Virus Hepatitis a, B, C, D y E

DOI: 10.1542/pir.13-6-203 1992;13;203-212 Pediatr. Rev.

Saul Krugman Viral Hepatitis: A, B, C, D and E—Infection

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This is the first part of a two-part article about viral hepatitis. The secondpart, on prevention, will appear in the July 1992 issue of Pediatrics inReview. I?. J. H.

FOCUS QUESTIONS

1. What vh,ises are associated withhepatitis, and which of these areregarded as primary agents forhepatitis?

2. What are the primary routes oftransmission of the viralhepatltldes?

3. What complications are associatedwith hepatitis due to hepatitisviruses?

4. What factors determine the periodof transmissibility of virus In per-Sons with various forms ofhepatitis?

5. What readily available tests canestablish the diagnosis of variousforms of hepatitis and their trans.missibility In the Infected patient?

ABBREVIATIONS

ALT alanine aminotransferaseanti-HAV antibody to hepatitis A

virusanti-HBc antibody to HBcAganti.HBe antibody to HBeAganti-HBs antibody to HBsAganti-HCV antibody to hepatitis C

virusanti-HDV antibody to hepatitis D

virusET-NANB enterically transmitted

non-A, non-B hepatitisHAV hepatitis A virusHBcAg hepatitis B core antigenHBeAg hepatitis B e antigenHB5Ag hepatitis B surface

antigenHBV hepatitis B virusHCV hepatitis C virusHDV hepatitis D virusHEV hepatitis E virusNANB non-A, non-B hepatitisPHC primaty hepatocellular

carcinomaPT-NANB parenterally transmitted

non-A, non-B hepatitis

*Pmftssor of Pediatrics, NYU Medical

Center, 550 First Avenue, New York, NY10016.

Pediatrics in Review Vol. 13 No. 6 June 1992 203

Viral Hepatitis: A, B, C, D andF - InfectionSaul Krugman, MD*

ARTICLE

Viral hepatitis is caused by at leastfive etiologically and immunologic-ally distinct viruses: hepatitis A(HAy), hepatitis B (HBV), hepatitisC (HCV), hepatitis D (HDV), andhepatitis E (HEy). The clinical, epi-demiologic, and immunologic fea-tures of these five forms of viralhepatitis may be similar or different.Hepatitis also may occur during thecourse of disease caused by cytomeg-alovirus, Epstein-Barr virus, herpessimplex virus, varicella-zoster virus,adenoviruses, enteroviruses, rubellavirus, arboviruses, and other agents.

Hepatitis A is synonymous with“infectious hepatitis,” an ancientdisease described by Hippocrates andformerly known as epidemic jaun-dice, acute catarrhal jaundice, andother designations. The fulminantform of the disease was called acuteyellow atrophy of the liver.

Hepatitis B is synonymous with“serum hepatitis,” a disease with amore recent history. The first knownoutbreak occurred during 1883among a group of shipyard workerswho were vaccinated against small-

pox with glycerinated lymph ofhuman origin. Later, an increased in-cidence of the disease was observedamong patients attending venerealdisease clinics, diabetes clinics, andother facilities where multiple injec-tions were given with inadequatelysterilized syringes and needles con-taminated with the blood of a viralcarrier. The most extensive outbreakoccurred in 1942, when yellow fevervaccine containing human serumcaused 28 585 cases of hepatitis Binfection with jaundice among UnitedStates military personnel. It was Un-known at the time of vaccination thatthe human serum component of thevaccine was contaminated with HBV.The various aliases of hepatitis B re-corded in the literature include serumhepatitis, homologous serum jaun-dice, transfusion jaundice, syringejaundice, and postvaccinal jaundice.

Hepatitis C formerly was desig-nated “parenterally transmitted non-A, non-B hepatitis” (PT-NANB).PT-NANB hepatitis was recognizedas a clinical entity during the 1970s,when specific tests for identificationof HAV and HBV infections becameavailable. Absence of HAV andHBV serologic markers of infectionsuggested the presence of PT-NANBhepatitis. Identification of HCV asthe most common cause of PT-NANB hepatitis was reported during1989. Extensive serologic studieshave revealed that HCV is a cause ofsporadic as well as posttransfusionhepatitis.

Hepatitis D virus is essentially adefective RNA virus that can repli-cate only in the presence of acute orchronic HBV infection. The genomeof HDV codes for an internal anti-gen, but the virus is encapsulated byhepatitis B surface antigen (HBsAg)of the helper HBV.

Hepatitis E previously was called“enterically transmitted NANB”(ET-NANB). Serologic studies of

various outbreaks of ET-NANB hep-atitis revealed no evidence of HAVor HBV infection. In retrospect, it isclear that these outbreaks werecaused by HEV, an agent that wascloned during 1990.

Etiology

HEPATITIS A

The hepatitis A virus, a 27-nm parti-cle, has physical, chemical, and bio-logical characteristics that resemblethose of an enterovirus. An electron-micrograph comparing HAV withHBV is shown in Figure 1. It is asimple, nonenveloped virus with anucleocapsid that has been designatedthe hepatitis A antigen. A single-stranded molecule of RNA is presentinside the capsid. HAV can be culti-vated in various cell cultures, and itsgenome has been cloned.

HEPATITIS B

The hepatitis B virus, a complex43-nm virion, is a member of a newclass of viruses, designated“hepadna.” Unlike HAV, HBV hasnot been propagated successfully incell cultures. Nevertheless, its bio-



�n micrographs of type A .. -- � hepaLJ viruses. L.r.�.. .4 virus

(HAV�l: Note 27-nm particles, uniform in size.) 1,�Js B virus (HBV): Note 43-nm Dane

particle (hepatitis B virus) as well as spherical and filamentous particles 20 nm in diameter

(hepatitis B surface antigen). Reprinted with permission from Provost PJ, Wolanski BS, Miller

WJ, Ittensohn OL, McAleer WJ, Hilleman MR. Biophysical and biochemical properties of CR326

human hepatitis A virus. Am J Med Sci. 1975;270:87.

