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285
Acute

VIRAI

HEPATITIS

Jaundic

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Anti-HAV

vil hepatitis is a systemic irilection a.ffecting the liver predooinantly. Alnost all cases of acute viIal hepatitis are caused by otre of frve vilal ageDts: hepatitis A virus (HAy), hepatitis B virus (HB\,), hepatitis C vins (IICV), the lIBv-associated delra agent or hepatitis D virus QID\), and hepatitis E vi s (HED. Other transtusion-transmitted agents, e.g., "hepatitis G" vi s imd'TI" virus, have been
identified but do not cause hepatitis. All these humalt hepatitis yiruses arc RNA vi.uses, except for hepatitis B, which is a DNA virus. Alihough these agents caa be distinglished by the molecular and antigenic properties, all types of yiral hepatitis Foduce cliicaly similar illnesses. These range Irom asymptomatic and inapparent to fulminant and fatal acute idections comrnon to all types, on the one hand, and from subclinical persistent hfections to rapidty Fogrcssive chrcnic liver disease with cirhosis and even hepatocellular calcinoma, common to the bloodbome t ?es (IIBV, HCV, atrd HDV), on the
other.

-0
IIGURI

4
285-2
Scheme

12

18

Weeks atter exposurc

of tgp,crl clinical and labontory featurcs of

flpatitis Hepatitis B vims is a DNA virus with a pact gedomic sEucturo; despite its small, circulaa,

m0[0GY H.patili5 Hepatitis A virus is a ronenveloped 27-nm, heat-, acid-, and ether-resistait RNA virus in the hepatovirus genus of tle picomavins family (Fig. 285-1). Its yirioD contains foul capsid polr?eptides, designated to VP4, which are
Vltl)L()GY AilD

\?l

HBV DNA codes for four sets of viral Foducts wilh a tiparticle structuie. HBV achieves its genomic economy by an efficieat strategy of encoding Foteins ftom four S, C, P, alld X (Fig. 285-3), as detailed below. ODce niqe among viruses, HBV is now recogDized as one of anirnal viruses, hepadnaviruses (hepatoopic DNA
classifed as hepadnavirus type 1 . Similar yiruses iofect of woodchuck, ground and uee squhrels, and Peki ducks, the most carefirlly characierized. Like HBV, all have e tinctive thrce morphologic forms, have conterparts to and ncleocapsid virus ntigens of IiBV, replicate iDthe i{ extGhepatic sites, contain their orn endogenos DNA
have artially double-shanded aDd pattially are associated with acute and chrcoic hepatitis and cinomq and rcly on a replicative strategy unique among bur q?ical of retroviruse. stead of DNA replication d DNA template, hepadnaviflses rcly on leverse traDscriptio by the DNA polymerase) of mirus-srand DNA from a RNA intermediate. Then plus-strand DNA is hanscdbd

cleaved postfanslationally from the polyprotein product of a 7500nucleotide genome. Inaclivation of viral activjry can be achjeved by boiling for 1 min, by contact with formaldehyde and chlorine, or by ultaviolet idadiation. Despite trucleotide sequsnce variatio[ of up to 2070 among isolates ol HAV, all stains of this virus are itrlmnologicaly indistinguishable and belong to one serotype. Hepatitis A has an incubation period of approximately 4 weeks. Its replication is limited to the liver, but the virus is present iII the liver, bile, Etools, alld blood dudng the late inorbation period and acute Feicteric phase ol illress. Despiie prsislence of virus in Lhe liver, viml shedding in feces, vi-remia, and infectivity diminish rapidly once jaundice becomes appareol. HAV can be cultivared reproducibly in viEo. Antibodies to }lAV (anti-HAV) can be detectd dudog acte illness when serum aminotransfetase activity is elevated and fecal HAV shedding is still occuIrilg. This early antibody rcsponse is predominantly of the IgM class and pe$ists for seveml months, rely for 6 to 12 months. DinE convalescence, howevet, anti-HAV of the IgG class trecomes the predominant antibody (Fig. 285-2). Therefore, the diagnosis of hepatitis A is made duriag acute illness by demomfatiBg antiHAV of the IgM class. Afle! acute illdess, a i-HAV of the Igc class ,emains detectable indefrnitely, and patienls with serum anti-HAV are iinuoe to rcinfection. Neutratizing antibody activity parallels lhe appea.rance of anti-HAV, and the IgG anti-HAV Fesent in imoune globulin accounls for the protection ir affords against IIAV infectioo.

