Hepatitis B
Hepatitis B is a viral infection caused by the hepatitis B virus (HBV) that targets the liver, potentially leading to acute or chronic inflammation, cirrhosis, and hepatocellular carcinoma.
Hepatitis B
Hepatitis B is a systemic infection caused by the Hepatitis B virus (HBV), a member of the family Hepadnaviridae (from "hepa" = liver, "dna" = DNA virus), that primarily targets the liver. The virus itself is not directly cytopathic — liver damage is mediated by the host's immune response attempting to clear infected hepatocytes. HBV can manifest as:
- Acute hepatitis B — a self-limited infection lasting < 6 months, ranging from asymptomatic seroconversion to fulminant hepatic failure.
- Chronic hepatitis B (CHB) — defined as persistence of HBsAg for > 6 months [1][2], reflecting failure of immune clearance. CHB is the major clinical burden, progressing through well-defined immunological phases towards cirrhosis and hepatocellular carcinoma (HCC).
The distinction between acute and chronic is fundamentally about whether the immune system can eradicate the virus within 6 months.
Why is HBV not directly cytopathic?
HBV replicates quietly inside hepatocytes using the covalently closed circular DNA (cccDNA) template. It does not kill the cell. Instead, cytotoxic CD8+ T-lymphocytes recognise viral antigens (HBcAg, HBeAg) displayed on the hepatocyte surface via HLA class I molecules and destroy the infected cell. This is why immunosuppressed patients (e.g. neonates) tolerate high viral loads with minimal liver injury (immune tolerance phase), and why immunosuppressant withdrawal causes devastating flares — the unleashed immune system attacks a liver full of virus.
Hepatitis B is a notifiable disease in Hong Kong. [3]
2. Epidemiology
- ~1/3 of the world's population has been infected by HBV at some point [4].
- ~240 million people worldwide are chronic HBsAg carriers, of which ~75% are Chinese [4].
- HBV is more common in Southern China compared to Northern China [4].
- HBV is the leading cause of cirrhosis and HCC globally, accounting for ~50% of HCC cases worldwide.
- ~1 in 13 (approximately 8%) of the Hong Kong population are chronic HBsAg carriers [4].
- HBV is by far the most common cause of cirrhosis in Hong Kong — WHO pooled analysis estimates 64%, but verbally estimated at ~75% by local hepatologists [5].
- Universal neonatal HBV vaccination was introduced in Hong Kong in 1988, which has dramatically reduced the carrier rate in younger cohorts (< 1% in those born after 1988 vs. ~10% in those born before).
- HBV-related HCC remains the 3rd leading cause of cancer mortality in Hong Kong [6].
HBV requires at least a mucosal breach for transmission (parenteral transmission) [4]:
| Route | Details |
|---|---|
| Vertical (mother-to-child) | Most important route in endemic areas like HK. Occurs perinatally. Not all siblings are necessarily affected — younger siblings may escape if the mother has undergone e-seroconversion (↓ viral load) [4] |
| Horizontal close contact | Common in toddlers — from playmates or father. Unprotected cuts in children's hands in kindergarten [7] |
| Percutaneous/parenteral | Blood transfusion (now rare with screening), IVDU, acupuncture, tattoos, needle-stick injuries |
| Sexual contact | Particularly MSM; HBV is ~100× more infectious than HIV |
| (Salivary) | High HBV DNA in saliva of HBeAg+ children and adults, but no definite proof of transmission [4] |
High Yield — Vertical Transmission
Vertical transmission is the dominant route in HK and explains the high chronic carrier rate. Neonates infected perinatally have a 90% risk of chronicity (vs. 2% in immunocompetent adults), because their immature immune system fails to mount an adequate response against HBV.
To understand HBV pathophysiology, you need to appreciate liver microanatomy:
- Hepatocytes — the target cells for HBV. They express HLA class I molecules on their surface, which display viral peptides to cytotoxic T cells.
- Kupffer cells — resident macrophages in the hepatic sinusoids. They are part of the reticuloendothelial system and play a role in innate immune defence. HBeAg can down-regulate TLR-2 expression on Kupffer cells [8], weakening innate immunity.
