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Acute Viral Hepatitis

Chapter 350 | Part 10: Disorders of the Gastrointestinal System · Part 10 – Gastrointestinal Disorders

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. HAV incubation period is approximately 3–4 weeks; replication is limited to the liver but virus is present in liver, bile, stools, and blood during late incubation and acute preicteric phase.
  2. HBV entry into hepatocytes is mediated by binding to the sodium taurocholate cotransporting polypeptide (NTCP) receptor.
  3. HCV RNA is the most sensitive indicator of HCV infection; neutralizing antibodies to HCV are short-lived and do not indicate protection against reinfection.
  4. HDV is a defective RNA virus that requires the helper function of HBV for replication and expression.
  5. HBV genotype B appears to be associated with less rapidly progressive liver disease and cirrhosis and a lower likelihood of hepatocellular carcinoma than genotype C, D, or F.
  6. HCV does not integrate into the host genome because it does not replicate via a DNA intermediate.
  7. Precore mutations in HBV (e.g., G1896A substitution) render the virus incapable of encoding HBeAg, leading to HBeAg-negative chronic hepatitis.
  8. HDV antigen is expressed primarily in hepatocyte nuclei and is occasionally detectable in serum.
  9. HCV replication rate is very high (10^12 virions per day) with a half-life of 2.7 hours.
  10. In chronic HBV infection, HBsAg remains detectable beyond 6 months, distinguishing it from acute infection where HBsAg becomes undetectable 1–2 months after onset of jaundice.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🔀 Flowchart Scheme of typical clinical and laboratory features of hepatitis A virus (HAV)
2 🔀 Flowchart Scheme of typical clinical and laboratory features of acute hepatitis B
3 🔀 Flowchart Scheme of typical laboratory features of wild-type chronic hepatitis B
1 🖼 Figure Organization of the hepatitis C virus genome and its associated, 3000-amino-acid (AA)...
2 🖼 Figure Electron micrographs of hepatitis A virus particles and serum from a 27-nm...

1. DEFINITION & OVERVIEW

  • Acute viral hepatitis is a systemic infection affecting the liver predominantly.
  • Almost all cases of acute viral hepatitis are caused by one of five viral agents: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), the HBV-associated delta agent or hepatitis D virus (HDV), and hepatitis E virus (HEV).
  • All these human hepatitis viruses are RNA viruses, except for hepatitis B, which is a DNA virus but replicates like a retrovirus.
  • These agents can be distinguished by their molecular and antigenic properties, but all types of viral hepatitis produce clinically similar acute illnesses.
  • These illnesses range from asymptomatic and inapparent to fulminant and fatal acute infections, which can be observed in all types.
  • The bloodborne types (HBV, HCV, HDV) may also manifest a spectrum of chronic disease, from subclinical, persistent infections to rapidly progressive chronic liver disease with cirrhosis and even hepatocellular carcinoma.
  • Rarely, infections with other viruses (e.g., cytomegalovirus, Epstein-Barr virus, other herpes viruses, SARS-CoV-2) can be associated with mild or severe, even fulminant, hepatitis, more often in immunocompromised hosts but also in otherwise healthy persons.
  • In 2021 and 2022, after the peak years of the COVID-19 pandemic, multiple reports appeared globally of severe acute, often fulminant, hepatitis in previously healthy children.
  • While these instances of severe acute hepatitis remain unexplained, links have been reported of infection with adenovirus type 41 and adeno-associated virus 2, ordinarily not causes of liver injury.
  • A reduction in circulating respiratory virus infections during the isolation of the COVID-19 pandemic has been postulated to have accounted for the increased susceptibility to and severity of the acute hepatitis associated with these nonhepatotropic viruses.

1.1 Human Hepatitis Virus Host Range

  • Human HAV can infect and cause hepatitis in chimpanzees, tamarins (marmosets), and several monkey species.
  • HAV-like heptoviruses have also been identified in small mammals, including bats and rodents.

2. EPIDEMIOLOGY

  • Geographic distribution of HBV genotypes and subtypes varies; genotypes A (corresponding to subtype adw) and D (ayw) predominate in the United States and Europe, whereas genotypes B (adw) and C (adr) predominate in Asia.
  • These geographic distinctions have been blunted by recent-decade migration across continents.
  • Clinical course and outcome are independent of subtype, but genotype B appears to be associated with less rapidly progressive liver disease and cirrhosis and a lower likelihood, or delayed appearance, of hepatocellular carcinoma than genotype C, D, or F.
  • In a large Japanese cohort, after acute infection, patients with genotype A were more likely to have persistent infection (23.4% with genotype A vs 8.6% with non-A genotypes).
  • Genotype may influence response to treatment with interferon and other antiviral agents; for example, higher rates of HBeAg and HBsAg loss have been observed in patients with genotype A.