nus-sfand DNA template by the DNA-depeodeDr DNA

and converted in the hepatoc).te nucleus to a covalently as . template for messenger RNA and RNA. Vilal proteins are taNlated by the messenger proteins and ge[ome are packaged into virions and hepaloc,,te. AldEugh IIBV is difficult to cultivate in vitro ventional sense from clinical material, several cell lines

DNA, which sefles

transfected witi HBV DNA. such transfected cells rcplication of the intact virus and its compoDent prcteiDs.
ylML FRlTElllS AND PARITCIES Ofthe three particulate forms ble 285-l), the most numerous are the 22-nm particles, as pherical or long these are antigenically from the outer surface or ofHBV and arc thought to viral e[velope prctein. rum by a factor of 100 or 1000 parcd with the spheres aad large, 42-nm. double-shelled ticles, which Epresent the

B virion (Fig. 285-l) . The

teilr eipressed on the outer afld on the smaller bular shuctuaes is refeEed to a surface antigen (HBsAg). The tion of IlBsAg aod virus

vtion
285-1 letr. Ele.lrcn dicroqraph of 2r-nm hepatils A virus panicle! purjfied from stoot of a patient lYith acule hepatitjs A virus infection and aqqrcgated bq hepatitis A anbodu. Rig,tt. Bectron microqraph of concentrated serufi from a patient tyith hepatls B infeclioa, demonsirating lhe 4z-nm $rions, tubular foms, and spherjral 22-nm parlicles oi hepatith B surface antigen. 132,000x. (Hepatitir D rcsembes 42-nm vfions of hepatitis B but is smaller, 35 t0 3i nm, hepatilis E resembes hepatilis A virus but is slightlu laEer, 32 to:t4 nm; hepatitis C as not been rsualted defnitivelU.) 18ZZ

tl6l]ll

btood may rcach 500

pgtnl- ad

particles per milliliter, envelope Fotein, HBsAg, is drc

the S gene of

IIBV,

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(DNA)

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t=tr
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during which all three forms of HBV circulate, including intact vftiotrs. Over time, the replicative phase of chrcnic IIBV infection gives way to a relatively nonreplicatiye praJe. This occurs at a te of apprcximxely l\Vo per year and is accompanied by setoconve$ion ftom I{BeAg:positive to antiHBe-positive. In most cases, this seioconversion coincides wi a aansient, aute hepatitis-like elevation in amino[ansferase activiry, believed to rcflect cell-mediated immune cleatance of virus-infected hepatorytes. In the nomeplicative phase of

812 16 20 24 28 32
'285-4

36

100

Weeks atter exposure

Srheme of gpical clnical and laboratoru features of aclle viral hep-

cfuonic'inlection. \yhen HBV DNA is demonstrable in hepatocyle nuclei, it teDds to be integated into the host genome. In this phase, only sphercal and tubular lolms of PBy, not intact yiriorr, circulate, atrd liver injry tends to subside. Most such patie s would be characterized as inactil)e HBV calar'?ru. In teality, the design tions replicatfue xrd nonreplicative ue only relativei even in the so-called nomeplicative phase, HBV replication can be detected with highly sensitive amplncation probes such as the polltnemse chain rcactio! eCR). Still, the distinctions are pathophysiplogically and clinicaly meaningful. Occasionally, noEeplicative HBV infection convefis back to rcplicative infection, Such sponta{eous rcactivarions arc accompanied by reexpression of lIBeAg and HBV DNA, and sometimes of IgM aotiHBc. as well as by exacerbarions of liver injury.
MAECUUR

