Hepatitis Viruses
Microbiology · Virology · lean revision notes
Hepatitis Viruses
The hepatotropic viruses (HAV, HBV, HCV, HDV, HEV) are a perennial NEET PG favourite, with the single most-tested theme being HBV serology interpretation across acute, window, resolved, carrier and vaccinated states. This note builds the virology, then drills the serological patterns and the high-yield clinical pearls (pregnancy in HEV, chronicity in HCV, superinfection in HDV).
Classification & basic virology
The five primary hepatitis viruses belong to completely unrelated families — a classic exam trap. Group them first by route of transmission:
- Enteric (faeco-oral): HAV and HEV → "the vowels hit the bowels" (A and E are vowels). Cause acute, self-limiting hepatitis; never chronic (except HEV genotype 3 in the immunocompromised, e.g. transplant patients).
- Parenteral / blood-borne / sexual: HBV, HCV, HDV → can cause chronic infection, cirrhosis and hepatocellular carcinoma (HCC).
| Virus | Family | Genome | Envelope | Transmission | Chronicity | Incubation |
|---|---|---|---|---|---|---|
| HAV | Picornaviridae (Hepatovirus) | ssRNA (+), linear | Non-enveloped | Faeco-oral | None | 15–45 d (~4 wk) |
| HBV | Hepadnaviridae | partially dsDNA, circular | Enveloped | Parenteral, sexual, vertical | 5–10% adults; 90% neonates | 30–180 d (~12 wk) |
| HCV | Flaviviridae (Hepacivirus) | ssRNA (+), linear | Enveloped | Parenteral (esp. IVDU) | ~80% (highest) | 15–150 d (~7 wk) |
| HDV | unassigned (Deltavirus); defective | ssRNA (−), circular | HBsAg coat (borrowed) | Parenteral, sexual | With superinfection | 30–180 d |
| HEV | Hepeviridae (Orthohepevirus) | ssRNA (+), linear | Non-enveloped | Faeco-oral (waterborne) | None (except genotype 3) | 15–60 d (~6 wk) |
High-yield: HBV is the only DNA virus among the hepatitis viruses, and it is the only one that replicates via a reverse-transcriptase (it has an RNA intermediate / pregenomic RNA) — hence reverse-transcriptase inhibitors (tenofovir, entecavir) work against it.
High-yield: HDV is a defective / satellite virus — it cannot package itself without HBsAg from HBV. Therefore HDV infection only occurs in the presence of HBV, and HBV vaccination simultaneously protects against HDV.
Mnemonic for incubation periods (shortest → longest, weeks): A → E → C → B roughly (HAV ~4, HEV ~6, HCV ~7, HBV ~12). The DNA virus (HBV) has the longest incubation.
Hepatitis A virus (HAV)
A non-enveloped picornavirus shed in faeces; spreads via contaminated water/food (shellfish), poor sanitation, and travel. Single serotype → lifelong immunity and an effective killed vaccine.
- Clinical: Most childhood infections are subclinical/anicteric; symptomatic icteric disease rises with age. Prodrome (fever, anorexia, nausea, classic distaste for smoking in smokers) → icteric phase (jaundice, dark urine, pale stool, tender hepatomegaly).
- Course: Self-limiting over weeks. No chronic carrier state. Fulminant hepatic failure is rare (<0.1%).
- Serology / diagnosis:
- IgM anti-HAV → marker of acute/recent infection (best initial test; positive for ~3–6 months).
- IgG anti-HAV → past infection or vaccination → lifelong immunity.
- Prophylaxis: Killed (inactivated) vaccine; post-exposure — vaccine ± immunoglobulin depending on age/comorbidity.
High-yield: IgM anti-HAV = acute hepatitis A. IgG alone = immune (recovered or vaccinated).