- Hepatic stellate cells (Ito cells) — when activated by chronic inflammation, they produce collagen, leading to fibrosis and eventually cirrhosis.
- Liver capsule (Glisson's capsule) — the liver parenchyma itself has no pain fibres. The dull RUQ ache in hepatitis is caused by distension of the liver capsule from inflammatory swelling [9]. This also explains why HCC can grow to enormous sizes silently — it expands the parenchyma without stretching the capsule until very late.
- Bile canaliculi — hepatocyte swelling during inflammation compresses canaliculi, causing intrahepatic cholestasis (explains the dark urine, pale stools, and transient pruritus of the preicteric phase).
4. Virology — Understanding the Virus to Understand the Disease
HBV is a small (42 nm), partially double-stranded DNA virus — unique among hepatitis viruses, which are otherwise RNA viruses. The name Hepadnaviridae literally tells you: "hepa" (liver) + "DNA" (its genome type).
Key structural components:
| Component | Function | Clinical Relevance |
|---|---|---|
| HBsAg (surface antigen) | Outer envelope protein | Marker of infection (acute or chronic). Excessive production acts as a "decoy" for the immune system [8] |
| HBcAg (core antigen) | Inner nucleocapsid protein | Found inside virus or hepatocytes, NOT in serum — you cannot detect it in blood [10] |
| HBeAg (e antigen) | Secreted derivative of HBcAg, processed via the pre-core region through the ER and Golgi | Marker of active viral replication and high infectivity. Its presence/absence defines the natural history phases [10] |
| HBV DNA | Partially dsDNA genome (~3.2 kb) | Marker of viral replication; quantification (viral load) guides treatment decisions |
| HBV polymerase | Reverse transcriptase + DNA polymerase | Target of nucleos(t)ide analogues (e.g. entecavir, tenofovir) |
The HBV genome is remarkably compact (~3.2 kb) with four overlapping open reading frames (ORFs):
1. Gene S (Surface) — Encodes the three envelope proteins: pre-S1, pre-S2, and HBsAg [10]
- HBsAg is produced in massive excess (up to 10¹³ particles/mL) — acts as a decoy for HBV-specific humoral and T-cell responses [8]
2. Gene C (Core) — Encodes HBcAg [10]
- HBcAg is found inside virus or hepatocytes, not in serum — so you cannot detect it directly [10]
- The pre-C region helps form HBeAg from HBcAg. The first 19 amino acids constitute a signal peptide for processing HBeAg via the ER and Golgi [10]
Pre-core Mutant — Why HBeAg Can Be Misleading
A mutant strain with a stop codon (TAG) in the pre-core region causes inability to produce HBeAg [10]. This means the patient appears to have undergone e-seroconversion (HBeAg negative), but the virus is still actively replicating. The mutation is detected around e-seroconversion, probably because immune factors select against HBeAg-producing viruses [10]. This is why e-seroconversion has less meaning nowadays given how prevalent this mutant strain is [10]. Always check HBV DNA levels regardless of HBeAg status.
3. Gene P (Polymerase) — Encodes the viral polymerase (reverse transcriptase)
- Suppresses myeloid differentiation protein → decreases toll-like receptor (TLR) function → decreases immune clearance [8]
4. Gene X — Encodes the HBx protein [10]
- Products for transactivation — HBV DNA integrates into the host genome; HBx can activate adjacent host genes
- May be related to carcinogenesis — if it activates an oncogene [10]
- Inhibits degradation of viral protein → reduces antigen presentation → reduces immune clearance [8]
Direct Repeat I and II (DR-I and DR-II) [10]:
- Initiate long strand and short strand synthesis respectively
- Form a preferential site for integration into the host genome — this is why HBV can cause HCC even without cirrhosis (direct DNA integration and transactivation of oncogenes)
Understanding this explains why HBV is so hard to cure:
- Attachment: HBV binds to hepatocyte via NTCP (sodium taurocholate co-transporting polypeptide) receptor on the hepatocyte surface (identified 2012).