HEPATITIS B VIRUS AND ANTIGENS

ymerase

�oubIe-- tranded�ircuIarDNA

DNA

FIGURE 2. Schematic illustration of the hepatitis B virus (HBV) and its antigens: hepatitis B

surface antigen (HBs.4g), hepatitis B core antigen (HBcAg), and hepatitis B e antigen (HBeAg).

204 Pediatrics in Review Vol. 13 No. 6 June 1992

INFECTIOUS DISEASEHepatitis -

physical and biochemical propertieshave been well characterized, and theHBV genome has been cloned andsequenced.

A schematic illustration of thestructure of HBV and its antigens isshown in Figure 2. The virus is adouble-shelled particle; its outer sur-face component, the hepatitis B sur-face antigen (HBsAg), is immunolo-

gically distinct from the inner corecomponent, the hepatitis B core anti-gen (HBcAg). The core contains thegenome of HBV, a single moleculeof partially double-stranded DNA.One of the strands is incomplete,leaving a single-stranded or gap re-gion. Additional components of thecore include DNA-dependent DNApolymerase and hepatitis B e antigen

(HBeAg).A simple, direct molecular hybridi-

zation test has been developed to de-tect HBV DNA in serum. Studies byvarious investigators have revealedthat most HBeAg-positive sera havedetectable HBV DNA.

Various tests for the detection ofHBsAg and antibody for HBsAg(anti-HBs) have been developed.These techniques have proved to bevery useful for various studies in-volving: 1) the testing of blood do-nors and blood products, 2) diagnosisof acute and chronic hepatitis and thehepatitis B carrier state, 3) epide-miology of hepatitis B infections,4) various investigations designed toenhance knowledge of the pathogen-esis and immunologic aspects of thedisease, and 5) the evaluation of ac-tive and passive immunization proce-dures for preventing HBV infections.

HEPATITIS C

Studies using chimpanzees revealedthe presence of a transmissible agentin blood products that caused NANBhepatitis. The agent was sensitive toorganic solvents, and it was < 80 nmin diameter, as assessed by filtration.The genome of this agent, which hasbeen designated hepatitis C virus(HCV), has been cloned using largequantities of well-characterizedhighly infectious plasma as a sourceof virus. The physical characteristicsof HCV indicate that it is a flavivi-rus-like agent; it contains a positivesingle-stranded RNA molecule.

HEPATITIS D

The 35-nm HDV double-shelled par-tide resembles HBV when examinedwith electronmicroscopy. It has anexternal coat antigen of HBsAg pro-vided by the genome of HBV (thehelper virus) and an internal deltaantigen that is provided by the HDVgenome. A small circular RNA mole-cule is associated with the internaldelta antigen; it is single-stranded.The structure and replicative cycle ofHDV place it outside of any knownfamily of animal viruses.

HEPATITIS E

Virus-like particles, 27 to 30 nm indiameter, were detected in fecal sam-ples from a volunteer who ingestedan aqueous extract of feces obtained



Table. Viral Hepatitis Types A, B, C,D,andE: Comparison of Clinical, Epidemiologic,and Immunologic Features

FEATURES HEPATITIS A HEPATITIS B HEPATITIS C HEPATITIS D HEPATITIS E

Virus HAV HBV HCV HDV HEVFamily Picornavirus Hepadnavirus Flavivirus Satellite CalcivirusGenome RNA DNA RNA RNA RNA

Incubation 15 to 40 d 50 to 180 d 1 to 5 mo 21 to 90 d 2 to 9 wkperiod

Type of Usually Usually Usually Usually Usuallyonset acute insidious insidious acute acute

Prodrome: Not May be May be Unknown NotArthritis present present present present

and rash

Mode oftransmission:

Oral (fecal) Usual No No No UsualParenteral Rare Usual Usual Usual NoOther Food or Intimate

water-borne (sexual)contact

Perinatal

Intimate(sexual)contactless common

Intimate(sexual)contactless common

Water-bornetransmissionin developingcountries

Sequelae:Carrier No Yes Yes Yes NoChronic No cases Yes Yes Yes No cases

hepatitis reported reported

Mortality 0.1% to 0.2% 0.5% to 2.0% in 1% to 2% in 2% to 20% 20% inuncomplicatedcases; may behigher in com-plicated cases

uncomplicatedcases; may behigher in com-plicated cases

pregnant woman;1% to 2% ingeneralpopulation

Yes Yes Yes Yes YesNo No No No No


INFECTIOUS DISEASEHepatitis

from patients carrying enterically-transmitted NANB hepatitis. A simi-lar agent has been transmitted tomarmosets and chimpanzees. Thiscause of ET-NANB hepatitis is calledthe hepatitis E virus (HEy). The vi-rus appears to be very labile. Its bio-physical properties indicate that it isa calcivirus-like agent, a single-stranded RNA virus.

Pathogenesis

HEPATITIS A

Hepatitis A antigen is detected in thecytoplasm of hepatocytes shortly be-fore onset of acute hepatitis. Viralexpression decreases rapidly after theappearance of clinical and histologicmanifestations and 1gM-specific anti-HAV. Hepatocellular damage iscaused primarily by immunologicrather than cytotoxic factors. Propa-gation of HAV in tissue culture is

Immunity:HomologousHeterologous

not associated with a cytopathiceffect.

HEPATITIS B, C, AND D

The pathologic and clinical conse-quences of hepatitis B, C, and D in-fections are related to at least twofactors: 1) that HBV, HCV, andHDV are not cytopathogenic; and 2)that liver cell necrosis is largely theresult of host defenses. Cell necrosismay be the result of a cellular andimmune response to HBV and HCVinfection. Acute hepatitis with recov-ery may be associated with an effi-cient immune response thateliminates virus-infected cells bymeans of spotty necrosis. Viral anti-gens (HBsAg and HBcAg) that maybe present in the liver before elicita-tion of the immune response areeliminated at the height of the acutedisease. In contrast, chronic forms ofhepatitis B and C may be the result

of a quantitatively or qualitatively (orboth) ineffective immune response.

