Hepatitis Viruses
The five hepatitis viruses ★★★
Hepatitis is a pathological definition; viral hepatitis is hepatitis caused by a virus. The primary hepatitis viruses are HAV, HBV, HCV, HDV and HEV. Other viruses can also cause hepatitis: yellow fever virus (YFV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV).
| Virus | Former name |
|---|---|
| HAV | Infectious hepatitis |
| HBV | Serum hepatitis |
| HCV | Non-A, non-B hepatitis |
| HDV | Delta hepatitis |
| HEV | A virus transmitted through the faeces of an infected person |
⭐ The comparison the deck's key-points slide demands
| HAV | HBV | HCV | HDV | HEV | |
|---|---|---|---|---|---|
| Family | Picornaviridae (Hepatovirus) | Hepadnavirus | Flaviviridae | Subviral “satellite” virus | A calicivirus |
| Size | 27 nm | 42 nm | 30–60 nm | — | 27–34 nm |
| Genome | +ssRNA | Partly double-stranded circular DNA, 3.2 kb | +ssRNA | ssRNA | +ssRNA |
| Envelope | NAKED | Enveloped | Enveloped | Uses HBsAg | NAKED |
| Transmission | Faecal–oral | Blood · maternal–infant · sexual · close contact | Blood | With HBV | Faecal–oral |
| Chronic? | Acute, rarely chronic | Yes | Yes — 50–60% | Yes | Generally no |
That table has one organising rule, and it is Unit 18 §3 applied to a single organ.
HAV and HEV are naked — no lipid envelope to be destroyed by bile and stomach acid. Both are faecal–oral, both cause acute illness that does not become chronic, and both are diseases of sanitation.
HBV, HCV and HDV are enveloped — fragile outside the body, so they need a direct route: blood, sex, or mother to child. All three can become chronic, and it is the chronic ones that cause cirrhosis and hepatocellular carcinoma.
So the mnemonic is not arbitrary: the vowels (A and E) go through the bowel. Learn the structural reason and the transmission, chronicity and cancer risk all follow from it.
- Name the five primary hepatitis viruses and their former names. → HAV (infectious hepatitis), HBV (serum hepatitis), HCV (non-A non-B), HDV (delta), HEV
- Which other viruses cause hepatitis? → Yellow fever virus, EBV, CMV
- Which are naked, and what follows? → HAV and HEV — faecal–oral spread, acute illness that rarely becomes chronic
- Which are enveloped, and what follows? → HBV, HCV, HDV — blood, sexual and vertical spread, chronic infection, cirrhosis and hepatocellular carcinoma
Hepatitis A virus ★★★
| Property | Detail |
|---|---|
| Classification | Picornaviridae, genus Hepatovirus — Unit 23's enterovirus 72 |
| Structure | 27 nm · spherical · +ssRNA · NO envelope · icosahedral · ONLY ONE SEROTYPE |
| Cultivation | Animal inoculation in primates; cell cultivation shows NO CPE |
| Resistance | STRONG — resistant to low pH, organic solvents and detergents, heat and water. Sensitive to chloride |
| Source and transmission | Humans; the oral–faecal route |
| Pathogenesis | Little impairment to the gut; mainly replicates in the LIVER |
| Clinical | Detail |
|---|---|
| Course | Acute, rarely chronic |
| Asymptomatic | Common |
| Jaundice | Observed in 2 of 3 adults, but only 1–2 of 10 children |
| Fulminant hepatitis | 1–3 cases per 1000 patients; mortality rate 80% |
| Marker | Meaning |
|---|---|
| Anti-HAV IgM | EARLY infection |
| Anti-HAV IgG | Previous infection or vaccination |
Prevention: improved hygiene, and vaccination with effective KILLED vaccines. Treatment: no specific drug; supportive care; immune globulin.