Hepatitis E virus (HEV)
Waterborne (faeco-oral) calicivirus-like agent causing large epidemic outbreaks in the Indian subcontinent (contaminated drinking water, monsoon/flood related). Genotypes 1 & 2 = human, waterborne, epidemic; genotypes 3 & 4 = zoonotic (pork, deer), sporadic, can chronify in the immunosuppressed.
- Clinical: Usually acute self-limiting, similar to HAV.
- THE pearl — Pregnancy: HEV in pregnancy (especially third trimester) carries fulminant hepatic failure and mortality up to 20%. This is the single most tested HEV fact.
- Diagnosis: IgM anti-HEV (acute); HEV-RNA by PCR.
- No widely available vaccine in most settings (an HEV vaccine exists in China — Hecolin); management is supportive.
High-yield: HEV is the leading cause of fulminant hepatitis in pregnancy (~20% mortality, 3rd trimester). HAV is the commonest cause of acute viral hepatitis in children.
Hepatitis B virus (HBV) — virology
The Hepadnavirus virion (Dane particle, 42 nm) is the complete infectious unit. Key antigens:
- HBsAg (surface) — the envelope antigen; first marker to appear; persistence >6 months = chronic. Also produced in excess as non-infectious spheres/filaments.
- HBcAg (core) — not detectable in serum (intracellular); but anti-HBc antibody is crucial.
- HBeAg — secreted soluble protein; marker of high replication and high infectivity.
- HBV-DNA — direct measure of viral load (best correlate of replication/infectivity).
Replication peculiarity: HBV DNA polymerase has reverse-transcriptase activity; replicates through a pre-genomic RNA intermediate → covalently closed circular DNA (cccDNA) persists in the hepatocyte nucleus and explains why cure is hard.
HBV serological markers — what each means
| Marker | Meaning |
|---|---|
| HBsAg | Active infection (acute or chronic). First to appear, ~1–10 weeks post-exposure. |
| Anti-HBs | Immunity — either past resolved infection or vaccination (vaccine gives anti-HBs only). |
| HBeAg | Active replication, high infectivity |
| Anti-HBe | Lower replication/infectivity; seroconversion = improving |
| IgM anti-HBc | Acute infection / window period (key!) |
| IgG anti-HBc | Past or chronic infection (persists for life) |
| HBV-DNA | Viral load — best marker of replication |
The "window period" — the classic question
During acute resolving HBV there is a phase where HBsAg has disappeared but anti-HBs has not yet appeared. In this window period, the only positive marker is IgM anti-HBc. Missing it can falsely label a patient as not infected.
Sequence in acute self-limiting HBV: HBsAg + HBeAg appear → IgM anti-HBc appears (symptoms/raised ALT) → HBsAg & HBeAg clear → window period (only anti-HBc) → anti-HBe then anti-HBs appear → recovery with lifelong IgG anti-HBc + anti-HBs.
High-yield: In the window period the sole serological marker is IgM anti-HBc. Therefore anti-HBc IgM is the key test to diagnose acute HBV when HBsAg is already negative.
HBV serology interpretation table — memorise this
| State | HBsAg | Anti-HBs | IgM anti-HBc | Total/IgG anti-HBc | HBeAg |
|---|---|---|---|---|---|
| Acute infection | + | − | + | + | + |
| Window period | − | − | + | + | ± |
| Resolved (immune from infection) | − | + | − | + | − |
| Vaccinated (immune) | − | + | − | − | − |
| Chronic — high infectivity | + | − | − | + (IgG) | + |
| Chronic — low infectivity | + | − | − | + (IgG) | − (anti-HBe +) |
High-yield: The single discriminator between vaccination and past natural infection is anti-HBc: vaccinated = anti-HBs only; recovered = anti-HBs + anti-HBc. (Vaccine contains only HBsAg, so no core antibody is made.)
High-yield: HBsAg persisting >6 months = chronic HBV. HBeAg-positive chronic = highly infectious; "precore mutant" can be HBeAg-negative yet still have high HBV-DNA.