Under the conditions of high-gradeimmunosuppression, such as occursin kidney transplant recipients, HBVmay persist in the liver without anysubstantial liver cell damage. On theother hand, in the case of chronic ad-tive hepatitis, the occurrence ofpiecemeal necrosis may be a conse-quence of a partially deficient im-mune state. The available evidenceindicates that an immune defect re-sulting in the incomplete eliminationof infected hepatocytes is a cause ofchronic HBV infection.

Clinical ManifestationsThe similarities and differences ofthe clinical manifestations of viralhepatitis types A, B, C, D, and E arelisted in the Table. The incubationperiod of hepatitis A ranges between15 and 40 days, and the onset of



/ HB�A�

1224

Months After Exposure

ii

FIGURE 3. Typical course of a case of acute

hepatitis A. Abbreviations: ALT, alanineaminotransferase; HAV, hepatitis A virus;anti-HAV, antibody to HAV. Reproduced with

permission from Hoofnagle JH and DiBisceglie

Aid. Serologic diagnosis of acute and chronicviral hepatitis. Semin Liver Dis. 1991;11:73-

83.



symptoms is usually acute. In con-trast, the incubation period of hepati-tis B is longer (50 to 180 days), andthe onset is more apt to be insidious.The incubation period of hepatitis Cmay be the same as either type A ortype B hepatitis, ranging from 1 to 5months. In general, the clinical fea-tures of hepatitis C resemble type Binfection more than type A.

The clinical picture of hepatitisvaries. In children, acute disease isgenerally milder and its courseshorter than in adults. In children oradults, jaundice may be inapparent orevanescent, or it may persist formany weeks. The course of the dis-ease often may be separated into twophases: preicteric and icteric. How-ever, jaundice occasionally may bethe initial symptom.

PREICFERIC PHASE

Fever, when present, appears duringthe preicteric phase of the disease.Often it is absent or fleeting in thecase of young children, but in ado-lescents and adults it may last for aslong as 5 days. Temperature rangesbetween 37.8#{176}and 40#{176}C (100#{176}and104#{176}F) and generally is accompaniedby headache, lassitude, anorexia,nausea, vomiting, and abdominalpain. Urticaria and arthralgia or ar-thritis occurring during the preictericphase usually are manifestations ofhepatitis B. The liver may be en-larged and tender, and splenomegalyand lymphadenopathy may be presentin some patients.

ICTERIC PHASE

Jaundice begins to emerge as the fe-ver subsides; it usually is precededby the appearance of dark urine (bili-uria). In young children, the transi-tion to the icteric phase most often ismarked by disappearance of symp-toms. In adults and older children,on the other hand, the icteric phasemay be accompanied by an exacerba-tion of some of the original symp-toms, such as anorexia, nausea,vomiting, and abdominal pain. Men-tal depression, bradycardia, and pru-ritus all frequently occur in adults butare uncommon in children. Stoolsmay be clay-colored, but this is aninconstant finding. The icteric phasepersists from a few days to as longas 1 month, the average duration

being about 8 to 1 1 days in children(in contrast to 3 to 4 weeks inadults). As jaundice fades, symptomssubside and, as a rule, convalescenceis rapid and uneventful. Excessiveweight loss is more common inadults than in children. In infants andchildren younger than 3 years, hepa-titis is usually anicteric.

Jaundice is a very rare manifesta-tion of neonatal hepatitis B infection.Most HBV-infected infants, born tomothers who are HBV carriers, havea chronic asymptomatic infection.

HEPATITIS A

The course of hepatitis A is shown inFigure 3. After an incubation periodof approximately 30 days, there is aspiking rise in serum alanine amino-transferase (ALT) levels. The dura-tion of abnormal ALT levels inchildren is brief, rarely exceeding 2to 3 weeks.

The serum bilirubin value usuallybecomes abnormal when ALTreaches peak levels. The increasedlevel of serum bilirubin may be tran-sient, and the duration may be asshort as 1 day, or it may persist forlonger than 1 month. In general,jaundice is transient in children andmore apt to be prolonged in adults.

Radioimmunoassay and enzymeimmunoassay are used for detectinghepatitis A antibody (anti-HAV). Asindicated in Figure 3, anti-HAV isdetected very early, at the time ofonset of disease. Initially, anti-HAVis predominantly 1gM; later, it is ex-

0 1 2 3 4 5 6 12 24

Month a After Exposure


hepatitis B. Abbreviations: ALT, alanineaminotransferase; HBSAg, hepatitis B surface

antigen; HBeA& hepatitis B e antigen; HBV

DNA, hepatitis B virus deo.ryribonucleic acid;anti-HBc, antibody to hepatitis B core antigen;

anti-HBe, antibody to HBeAg; anti-HBs,

antibody to HBsAg; P#{231}R,polymerase chainreaction. Reproduced with permission from

Hoofnagle JH and DiBisceglie AM. Serologic

diagnosis of acute and chronic viral hepatitis.

Semin Liver Dis. 1991;11:73-83.

clusively IgG. The time of appear-ance of enzyme immunoassay anti-HAV is the same as radioimmuno-assay, and the tests appear to beequally sensitive.

The duration of illness caused byHAV is variable, ranging from sev-eral weeks to several months. Thedegree of morbidity and the durationof jaundice correlate directly withage. Even in the case of prolongedacute illness lasting several months,complete resolution of hepatitis usu-ally occurs. Unlike hepatitis B, C,and D, HAV infection does not causechronic liver disease. Viremia is tran-sient; it is not characterized by achronic carrier state. The outcome ofHAV infection usually is favorable.Fulminant hepatitis may occur, but itis very rare.