with current or recenl acuE hepadtis B. including ose in e window, have IgM anti-HBc in their serum. In patients who from hepatitis B in the temote past as well as those HBV iDfection, a !IBc is predominantly of the IgG IDfrequently, in no more thaa 1 to 57o of patients wirh acute levels of HBsAg are too low to be detected; in such e presence of IgM a[ti-HBc estabishes the diaglosis of acute B. When isolated anti-Imc occuts h the rare patient with hepatitis B whose HBsAg level is below the sensitivity thrcsheontemporary immunoassays (a low-level carrier), the anti-IBc IgG class. Geoerally, in pe$ons who have recovercd ftom B, anti-HBs and anti-IBc persist indefinitely. temporal association btween the appearance of anti-HBs and of HBV infection as well as ihe observation that persons in serum are protected against rcinfection with IIBV at anti-HBs is the protect)e antibod), Therclorc, strategies of HBV inJection are based on Foviding susceptible with circulating anti-HBs (see belov). Occasionally, in 10 to patients with chonic hepatitis B, ow-level, low-affinity antibe detected. This antibody is directed against a subtype dedifferent from at represented by the prient's IIBsAg; irs is thought to reflect the stimulation of a rcated clone of cells, but it has no clinical rclevance and does not clearance of hepatitis B. other readily detectable serologic marker of HBV infection, appea$ concrrendy with or shtrfily after HBsAg. 1ts ape coincides temporally with high levels of virus replication and ihe presenge- of circulatirg intact vidons and detectabte HBV Pre-Sl and prc-S2 proteins ae also expressed dudng periods but assays for thee gene products are not routinely In selflimited HBV iafections, HBeAg-becomes undetectafter peak elevations iII afiinotansfese activity, beforc of HBsAg, and gnti-HBe then becomes detectable, with a period of relatively lower infectivity (Fig. 285-4). harkers of IIBV replica'tion appear Ealsiently during acute testing for such markers is of little clinical utility in typical acte IIBV iDJection. In contast, marke$ of HBV replication valuable information in patients \eith prohacted infections. ftom the pattem ?ical of acute HBV infections, in HBV infection, HBsAg rcmains detectable beyond 6 months, is primadly of the IgG class, and anti-HBs is either undele or detectable at low levels (see'Laboratory Fearures,' below) 285-51. During early chronic i{BV infecon, HBV DNA can be both in sem and in hepatocyte nuclei, wherc it is preslnt in episomal form. This replicatire Jrage of HBV infection is the maximal infectivity and liver injury; HBeAg is a qualitative and HBV DNA a quantitative ma*e of this replicative phase,

y;RA

15

Variation occurs throughout the HBV genome,

aIlal

clhical isolates of HBV diat do not exp.ess srpical vial poteins have been attributed to mutations in individual or even multiple gene 1ocations. For example, variants have Leet described that lack nucleocapsid proteins, envelope prcteins, or boih. Two categdries of HBV have attractd the most attention. One of these was identified initially in Mediterranean contries among patients with an unusual serclogicclinical profile. They have severc chrcnic HBV infection and detectable llBV DNA but with arti-HBe iNtead of IIBeAg. These patients were found to be infected widr an HBV mutaflt that contained an alteration in the precore rcgion rcndering the virus incapable of encoding HBeAg. Although several potertial mutation sites exist_ifl the pre-C region, the regioriof the C gine necessary for the express'ion of IlBeAg (see '.vfuology and Etiology," above), ihe most commonly encountered in such patients is a single base substitutioq ftom G to A, which occurs in the second to last codon of the pre-C gene at nrcleotide 1896. This substitution results in the rcplacement of the TGG tryptoph;n codon by a stop coalon (TG), which plevent5 the tmnslation ol HBeAg. Another mutation, in the core prcmoter region, prcvents transcriptiofl of the coding region for IIBeAg and yields ar

AntiHBe

HBV DNA
HBsAg Anti-HBc

\
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lgM anli-HBc

12 24 36 4A 60
Months after exposure

120

285-5 Scheme of tupical labordtoru features of chroni. viral hepatitis B. iBeg ard HBv DNA can be oeteded rn seun during lhe replEonve phase ol ehrcnit infedon, whkh is assorated with i fectir/itu and liver injuru. SeroconveEon from the replicative phase la the nonrcplicdlve phose occu6 at a te ot approrjmatelu l0 1o 15% per Uear aid is hended bg an acute hepallis-lik elevaton of ALT actjvit!; du nq the nonreplicaiive phase, intectivitq and Iver iijury are Irnled.

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