HBV — clinical & management
- Vertical transmission is the dominant route in endemic areas; neonates have ~90% chronicity (immune tolerance) vs ~5% in immunocompetent adults — inverse relationship between age and chronicity.
- Extrahepatic: polyarteritis nodosa (PAN) and membranous glomerulonephritis (immune-complex).
- DOC / first-line antivirals: Tenofovir and Entecavir (high barrier to resistance). Pegylated interferon-α is an option (finite duration, used in selected). Lamivudine is now avoided (resistance).
- Prevention: Recombinant HBsAg vaccine (give at 0, 1, 6 months); part of pentavalent in India. Birth dose within 24 h is critical.
- Post-exposure / neonate of HBsAg+ mother: HBIG + vaccine within 12–24 h.
High-yield: Newborn of HBsAg-positive mother → Hepatitis B immunoglobulin (HBIG) + HBV vaccine within 12 hours of birth (passive + active immunisation).
Hepatitis C virus (HCV)
Enveloped flavivirus; highly variable envelope (E2/HVR) → no effective vaccine and ability to escape immunity. Major route = percutaneous (IV drug use, unscreened transfusion historically).
- Clinical: Acute infection is usually mild/asymptomatic ("silent") — and that is exactly why it chronifies undetected.
- Chronicity: ~80% become chronic — the highest chronicity of all hepatitis viruses → cirrhosis, HCC. Often discovered incidentally on raised transaminases or screening.
- Extrahepatic: mixed cryoglobulinaemia, membranoproliferative GN, porphyria cutanea tarda, lichen planus.
- Diagnosis: Screen with anti-HCV antibody (ELISA) → confirm active infection with HCV-RNA (PCR). Antibody positive but RNA negative = past/cleared infection.
- Treatment — the modern revolution: Direct-acting antivirals (DAAs) give >95% cure (SVR). Targets:
- NS3/4A protease → "-previr" (e.g. grazoprevir, glecaprevir)
- NS5A → "-asvir" (e.g. ledipasvir, velpatasvir, pibrentasvir)
- NS5B RNA-dependent RNA polymerase → sofosbuvir (nucleotide inhibitor) and "-buvir" drugs
- Pan-genotypic combos: sofosbuvir + velpatasvir, glecaprevir + pibrentasvir.
High-yield: HCV has the highest rate of chronicity (~80%); sofosbuvir targets NS5B polymerase; "-asvir" = NS5A inhibitors; "-previr" = NS3/4A protease inhibitors. There is no HCV vaccine (high genomic variability).
Hepatitis D virus (HDV)
Defective satellite RNA virus requiring HBsAg. Two clinical scenarios — distinguish them, this is a favourite MCQ:
| Feature | Co-infection (HBV + HDV together) | Superinfection (HDV on chronic HBV) |
|---|---|---|
| Setting | Simultaneous acquisition | Pre-existing HBV carrier |
| Severity | Usually self-limiting (clears with HBV) | Severe, accelerated to cirrhosis |
| Chronicity | Low (~<5%) | High (~80%) |
| Marker clue | IgM anti-HBc positive (acute HBV) | IgM anti-HBc negative (old HBV) |
- Diagnosis: anti-HDV antibody, HDV-RNA; HBsAg is always present.
- Prevention: HBV vaccine prevents HDV (no HBsAg → no HDV).
High-yield: Superinfection (HDV on a chronic HBV carrier) → more severe disease, higher chronicity and faster cirrhosis than co-infection. The acute-HBV core marker (IgM anti-HBc) distinguishes them — positive in co-infection, negative in superinfection.
Approach to suspected acute viral hepatitis (flow)
Jaundice + raised transaminases (ALT > AST, often >1000) → first-line serology panel: IgM anti-HAV → HBsAg + IgM anti-HBc → anti-HCV → IgM anti-HEV (esp. pregnancy) → if HBsAg+, add HBeAg, HBV-DNA, anti-HDV → interpret pattern → assess for fulminant failure (INR/PT, encephalopathy).
- Markedly raised ALT (hepatocellular pattern), ALT > AST favours viral over alcoholic (alcoholic: AST:ALT ratio >2:1).
- Pregnant + epidemic setting + fulminant → think HEV.
- IV drug user, asymptomatic, mildly raised ALT → think HCV.
- Worsening of a known HBV carrier → look for HDV superinfection.
Complications
- Fulminant hepatic failure (acute liver failure): highest absolute numbers historically from HBV; HEV in pregnancy has the highest case-fatality; HDV increases the risk in HBV.
- Chronic hepatitis → cirrhosis → portal hypertension.
- Hepatocellular carcinoma (HCC): HBV can cause HCC even without cirrhosis (integrates into host genome — oncogenic DNA virus); HCV causes HCC almost always via cirrhosis.
- Extrahepatic: HBV → PAN, membranous GN; HCV → cryoglobulinaemia, MPGN, PCT.
High-yield: HBV can cause HCC without preceding cirrhosis (direct integration / oncogenesis); HCV-related HCC almost always arises in a cirrhotic liver.
Key differentials
- Other viral causes of hepatitis: EBV, CMV (often AST/ALT modestly raised + atypical lymphocytes / mononucleosis picture), HSV (pregnancy, can be fulminant), yellow fever, dengue.
- Non-viral: alcoholic hepatitis (AST:ALT >2), drug-induced (paracetamol overdose — massive ALT, history), autoimmune hepatitis (ANA/anti-SM, hypergammaglobulinaemia), Wilson disease (young, low ceruloplasmin), ischaemic hepatitis.
- Obstructive/cholestatic jaundice (raised ALP/GGT, dilated ducts) — distinguishes from hepatocellular pattern.
Recently asked / exam angle
- Serology grids are asked almost every year: "HBsAg −, anti-HBs −, IgM anti-HBc + → window period." Memorise the discriminators (anti-HBc for vaccine vs infection; IgM anti-HBc for acute/window).
- HEV + 3rd trimester pregnancy + fulminant → ~20% mortality.
- Highest chronicity = HCV (~80%); neonatal HBV chronicity ~90%.
- DAAs: match drug → target — sofosbuvir = NS5B polymerase, ledipasvir/velpatasvir = NS5A, "-previr" = NS3/4A protease.
- HDV co-infection vs superinfection — chronicity and IgM anti-HBc status.
- Which is a DNA virus / uses reverse transcriptase → HBV.
- Vaccine availability: HAV and HBV have vaccines; no HCV vaccine; HBV vaccine protects against HDV.
- HBV vaccine gives anti-HBs only (recombinant HBsAg) — anti-HBc negative.
- HCC without cirrhosis → HBV.
- Cause of fulminant hepatitis in pregnancy → HEV; in children commonest AVH → HAV.
Rapid revision
- Vowels (A, E) → bowels: faeco-oral, acute only, no chronic carrier.
- HBV is the only DNA virus, uses reverse transcriptase, longest incubation (~12 wk).
- IgM anti-HAV / IgM anti-HEV = acute A / E infection respectively.
- HEV in 3rd-trimester pregnancy → fulminant failure, ~20% mortality.
- Window period = only IgM anti-HBc positive (HBsAg gone, anti-HBs not yet up).
- Vaccinated = anti-HBs only; recovered = anti-HBs + anti-HBc (vaccine → no core Ab).
- HBsAg >6 months = chronic; HBeAg = high infectivity; HBV-DNA = viral load.
- HCV = highest chronicity (~80%); neonatal HBV = ~90% chronic.
- Sofosbuvir → NS5B polymerase; -asvir → NS5A; -previr → NS3/4A protease; no HCV vaccine.
- HDV is defective (needs HBsAg); superinfection > co-infection in severity & chronicity.
- DOC chronic HBV = tenofovir / entecavir; HBV vaccine also prevents HDV.
- HBV → HCC even without cirrhosis; HBV → PAN & membranous GN; HCV → cryoglobulinaemia & MPGN.