- Entry and uncoating: Virus enters by endocytosis; nucleocapsid releases relaxed circular DNA (rcDNA) into the nucleus.
- Formation of cccDNA: rcDNA is converted to covalently closed circular DNA (cccDNA) in the nucleus — this is the "minichromosome" that serves as the transcriptional template. cccDNA is the reason we cannot truly "cure" HBV — it persists in hepatocyte nuclei even after HBsAg loss ("functional cure").
- Transcription: cccDNA is transcribed into pregenomic RNA (pgRNA) and subgenomic mRNAs.
- Reverse transcription: pgRNA is reverse-transcribed by the viral polymerase into new rcDNA within the nucleocapsid (this is why nucleos(t)ide analogues work — they inhibit the reverse transcriptase step).
- Assembly and secretion: New virions are enveloped and secreted. Excess HBsAg is also secreted as non-infectious subviral particles.
- Integration: HBV DNA can integrate into the host genome via DR-I/DR-II → this is independent of cccDNA and is the mechanism for direct carcinogenesis [10].
Why Can't We Truly Cure HBV?
The persistence of cccDNA in hepatocyte nuclei means that even if all circulating virus is suppressed and HBsAg clears ("functional cure"), the template for viral production remains. This is why occult HBV exists (HBsAg negative but HBV DNA detectable), and why immunosuppression (steroids, anti-CD20 agents like rituximab) can cause devastating reactivation — the cccDNA reactivates when immune surveillance drops [7].
5. Etiology and Risk Factors (Hong Kong Focus)
| Risk Factor | Explanation |
|---|---|
| Born to HBsAg+ mother | Dominant risk in HK; 90% chronicity risk if unvaccinated |
| Born before 1988 in HK | Before universal vaccination programme |
| Close household contact | Especially in childhood |
| IVDU | Sharing needles |
| MSM / multiple sexual partners | HBV is highly infectious sexually |
| Healthcare workers | Needle-stick injuries |
| Blood transfusion recipients (historical) | Rare now with screening |
| Tattoos, acupuncture (non-sterile) | Percutaneous inoculation |
| Factor | Detail |
|---|---|
| Age at acquisition | 90% chronicity if < 1 y/o; 30% if 1-6 y/o; 2% if > 6 y/o [4] |
| High HBV DNA level | Very high serum HBV DNA titer → prone to develop cirrhosis and HCC [11] |
| HBeAg positivity | Indicates active replication; annual incidence of cirrhosis 2.4% in HBeAg+ vs. 1.3% in anti-HBe+ patients [12] |
| Pre-core/core promoter mutations | Can cause HBeAg-negative hepatitis with ongoing liver damage |
| Co-infection (HDV, HCV, HIV) | Accelerates fibrosis |
| Concomitant MAFLD | Common in HK — dual liver disease (HBV + MAFLD) [13] |
| Alcohol use | Synergistic liver injury |
| Male sex | Higher risk of HCC |
| Family history of HCC | Genetic susceptibility |
| Aflatoxin exposure | Dietary carcinogen (less relevant in HK) |
6. Pathophysiology
The central concept: HBV is not directly cytopathic. All liver damage is immune-mediated.
-
Innate immunity: HBV is a "stealth virus" that largely evades innate immune detection. The viral proteins (HBeAg, HBx, polymerase) actively suppress innate immune responses:
- HBeAg down-regulates TLR-2 expression on Kupffer cells, hepatocytes, and monocytes [8]
- HBeAg down-regulates CD28 on T cells and CD86 on monocytes and Kupffer cells [8]
- HBx protein inhibits degradation of viral protein → reduces antigen presentation [8]
- Polymerase protein suppresses myeloid differentiation protein → decreases TLR function [8]
-
Adaptive immunity (the real battleground):
- CD8+ cytotoxic T lymphocytes (CTLs): Recognise viral peptides (primarily HBcAg-derived) presented on hepatocyte HLA class I → kill infected hepatocytes → this killing causes ALT/AST elevation (the "hepatitis").