- Describe HAV. → 27 nm, spherical, naked, icosahedral, +ssRNA, one serotype; a Picornavirus of genus Hepatovirus
- Where does it replicate? → Mainly in the liver, with little impairment to the gut
- How common is jaundice? → 2 of 3 adults but only 1–2 of 10 children
- How often is it fulminant? → 1–3 per 1000 patients, with 80% mortality
- Interpret anti-HAV IgM and IgG. → IgM: early infection. IgG: previous infection or vaccination
HBV — structure and antigens ★★★
The Hepadnavirus family derives its name from its HEPAtotropic nature and its double-stranded DNA (DNA) genome. Baruch Blumberg received the Nobel Prize in Physiology or Medicine in 1976 for the discovery of the Australia antigen — HBsAg.
| Property | Detail |
|---|---|
| Size and shape | 42 nm · enveloped |
| Genome | PARTLY double-stranded, CIRCULAR DNA, 3.2 kb |
| Resistance | STRONG — resistant to organic solvents, low pH, low temperature, drying, UV and 70% alcohol. Sensitive to autoclaving and chloride |
| Cultivation | Difficult |
⭐ The three particles in serum
| Particle | Description |
|---|---|
| Dane particle | 42 nm, enveloped, with a core — the INTACT, MATURE, INFECTIOUS HBV virion |
| Small spherical particle | 22 nm, enveloped |
| Tubular / filamentous particle | 22 nm diameter, 50–500 nm long, enveloped |
The virion has an envelope carrying HBsAg (S), PreS2 Ag and PreS1 Ag, and a core containing HBcAg, viral DNA and polymerase. The subviral particles — the small spherical and tubular forms — have the envelope antigens only, and no DNA.
⭐ The four genome regions
| Region | Product |
|---|---|
| S region | HBsAg (S) · PreS2 Ag (S+S2, M) · PreS1 Ag (M+S1, L) |
| C region | HBeAg · HBcAg |
| P region | P protein: DNA polymerase, REVERSE TRANSCRIPTASE, RNase H |
| X region | HBxAg |
Two oddities on these slides are worth pausing over.
The P region encodes a reverse transcriptase, in a virus whose genome is DNA. This is Unit 18 §5's seventh replication category: dsDNA with an RNA intermediate (HBV). The virus transcribes its DNA into an RNA pregenome, then reverse-transcribes that back into DNA. Two consequences: the genome is only partly double-stranded because the process is incomplete at packaging; and lamivudine, a drug developed against HIV's reverse transcriptase, works against hepatitis B.
The small spherical and tubular particles vastly outnumber the Dane particles, and they carry no DNA — they are pure envelope, harmless and non-infectious. Why make them? They act as antibody decoys, mopping up anti-HBs before it reaches the real virion.
And they are why HBsAg is the screening test: it is the most abundant thing in the patient's serum. It is also why the vaccine can be a pure subunit vaccine — HBsAg alone, with no virus at all.
- Describe the HBV genome. → Partly double-stranded circular DNA, 3.2 kb, in the Hepadnavirus family
- Name the three particles. → Dane particle (42 nm, the intact infectious virion), small spherical particle (22 nm), tubular particle (22 nm × 50–500 nm)
- What is in the virion envelope and core? → Envelope: HBsAg, PreS1 and PreS2. Core: HBcAg, viral DNA and polymerase
- Name the four genome regions and their products. → S → HBsAg, PreS1, PreS2 · C → HBeAg and HBcAg · P → DNA polymerase, reverse transcriptase, RNase H · X → HBxAg
- What is HBV resistant to? → Organic solvents, low pH, low temperature, drying, UV and 70% alcohol; sensitive to autoclaving and chloride
⭐ HBV markers and their interpretation ★★★
“How can hepatitis B be diagnosed in a clinical laboratory? Describe the interpretation of the results.” — TMU homework list, and “HBV marker and interpretation” on the deck's own key-points slide. Two methods: detection of HBV DNA (DNA hybridisation, PCR, RT-PCR, real-time PCR) and detection of antigen and antibody.