3. ETIOLOGY & PATHOPHYSIOLOGY

  • Hepatitis A HAV is a nonenveloped 27-nm, heat-, acid-, and ether-resistant, single-stranded, positive-sense RNA virus in the Hepatovirus genus of the picornavirus family.
  • Quasi-enveloped virus particles encased in host plasma membrane-derived membranous vesicles circulate in the bloodstream.
  • The virion contains four structural capsid polypeptides, designated VP1–VP4, as well as six nonstructural proteins, which are cleaved posttranslationally from the polyprotein product of a 7500-nucleotide genome.
  • Inactivation of viral activity can be achieved by boiling for 1 min, by contact with formaldehyde and chlorine, or by ultraviolet irradiation.
  • Despite nucleotide sequence variation of up to 20% among isolates of HAV and despite the recognition of six genotypes (three of which affect humans), all strains of this virus are immunologically indistinguishable and belong to one unique group.
  • Hepatitis B HBV is a DNA virus with a remarkably compact genomic structure; despite its small, circular, 3200-bp size, HBV DNA codes for four sets of viral products with a complex, multiparticle structure.
  • HBV achieves its genomic economy by relying on an efficient strategy of encoding proteins from four overlapping genes: S, C, P, and X.
  • HBV is now recognized as one of a family of animal viruses, hepadnaviruses (hepatotropic DNA viruses), and is classified as hepadnavirus type 1.
  • Similar viruses infect certain species of woodchucks, ground and tree squirrels, and Pekin ducks, to mention the most carefully characterized; genetic evidence of ancient HBV-like virus forbears has been found in fossils of ancient birds, and an HBV-like virus has been identified in contemporary fish.
  • Studies of ancient HBV genomes date an association between HBV and human beings back as long as 21,000 years ago; primate HBV-like viruses date back millions of years, suggesting that HBV predated the emergence of modern humans.
  • Like HBV, all have the same distinctive three morphologic forms, have counterparts to the envelope and nucleocapsid virus antigens of HBV, replicate in the liver but exist in extrahepatic sites, contain their own endogenous DNA polymerase, have partially double-strand and partially single-strand genomes, are associated with acute and chronic hepatitis and hepatocellular carcinoma, and rely on a replicative strategy unique among DNA viruses but typical of retroviruses.
  • Entry of HBV into hepatocytes is mediated by binding to the sodium taurocholate cotransporting polypeptide (NTCP) receptor.
  • Instead of DNA replication directly from a DNA template, hepadnaviruses rely on reverse transcription (effected by the DNA polymerase) of minus-strand DNA from a “pregenomic” RNA intermediate.
  • Then, plus-strand DNA is transcribed from the minus-strand DNA template by the DNA-dependent DNA polymerase and converted in the hepatocyte nucleus to a covalently closed circular DNA, which serves as a template for messenger RNA and pregenomic RNA.
  • Viral proteins are translated by the messenger RNA, and the proteins and genome are packaged into virions and secreted from the hepatocyte.
  • Hepatitis B virus has been difficult to cultivate in vitro from clinical materials; therefore, a model that recapitulates the entire HBV life cycle has been particularly elusive.
  • In recent decades, however, advances in molecular virology have permitted the comprehensive study of HBV replication and its viral genes and proteins.
  • Hepatitis C Hepatitis C virus, which, before its identification, was labeled “non-A, non-B hepatitis,” is a linear, single-strand, positive-sense, 9600-nucleotide RNA virus, the genome of which is similar in organization to that of flaviviruses and pestiviruses; HCV is the only member of the genus Hepacivirus in the family Flaviviridae.
  • The HCV genome contains a single, large open reading frame (ORF) (gene) that codes for a virus polyprotein of ~3000 amino acids, which is cleaved after translation to yield 10 viral proteins.
  • The 5′ end of the genome consists of an untranslated 500 region (containing an internal ribosomal entry site [IRES]) adjacent to the genes for three structural proteins, the Core nucleocapsid core protein, C, and two envelope glycoproteins, E1 and E2.
  • The 5′ untranslated region and core gene are highly conserved among genotypes, but the envelope proteins are coded for by the hypervariable region, which varies from isolate to isolate and may allow the virus to evade host immunologic containment directed at accessible virus envelope proteins.
  • The 3′ end of the genome also includes an untranslated region and contains the genes for seven nonstructural (NS) regions—p7, a membrane protein adjacent to the structural proteins that appears to function as an ion channel; NS2, which codes for a cysteine protease; NS3, which codes for a serine protease and an RNA helicase; NS4 and NS4B; NS5A, a multifunctional membrane-associated phosphoprotein, an essential component of the viral replication membranous web; and NS5B, which codes for an RNA-dependent RNA polymerase.
  • After translation of the entire polyprotein, individual proteins are cleaved by both host and viral proteases.
  • p7 is a membrane ion channel protein necessary for efficient assembly and release of HCV.
  • The NS2 cysteine protease cleaves NS3 from NS2, and the NS3-4A serine protease cleaves all the downstream proteins from the polyprotein.
  • Important NS proteins involved in virus replication include the NS3 helicase; NS3-4A serine protease; the multifunctional membrane-associated phosphoprotein NS5A, an essential component of the viral replication membranous web (along with NS4B); and the NS5B RNA-dependent RNA polymerase.
  • Because HCV does not replicate via a DNA intermediate, it does not integrate into the host genome.
  • Because HCV tends to circulate in relatively low titer, 10^3−10^7 virions/mL, visualization of the 50- to 80-nm virus particles remains difficult.
  • Still, the replication rate of HCV is very high, 10^12 virions per day; its half-life is 2.7 h.
  • Historically, the study of HCV had been hampered by few adequate in vitro and animal models.
  • In 2005, however, complete replication of HCV and intact 55-nm virions was described in cell culture systems.
  • These and other subsequent models were fundamental toward the development of targeted, effective antiviral therapies for HCV infection.
  • Still, the continued absence of robust animal models poses a barrier to much-needed vaccine development.
  • Albeit a helpful animal model, the chimpanzee is cumbersome to study, and access to chimpanzees for medical research has been curtailed substantially.
  • In addition, while HCV replication has been documented in a xenograft immunodeficient mouse model containing explants of human liver and in transgenic mouse and rat models, a tractable immunocompetent murine model has remained elusive.
  • In vitro study has also elucidated important cofactors for the HCV hepatitis C viral life cycle.
  • For example, HCV entry into the hepatocyte occurs via the non-liver-specific CD81 receptor and the liver-specific tight junction protein claudin-1.
  • A growing list of additional host cofactors for the HCV hepatitis C viral life cycle has been identified.
  • Hepatitis D The delta hepatitis agent, or HDV, the only member of the genus Deltavirus, is a defective RNA virus that co-infects with and requires the helper function of HBV (or other hepadnaviruses) for its replication and expression.
  • Slightly smaller than HBV, HDV is a formalin-sensitive, 35- to 37-nm virus with a hybrid structure.
  • Its nucleocapsid expresses HDV antigen (HDAg), which bears no antigenic homology with any of the HBV antigens, and contains the virus genome.
  • The HDV core is “encapsidated” by an outer envelope of HBsAg, indistinguishable from that of HBV except in its relative compositions of major, middle, and large HBsAg component proteins.
  • The genome is a small, 1700-nucleotide, circular, single-strand RNA negative polarity that is nonhomologous with HBV DNA (except for a small area of the polymerase gene) but that has features and the rolling circle model of replication common to genomes of plant satellite viruses or viroids.
  • HDV RNA contains many areas of internal complementarity; therefore, it can fold on itself by internal base pairing to form an unusual, very stable, rod-like structure that contains a very stable, self-cleaving and self-ligating ribozyme.
  • HDV RNA requires host RNA polymerase II for its replication in the hepatocyte nucleus via RNA-directed RNA synthesis by transcription of genomic RNA to a complementary antigenomic (plus strand) RNA; the antigenomic RNA, in turn, serves as a template for subsequent genomic RNA synthesis effected by host RNA polymerase I.
  • HDV RNA has only one open reading frame, and HDAg, a product of the antigenomic strand, is the only known HDV protein; HDAg exists in two forms: a small, 195-amino-acid species, which plays a role in facilitating HDV RNA replication, and a large, 214-amino-acid species, which appears to suppress replication but is required for assembly of the antigen into virions.
  • HDV antigens have been shown to bind directly to RNA polymerase II, resulting in stimulation of transcription.
  • Viral assembly requires farnesylation of the large HDAg for ribonucleoprotein anchoring to HBsAg.
  • Both HBV and HDV enter hepatocytes via the NTCP receptor.
  • Although complete hepatitis D virions and liver injury require the cooperative helper function of HBV, intracellular replication of HDV RNA can occur without HBV.
  • Genomic heterogeneity among HDV isolates has been described.
  • Although pathophysiologic and clinical consequences of this genetic diversity have not been established definitively, preliminarily, genotype 2 has been linked to milder disease and genotype 3 to severe acute disease.
  • The clinical spectrum of hepatitis D is common to all eight genotypes identified, the predominant of which is genotype 1.
  • HDV can either infect a person simultaneously with HBV (co-infection) or superinfect a person already infected with HBV (superinfection).
  • In instances of superinfection, when HDV infection is transmitted from a donor with one HBsAg subtype to an HBsAg-positive recipient with a different subtype, HDV assumes the HBsAg subtype of the recipient, rather than the donor.
  • Because HDV relies absolutely on HBV for its replication, the duration of HDV infection is determined by the duration of (and cannot outlast) HBV infection.
  • HDV replication tends to suppress HBV replication; therefore, patients with hepatitis D tend to have lower levels of HBV replication.
  • HDV antigen is expressed primarily in hepatocyte nuclei and is occasionally detectable in serum.
  • During acute HDV infection, anti-HDV of the IgM class predominates, and 30–40 days may elapse after symptoms appear before anti-HDV can be detected.
  • In self-limited infection, anti-HDV is low-titer and transient, rarely remaining detectable beyond the clearance of HBsAg and HDV antigen.
  • In chronic HDV infection, anti-HDV circulates in high titer, and both IgM and IgG anti-HDV can be detected.
  • HDV antigen in the liver and HDV RNA in serum and liver can be detected during HDV replication.
  • Hepatitis E HEV is a nonenveloped icosahedral virus with a 7.6-kb RNA genome.
  • HEV is the agent of enterically transmitted hepatitis; rare in the United States; occurs in Asia, Mediterranean countries, Central America.