HEPATITIS B

The course of acute HBV infection isshown in Figure 4. The incubationperiod may range between 2 and 6months. Detection of HBsAg in theblood of a patient who has acute hep-atitis is indicative of HBV infection.HBsAg may be detected by radioim-munoassay 6 to 30 days after a par-enteral exposure and 56 to 60 daysafter an oral exposure. The antigenmay be detected about 1 week to 2months before the appearance of ab-normal levels of ALT and jaundice.In most patients who have acute hep-



FIGURES. Typical course of a case ofchronic hepatitis B in which acute infection isfollowed by chronic infection. Forabbreviations, see Fig 4 legend. Reproduced

with permission from Hoofnagle JH and

DiBisceglie AM. Serologic diagnosis of acuteand chronic viral hepatitis. Semin Liver Dis.1991;11:73-83.


hepatitis C that progresses to chronic infection

and disease. Abbreviations: ALT, alanineaminotransferase; HCVRNA, hepatitis C virus

ribonucleic acid; anti-HCV, antibody to

hepatitis C virus. Reproduced with permissionfrom Hoofnagle JH and DiBisceglie AM.

Serologic diagnosis of acute and chronic viral

hepatitis. Semin Liver Dis. 1991;11:73-83.


atitis B, HBsAg is present consis-tently during the latter part of theincubation period and during thepreicteric phase of the disease. Theantigen may become undetectableshortly after onset of jaundice.

As shown in Figure 4, after an in-cubation period of approximately 50days, the serum ALT values becomeabnormal, rising gradually over sev-eral weeks. The duration of abnormalALT activity may be prolonged, usu-ally exceeding 30 to 60 days.

The first antibody to be detectableis anti-HBc, which appears approxi-mately 1 week or more after onset ofhepatitis. The anti-HBc titers, pre-dominantly 1gM, are usually high forseveral months. Thereafter, 1gM val-ues decline to low or undetectablelevels, but anti-HBc persists formany years. The commercially avail-able test for anti-HBc 1gM is a solid-phase immunoassay; its cut-off assayvalue was established to differentiatehigh levels of antibody (positive)from low or undetectable levels (neg-ative). The test is negative in healthyHBsAg carriers and in patients whohave cirrhosis. It may be positive inthose who have chronic active hepati-tis characterized by marked inflam-matory changes without cirrhosis.

The anti-HBc 1gM assay should beuseful for differentiating recent frompast HBV infections and for identify-ing acute hepatitis B in patientswhose HBsAg has declined to unde-tectable levels before appearance ofanti-HBs (window-phase). Antibody

to HBsAg usually appears late, ap-proximately 2 weeks to 2 monthsafter HBsAg is no longer detectable.Anti-HBs is detected in approxi-mately 80% of patients with hepatitisB who eventually become HBsAg-negative. In the remainder, the anti-body levels are too low to be de-tected. Anti-HBs may be detected inabout 5% to 10% of HBsAg carriers.

The course of chronic hepatitis Binfection is shown in Figure 5. Pro-gression to chronic infection has beenreported in 3% to 13% of adults.However, the risk may exceed 60%in infants born to mothers who areHBsAg- and HBeAg-positive. Otherserious consequences of hepatitis Binfection include fulminant hepatitis,cirrhosis, and hepatocellularcarcinoma.

HEPATITIS C

Most patients who have HCV infec-tion are anicteric, especially thosewho have the contact-acquired spo-radic form. The incubation periodmay range from 1 to 5 months. Clin-ical signs and symptoms of the acuteillness are milder than HAV andHBV infections. However, biochemi-cal evidence of chronic liver diseasedevelops in about 50% of patientswith posttransfusion hepatitis C. Asindicated in Figure 6, the serum ALTlevels fluctuate over prolonged peri-ods of time.

The interval between exposure toHCV or onset of illness and detection

INFECTIOUS DISEASEHepatitis _____

of anti-HCV by serum enzyme im-munoassay may be prolonged. Intransfusion recipients, the mean inter-val from onset of hepatitis to detec-tion of anti-HCV may be 15 weeks(range, 4 to 32 weeks). In general,anti-HCV persists in patients whohave chronic disease; it may disap-pear in those who have acute resolv-ing hepatitis C.

In the patient whose disease courseis depicted in Figure 6, evidence ofviremia in chronic hepatitis C wasdetected with polymerase chain read-tion technology 2 weeks after a trans-fusion of HCV-contaminated blood.(Unfortunately, polymerase chain re-action is a research tool not availablein clinical practice.) The first in-crease in serum ALT values was de-tected at 6 to 8 weeks, and anti-HCVwas detectable at about 14 weeks. A6-y follow-up revealed persistence ofpositive polymerase chain reaction,detectable anti-HCV, and biopsy evi-dence of chronic active hepatitis.Long-term prospective studies of pa-tients contracting posttransfusionNANB hepatitis (HCV disease) haverevealed evidence of progression tocirrhosis and to hepatocellular carci-noma.

HEPATITIS D

The clinical manifestations andcourse of type D hepatitis resembleacute or chronic hepatitis B. In gen-eral, however, hepatitis D is a moresevere disease. The mortality rate ofacute HDV hepatitis has ranged from2% to 20%, as compared with lessthan 1% for acute hepatitis B. In ad-dition, cirrhosis and complications ofportal hypertension occur more oftenand progress more rapidly in hepatitisD.

Acute delta hepatitis occurs aseither a coinfection or superinfectionof hepatitis B (Figs 7 and 8). In thecase of coinfection, there is simulta-neous onset of acute HBV and HDVinfection. In the case of superinfec-tion, a chronic HBV carrier is in-fected with HDV.

HBsAg appears during the latterpart of the incubation period in acutedelta coinfection (Fig 7), followed byHDV RNA. Thereafter, serum ALTlevels begin to rise and clinicalsymptoms and jaundice develop.Serum ALT activity is often bi-



HUsAg

II

123456

FIGURE 7. Typical course of a case of acutedelta hepatitis coinfection. Abbreviations:ALT, alanine aminotransferase; HBsAg�hepatitis B surface antigen; HDVRNA,hepatitis delta virus ribonucleic acid; anti-HDV, antibody to HDV; anti-HBs, antibody toHBSAg. Reproduced with permission fromHoofnagle JH and DiBisceglie AM. Serologicdiagnosis of acute and chronic viral hepatitis.Semin Liver Dis. 1991;11:73-83.

