Hepatitis B
Description
- Partially dsDNA hepadnavirus; replicates through an RNA intermediate via error-prone reverse transcriptase
- cccDNA in the hepatocyte nucleus = persistent template
- Why NA therapy suppresses but never cures - stopping usually means relapse
- Antigens
- HBsAg - surface; envelope. Defines current infection
- HBcAg - core. Not detectable in serum (antibody is)
- HBeAg - non-structural, secreted; marker of active replication, tracks HBV DNA
- Integrates into host hepatocyte DNA -> direct oncogenesis, HCC without cirrhosis
- Genotypes A-J; C = worse outcomes, higher HCC (predominant East Asia)
- Genotype C4 essentially unique to Aboriginal Australians in the NT
Epidemiology
- ~1% of Australians chronically infected (~220,000); global ~250-300 million
- 60-80% of primary liver cancer worldwide
- Australian priority populations
- Born in high/intermediate-prevalence countries (Asia-Pacific, sub-Saharan Africa) - majority of AU cases
- Aboriginal and Torres Strait Islander peoples
- ~1/3 of Australians with chronic HBV remain undiagnosed
Aetiopathogenesis
Transmission
- Parenteral, sexual, perinatal (perinatal/early childhood dominates in high-prevalence settings)
- High-risk fluids: blood, serum, wound exudate, semen, vaginal fluid
- MTCT occurs predominantly at delivery, not in utero - hence birth-dose vaccine + HBIG works
Liver injury is immune-mediated, not cytopathic
- Infected hepatocytes display HBcAg/HBeAg -> CD8 CTL attack -> hepatocyte death
- Corollaries she needs:
- Immunosuppression -> high HBV DNA, low ALT (virus unopposed, no immune attack)
- Immune reconstitution/drug withdrawal -> flare, can be fulminant
- ALT reflects the host response, not viral load
HBeAg-negative disease
- Pre-core or basal core promoter mutations abolish/downregulate HBeAg
- Replication unimpaired
- -> assess replication by HBV DNA, not HBeAg
- HBeAg-positive generally carries higher HBV DNA than HBeAg-negative
HCC risk factors in CHB
- Host - age >50, male, cirrhosis, FHx HCC, African/Asian ethnicity, obesity, diabetes, recurrent flares, persistently inc ALT
- Viral - high HBV DNA, genotype C > B, basal core promoter mutation, persistent HBeAg
- Environmental - HCV/HDV/HIV coinfection, alcohol, aflatoxin
Diagnosis
Serology
| Marker | Means |
|---|---|
| HBsAg | Current infection. >6 months = chronic |
| Anti-HBs | Immunity - vaccine OR resolved infection |
| Anti-HBc | Exposure. Only infection makes it - distinguishes vaccine from cured |
| IgM anti-HBc | Acute infection, or severe flare of chronic |
| HBeAg | Active replication, high infectivity |
| Anti-HBe | Seroconversion, replication falling |
| HBV DNA | The quantitative measure. Drives treatment decisions |
- Active: HBsAg+, anti-HBc+, anti-HBs-, DNA+ (HBeAg either way)
- Resolved: HBsAg-, anti-HBc+, anti-HBs+, DNA-
- Vaccinated: anti-HBs+ alone
- Occult: HBV DNA detectable with HBsAg-negative
- Still progresses to cirrhosis/HCC; reactivates under immunosuppression
- Isolated anti-HBc may be the only clue
Timing
- Incubation 60-180 days
- HBsAg detectable 2-10 weeks post-exposure - before symptoms and before ALT rise
- Clears within 4-6 months in resolving acute infection
- IgM anti-HBc fills the window between HBsAg loss and anti-HBs appearance
Phases of chronic infection
| Phase | HBV DNA | ALT | HBeAg |
|---|---|---|---|
| Immune tolerant | Very high | Normal | + |
| Immune clearance | High | Raised | + |
| Immune control (inactive carrier) | Low | Normal | - (anti-HBe+) |
| Immune escape | High | Raised | - (anti-HBe+) |
- The two raised-ALT phases carry the cirrhosis/HCC risk
- Phases are not one-way - reactivation happens; a single set of bloods cannot assign a phase
- Indeterminate/"grey zone" up to 40% - does not fit any phase
Every new diagnosis
- HBV DNA, ALT, HBeAg/anti-HBe, LFT, FBE, INR
- Anti-HDV once in every HBsAg-positive person
- Anti-HCV, HIV, anti-HAV (vaccinate if non-immune)
- Fibrosis stage: elastography, APRI/FIB-4
- Liver US
Management
Who to test
- Born in high/intermediate-prevalence country; Aboriginal and Torres Strait Islander
- Pregnancy; infants of infected mothers; household and sexual contacts
- PWID, MSM, prior STI, multiple partners, prisoners, blood/needlestick exposure
- HIV; unexplained inc ALT
- Before any immunosuppression - chemo, transplant, rituximab, interferon-alfa, corticosteroids >2 weeks
Acute HBV
- Supportive; monitor INR and encephalopathy for progression to ALF
- Antivirals only for severe/protracted acute hepatitis or ALF
- <5% of adults progress to chronic - do not commit to lifelong therapy on an acute episode
Who to treat - chronic
Threshold has moved substantially lower. Treat, do not just monitor.
- Cirrhosis + any detectable HBV DNA - treat regardless of ALT
- Immune clearance or immune escape - HBV DNA >2000 IU/mL with ALT above ULN
- ULN taken as 35 U/L (M) / 25 U/L (F), not the lab's reference range
- Immune tolerant - treat if age >40, or >=F2 fibrosis, or >=grade 2 inflammation
- Indeterminate phase - now treat by shared decision-making (favouring factors: age >40, male, platelets <180)
- Extrahepatic manifestations, HCC, coinfection, family history of HCC
Antivirals
- Entecavir, tenofovir disoproxil or tenofovir alafenamide - all first-line, no resistance with long-term use
- TDF: monitor renal function and bone; TAF preferred if CKD/osteoporosis
- Entecavir: not if lamivudine-experienced (cross-resistance)
- Peg-interferon alfa: finite 48-week course, higher HBsAg loss, poorly tolerated - rarely used now
- Endpoint is HBsAg loss ("functional cure") - uncommon, ~1%/yr
- Do not stop NA before HBsAg loss
- Stopping -> ALT flare ~27%, retreatment ~42% at 5 years
Prophylaxis before immunosuppression
- HBsAg-positive - prophylax for any significant immunosuppression
- HBsAg-negative / anti-HBc-positive - prophylax if anti-CD20 (rituximab) or stem cell transplant; otherwise monitor
- Entecavir or tenofovir, continue >=12 months after finishing (18 months post-rituximab)
Pregnancy
- Tenofovir disoproxil from week 28 if HBV DNA >200,000 IU/mL
- Infant: HBIG + birth-dose vaccine within 12 hours, then full schedule
- -> transmission <2%
- Breastfeeding is not contraindicated
HCC surveillance
- 6-monthly liver ultrasound +/- AFP
- All cirrhosis; FHx HCC; HBV/HDV, HBV/HIV, HBV/HCV coinfection
- Non-cirrhotic: Asian men >40, Asian women >50, Africans >20
- Continue after HBsAg loss if male >40 or female >50 at clearance
Prevention
- Universal infant vaccination (AU since 2000) + birth dose
- Vaccinate non-immune contacts, PWID, MSM, dialysis, healthcare workers
- Check anti-HBs >=10 IU/L for response
- Notifiable disease; contact tracing
Associations
- HDV - only in HBsAg-positive; coinfection or superinfection. Fastest-progressing viral hepatitis
- Polyarteritis nodosa - immune complex
- Membranous glomerulonephritis (also MPGN)
- Guillain-Barre syndrome
- Cryoglobulinaemia (far more HCV)
- Papular acrodermatitis (Gianotti-Crosti) in children
- HIV and HCV - shared transmission routes
Natural history & complications
Chance of chronicity - by age at infection
- Neonatal ~90%
- Age 1-5 years 20-30%
- Adult <5%
- Inverse to the strength of the immune response - the same reason adults get symptomatic hepatitis and neonates do not
Outcomes
- Cirrhosis, then decompensation
- HCC
- ~20% of HBV-related HCC arises without cirrhosis - via viral DNA integration
- Unique among the common chronic liver diseases - surveillance cannot be restricted to cirrhotics
- Acute liver failure - uncommon in acute infection (<1%)
- Reactivation - spontaneous flare, or immunosuppression-triggered
Monitor
- Untreated: HBV DNA + ALT 6-12 monthly, fibrosis stage periodically
- Treated: HBV DNA to confirm suppression, adherence, renal function on TDF
- HCC surveillance as above, indefinitely
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