3.1 HBV Genomic Structure and Proteins

  • HBV is a DNA virus with a remarkably compact genomic structure; despite its small, circular, 3200-bp size, HBV DNA codes for four sets of viral products with a complex, multiparticle structure.
  • HBV achieves its genomic economy by relying on an efficient strategy of encoding proteins from four overlapping genes: S, C, P, and X.
  • The S gene (and detectable HBV DNA) codes for the “major” envelope protein, HBsAg.
  • Pre-S1 and pre-S2, upstream of S, combine with S to code for two larger proteins, “middle” protein, the product of pre-S2 + S, and “large” protein, the product of pre-S1 + pre-S2 + S.
  • The largest gene, P, codes for DNA polymerase.
  • The C gene codes for two nucleocapsid proteins, HBeAg, a soluble, secreted protein (initiation from the pre-C region of the gene), and HBcAg, the intracellular core protein (initiation after pre-C).
  • The X gene codes for HBxAg, which can transactivate the transcription of cellular and viral genes; its clinical relevance is not known, but it may contribute to carcinogenesis by binding to p53.
  • Three particulate forms of HBV gene products are synthesized: the complete virion and two incomplete or subviral particles.
  • Of these, the most numerous are the 22-nm particles, which appear as spherical or long filamentous forms; these are antigenically indistinguishable from the outer surface or envelope protein of HBV and are thought to represent excess viral envelope protein.
  • Outnumbered in serum by a factor of 100 or 1000 to 1 compared with the spheres and tubules are large, 42-nm, double-shelled spherical particles, which represent the intact hepatitis B virion.
  • The envelope protein expressed on the outer surface of the virion and on the smaller spherical and tubular structures is referred to as hepatitis B surface antigen (HBsAg).
  • The concentration of HBsAg and virus particles in the blood may reach 500 μg/mL and 10 trillion particles per milliliter, respectively; HBsAg assays in common clinical use detect all forms of HBsAg (virion and subviral particles).
  • The envelope protein, HBsAg, is the product of the S gene of HBV.
  • HBV isolates fall into 10 different genotypes (A–J) and multiple subtypes, which are determined by unique gene sequences of the envelope and core region.
  • The pre-S region actually consists of both pre-S1 and pre-S2.
  • Depending on where translation is initiated, three potential HBsAg appear in the circulation (Table 350-1), the complete virion and two incomplete or subviral particles.
  • Of these, the most numerous are the 22-nm particles, which appear as spherical or long filamentous forms; these are antigenically indistinguishable from the outer surface or envelope protein of HBV and are thought to represent excess viral envelope protein.
  • Outnumbered in serum by a factor of 100 or 1000 to 1 compared with the spheres and tubules are large, 42-nm, double-shelled spherical particles, which represent the intact hepatitis B virion.
  • The envelope protein expressed on the outer surface of the virion and on the smaller spherical and tubular structures is referred to as hepatitis B surface antigen (HBsAg).
  • The concentration of HBsAg and virus particles in the blood may reach 500 μg/mL and 10 trillion particles per milliliter, respectively; HBsAg assays in common clinical use detect all forms of HBsAg (virion and subviral particles).
  • The envelope protein, HBsAg, is the product of the S gene of HBV.
  • HBV isolates fall into 10 different genotypes (A–J) and multiple subtypes, which are determined by unique gene sequences of the envelope and core region.

Table 1 — Table 350-1 Nomenclature and Features of Hepatitis Viruses

HEPATITIS TYPE VIRUS PARTICLE, nm MORPHOLOGY GENOME CLASSIFICATION ANTIGEN(S) ANTIBODIES REMARKS
HAV 27 Icosahedral nonenveloped 7.5-kb RNA, linear, ss, + Hepatovirus HAV Anti-HAV Early fecal shedding Diagnosis: IgM anti-HAV Previous infection: IgG anti-HAV
HBV 42 Double-shelled virion (surface and core) spherical 3.2-kb DNA, circular, ss/ds Hepadnavirus HBsAg HBcAg HBeAg Anti-HBs Anti-HBc Anti-HBe Bloodborne virus; carrier state Acute diagnosis: HBsAg, IgM anti-HBc Chronic diagnosis: IgG anti-HBc, HBsAg Markers of replication: HBeAg, HBV DNA
HBV (Nucleocapsid core) 27 Spherical and filamentous; represents excess virus coat material N/A N/A HBcAg Anti-HBc Liver, lymphocytes, other organs
HBV (HBeAg) N/A N/A N/A N/A HBeAg Anti-HBe Nucleocapsid contains DNA and DNA polymerase; present in hepatocyte nucleus; HBcAg does not circulate; HBeAg (soluble, nonparticulate) and HBV DNA circulate—correlate with infectivity and complete virions
HCV 55 Enveloped 9.4-kb RNA, linear, ss, + Hepacivirus HCV core antigen Anti-HCV Bloodborne agent, formerly labeled non-A, non-B hepatitis Acute diagnosis: anti-HCV, HCV RNA Chronic diagnosis: anti-HCV, HCV RNA; cytoplasmic location in hepatocytes
HDV 35–37 Enveloped hybrid particle with HBsAg coat and HDV core 1.7-kb RNA, circular, ss, – Resembles viroids and plant satellite viruses (genus Deltavirus) HBsAg HDAg Anti-HBs Anti-HDV Defective RNA virus, requires helper function of HBV Diagnosis: anti-HDV, HDV RNA; HBV/HDV co-infection—IgM anti-HBc and anti-HDV; HDV superinfection—IgG anti-HBc and anti-HDV
HEV 32–34 Nonenveloped icosahedral 7.6-kb RNA, linear, ss, + Orthohepevirus HEV antigen Anti-HEV Agent of enterically transmitted hepatitis; rare in the United States; occurs in Asia, Mediterranean countries, Central America Diagnosis: IgM/IgG anti-HEV (assays not routinely available); virus in stool, bile, hepatocyte cytoplasm