F� 8. Typical course of a case of acutedelta hepatitis superinfection. Forabbreviations, see Fig. 7 legend. Reproducedwith permission from Hoofnagle JH andDiBisceglie AM. Serologic diagnosis of acuteand chronic viral hepatitis. Semin Liver Dis.1991;11:73-83.


I INFECTIOUS DISEASE____ HepatitIs ____

phasic. Acute liver disease resolvesafter HBsAg is cleared and HDVreplication ceases. The antibody toHDV (anti-HDV) that appears shortlyafter onset of clinical disease istransient.

The course of one patient withacute delta superinfection followedby the development of chronic deltahepatitis is shown in Figure 8. At thetime of exposure to HDV, this pa-tient was an asymptomatic chronicHBsAg carrier with normal ALT val-ues. At the end of the incubation pe-riod there was: 1) a rise in serumALT values, 2) appearance and per-sistence of HDV RNA, 3) appear-ance of 1gM anti-HDV, which wastransient, and 4) a rise of IgG anti-HDV to high levels, which persisted.

HEPATITIS E

The clinical manifestations andcourse of hepatitis E are essentiallythe same as hepatitis A, except forseveral striking differences. Duringvarious epidemics, the disease hasbeen rare in children and common inadolescents and young adults.

HEV, like HAV, does not causechronic liver disease. In most pa-tients the illness is self-limiting, andthere is no evidence of a chronic car-rier state. However, unlike hepatitisA, hepatitis E can be a devastatingdisease in pregnant women. Whereasthe mortality from hepatitis A inpregnancy is <1%, it has ranged be-

tween 10% and 20% in outbreaks ofhepatitis E. The deaths are caused byfulminant hepatitis. Mortality is high-est during the third trimester andlowest during the first trimester. Themortality rate in nonpregnant womenis the same as that among men,<1%.

At the present time, a practical se-rologic test to confirm a diagnosis ofhepatitis E is not available. Immuneelectron microscopy was the first-generation test to be used by investi-gators. Second-generation tests, suchas radioimmunoassay and enzymeimmunoassay, are being evaluatedfor their sensitivity and specificity.

Neonatal Hepatitis InfectionHepatitis B virus is the most com-mon and most important cause ofneonatal hepatitis infection. To date,perinatal transmission of HAV,HCV, HDV, and HEV has not beenwell documented. It is unlikely thatHAV and HEV will prove to be aproblem because these infections arenot characterized by a chronic carrierstate. The risk of perinatal transmis-sion of HCV is unknown at present.

The availability of tests to detectHBsAg has enabled various investi-gators to study infants whose mothershad acute hepatitis B or an asympto-matic chronic carrier state duringpregnancy. About 5% of infants areinfected in utero and evidence ofantigenemia is present at the time ofbirth. These infections cannot be pre-vented. Fortunately, about 95% of

infants have no evidence of HBV in-fection at the time of birth; antigene-mia may occur several weeks tomonths later. These infections can beprevented. Certain infants escape in-fection completely, others developonly persistent antigenemia withoutliver disease, others may develop se-vere chronic active hepatitis, and stillothers may develop fulminanthepatitis.

Perinatal transmission of hepatitisB infection depends in great part onthe presence of maternal HBeAg,HBV DNA, or both. Infection ismost likely to occur if the mother isHBeAg-positive. Infants born toHBeAg-positive carrier mothers havea 60% to 90% chance of contractingchronic hepatitis B infection and pos-sible subsequent progression to cir-rhosis and hepatocellular carcinoma.In contrast, the attack rate of hepati-tis B in infants whose HBsAg-pos-itive mothers are HBeAg-negative is< 20%. These infants usually recovercompletely and chronic hepatitisrarely develops, but occasionally theinfection may be fulminant and fatal.

Possible routes of transmissionfrom mother to baby include:1) leakage of virus across the pla-centa late during pregnancy or duringlabor, 2) ingestion of amniotic fluidor maternal blood, and 3) breast-feeding, especially if the mother hascracked nipples. Studies withHBsAg-positive and HBeAg-positivepregnant chimpanzees revealed thatcesarean section and postdelivery iso-lation did not prevent infection ofnewborn chimpanzees. They becameHBsAg-positive in spite of these pre-cautions. Studies involving pregnantwomen have yielded similar results.

Disease Course andComplicationsVarious factors may affect the courseof hepatitis: age, type of virus, andimmunocompetence. In general, hep-atitis A and E are mild or inapparentinfections in infants and children.However, they are generally more se-vere in adults. In contrast, infants in-fected with HBV are more likely todevelop chronic infection than olderchildren and adults. Unlike hepatitisA, hepatitis B, C, and D infectionsare more likely to progress to chronicliver disease.




Patients who have post-transfusion and

community-acquired hepatitis C have a

high (approximately 50%) incidence of

chronic liver disease.


ACUTE HEPATITIS

The duration of illness caused byHAV is variable, ranging from sev-eral weeks to several months. Thedegree of morbidity and duration ofjaundice correlate directly with age.Even with prolonged acute illnesslasting several months, complete res-olution of hepatitis usually occurs.Most patients who have hepatitis Arecover completely. Hepatitis B, C,and D, on the other hand, are associ-ated with more debility and a sub-stantial risk of chronic liver disease.In rare instances, acute hepatitis mayprogress to a fulminant fatal out-come.

CHRONIC PERSISTENT HEPATITIS

Chronic persistent hepatitis is apathologic diagnosis based on a liverbiopsy. It is an inflammatory processinvolving only the portal areas. Thisform of hepatitis usually endureslonger than 6 months, and it is morecommon and less severe than chronicactive hepatitis. In general, the pa-tient is asymptomatic and usually hasa mild hepatomegaly and moderateelevation of serum ALT withoutjaundice. Chronic persistent hepatitismay resolve after several years orprogress to chronic active hepatitis.These patients may be HBsAgcarriers.