| Marker | Interpretation |
|---|---|
| HBsAg | The presence of HBV infection, or a carrier |
| Anti-HBs | Previous HBV vaccination, or previous infection which has recovered. The individual has PROTECTION against re-infection |
| HBeAg | The multiplication of HBV virions. The patient's serum is HIGHLY INFECTIOUS. A persistent high titre indicates conversion to chronicity |
| Anti-HBe | The patient is recovering and has partial immunity to HBV |
| Anti-HBc IgM | Acute hepatitis B, or a recent HBV infection in which viral replication is present |
| Anti-HBc IgG | Previous HBV infection, or chronic HBV infection |
⭐ The four patterns — memorise this table
| HBsAg | HBeAg | Anti-HBs | Anti-HBe | Anti-HBc | Clinical status |
|---|---|---|---|---|---|
| + | − | − | − | − | HBV infection or asymptomatic carrier |
| + | + | − | − | + | Acute or chronic ACTIVE hepatitis — strongly infectious (“3+”, the “big three positives”) |
| − | − | + | + | +/− | Convalescent stage |
| − | − | + | − | − | Previously infected or VACCINATED |
Applications: screening blood donors · diagnosing hepatitis B · evaluating prognosis and outcome · investigating epidemiology and detecting chronic or asymptomatic carriers · evaluating immunity level and the effect of vaccination.
Do not memorise sixteen combinations. Ask three questions in order.
1 · Is HBsAg present? Yes — the patient is infected now, whether as carrier, acute or chronic. No — they are not currently infected.
2 · Is HBeAg present? This is the infectivity question. HBeAg means virions are multiplying and the serum is highly infectious. Its persistence signals chronicity; its disappearance and replacement by anti-HBe means the patient is recovering.
3 · Is anti-HBc present? This is the have they ever met the real virus? question — and it is the one that separates vaccinated from recovered. Both have anti-HBs. Only the recovered patient has anti-HBc, because the vaccine is a subunit vaccine of HBsAg alone and contains no core antigen at all.
That last point is the single most examinable line in the unit: anti-HBs alone = vaccinated; anti-HBs plus anti-HBc = recovered from infection.
And the reason HBcAg itself never appears in the serum panel: it stays inside the hepatocyte and inside the core, so only the antibody to it is measurable.
- What does HBsAg mean? → Current HBV infection or carrier state
- What does anti-HBs mean? → Previous vaccination or recovered infection — protection against re-infection
- What does HBeAg mean? → HBV virions are multiplying; the serum is highly infectious; a persistent high titre indicates chronic conversion
- What do anti-HBc IgM and IgG mean? → IgM: acute or recent infection with replication. IgG: previous or chronic infection
- How do you distinguish vaccination from recovered infection? → Both have anti-HBs, but only recovery gives anti-HBc — the vaccine contains HBsAg only
- Describe the 'three positives' pattern. → HBsAg, HBeAg and anti-HBc positive — acute or chronic active hepatitis, strongly infectious
HBV pathogenesis and carcinogenesis ★★★
| Detail | |
|---|---|
| Source and transmission | Human. Blood transmission · maternal–infant transmission · sexual contact · close contact |
| Incubation | 60–90 days |
| Clinical types | Acute · chronic · severe (fulminating) hepatitis · hepatocirrhosis · chronic carrier |
| Carcinogenesis | Hepatocellular carcinoma |
Mechanism of liver damage
- Damage of liver cells by viral replication
- Immune response to liver cells infected by HBV — this is the MAIN mechanism: immunopathologic injury
| Immunopathologic mechanism | Detail |
|---|---|
| CTL-mediated | HBcAg on the surface of hepatocytes |
| Type II hypersensitivity | Autoimmune damage — liver-specific protein (LSP), liver membrane antigen (LMAg) |
| Type III hypersensitivity | Immune complexes: HBsAg with anti-HBs; HBeAg with anti-HBe |
⭐ Carcinogenesis — evidence and mechanism
| The evidence | The mechanisms |
|---|---|
| Hepatoma incidence is higher in hepatitis B patients than in non-hepatitis-B patients | Liver cirrhosis, with proliferation of liver cells |
| HBV infection is detected more often in hepatoma patients than in normal people | HBV DNA is integrated into the chromosome |
| Integrated HBV DNA (X region) is found in the hepatocyte nucleus in hepatoma | HBxAg can bind p53, an anti-oncogene |
| Animal hepatitis viruses induce hepatoma in animals, with integrated viral DNA in the hepatocyte nucleus |
Prevention: general measures · active immunity with a SUBUNIT vaccine · passive immunity with anti-HBV immune globulin. Treatment: supportive care is the mainstay; drugs are interferon (IFN) and lamivudine.
This is Unit 20 §5's immunopathogenesis in its most important clinical example, and the deck states it plainly: the immune response is the main mechanism.