3.2 HBV Serologic and Virologic Markers

  • After a person is infected with HBV, the first virologic marker detectable in serum within 1–12 weeks, usually between 8 and 12 weeks, is HBsAg.
  • Circulating HBsAg precedes elevations of serum aminotransferase activity and clinical symptoms by 2–6 weeks and remains detectable during the entire icteric or symptomatic phase of acute hepatitis B and beyond.
  • In typical self-limited cases, HBsAg becomes undetectable 1–2 months after the onset of jaundice and rarely persists beyond 6 months.
  • After HBsAg disappears, antibody to HBsAg (anti-HBs) becomes detectable in serum and remains detectable indefinitely thereafter.
  • Because HBcAg is intracellular and, when in the serum, sequestered within an HBsAg coat, naked core particles do not circulate in serum, and therefore, assays for HBcAg are not included in routine clinical testing.
  • By contrast, anti-HBc is readily demonstrable in serum, beginning within the first 1–2 weeks after the appearance of HBsAg and preceding detectable levels of anti-HBs by weeks to months.
  • Because variability exists in the time of appearance of anti-HBs after HBV infection, occasionally a gap of several weeks or longer may separate the disappearance of HBsAg and the appearance of anti-HBs.
  • During this “gap” or “window” period, IgM anti-HBc may represent the only serologic evidence of current or recent HBV infection, and blood containing anti-HBc in the absence of HBsAg and anti-HBs had been implicated in the past in transfusion-associated hepatitis B.
  • In part because the sensitivity of immunoassays for HBsAg and anti-HBs has increased, however, this window period is rarely encountered.
  • In some persons, years after HBV infection, anti-HBc may persist in the circulation longer than anti-HBs.
  • Therefore, isolated anti-HBc does not necessarily indicate active virus replication; most instances of isolated anti-HBc represent hepatitis B infection in the remote past.
  • Rarely, however, isolated anti-HBc represents low-level hepatitis B viremia, with HBsAg below the detection threshold, and occasionally, isolated anti-HBc represents a cross-reacting or false-positive immunologic specificity.
  • Recent and remote HBV infections can be distinguished by determination of the immunoglobulin class of anti-HBc.
  • Anti-HBc of the IgM class (IgM anti-HBc) predominates during the first 6 months after acute infection, whereas IgG anti-HBc is the predominant class of anti-HBc beyond 6 months.
  • Therefore, patients with current or recent acute hepatitis B, including those in the anti-HBc window, have IgM anti-HBc in their serum.
  • In patients who have recovered from hepatitis B in the remote past as well as those with chronic HBV infection, anti-HBc is predominantly of the IgG class.
  • Infrequently, in ≤1–5% of patients with acute HBV infection, levels of HBsAg are too low to be detected; in such cases, the presence of IgM anti-HBc establishes the diagnosis of acute hepatitis B.
  • When isolated anti-HBc occurs in the rare patient with chronic hepatitis B whose HBsAg level is below the sensitivity threshold of contemporary immunoassays (a low-level carrier), anti-HBc is of the IgG class.
  • Generally, in persons who have recovered from hepatitis B, anti-HBs and anti-HBc persist indefinitely.
  • The other readily detectable serologic marker of HBV infection, HBeAg, appears concurrently with or shortly after HBsAg.
  • Its appearance coincides temporally with high levels of virus replication and reflects the presence of circulating intact virions and detectable HBV DNA (with the notable exception of patients with precore mutations who cannot synthesize HBeAg—see “Molecular Variants”).
  • Pre-S1 and pre-S2 proteins are also expressed during periods of peak replication, but assays for these gene products are not routinely available.
  • In self-limited HBV infections, HBeAg becomes undetectable shortly after peak elevations in aminotransferase activity, before the disappearance of HBsAg, and anti-HBe then becomes detectable, coinciding with a period of relatively lower infectivity.
  • Because HBeAg appears transiently (and HBV DNA, see below, is always present) during typical cases of acute infection, testing for HBeAg and HBV DNA is of limited clinical utility; in contrast, testing for the presence of these markers is of substantial importance in patients with chronic infection.
  • Departing from the pattern typical of acute HBV infections, in chronic HBV infection, HBsAg remains detectable beyond 6 months, distinguishing it from acute infection where HBsAg becomes undetectable 1–2 months after onset of jaundice.

4. CLINICAL FEATURES

  • Acute viral hepatitis is a systemic infection affecting the liver predominantly.
  • These illnesses range from asymptomatic and inapparent to fulminant and fatal acute infections, which can be observed in all types.
  • On the other hand, the bloodborne types (HBV, HCV, HDV) may also manifest a spectrum of chronic disease, from subclinical, persistent infections to rapidly progressive chronic liver disease with cirrhosis and even hepatocellular carcinoma.
  • Rarely, infections with other viruses (e.g., cytomegalovirus, Epstein-Barr virus, other herpes viruses, SARS-CoV-2) can be associated with mild or severe, even fulminant, hepatitis, more often in immunocompromised hosts but also in otherwise healthy persons.

5. DIFFERENTIAL DIAGNOSIS

  • Rarely, infections with other viruses (e.g., cytomegalovirus, Epstein-Barr virus, other herpes viruses, SARS-CoV-2) can be associated with mild or severe, even fulminant, hepatitis, more often in immunocompromised hosts but also in otherwise healthy persons.
  • In 2021 and 2022, after the peak years of the COVID-19 pandemic, multiple reports appeared globally of severe acute, often fulminant, hepatitis in previously healthy children.
  • While these instances of severe acute hepatitis remain unexplained, links have been reported of infection with adenovirus type 41 and adeno-associated virus 2, ordinarily not causes of liver injury.