CHRONIC ACTWE HEPATITIS

This form of hepatitis, also referredto as chronic aggressive hepatitis, ismore likely than acute or chronicpersistent hepatitis to progress to cir-rhosis. The disease is characterizedby chronic and recurrent episodes ofjaundice, abnormal levels of serumaspartate aminotransferase (AST) andALT, and evidence of portal hyper-tension with ascites if the diseaseprogresses to cirrhosis. Severe epi-sodes of hepatic necrosis may termi-nate in hepatic failure.

Most patients who have chronichepatitis (persistent or active) havenot had a past history of acute illnesswith jaundice. The disease usuallyfollows mild, anicteric forms ofhepatitis.

FULMINANT HEPATITIS

The occurrence of hepatic failurewithin the first few days or within 4weeks after onset of acute hepatitis

indicates a fulminant course. Whenthe course is more prolonged and he-patic failure occurs after 1 to 3months of illness, the term subacutehepatitis is used; it is associated withportal hypertension, ascites, and sub-massive hepatic necrosis.

Fulminant hepatitis usually is char-acterized by mental confusion, emo-tional instability, restlessness,bleeding manifestations, and coma.The progressive jaundice and comaare associated with a shrinking liver.The Fulminant Hepatic Failure Sur-veillance Study included 142 patientswith fulminant viral hepatitis. Thesurvival rate was influenced by theage of the patient. Of 27 patientsyounger than 15 years, 10 (37%) sur-vived; of 73 patients 15 to 44 yearsof age, 12 (16%) survived; and of 42patients 45 to > 75 years of age, 3(7%) survived. The overall survivalrate was 18%.

Each of the hepatitis viruses cancause fulminant hepatitis with similarcourses and prognoses, and there areno clinical or prognostic differencesbetween these different forms of ful-minant viral hepatitis. Superinfectionof chronic hepatitis B with HDVseems to increase liver necrosis andto favor the development of fulmi-nant hepatitis B.

HEPATOMA

The striking association betweenchronic hepatitis B infection and pri-mary hepatocellular carcinoma (PHC)has been well established. The rela-tionship is supported by the follow-ing factors: 1) geographic distributionof PHC, 2) presence of serumHBsAg in patients who have PHC,3) detection of HBV markers in tu-mor tissue and PHC cell lines, 4) oc-currence of PHC in certain animalsinfected with hepadna viruses, and5) integration of the HBV genome inthe tumor cell genome.

Worldwide seroepidemiologic stud-

ies have revealed a remarkable corre-lation between the prevalence ofHBsAg carriers and the incidence ofPHC. The highest frequency of car-rier and PHC rates has been observedin Southeast Asia and sub-SaharanAfrica. Various studies have revealedthat the prevalence of HBsAg is sig-nificantly higher in patients who havePHC than in comparable controls.

Histochemical and immunochemi-cal methods have revealed the pres-ence of HBsAg and HBcAg in thelivers of patients who have PHC.HBsAg has been detected in the tu-mor as well as in the surroundingliver tissue. In addition, cultured celllines derived from human PHC se-crete enormous quantities of HBsAginto supernatant culture media. Inte-gration of the HBV genome has beendemonstrated by molecular hybridiza-tion analysis of DNA extracted fromhuman PHC. These studies revealed

HBV DNA sequences integrated intothe tumor cell genome.

Extrahepatic Manifestationsof Viral HepatitisIt is well recognized that HBV infec-tions may be associated with a van-ety of extrahepatic manifestations.The following sites may be affected:skin, joints, small arteries and arter-ioles, and renal glomeruli. The un-derlying pathology is usually adiffuse and widespread immune com-plex-type vasculitis. The followingsyndromes have been identified:1) serum sickness-like prodrome,2) polyarteritis nodosa, 3) glomerulo-nephritis, and 4) other extrahepaticsyndromes (ie, essential mixed cry-oglobulinemia, polymyalgia rheuma-tica, and infantile papular acroderma-titis ([Gianotti-Crosti syndrome]).

SERUM SICKNESS-LIKE

PRODROME

Serum sickness-like prodrome ischaracterized by a transient erythem-



Hepatitis A infection is spread duringthe preicteric phase and is generally

not communicated after the first weekof jaundice.



atous maculopapular eruption, poly-arthralgia, and occasionally actualarthritis as well as urticaria. Thesesymptoms and signs usually occurduring the latter part of the incuba-tion period or early acute phase ofthe disease and endure only a fewdays. During the early phase of theskin and joint manifestations, theremay be a transient suppression of thecomplement titer and of C3 and C4.The critical role that the compositionof the immune complex plays incausing tissue injury has been dem-onstrated in studies on the pathogen-esis of arthritis associated withhepatitis B.

POLYARTERITIS NODOSA

Polyarteritis nodosa is associatedwith persistent hepatitis B antigene-mia. The illness usually begins withfever, polyarthralgia, myalgia, rash,

and urticaria. The syndrome mayevolve over a period of months, andit is characterized by various mani-festations of acute vasculitis, includ-ing peripheral neuropathies, hyper-tension, and evidence of renal dam-age. Biopsy reveals lesions in smallarteries characterized by typical fibri-noid necrosis and perivascular infil-tration. About 30% to 40% ofpatients who have polyarteritis no-dosa have high titers of HBsAg, butthe liver involvement that is presentis not the primary problem.

Circulating immune complexescomposed of HBsAg and anti-HBsare present during the acute phase ofthe disease. At this time, the wholecomplement titer and C3 levels aredecreased. Immunofluorescent studiesof biopsy specimens reveal deposi-tion of HBsAg, 1gM, IgG, and C3 ina nodular pattern along the elasticmembrane of damaged vessels.

GLOMERULONEPHRITIS

The association of glomerulonephritiswith chronic hepatitis B has been

studied by various investigators.They observed typical immune com-plex deposits along the subepithelialsurface of the glomerular basementmembrane by electron microscopy.Fluorescent antibody studies showednodular deposition of HBsAg, immu-noglobulin, and C3 in the glomeruli.The glomerulonephritis is usually ofthe membranous or membranoproli-ferative type.

Epidemiology

HEPATITIS A

Hepatitis A is distributed worldwide.It is endemic in parts of the world,such as the Mediterranean littoral andparts of Africa, South and CentralAmerica, and the Orient, where itspresence creates a danger to suscepti-ble military and civilian personsworking or traveling in such areas.

Although no person of any age isimmune, the highest incidence in ci-vilian populations occurs among per-sons younger than 15 years. Inmilitary groups, the youngest personsare the ones chiefly affected. Personsof either sex seem to be equally sus-ceptible to infection.

The well-defined autumn-winterseasonal incidence has changed. Ingeneral, the incidence of hepatitis isfairly constant throughout the year.

There is abundant evidence favor-ing transmission through the fecal-oral route. Various studies have re-vealed that HAV is detectable inblood and stools during the latter partof the incubation period. Viremia isno longer detectable after onset ofjaundice, when anti-HAV appears.Fecal shedding of HAV persists forabout 1 week after onset of jaundice.These findings indicate that the infec-tion usually is spread during thepreicteric phase of the disease, and

that it generally is not communicableafter the first week of jaundice.

Epidemics have long been known

to occur in association with poor san-itation in military camps. Explosivewater-borne, milk-borne, and food-borne epidemics have been reported.Ingestion of raw shellfish from pol-luted waters is known to have causedmany epidemics. For example, anepidemic of hepatitis A in Shanghai,China, in 1988 involved > 300 000persons who had eaten raw hairyclams. HAV was isolated from thegills and digestive tracts of the con-taminated clams.

There also is evidence for humanassociation as the principal mode ofspread. HAV may be transmittedthrough the use of blood, blood prod-ucts, or contaminated needles, sy-ringes, and stylets. However, thispotential mode of transmission isvery rare, chiefly because viremia istransient in hepatitis A infection, anda carrier state does not exist.

When hepatitis A occurs in cir-cumscribed areas, such as house-holds, day-care centers, orphanages,institutions for mentally handicappedchildren, military installations, andchildren’s camps, it may smoulderfor months or years or it may strikein explosive outbreaks. Within fami-lies, secondary cases may occurwithin 20 to 30 days.

Seroepidemiologic surveys by var-ious investigators have providedvaluable information about the distri-bution of anti-HAV in various popu-lation groups. They observed astriking correlation between the pres-ence of anti-HAV and socioeconomicstatus. Persons from lower socioeco-nomic groups were more likely tohave detectable anti-HAV (past hepa-titis A infection) than those frommiddle and upper socoieconomicgroups. The detection of anti-HAVwas strongly correlated with age. InNew York City, the prevalence in-creased gradually in adults, reachingpeak levels in persons 50 years ofage or older. In Costa Rica, how-ever, peak levels were reached by 10years of age. It is clear that the prey-elance of anti-HAV varies amongdifferent population groups, increaseswith age, and is independent of sexand race.

It is likely that the continued im-provement of environmental and so-cioeconomic conditions will decreasethe probability of exposure to hepati-tis A, thereby changing a predomi-



Hepatitis C is transmitted bytransfusions, intravenous drug use, and

hemodialysis, and by health careworkers who have frequent blood

contact.


--


nantly childhood infection to one thatis more apt to occur in adults. Thischanging epidemiologic pattern wastypical for poliomyelitis during thefirst half of the twentieth century inthe United States. Poliomyelitis, likehepatitis A, is a more severe and dis-abling disease in adults than inchildren.

HEPATITIS B

Early epidemiologic concepts mdi-cated that HBV was transmitted cx-clusively by the parenteral route. Itnow is clear, however, that the fol-lowing modes of transmission playimportant roles in the disseminationof HBV: 1) oral-oral, 2) sexual,3) perinatal, and 4) intimate physicalcontact of any type. The antigen hasbeen detected in saliva, in semen,and in many other body fluids.

The major reservoir of HBV ischronic carriers. The infection istransmitted to susceptible persons bytransfusion of blood, plasma, orother blood products or by the use ofinadequately sterilized needles andsyringes. Medical, dental, paramedi-cal, and paradental personnel may beinfected by accidental inoculation oringestion of contaminated materials.Outbreaks have occurred among drugaddicts using unsterilized equipment.Tattooing and acupuncture also havebeen responsible for transmitting theinfection. Patients and personnel inthe following areas have been shownto be at high risk: renal dialysis, in-tensive care, and oncology units, aswell as various laboratories in whichpotentially contaminated blood andtissues are examined.

Seroepidemiologic surveys to de-tect the presence of HBsAg and anti-HBs have confirmed the worldwidedistribution of the disease. The anti-gen has been detected in all popula-tions, even in those living in themost remote areas devoid of paren-teral modes of transmission. The an-tigen is most prevalent amongpersons living under crowded condi-tions and with poor hygienic stan-dards. This accounts for theendemicity of the disease in institu-tions for mentally retarded personsand in certain developing countries ofthe world.

The HBsAg carrier rate may rangefrom 0.1% to >10%; it is dependent

on such factors as geographic loca-tion, age, and sex. The carrier rate ishigher in tropical, underdevelopedareas than in temperate, developedcountries, in urban than in rural corn-munities, and among males thanamong females. The prevalence ofanti-HB5 in various populations mayrange from 5% to 80%.

The period of infectivity of pa-tients who have hepatitis B dependson the presence or absence of a car-ncr state. HBsAg is detectable in theblood during the latter part of the in-cubation period and for a variable pe-nod after onset of jaundice. Infec-tivity also has been associated withthe presence of HBeAg and a high ti-ter of HBsAg.

HEPATITIS C

The availability of a specific sero-logic test to detect anti-HCV has

clarified the epidemiology of paren-terally transmitted and sporadic HCVinfection. The disease is distributedworldwide, with an estimated 100million HCV carriers. In the UnitedStates, hepatitis C may be the causeof 20% to 40% of all acute hepatitiscases. Persons at high risk of con-tracting HCV infection include:transfusion recipients, intravenousdrug users, hemodialysis patients,and health care workers with frequentblood contact. Unlike with hepatitisB, sexually promiscuous personshave a low risk of contracting HCVinfection. Perinatal transmission ofHCV has not been well documented.

HEPATITIS D

The epidemiology of hepatitis D ischaracterized by striking similaritiesto and certain differences from hepa-titis B (Table). The modes of trans-mission are the same except thatHDV perinatal infection is rare. Ingeneral, the prevalence of HDV cor-

relates with the prevalence of HBVin the following groups at increasedrisk: intravenous drug users, hemo-philiacs, and institutionalized men-tally retarded patients. In contrast,HDV has not been reported to beprevalent in groups at increased riskfor HBV infection (ie, homosexualmen and chronic carriers in suchhighly endemic areas as southeastAsia, southern Africa, and Alaska).

Superinfection of chronic HBVcarriers has been responsible for epi-demics of HDV-associated fulminanthepatitis in Venezuela, Colombia,and Brazil. HDV is most commonamong drug abusers in the UnitedStates and northern Europe.

HEPATITIS E

The epidemiology of hepatitis E ischaracterized by certain similaritiesto and many differences from hepati-

tis A (Table). Both hepatitis E andhepatitis A are enterically transmitteddiseases that are spread via the fecal-oral route.

Hepatitis A is worldwide in dis-tribution; it is predominantly a pedia-tric infection and the secondaryattack rate in household contacts isapproximately 10% to 20%. In con-trast, hepatitis E has occurred pre-dominantly in certain developingareas of the world during the courseof water-borne outbreaks. Hepatitis Ehas been most common in adults andrare in children. The secondary at-tack rate in household contacts hasbeen relatively low at <3%.

Hepatitis E epidemics have oc-curred in China, southeast and cen-tral Asia, northern and westernAfrica, Mexico, and Central Amer-ica. The epidemics have been eitherextensive, involving thousands ofpersons, or smaller focal outbreaks.With the exception of a few importedcases, hepatitis E has not occurred in




iNFECTiOUS DISEASEHepatitis

the United States. Hepatitis E, unlikehepatitis A, is a highly fatal diseasein infected pregnant women, inwhom the mortality rate may be 10%to 20%.

PrognosisThe prognosis of various types ofviral hepatitis has been discussed inthe sections devoted to clinical mani-festations, disease course, andcomplications.

Hepatitis A is a relatively benigndisease. Occasionally the illness maybe prolonged, but eventually there iscomplete recovery with no evidenceof chronic liver disease. Fatal fulmi-nant hepatitis A is an extraordinarilyrare phenomenon.

Most patients who have hepatitis Brecover completely. However, therisk of chronic infection is extremelyvariable; it may be low (about 3%)in young healthy adults or very high(60% to 90%) in infants born tomothers carrying HBsAg andHBeAg. The overall risk is about10%. Chronic hepatitis B infection

may progress to cirrhosis of the liverand primary hepatocellular carci-noma. The risk of fatal fulminanthepatitis B is low (< 2%) exceptwhen there is superinfection withHDV. Under these circumstances,the mortality rate may be as high as30%.

Observations of patients who haveposttransfusion and community-acquired hepatitis C have revealed arelatively high (approximately 50%)incidence of chronic liver disease.Fulminant hepatitis is an occasionaloutcome. The overall mortality rateis 1% to 2%. Studies in Japan haverevealed that HCV infection is asso-ciated with the development of hepa-tocellular carcinoma.

Hepatitis E is a relatively benigndisease that does not progress tochronic hepatitis. However, it ishighly fatal in pregnant women.

Suggested ReadIngsA list of suggested readings on this subjectwill be published with the second part of thearticle.

PIR QUIZ

1 . Each of the following statementsabout viral hepatitides is true,except:A. For hepatitis A, the carrier state

is common.B. Hepatitis D virus cannot produce

infection alone.C. Hepatitis C has chronic hepatitis

as a common sequela.D. The cellular damage in hepatitis

due to viruses A, C, and D in-volves predominantly the effectof defense mechanisms of thehost.

2. Each of the following statementsabout viral hepatitides is true,except:A. Fecal-oral transmission is typical

of hepatitis E.B. Transfusion hepatitis is typical

of hepatitis C.C. Perinatal transmission is most

typical of hepatitis B.D. Droplet infection is typical for

hepatitis A.

3. Features of hepatitis B include eachof the following, except:

A. The finding of hepatitis B sur-face antigen (HBsAg) in theblood of a patient who has hepa-titis indicates hepatitis Binfection.

B. HBsAg usually can be found inblood before the clinical signs ofhepatitis appear.

C. The finding of antibody to hepa-titis B core antigen 1gM (anti.HBc 1gM) in the blood of a pa-tient indicates recent infection bythe hepatitis B virus.

D. The risk of prenatal hepatitis cx-ceeds 20% in The infant of amother who has had an acutehepatitis B infection duringpregnancy or has been anasymptomatic carrier.

E. The newborn infant of anHBsAg-positive mother who hashepatitis B e antigen (HBeAg) inher blood is at greater risk ofperinatal infection than if themother lacks HBeAg.

4. Features of hepatitis C include eachof the following, except:A. Sexual transmission of the virus

of hepatitis C is common.B. Clinical manifestations of acute

hepatitis C generally are milderthan those of hepatitis A or B.

C. Progression to chronic hepatitisoccurs in > 25% of cases ofhepatitis C.

D. Progression of primary hepato-cellular hepatoma occurs in asignificant number of patients.



DOI: 10.1542/pir.13-6-203 1992;13;203-212 Pediatr. Rev.

Saul Krugman Viral Hepatitis: A, B, C, D and E—Infection

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Virus Hepatitis a, B, C, D y E

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