11.1 Viral Hepatitis A to E

Hepatology represents a cornerstone of the MRCP(UK) Part 1 examination. Candidates must master the interpretation of viral hepatitis serological matrices, the autoimmune serology and histopathology of autoimmune hepatitis, and the molecular genetics, clinical manifestations, diagnostic pathways, and targeted therapeutics of hereditary metabolic hepatopathies.

1. Viral Hepatitis (A through E)

Hepatitis A Virus (HAV)

• Virology & Transmission: Non-enveloped, single-stranded RNA picornavirus transmitted predominantly via the faecal-oral route through contaminated water or shellfish. Incubation period averages 2–6 weeks.
• Clinical Presentation: Typically an acute, self-limiting illness manifesting with systemic prodromal symptoms (malaise, anorexia, low-grade fever, nausea), followed by dark urine, pale stools, tender hepatomegaly, and jaundice. Fulminant hepatic failure occurs in <0.5% of cases (higher in pre-existing chronic liver disease).
• Diagnostic Serology:
  • Anti-HAV IgM: Appears at symptom onset, peaks within 2–3 weeks, and persists for 3–6 months. Diagnostic hallmark of acute Hepatitis A infection.
  • Anti-HAV IgG: Appears during convalescence and persists for life, conferring long-term immunity following natural infection or active immunization.
• Clinical Caveat: Hepatitis A never causes chronic hepatitis or a chronic carrier state.

Hepatitis B Virus (HBV)

• Virology & Transmission: Partially double-stranded circular DNA virus (Hepadnaviridae family) transmitted via percutaneous, sexual, and vertical (perinatal) exposure. Perinatal transmission carries a >90% risk of chronicity, whereas adult acquisition leads to chronic infection in only ~5% of immunocompetent hosts.
• Serological Markers:
  • HBsAg (Hepatitis B Surface Antigen): The first serological marker to appear in acute infection (1–10 weeks post-exposure). Indicates the presence of active infection. Persistence beyond 6 months defines chronic Hepatitis B infection.
  • Anti-HBs (Hepatitis B Surface Antibody): Neutralizing antibody indicating immunity and recovery. Appears after clearance of HBsAg or following successful vaccination. A titre >=10 mIU/mL is considered protective.
  • Anti-HBc (Hepatitis B Core Antibody): Marker of exposure to the natural virus; never induced by recombinant Hepatitis B vaccination.
    • Anti-HBc IgM: Marker of acute infection or an acute severe flare of chronic HBV. Crucially, it serves as the sole serological marker during the "window period" (the interval when HBsAg has fallen below detectable thresholds but anti-HBs has not yet reached measurable levels).
    • Anti-HBc IgG: Persists indefinitely after natural exposure, signifying past resolved infection or ongoing chronic infection.
  • HBeAg (Hepatitis B e Antigen): Secretory protein derived from the pre-core/core gene; serves as an indirect surrogate for active viral replication and high infectivity.
  • Anti-HBe (Hepatitis B e Antibody): Indicates seroconversion to a state of lower viral replication and reduced infectivity (except in pre-core mutant strains).
  • HBV DNA (PCR): Direct quantitative measurement of viral load. Used to assess replication, guide initiation of antiviral therapy, and monitor therapeutic response.

• Antiviral Management: Indications for treatment include HBV DNA >2,000 IU/mL with elevated ALT (>ULN) or evidence of significant fibrosis (>=F2). First-line therapies are oral nucleos(t)ide analogues with a high genetic barrier to resistance: Entecavir or Tenofovir (Tenofovir disoproxil fumarate [TDF] or Tenofovir alafenamide [TAF]; TAF is preferred in patients with renal impairment or osteoporosis). Pegylated Interferon-alpha-2a (48-week finite course) may be considered in young patients with mild disease and favorable genotypes.

Hepatitis C Virus (HCV)

• Virology & Transmission: Enveloped, single-stranded RNA flavivirus transmitted predominantly via blood (intravenous drug use, contaminated blood products prior to 1991 screening, unsterile needle exposure). Chronicity develops in 75–85% of infected individuals.
• Extrahepatic Manifestations: Mixed cryoglobulinaemia (Type II cryoglobulinaemia with palpable purpura, arthralgias, and membranoproliferative glomerulonephritis [MPGN]), porphyria cutanea tarda (PCT), lichen planus, Sjögren-like sialadenitis, and B-cell non-Hodgkin lymphoma.
• Diagnostic Algorithm:
  1. Anti-HCV Antibody: Initial screening immunoassay. Reflects exposure but cannot differentiate between active, chronic infection and resolved infection.
  2. HCV RNA PCR (Qualitative / Quantitative): If anti-HCV is positive, reflex HCV RNA testing is mandatory. Presence of HCV RNA confirms active viraemic infection.
• Therapy: Curative pan-genotypic Direct-Acting Antivirals (DAAs) administered orally for 8–12 weeks (e.g., Sofosbuvir + Velpatasvir or Glecaprevir + Pibrentasvir). DAAs target the viral NS3/4A protease, NS5A replication complex, or NS5B RNA-dependent RNA polymerase, achieving a Sustained Virological Response at 12 weeks (SVR12) in >95% of patients, equivalent to virological cure.

Hepatitis D Virus (HDV)

• Virology & Dependency: Defective, circular single-stranded RNA "delta agent" that lacks the genetic machinery to synthesize its own envelope proteins. It strictly requires Hepatitis B surface antigen (HBsAg) to assemble infectious virions and propagate.
• Infection Patterns:
  • Co-infection: Simultaneous acquisition of HBV and HDV. Manifests as severe acute hepatitis with high risk of acute liver failure, but chronicity occurs in <5% of immunocompetent adults.
  • Superinfection: Acquisition of HDV in a patient already chronically infected with HBV. Triggers acute severe hepatitis, accelerates hepatic fibrosis, leads to cirrhosis in 70–80% of patients within 5–10 years, and significantly elevates the risk of hepatocellular carcinoma.
• Diagnosis & Treatment: Detected via anti-HDV antibodies and HDV RNA PCR. Managed with Bulevirtide (entry inhibitor blocking NTCP receptor) or pegylated interferon-alpha.

Hepatitis E Virus (HEV)

• Virology & Transmission: Non-enveloped single-stranded RNA hepevirus.
  • Genotypes 1 & 2: Transmitted via contaminated drinking water; causes major waterborne epidemics in developing countries.
  • Genotypes 3 & 4: Zoonotic transmission via consumption of undercooked pork, wild boar, or venison; prevalent in the UK and Europe.
• Critical Exam Associations:
  1. High Mortality in Pregnancy: In pregnant women (especially during the third trimester), acute HEV infection (Genotypes 1/2) carries a catastrophic 20–25% maternal mortality rate secondary to acute liver failure.
  2. Chronic Hepatitis in Immunocompromised Hosts: In solid organ transplant recipients, haematological malignancy, or advanced HIV infection (CD4 <200), HEV (Genotype 3) can fail to clear, leading to chronic hepatitis and rapid development of cirrhosis within 2–3 years. Chronic HEV is treated by reducing immunosuppression and/or oral ribavirin for 12 weeks.