6. INVESTIGATIONS & DIAGNOSIS

  • Diagnosis of hepatitis A is made during acute illness by demonstrating anti-HAV of the IgM class.
  • After acute illness, anti-HAV of the IgG class remains detectable indefinitely, and patients with serum anti-HAV are immune to reinfection.
  • Neutralizing antibody activity parallels the appearance of anti-HAV, and the IgG anti-HAV present in immune globulin accounts for the protection it affords against HAV infection.
  • Hepatitis B HBsAg protein. Envelope HBsAg subdeterminants include a common group-reactive antigen, a, shared by all HBsAg isolates and one of several subtype-specific antigens—d or y, w or r.
  • Geographic distribution of genotypes and subtypes varies; genotypes A (corresponding to subtype adw) and D (ayw) predominate in the United States and Europe, whereas genotypes B (adw) and C (adr) predominate in Asia; however, these geographic distinctions have been blunted by recent-decade migration across continents.
  • Clinical course and outcome are independent of subtype, but genotype B appears to be associated with less rapidly progressive liver disease and cirrhosis and a lower likelihood, or delayed appearance, of hepatocellular carcinoma than genotype C, D, or F.
  • In a large Japanese cohort, after acute infection, patients with genotype A were more likely to have persistent infection (23.4% with genotype A vs 8.6% with non-A genotypes).
  • Also, genotype may influence response to treatment with interferon and other antiviral agents; for example, higher rates of HBeAg and HBsAg loss have been observed in patients with genotype A.
  • An additional important consequence of genotype is the propensity for “precore” mutations to emerge (see below).
  • Hepatitis C Hepatitis C virus, which, before its identification, was labeled “non-A, non-B hepatitis,” is a linear, single-strand, positive-sense, 9600-nucleotide RNA virus, the genome of which is similar in organization to that of flaviviruses and pestiviruses; HCV is the only member of the genus Hepacivirus in the family Flaviviridae.
  • The HCV genome contains a single, large open reading frame (ORF) (gene) that codes for a virus polyprotein of ~3000 amino acids, which is cleaved after translation to yield 10 viral proteins.
  • The 5′ end of the genome consists of an untranslated 500 region (containing an internal ribosomal entry site [IRES]) adjacent to the genes for three structural proteins, the Core nucleocapsid core protein, C, and two envelope glycoproteins, E1 and E2.
  • The 5′ untranslated region and core gene are highly conserved among genotypes, but the envelope proteins are coded for by the hypervariable region, which varies from isolate to isolate and may allow the virus to evade host immunologic containment directed at accessible virus envelope proteins.
  • The 3′ end of the genome also includes an untranslated region and contains the genes for seven nonstructural (NS) regions—p7, a membrane protein adjacent to the structural proteins that appears to function as an ion channel; NS2, which codes for a cysteine protease; NS3, which codes for a serine protease and an RNA helicase; NS4 and NS4B; NS5A, a multifunctional membrane-associated phosphoprotein, an essential component of the viral replication membranous web; and NS5B, which codes for an RNA-dependent RNA polymerase.
  • After translation of the entire polyprotein, individual proteins are cleaved by both host and viral proteases.
  • p7 is a membrane ion channel protein necessary for efficient assembly and release of HCV.
  • The NS2 cysteine protease cleaves NS3 from NS2, and the NS3-4A serine protease cleaves all the downstream proteins from the polyprotein.
  • Important NS proteins involved in virus replication include the NS3 helicase; NS3-4A serine protease; the multifunctional membrane-associated phosphoprotein NS5A, an essential component of the viral replication membranous web (along with NS4B); and the NS5B RNA-dependent RNA polymerase.
  • Because HCV does not replicate via a DNA intermediate, it does not integrate into the host genome.
  • Because HCV tends to circulate in relatively low titer, 10^3−10^7 virions/mL, visualization of the 50- to 80-nm virus particles remains difficult.
  • Still, the replication rate of HCV is very high, 10^12 virions per day; its half-life is 2.7 h.
  • Historically, the study of HCV had been hampered by few adequate in vitro and animal models.
  • In 2005, however, complete replication of HCV and intact 55-nm virions was described in cell culture systems.
  • These and other subsequent models were fundamental toward the development of targeted, effective antiviral therapies for HCV infection.
  • Still, the continued absence of robust animal models poses a barrier to much-needed vaccine development.
  • Albeit a helpful animal model, the chimpanzee is cumbersome to study, and access to chimpanzees for medical research has been curtailed substantially.
  • In addition, while HCV replication has been documented in a xenograft immunodeficient mouse model containing explants of human liver and in transgenic mouse and rat models, a tractable immunocompetent murine model has remained elusive.
  • In vitro study has also elucidated important cofactors for the HCV hepatitis C viral life cycle.
  • For example, HCV entry into the hepatocyte occurs via the non-liver-specific CD81 receptor and the liver-specific tight junction protein claudin-1.
  • A growing list of additional host cofactors for the HCV hepatitis C viral life cycle has been identified.
  • Hepatitis D The delta hepatitis agent, or HDV, the only member of the genus Deltavirus, is a defective RNA virus that co-infects with and requires the helper function of HBV (or other hepadnaviruses) for its replication and expression.
  • Slightly smaller than HBV, HDV is a formalin-sensitive, 35- to 37-nm virus with a hybrid structure.
  • Its nucleocapsid expresses HDV antigen (HDAg), which bears no antigenic homology with any of the HBV antigens, and contains the virus genome.
  • The HDV core is “encapsidated” by an outer envelope of HBsAg, indistinguishable from that of HBV except in its relative compositions of major, middle, and large HBsAg component proteins.
  • The genome is a small, 1700-nucleotide, circular, single-strand RNA negative polarity that is nonhomologous with HBV DNA (except for a small area of the polymerase gene) but that has features and the rolling circle model of replication common to genomes of plant satellite viruses or viroids.
  • HDV RNA contains many areas of internal complementarity; therefore, it can fold on itself by internal base pairing to form an unusual, very stable, rod-like structure that contains a very stable, self-cleaving and self-ligating ribozyme.
  • HDV RNA requires host RNA polymerase II for its replication in the hepatocyte nucleus via RNA-directed RNA synthesis by transcription of genomic RNA to a complementary antigenomic (plus strand) RNA; the antigenomic RNA, in turn, serves as a template for subsequent genomic RNA synthesis effected by host RNA polymerase I.
  • HDV RNA has only one open reading frame, and HDAg, a product of the antigenomic strand, is the only known HDV protein; HDAg exists in two forms: a small, 195-amino-acid species, which plays a role in facilitating HDV RNA replication, and a large, 214-amino-acid species, which appears to suppress replication but is required for assembly of the antigen into virions.
  • HDV antigens have been shown to bind directly to RNA polymerase II, resulting in stimulation of transcription.
  • Viral assembly requires farnesylation of the large HDAg for ribonucleoprotein anchoring to HBsAg.
  • Both HBV and HDV enter hepatocytes via the NTCP receptor.
  • Although complete hepatitis D virions and liver injury require the cooperative helper function of HBV, intracellular replication of HDV RNA can occur without HBV.
  • Genomic heterogeneity among HDV isolates has been described.
  • Although pathophysiologic and clinical consequences of this genetic diversity have not been established definitively, preliminarily, genotype 2 has been linked to milder disease and genotype 3 to severe acute disease.
  • The clinical spectrum of hepatitis D is common to all eight genotypes identified, the predominant of which is genotype 1.
  • HDV can either infect a person simultaneously with HBV (co-infection) or superinfect a person already infected with HBV (superinfection).
  • In instances of superinfection, when HDV infection is transmitted from a donor with one HBsAg subtype to an HBsAg-positive recipient with a different subtype, HDV assumes the HBsAg subtype of the recipient, rather than the donor.
  • Because HDV relies absolutely on HBV for its replication, the duration of HDV infection is determined by the duration of (and cannot outlast) HBV infection.
  • HDV replication tends to suppress HBV replication; therefore, patients with hepatitis D tend to have lower levels of HBV replication.
  • HDV antigen is expressed primarily in hepatocyte nuclei and is occasionally detectable in serum.
  • During acute HDV infection, anti-HDV of the IgM class predominates, and 30–40 days may elapse after symptoms appear before anti-HDV can be detected.
  • In self-limited infection, anti-HDV is low-titer and transient, rarely remaining detectable beyond the clearance of HBsAg and HDV antigen.
  • In chronic HDV infection, anti-HDV circulates in high titer, and both IgM and IgG anti-HDV can be detected.
  • HDV antigen in the liver and HDV RNA in serum and liver can be detected during HDV replication.
  • Hepatitis E HEV is a nonenveloped icosahedral virus with a 7.6-kb RNA genome.
  • HEV is the agent of enterically transmitted hepatitis; rare in the United States; occurs in Asia, Mediterranean countries, Central America.