- CD4+ T helper cells: Produce cytokines (IFN-γ, TNF-α) that activate macrophages and enhance CTL activity.
- B cells: Produce anti-HBs (neutralising), anti-HBc, anti-HBe. Anti-HBs is the protective antibody.
- Non-cytolytic clearance: CTLs can also clear HBV from hepatocytes via IFN-γ and TNF-α without killing the cell — this degrades cccDNA and suppresses replication.
-
Chronicity results from failure of immune clearance:
- In neonates: immature immune system + viral immune evasion strategies (see below)
- In adults: strong immune response → usually clears virus (only 2% chronicity)
This is a favourite exam topic. Both host and viral factors contribute [8]:
Host factors:
- Failure of host to recognise infected hepatocytes — immature neonatal immune system
- Covering of viral antigens displayed by HLA by maternal anti-HBc — maternal antibodies mask the antigens, preventing T-cell recognition [4]
Viral factors (all serve to evade or suppress the immune response) [8]:
- Excessive production of HBsAg → acts as a "decoy" for HBV-specific humoral and T-cell responses → immune system attacks empty viral particles instead of infected cells → modulation of immune signalling with suppression of inflammatory cytokines
- HBx protein → inhibits degradation of viral protein → reduces antigen presentation
- Polymerase protein → suppresses myeloid differentiation protein → decreases TLR function
- Pre-core/HBeAg → down-regulates TLR-2 expression on Kupffer cells, hepatocytes, and monocytes; down-regulates CD28 on T cells and CD86 on monocytes and Kupffer cells
Chronic inflammation → repeated hepatocyte necrosis and regeneration → hepatic stellate cell activation → collagen deposition → fibrosis → diffuse distortion of liver architecture and formation of regenerative nodules surrounded by fibrous bands = cirrhosis [5].
Fibrosis staging (Metavir):
- F0: No fibrosis
- F1: Portal fibrosis without septa
- F2: Portal fibrosis with rare septa
- F3: Numerous septa without cirrhosis
- F4: Cirrhosis
HBV causes HCC via two mechanisms — this is critical and distinguishes it from HCV [6]:
- Indirect (via cirrhosis): Chronic inflammation → cirrhosis → regenerative nodules → dysplastic nodules → HCC. Same pathway as any chronic liver disease.
- Direct (via DNA integration): HBV DNA integrates into the host genome via DR-I/DR-II → insertional mutagenesis can activate oncogenes or inactivate tumour suppressors. HBx protein can transactivate adjacent host genes, potentially including growth-promoting genes [10][11].
HBV Can Cause HCC WITHOUT Cirrhosis
This is a critical distinction from HCV. Since HBV can cause HCC without cirrhosis (via direct DNA integration and transactivation), HCC surveillance criteria are more stringent for HBV carriers [13]:
- Male ≥ 40 years old
- Female ≥ 50 years old
- Any age with underlying cirrhosis
- Family history of HCC
For other causes of HCC (e.g., MAFLD, HCV), cirrhosis is a requirement before HCC surveillance is indicated [13].
7. Classification
| Acute HBV | Chronic HBV | |
|---|---|---|
| Duration | < 6 months | > 6 months |
| HBsAg | Transient (clears within 6 months) | Persistent (> 6 months) |
| Anti-HBs | Develops after clearance | Does not develop (in most) |
| IgM anti-HBc | High titre | Low titre or negative (may be positive during acute flares, but lower than in acute infection) [7] |
| Risk in adults | 98% clear; 2% chronicity | N/A |
| Risk in neonates | 10% clear; 90% chronicity | N/A |
How to differentiate acute HBV from acute flare of chronic HBV? Sometimes we can't definitively tell. Check HBsAg at 6 months — if HBsAg clears within 6 months, it was acute [7]. In adults, acute infection is far more likely to resolve. IgM anti-HBc may help (very high titre favours acute) but is not definitive.