HBV is not directly cytopathic. Infected hepatocytes display HBcAg on their surface, and cytotoxic T cells kill them for it. The hepatitis is the immune response.
Three things follow, and each is examinable:
• A neonate infected vertically becomes a chronic carrier — the immature immune system does not mount the attack, so there is little hepatitis, and equally little clearance. Up to 90% become carriers, against under 10% of infected adults. A weak immune response means mild disease and lifelong infection.
• Fulminant hepatitis is an excessively strong response, not an especially virulent virus.
• Cancer is the price of chronicity. Decades of killing and regenerating hepatocytes gives cirrhosis and cell proliferation, while integrated HBV DNA and HBxAg binding p53 supply the genetic hits.
Which is why the single most effective anticancer intervention here is a vaccine — and why hepatitis B vaccine was the first vaccine against a human cancer.
- How is HBV transmitted? → Blood, maternal–infant, sexual contact, close contact
- Give the incubation and clinical types. → 60–90 days; acute, chronic, severe (fulminating), hepatocirrhosis, chronic carrier, and hepatocellular carcinoma
- What is the main mechanism of liver damage? → The immune response to infected liver cells — immunopathologic injury, not direct viral damage
- Name the three immunopathologic mechanisms. → CTL-mediated against HBcAg on hepatocytes · type II hypersensitivity (LSP, LMAg) · type III hypersensitivity (HBsAg/anti-HBs and HBeAg/anti-HBe complexes)
- Give the evidence and mechanisms of carcinogenesis. → Evidence: higher hepatoma incidence in HBV patients, more HBV in hepatoma patients, integrated X-region DNA in hepatoma nuclei, animal models. Mechanisms: cirrhosis with cell proliferation, integration of HBV DNA, HBxAg binding p53
- How is HBV prevented and treated? → Subunit vaccine for active immunity, anti-HBV immune globulin for passive; supportive care with interferon and lamivudine
HCV, HDV and HEV ★★★
| HCV | Detail |
|---|---|
| Classification and structure | Flaviviridae · 30–60 nm · icosahedral · +ssRNA · ENVELOPED |
| Key feature | HIGH VARIATION — HCV quasispecies |
| Source and transmission | Patients; BLOOD |
| Clinical | Acute hepatitis · CHRONIC hepatitis in 50–60% · cirrhosis · hepatocellular carcinoma |
| Prevention and treatment | General measures (close contact, sexual, drug injection), screening blood donors. NO VACCINE AVAILABLE. Supportive care and interferon |
| HDV | Detail |
|---|---|
| Discovery | In 1977 Dr Mario Rizzetto discovered a new antigen in the hepatocytes of patients with chronic type B hepatitis |
| Nature | A subviral “SATELLITE VIRUS”. HDV requires hepatitis B virus as a HELPER VIRUS to provide envelope proteins — Unit 19 §2's defective virus |
| Two clinical patterns | 1 · CO-INFECTION with HBV in a patient not previously exposed to HBV. 2 · SUPER-INFECTION of an HBV carrier |
| Super-infection | The most common form, and where delta infection produces its most deleterious effects — it may induce an acute hepatitic picture in a previously healthy carrier, and will aggravate the clinical picture in a carrier with pre-existing hepatitis |
| Prevention | The hepatitis B vaccine; supportive care and interferon |
| HEV | Detail |
|---|---|
| Structure | A CALICIVIRUS · spherical · 27–34 nm · +ssRNA · NAKED |
| Transmission | Faecal–oral. Most outbreaks are associated with faecally contaminated DRINKING WATER; person-to-person transmission is minimal |
| Clinical | Acute hepatitis E, generally no chronic hepatitis — very similar to HAV disease |
| ⚠️ Pregnancy | Pregnant women infected with HEV may have a high incidence of severe hepatitis, abortion and stillbirth, and about a 20% MORTALITY RATE |
| Prevention for travellers | Avoid drinking water (and beverages with ice) of unknown purity, uncooked shellfish, and uncooked fruit and vegetables not peeled or prepared by the traveller. Immune globulin from Western donors does not prevent infection |
Two viruses, opposite reasons.
HCV varies enormously — it exists in each patient as a swarm of related genomes, the quasispecies. Its RNA polymerase has no proofreading, so mutants appear faster than antibody can be raised against them. That is why 50–60% become chronic despite an immune response, and why no vaccine exists. It is the same problem as influenza drift in Unit 22, but continuous and within a single patient.
HDV needs no vaccine of its own because it cannot exist without HBV to supply its envelope. Vaccinate against hepatitis B and hepatitis D is prevented too — remove the helper and the defective virus is finished.
And note the one figure that surprises everyone: HEV kills about 20% of infected pregnant women, despite being an otherwise mild, self-limiting, HAV-like illness. That single sentence is a very likely fill-in-the-blank.
- Describe HCV. → A Flavivirus, 30–60 nm, icosahedral, enveloped, +ssRNA, with high variation as quasispecies; blood-borne; 50–60% become chronic, leading to cirrhosis and hepatocellular carcinoma; no vaccine
- What is HDV, and what does it need? → A subviral satellite virus requiring HBV as a helper to provide envelope proteins
- Give the two clinical patterns of HDV. → Co-infection with HBV in a previously unexposed patient, and super-infection of an HBV carrier — the commonest and most damaging form
- How is HDV prevented? → By the hepatitis B vaccine
- Describe HEV. → A calicivirus, 27–34 nm, naked, +ssRNA, faecal–oral from contaminated drinking water; acute illness like HAV, generally not chronic
- Why does HEV matter in pregnancy? → Severe hepatitis, abortion and stillbirth, with about 20% mortality
Revision
The deck's key-points slide
1 · Comparison of the structure, genome features and transmission of HAV, HBV, HCV, HDV and HEV — §1. 2 · Clinical findings of HBV and HCV infection — §§5–6. 3 · HBV markers and their interpretation — §4.
The whole unit on one screen
| Question | Answer |
|---|---|
| Naked viruses? | HAV and HEV — faecal–oral, acute only |
| Enveloped? | HBV, HCV, HDV — blood-borne, can be chronic |
| HAV jaundice? | 2 of 3 adults, 1–2 of 10 children |
| HBV genome? | Partly dsDNA, circular, 3.2 kb; replicates via an RNA intermediate |
| Dane particle? | 42 nm — the intact infectious virion |
| Genome regions? | S (HBsAg, PreS1/2) · C (HBeAg, HBcAg) · P (polymerase, RT, RNase H) · X (HBxAg) |
| ⭐ HBsAg? | Current infection or carrier |
| ⭐ HBeAg? | Replication; highly infectious |
| ⭐ Anti-HBs alone? | Vaccinated |
| ⭐ Anti-HBs + anti-HBc? | Recovered from infection |
| HBV liver damage? | Immunopathologic — CTL vs HBcAg, type II and type III hypersensitivity |
| HBV cancer? | Cirrhosis + integrated HBV DNA + HBxAg binding p53 |
| HCV chronicity? | 50–60%; quasispecies; no vaccine |
| HDV? | Defective — needs HBV envelope; prevented by the HBV vaccine |
| HEV in pregnancy? | ~20% mortality |
- How is hepatitis B diagnosed and interpreted? → HBV DNA by hybridisation or PCR; and antigen/antibody markers — HBsAg (current infection), anti-HBs (immune), HBeAg (replicating, highly infectious), anti-HBe (recovering), anti-HBc IgM (acute/recent), anti-HBc IgG (previous or chronic). Patterns: HBsAg alone = carrier; HBsAg + HBeAg + anti-HBc = active hepatitis; anti-HBs + anti-HBe + anti-HBc = convalescent; anti-HBs alone = vaccinated
- Compare the five hepatitis viruses. → HAV naked +ssRNA faecal–oral acute · HBV enveloped partly dsDNA blood/vertical/sexual chronic · HCV enveloped +ssRNA blood 50–60% chronic · HDV defective needing HBV · HEV naked +ssRNA faecal–oral acute, dangerous in pregnancy
- Why does HBV cause liver damage? → Mainly immunopathologically — CTLs killing hepatocytes bearing HBcAg, plus type II and III hypersensitivity
- How does HBV cause cancer? → Cirrhosis with hepatocyte proliferation, integration of HBV DNA into the chromosome, and HBxAg binding the anti-oncogene p53