6.1 HBV Serologic Markers

  • After a person is infected with HBV, the first virologic marker detectable in serum within 1–12 weeks, usually between 8 and 12 weeks, is HBsAg.
  • Circulating HBsAg precedes elevations of serum aminotransferase activity and clinical symptoms by 2–6 weeks and remains detectable during the entire icteric or symptomatic phase of acute hepatitis B and beyond.
  • In typical self-limited cases, HBsAg becomes undetectable 1–2 months after the onset of jaundice and rarely persists beyond 6 months.
  • After HBsAg disappears, antibody to HBsAg (anti-HBs) becomes detectable in serum and remains detectable indefinitely thereafter.
  • Because HBcAg is intracellular and, when in the serum, sequestered within an HBsAg coat, naked core particles do not circulate in serum, and therefore, assays for HBcAg are not included in routine clinical testing.
  • By contrast, anti-HBc is readily demonstrable in serum, beginning within the first 1–2 weeks after the appearance of HBsAg and preceding detectable levels of anti-HBs by weeks to months.
  • Because variability exists in the time of appearance of anti-HBs after HBV infection, occasionally a gap of several weeks or longer may separate the disappearance of HBsAg and the appearance of anti-HBs.
  • During this “gap” or “window” period, IgM anti-HBc may represent the only serologic evidence of current or recent HBV infection, and blood containing anti-HBc in the absence of HBsAg and anti-HBs had been implicated in the past in transfusion-associated hepatitis B.
  • In part because the sensitivity of immunoassays for HBsAg and anti-HBs has increased, however, this window period is rarely encountered.
  • In some persons, years after HBV infection, anti-HBc may persist in the circulation longer than anti-HBs.
  • Therefore, isolated anti-HBc does not necessarily indicate active virus replication; most instances of isolated anti-HBc represent hepatitis B infection in the remote past.
  • Rarely, however, isolated anti-HBc represents low-level hepatitis B viremia, with HBsAg below the detection threshold, and occasionally, isolated anti-HBc represents a cross-reacting or false-positive immunologic specificity.
  • Recent and remote HBV infections can be distinguished by determination of the immunoglobulin class of anti-HBc.
  • Anti-HBc of the IgM class (IgM anti-HBc) predominates during the first 6 months after acute infection, whereas IgG anti-HBc is the predominant class of anti-HBc beyond 6 months.
  • Therefore, patients with current or recent acute hepatitis B, including those in the anti-HBc window, have IgM anti-HBc in their serum.
  • In patients who have recovered from hepatitis B in the remote past as well as those with chronic HBV infection, anti-HBc is predominantly of the IgG class.
  • Infrequently, in ≤1–5% of patients with acute HBV infection, levels of HBsAg are too low to be detected; in such cases, the presence of IgM anti-HBc establishes the diagnosis of acute hepatitis B.
  • When isolated anti-HBc occurs in the rare patient with chronic hepatitis B whose HBsAg level is below the sensitivity threshold of contemporary immunoassays (a low-level carrier), anti-HBc is of the IgG class.
  • Generally, in persons who have recovered from hepatitis B, anti-HBs and anti-HBc persist indefinitely.
  • The other readily detectable serologic marker of HBV infection, HBeAg, appears concurrently with or shortly after HBsAg.
  • Its appearance coincides temporally with high levels of virus replication and reflects the presence of circulating intact virions and detectable HBV DNA (with the notable exception of patients with precore mutations who cannot synthesize HBeAg—see “Molecular Variants”).
  • Pre-S1 and pre-S2 proteins are also expressed during periods of peak replication, but assays for these gene products are not routinely available.
  • In self-limited HBV infections, HBeAg becomes undetectable shortly after peak elevations in aminotransferase activity, before the disappearance of HBsAg, and anti-HBe then becomes detectable, coinciding with a period of relatively lower infectivity.
  • Because HBeAg appears transiently (and HBV DNA, see below, is always present) during typical cases of acute infection, testing for HBeAg and HBV DNA is of limited clinical utility; in contrast, testing for the presence of these markers is of substantial importance in patients with chronic infection.
  • Departing from the pattern typical of acute HBV infections, in chronic HBV infection, HBsAg remains detectable beyond 6 months, distinguishing it from acute infection where HBsAg becomes undetectable 1–2 months after onset of jaundice.

6.2 HCV Serologic Markers

  • Currently available, third-generation immunoassays, which incorporate proteins from the core, NS3, and NS5 regions, detect anti-HCV antibodies during acute infection.
  • The most sensitive indicator of HCV infection is the presence of HCV RNA, which requires molecular amplification, for example, by PCR.
  • To allow standardization of the quantification of HCV RNA among laboratories and commercial assays, HCV RNA is reported as international units (IUs) per milliliter; quantitative assays with a broad dynamic range are available that allow detection of HCV RNA with a sensitivity as low as 5 IU/mL.
  • HCV RNA can be detected within a few days of exposure to HCV—well before the appearance of anti-HCV—and tends to persist for the duration of HCV infection.
  • Application of sensitive molecular probes for HCV RNA has revealed the presence of replicative HCV.

7. SPECIAL CONSIDERATIONS

  • HBV genotype B appears to be associated with less rapidly progressive liver disease and cirrhosis and a lower likelihood, or delayed appearance, of hepatocellular carcinoma than genotype C, D, or F.
  • In a large Japanese cohort, after acute infection, patients with genotype A were more likely to have persistent infection (23.4% with genotype A vs 8.6% with non-A genotypes).
  • Also, genotype may influence response to treatment with interferon and other antiviral agents; for example, higher rates of HBeAg and HBsAg loss have been observed in patients with genotype A.
  • An additional important consequence of genotype is the propensity for “precore” mutations to emerge (see below).
  • Hepatitis D The delta hepatitis agent, or HDV, the only member of the genus Deltavirus, is a defective RNA virus that co-infects with and requires the helper function of HBV (or other hepadnaviruses) for its replication and expression.
  • Slightly smaller than HBV, HDV is a formalin-sensitive, 35- to 37-nm virus with a hybrid structure.
  • Its nucleocapsid expresses HDV antigen (HDAg), which bears no antigenic homology with any of the HBV antigens, and contains the virus genome.
  • The HDV core is “encapsidated” by an outer envelope of HBsAg, indistinguishable from that of HBV except in its relative compositions of major, middle, and large HBsAg component proteins.
  • The genome is a small, 1700-nucleotide, circular, single-strand RNA negative polarity that is nonhomologous with HBV DNA (except for a small area of the polymerase gene) but that has features and the rolling circle model of replication common to genomes of plant satellite viruses or viroids.
  • HDV RNA contains many areas of internal complementarity; therefore, it can fold on itself by internal base pairing to form an unusual, very stable, rod-like structure that contains a very stable, self-cleaving and self-ligating ribozyme.
  • HDV RNA requires host RNA polymerase II for its replication in the hepatocyte nucleus via RNA-directed RNA synthesis by transcription of genomic RNA to a complementary antigenomic (plus strand) RNA; the antigenomic RNA, in turn, serves as a template for subsequent genomic RNA synthesis effected by host RNA polymerase I.
  • HDV RNA has only one open reading frame, and HDAg, a product of the antigenomic strand, is the only known HDV protein; HDAg exists in two forms: a small, 195-amino-acid species, which plays a role in facilitating HDV RNA replication, and a large, 214-amino-acid species, which appears to suppress replication but is required for assembly of the antigen into virions.
  • HDV antigens have been shown to bind directly to RNA polymerase II, resulting in stimulation of transcription.
  • Viral assembly requires farnesylation of the large HDAg for ribonucleoprotein anchoring to HBsAg.
  • Both HBV and HDV enter hepatocytes via the NTCP receptor.
  • Although complete hepatitis D virions and liver injury require the cooperative helper function of HBV, intracellular replication of HDV RNA can occur without HBV.
  • Genomic heterogeneity among HDV isolates has been described.
  • Although pathophysiologic and clinical consequences of this genetic diversity have not been established definitively, preliminarily, genotype 2 has been linked to milder disease and genotype 3 to severe acute disease.
  • The clinical spectrum of hepatitis D is common to all eight genotypes identified, the predominant of which is genotype 1.
  • HDV can either infect a person simultaneously with HBV (co-infection) or superinfect a person already infected with HBV (superinfection).
  • In instances of superinfection, when HDV infection is transmitted from a donor with one HBsAg subtype to an HBsAg-positive recipient with a different subtype, HDV assumes the HBsAg subtype of the recipient, rather than the donor.
  • Because HDV relies absolutely on HBV for its replication, the duration of HDV infection is determined by the duration of (and cannot outlast) HBV infection.
  • HDV replication tends to suppress HBV replication; therefore, patients with hepatitis D tend to have lower levels of HBV replication.
  • HDV antigen is expressed primarily in hepatocyte nuclei and is occasionally detectable in serum.
  • During acute HDV infection, anti-HDV of the IgM class predominates, and 30–40 days may elapse after symptoms appear before anti-HDV can be detected.
  • In self-limited infection, anti-HDV is low-titer and transient, rarely remaining detectable beyond the clearance of HBsAg and HDV antigen.
  • In chronic HDV infection, anti-HDV circulates in high titer, and both IgM and IgG anti-HDV can be detected.
  • HDV antigen in the liver and HDV RNA in serum and liver can be detected during HDV replication.
  • Hepatitis E HEV is a nonenveloped icosahedral virus with a 7.6-kb RNA genome.
  • HEV is the agent of enterically transmitted hepatitis; rare in the United States; occurs in Asia, Mediterranean countries, Central America.

7.1 HBV Molecular Variants

  • Variation occurs throughout the HBV genome, and clinical isolates of HBV that do not express typical viral proteins have been attributed to mutations in individual or even multiple gene locations.
  • For example, variants have been described that lack nucleocapsid proteins (commonly), envelope proteins (very rarely), and or both.
  • Two categories of naturally occurring HBV variants have attracted the most attention: precore mutations and escape mutations.
  • One precore mutation was identified initially in Mediterranean countries among patients with severe chronic HBV infection and detectable HBV DNA, but with anti-HBe instead of HBeAg.
  • These patients were found to be infected with an HBV mutant that contained an alteration in the precore region, rendering the virus incapable of encoding HBeAg.
  • Although several potential mutation sites exist in the pre-C region, the region of the C gene necessary for the expression of HBeAg (see “Virology and Etiology”), the most commonly encountered in such patients is a single base substitution, from G to A in the second to last codon of the pre-C gene at nucleotide 1896.
  • This substitution results in the replacement of the TGG tryptophan codon by a stop codon (TAG), which prevents the translation of HBeAg.
  • Another mutation, in the core-promoter region, prevents transcription of the coding region for HBeAg and yields an HBeAg-negative phenotype.
  • Patients with such mutations in the precore region and who are unable to secrete HBeAg may have severe liver disease that progresses more rapidly to cirrhosis, or alternatively, they are identified clinically later in the course of the natural history of chronic hepatitis B, when the disease is more advanced.
  • Both “wild-type” HBV and precore-mutant HBV can coexist in the same patient, or mutant HBV may arise late during wild-type HBV infection.
  • Clusters of fulminant hepatitis B have been observed in Japan and Israel among patients with precore mutant mutations, although, typically, in Europe and North America, most cases of fulminant hepatitis B occur in patients with wild-type virus.
  • HBeAg-negative chronic hepatitis with mutations in the precore region is now the most frequently encountered form of hepatitis B in Mediterranean countries and in Europe.
  • In the United States, where HBV genotype A (less prone to G1896A mutation) is prevalent, precore-mutant HBV had been much less common; however, as a result of immigration from Asia and Europe, the proportion of HBeAg-negative hepatitis B–infected persons has increased in the United States, now accounting for ~30–40% of patients with chronic hepatitis B.
  • Characteristic of such HBeAg-negative chronic hepatitis B are lower levels of HBV DNA (usually ≤10^5 IU/mL) and one of several patterns of aminotransferase activity—persistent elevations, periodic fluctuations above the normal range, and periodic fluctuations between the normal and elevated range.
  • The second important category of HBV mutants consists of escape mutants, in which a single amino acid substitution, from glycine to arginine, occurs at position 145 of the immunodominant common to all HBsAg subtypes.
  • This HBsAg alteration leads to a critical conformational change that results in a loss of neutralizing activity by anti-HBs.
  • This specific HBV/a mutant has been observed in two situations, active and passive immunization, in which humoral immunologic pressure may favor evolutionary change (“escape”) in the virus—in a small number of hepatitis B vaccine recipients who acquired HBV infection despite the prior appearance of neutralizing anti-HBs and in HBV-infected liver transplant recipients treated with a high-potency human monoclonal anti-HBs preparation.
  • Although such mutants have not been recognized frequently, their existence can raises a concern that may complicate vaccination strategies and serologic diagnosis.
  • Different types of mutations emerge during antiviral therapy of chronic hepatitis B with nucleoside analogues; such YMDD and similar mutations in the polymerase motif of HBV are described in Chap. 352.

7.2 HBV Extrahepatic Sites

  • Hepatitis B antigens and HBV DNA have been identified in extrahepatic sites, including the lymph nodes, bone marrow, circulating lymphocytes, spleen, and pancreas.
  • Although the virus does not appear to be associated with tissue injury in any of these extrahepatic sites, its presence in these “remote” reservoirs has been invoked (but is not necessary) to explain the recurrence of HBV infection after orthotopic liver transplantation.
  • The clinical relevance of such extrahepatic HBV is limited.

8. KEY PEARLS & CLINICAL TRAPS

  • HAV incubation period is approximately 3–4 weeks; replication is limited to the liver but virus is present in liver, bile, stools, and blood during late incubation and acute preicteric phase.
  • HBV entry into hepatocytes is mediated by binding to the sodium taurocholate cotransporting polypeptide (NTCP) receptor.
  • HCV RNA is the most sensitive indicator of HCV infection; neutralizing antibodies to HCV are short-lived and do not indicate protection against reinfection.
  • HDV is a defective RNA virus that requires the helper function of HBV for replication and expression.
  • HBV genotype B appears to be associated with less rapidly progressive liver disease and cirrhosis and a lower likelihood of hepatocellular carcinoma than genotype C, D, or F.
  • HCV does not integrate into the host genome because it does not replicate via a DNA intermediate.
  • Precore mutations in HBV (e.g., G1896A substitution) render the virus incapable of encoding HBeAg, leading to HBeAg-negative chronic hepatitis.
  • HDV antigen is expressed primarily in hepatocyte nuclei and is occasionally detectable in serum.
  • HCV replication rate is very high (10^12 virions per day) with a half-life of 2.7 hours.
  • In chronic HBV infection, HBsAg remains detectable beyond 6 months, distinguishing it from acute infection where HBsAg becomes undetectable 1–2 months after onset of jaundice.

Flowcharts & Algorithms

Reproduced from Harrison's 22nd Edition.

Flowchart 1

Scheme of typical clinical and laboratory features of hepatitis A...

Caption: FIGURE 350-2 Scheme of typical clinical and laboratory features of hepatitis A virus (HAV). ALT, alanine aminotransferase.

Flowchart 2

Scheme of typical clinical and laboratory features of acute hepatitis...

Caption: FIGURE 350-4 Scheme of typical clinical and laboratory features of acute hepatitis B. ALT, alanine aminotransferase.

Flowchart 3

Scheme of typical laboratory features of wild-type chronic hepatitis B

Caption: FIGURE 350-5 Scheme of typical laboratory features of wild-type chronic hepatitis B. HBeAg and hepatitis B virus (HBV) DNA can be detected in serum during the relatively replicative phase of chronic infection, which is associated with infectivity and liver injury. Seroconversion from the replicative phase to the relatively nonreplicative phase occurs at a rate of ~10% per year and is heralded by in an acute hepatitis–like elevation of alanine aminotransferase (ALT) activity; during the nonreplicative phase, infectivity and liver injury are limited. In HBeAg-negative chronic hepatitis B associated with mutations in the precore region of the HBV genome, replicative chronic hepatitis B occurs in the absence of HBeAg.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Organization of the hepatitis C virus genome and its associated,...

Caption: FIGURE 350-6 Organization of the hepatitis C virus genome and its associated, 3000-amino-acid (AA) proteins. The three structural genes at the 5′ end are the core region, C, which codes for the nucleocapsid, and the envelope regions, E1 and E2, which code for envelope glycoproteins. The 5′ untranslated region and the C region are highly conserved among isolates, whereas the envelope domain E2 contains the hypervariable region. At the 3′ end are seven nonstructural (NS) regions—p7, a membrane protein adjacent to the structural proteins that appears to function as an ion channel; NS2, which codes for a cysteine protease; NS3, which codes for a serine protease and an RNA helicase; NS4 and NS4B; NS5A, a multifunctional membrane-associated phosphoprotein, an essential component of the viral replication membranous web; and NS5B, which codes for an RNA-dependent RNA polymerase. After translation of the entire polyprotein, individual proteins are cleaved by both host and viral proteases. cleaves NS3 from NS2, and (e.g., hepatic steatosis and clinical progression are more likely in geno- — Figure 350-1 Electron micrographs of hepatitis A virus particles and serum from a patient with hepatitis B. Left: 27-nm hepatitis A virus particles purified from stool of a patient with acute hepatitis A and aggregated by antibody to hepatitis A virus. Right: Concentrated serum from a patient with hepatitis B, demonstrating the 42-nm virions, tubular forms, and spherical 22-nm particles of hepatitis B surface antigen.

Figure 2

Electron micrographs of hepatitis A virus particles and serum from...

Caption: FIGURE 350-1 Electron micrographs of hepatitis A virus particles and serum from a 27-nm hepatitis A virus particles purified from stool of a patient with acute hepatitis A hepatitis A virus. Right: Concentrated serum from a patient with hepatitis B, forms, and spherical 22-nm particles of hepatitis B surface antigen. 132,000×. (Hepatitis hepatitis B but is smaller, 35–37 nm; hepatitis E resembles hepatitis A virus but is slightly has been visualized as a 55-nm particle.) — Figure 350-6 Organization of the hepatitis C virus genome and its associated, 3000-amino-acid (AA) proteins. The three structural genes at the 5′ end are the core region, C, which codes for the nucleocapsid, and the envelope regions, E1 and E2, which code for envelope glycoproteins. The 5′ untranslated region and the C region are highly conserved among isolates, whereas the envelope domain E2 contains the hypervariable region. At the 3′ end are seven nonstructural (NS) proteins: p7, NS2, NS4 and NS4B; NS3, NS4A, NS4B, NS5A, and NS5B.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.