The natural history of chronic HBV is classically divided into phases defined by the interplay between viral replication and immune response. The updated EASL 2017/AASLD 2018 nomenclature is shown alongside the traditional terminology [14]:
| Traditional Name | Updated Nomenclature (EASL) | HBeAg | HBV DNA | ALT | Liver Histology | Duration |
|---|---|---|---|---|---|---|
| Immune Tolerance | HBeAg-positive chronic HBV infection | + | Very high (>10⁷-10⁸ IU/mL) | Normal | Minimal inflammation | 2-3 decades (in perinatally acquired) |
| Immune Clearance (Viral Clearance) | HBeAg-positive chronic hepatitis B | + | Fluctuating | Fluctuating (elevated) | Active hepatitis ± fibrosis/cirrhosis | Variable |
| Inactive Carrier (Low Replicative) | HBeAg-negative chronic HBV infection | − (anti-HBe +) | Low (<2000 IU/mL) | Normal | Minimal inflammation | May be lifelong |
| HBeAg-negative Hepatitis | HBeAg-negative chronic hepatitis B | − (anti-HBe +) | Moderate-high | Elevated | Active hepatitis ± fibrosis/cirrhosis | Variable |
| HBsAg-negative phase | "Functional cure" | − | Often undetectable | Normal | Cirrhosis/HCC can still occur | Lifelong |
Understanding the Phases — Think of it as a War
Phase 1 (Immune Tolerance): The immune system doesn't recognise the enemy. The virus replicates freely (very high HBV DNA), but because there's no immune attack, the liver is undamaged (normal ALT). This phase lasts 2-3 decades in perinatally infected individuals — typically children and young adults.
Phase 2 (Immune Clearance): The immune system finally realises the virus is foreign [7]. Massive immune attack against infected hepatocytes → ALT rises (hepatitis). But the immune system is generally not successful initially — HBV DNA reduces slightly but not to zero [7]. The longer you have inflammation, the more likely you develop fibrosis/cirrhosis. This is the dangerous phase.
Phase 3 (Inactive Carrier): After e-seroconversion (loss of HBeAg, gain of anti-HBe), viral replication is suppressed. But a lot of patients will still have active viral loads [7] — don't be falsely reassured.
Phase 4 (HBeAg-negative Hepatitis): Pre-core mutant viruses that cannot produce HBeAg continue replicating and causing hepatitis. This is the "trap" — the patient looks like they've seroconverted but still has active disease.
Phase 5 (Functional Cure): In very rare cases, HBsAg becomes negative — called "functional cure" but never a true cure because cccDNA persists. This is dangerous when prescribing steroids or immunosuppressants [7] as occult HBV can reactivate.
The fluctuations in Phase 2 are interesting: HBV DNA and ALT/AST CORRELATE with each other [12]:
- HBV DNA rises with viral replication → immune system gets more activated → more cytotoxic killing → more AST/ALT release
- More virus killed → HBV DNA falls → immune system calms down → ALT/AST fall → but then virus can replicate again
- The cycle continues until either the immune system wins (e-seroconversion) or fibrosis/cirrhosis develops
There are 10 HBV genotypes (A-J). In Hong Kong:
- Genotype B and C are most common
- Genotype C is associated with worse outcomes (delayed e-seroconversion, higher risk of cirrhosis and HCC)
This is absolutely critical for exams. Every marker tells you something specific about where the patient is in their disease course [14][1]:
| Marker | What it represents | Interpretation |
|---|---|---|
| HBsAg | Viral surface antigen | Present = infected (acute or chronic). Persistence > 6 months = chronic |
| Anti-HBs | Antibody against HBsAg | Protective/neutralising antibody. Present after vaccination or after clearance of acute infection |
| HBeAg | Secreted e-antigen (from pre-core region) | Marker of active viral replication and high infectivity |
| Anti-HBe | Antibody against HBeAg | Indicates e-seroconversion — generally means lower replication, but beware pre-core mutants |
| Anti-HBc IgM | Acute-phase antibody against core antigen | Marker of acute/recent infection. Also positive in acute flares of chronic infection (but lower titre) |
| Anti-HBc IgG (total) | Antibody against core antigen | Marker of past or current infection (persists lifelong). NOT present after vaccination alone |
| HBV DNA | Viral load quantification | Direct measure of viral replication. Most important marker for treatment decisions |
8.1 Serological Patterns — Quick Reference
| Scenario | HBsAg | Anti-HBs | HBeAg | Anti-HBe | Anti-HBc IgM | Anti-HBc total | HBV DNA |
|---|---|---|---|---|---|---|---|
| Acute infection (early) | + | − | + | − | + (high) | + | High |
| Acute infection (window period) | − | − | − | ± | + | + | Low/undetectable |
| Acute infection (recovery) | − | + | − | + | − | + | Undetectable |
| Chronic (immune tolerance) | + | − | + | − | − | + | Very high |
| Chronic (immune clearance) | + | − | + | − | ± (low) | + | Fluctuating |
| Chronic (inactive carrier) | + | − | − | + | − | + | Low |
| Chronic (HBeAg-neg hepatitis) | + | − | − | + | − | + | Moderate-high |
| Functional cure | − | ± | − | + | − | + | Undetectable |
| Vaccination | − | + | − | − | − | − | Undetectable |
Window Period
During the window period, HBsAg has been cleared but anti-HBs has not yet appeared. The only positive marker is anti-HBc IgM [3]. If you only test HBsAg, you will miss the diagnosis. This is why anti-HBc IgM is included in the initial workup of acute hepatitis.
Vaccination vs. Past Infection
A vaccinated person has anti-HBs ONLY. A person with past resolved infection has both anti-HBs AND anti-HBc (total). The key difference is the presence of anti-HBc — you only make anti-HBc if you were actually infected (the vaccine contains HBsAg only, not HBcAg).
9. Clinical Features
9.1 Acute Hepatitis B — Symptoms
A large proportion of acute hepatitis B cases are asymptomatic, especially in younger patients [9]:
The clinical course of symptomatic acute hepatitis B follows a triphasic pattern [9]:
| Symptom | Pathophysiological Basis |
|---|---|
| Low-grade fever (usually < 39°C) | Cytokine release (IL-1, IL-6, TNF-α) from immune activation against HBV-infected hepatocytes |
| Severe loss of appetite (anorexia) | Cytokine-mediated effect + hepatic dysfunction altering metabolism of appetite-regulating peptides |
| Severe fatigue, myalgia | Systemic cytokine response (similar to any viral prodrome) |
| Diarrhea | More common in enteric hepatitis (A/E) but can occur in HBV; mechanism unclear, possibly bile salt malabsorption |
| RUQ dull ache | Distension of the liver capsule (Glisson's capsule) — liver parenchyma has no nerve fibres, only capsule stretching from inflammatory swelling causes pain [9] |
| Darkening of urine (tea-coloured) | Conjugated bilirubin in urine — hepatocyte swelling compresses bile canaliculi → intrahepatic cholestasis → conjugated bilirubin refluxes into blood → filtered by kidneys (water-soluble) [9] |
| Transient pruritus | Mimics obstructive jaundice — bile salt retention due to intrahepatic cholestasis from hepatocyte swelling [9] |
| Pale stools | Decreased bilirubin excretion into gut → decreased conversion to stercobilinogen/stercobilin |
| Symptom | Pathophysiological Basis |
|---|---|
| Jaundice | Elevated conjugated bilirubin (predominantly direct > indirect) due to impaired hepatocyte excretory function and intrahepatic cholestasis |
| All preicteric symptoms begin to subside | As immune response peaks and begins to control infection, inflammatory cytokine levels decrease |
- Resolution of jaundice and normalisation of liver enzymes
- Bilirubin may remain elevated long after clinical and essential histological recovery — this is the cholestatic phase and does not imply ongoing hepatocyte damage [9]
| Sign | Pathophysiological Basis |
|---|---|
| Jaundice (scleral icterus first, then skin) | Bilirubin deposited in tissues with high elastin content (sclera has affinity for bilirubin) |
| Hepatomegaly (tender) | Inflammatory swelling of liver parenchyma |
| Low-grade fever | Immune-mediated cytokine release |
| RUQ tenderness | