANT HYDATID HYDATID CYST HYPERGLOBULINAEMIA HYPOALBUMINAEMIA
), IMMUNE RESPONSE IMMUNOMODULATORY AGENT INFECTIOUS HEPATITIS )../ )../ INTERFERON )&. n n INTERFERON _ )&. _ INTERFERON a )&. a INTERFERON OMEGA )NTERNATIONAL #OMMITTEE ON 4AXONOMY OF 6IRUSES )#46 INTESTINAL EPITHELIA INTRAVASCULAR COAGULATION )SHAKS MODIlED HISTOLOGICAL ACTIVITY INDEX M(!) )4-. *APANESE PATIENT WITH FULMINANT HEPATITIS *&( +UPFFER CELL +UPFFER CELL ACTIVATION LACTULOSE LAMIVUDINE LAPAROSCOPY LARGE ENVELOPE PROTEIN ,EISHMANIA n ,EPTOSPIRA ICTEROHAEMORRHAGIAE LEPTOSPIROSIS LIFE EXPECTANCY ,INGUATULA LIPOGRANULOMA ,ISTERIA MONOCYTOGENES LIVER BIOPSY n LIVER BIOPSY SCORE LIVER CIRRHOSIS n LIVER CONSENSUS GROUP LIVER ENZYME LIVER mUKE LIVER PROGENITOR CELL LIVER SINUSOIDAL ENDOTHELIAL CELL ,3%# n n LIVER TRANSPLANTATION , ORNITHINE , ASPARTATE MALARIA n -ALLORYS HYALINE NUCLEI METABOLIC LIVER DISEASE -%4!6)2 METRONIDAZOLE MOUSE MODEL MULTISYSTEMIC EOSINOPHILIC EPITHELIOTROPHIC DISEASE -%%$
-YCOBACTERIUM TUBERCULOSIS MYCOPHENOLATE MOFETIL --& MYRISTOYLATION . ACETYLCYSTEINE NALIDIXINE ACID .EISSERIA GONORRHOEAE .EISSERIA MENINGITIDIS NEOMYCIN NEPHROTIC SYNDROME .& g" NITRIC OXIDE ./ . MYC . MYC LOCUS NON ALCOHOLIC STAETOHEPATITIS .!3( NUCLEOSIDE ANALOG ONCOGENE /PISTHORCHIS n ORTHOHEPADNAVIRUS OXIDATIVE DAMAGE 0ARASCARIS EQUORUM 0EGASYS PEGYLATED INTERFERON _ 0%' )&._ PENICILLAMINE PERICELLULAR lBROSIS PHYLOGENETIC TREE BIRDS PHYLOGENETIC TREE MAMMALS 0ICORNAVIRIDAE 0LASMODIUM n POLYMERASE ("6 0OROCEPHALUS PORTOSYSTEMIC ACQUIRED COLLATERAL PREDNISOLONE PREGENOMIC 2.! PG2.! PREGNANCY PRENEOPLASTIC FOCUS PRIMARY BILIARY CIRRHOSIS 0"# PRIMARY SCLEROSING CHOLANGITIS 03# PROGENITOR CELL PROTOZOAN PSEUDOTYPING PULMONARY METASTASE 2 2 2 2 REGULATORY 4 CELL 4REG RELAXED CIRCULAR $.! RC $.!
)NDEX
RC $.! IN HEPADNAVIRAL REPLICATION REPLICASE REPLICON SYSTEM RESIQUIMOD RETROPOSON REVERSE TRANSCRIPTION 24 RIBAVIRIN 2.! PREGENOMIC PG2.! 2.! SHORT HAIRPIN SH2.! 2.! SMALL INTERFERING SI2.! 2.! POLYMERASE 2OSSS GOOSE HEPATITIS " VIRUS 2'("6 RUBEANIC ACID STAIN SANDED NUCLEI 3CH 3CHISTOSOMA n 3#)$ MOUSE SERUM ENZYMES SERUM HEPATITIS SHORT HAIRPIN 2.! SH2.! SILYMARIN SMALL INTERFERING 2.! SI2.! SMALL MOLECULE TREATMENT SNOW GOOSE HEPATITIS " VIRUS 3'("6 STAGING 3TAPHYLOCOCCUS STEATOHEPATITIS STORK HEPATITIS " VIRUS 34("6 3TREPTOCOCCUS 3TRONGYLUS SULFONAMIDE SUSTAINED VIROLOGIC RESPONSE 362 TARIBAVIRIN 4 CELL RECEPTOR 4 CELL RESPONSE TELAPREVIR TELBIVUDINE TENOFOVIR TENOFOVIR DISOPROXIL FUMARATE 4HEILERS DISEASE TISSUE TROPISM TRANSCYTOSIS n TRANSGENIC MOUSE STRAIN EXPRESSING ("6 GENOME TRAVELLERS HEPATITIS 4REPONEMA PALLIDIUM 4RYPANOSOMA CRUZI n ULTRASONOGRAPHY U0!3#)$ MOUSE
)NDEX
UREA IN SERUM 54 " VALOPICITABINE VALTORCITABINE VARICELLA ZOSTER VIRUS 6:6 6#( VERY LOW DENSITY LIPOPROTEIN 6,$, 6'8 # VIRAL HEPATITIS EQUINE VIRAL INFECTION PERMISSIVITY AND RESTRICTION FACTORS VIRAL INTEGRATION VIRAL POLYMERASE 7( CORE ANTIGEN 7(C!G WHITE STORK HEPATITIS " VIRUS 73("6
7(6 SURFACE ANTIGEN 7(S!G 7(6. MYC TRANSGENE 7(8 PROTEIN 7ILSON DISEASE WITHDRAWAL TREATMENT WOODCHUCK HEPATITIS VIRUS 7(6 n WOOLLY MONKEY HEPATITIS " VIRUS 7-("6 8 GENE ZINC GLUCONATE ZONAL PATTERN LIVER ACINUS ZONE COPPER ACCUMULATION IN LIVER LOBULES
4HE "!)$ 3ERIES "IRKHËUSER !DVANCES IN )NFECTIOUS $ISEASES )NFECTIOUS DISEASES REMAIN A SUBSTANTIAL DRAIN ON HUMAN WELL BEING AND ECONOMIES DESPITE THE AVAILABILITY OF MODERN DRUGS .EW PATHOGENS EMERGE AND KNOWN PATHOGENS CHANGE THEIR GEOGRAPHICAL DISTRIBUTION AND THEIR SUSCEPTIBILITY TO THE AVAILABLE DRUGS !N UNDERSTANDING OF THE STRUCTURE AND FUNCTION OF INFECTIOUS DISEASE PATHOGENS IS A MAJOR SCIENTIFIC CHALLENGE WITH IMPORTANT POTENTIAL APPLICATIONS 4HIS NEW CROSS DISCIPLINARY MONOGRAPH SERIES WILL PROVIDE UP TO DATE INFORMATION ON THE LATEST DEVELOPMENTS IN INFECTIOUS DISEASE RESEARCH 4HE MULTI AUTHORED VOLUMES WILL COVER BASIC BIOLOGY AND BIOCHEMISTRY OF PATHO GENS AS WELL AS APPLIED MEDICAL ASPECTS AND IMPLICATIONS FOR PUBLIC HEALTH AND POLICY 4HE CONTRIBUTIONS ARE WRITTEN BY LEADING INFECTIOUS DISEASE RESEARCHERS AND PHARMACEUTICAL SCIENTISTS WITH A WIDE RANGE OF EXPERTISE 4HE ENVISAGED READERSHIP INCLUDES ACADEMIC AND INDUSTRIAL RESEARCHERS IN MEDICINE AND INFECTIOUS DISEASES AS WELL AS CLINICIANS AND OTHERS INVOLVED IN DIAGNOSTICS AND DRUG DEVELOPMENT
!VAILABLE VOLUMES #ORONAVIRUSES WITH 3PECIAL %MPHASIS ON &IRST )NSIGHTS #ONCERNING 3!23 ! 3CHMIDT -( 7OLFF / 7EBER %DITORS 4HE 'RAND #HALLENGE FOR THE &UTURE 6ACCINES FOR 0OVERTY 2ELATED $ISEASES FROM "ENCH TO &IELD 3(% +AUFMANN AND 0 ( ,AMBERT %DITORS #OMMUNITY !CQUIRED 0NEUMONIA . 3UTTORP 4 7ELTE 2 -ARRE %DITORS 0OXVIRUSES ! -ERCER ! 3CHMIDT / 7EBER %DITORS 0EDIATRIC )NFECTIOUS $ISEASES 2EVISITED ( 3CHROTEN 3 7IRTH %DITORS )NFLUENZA 6ACCINES FOR THE &UTURE 2 2APPUOLI %DITOR
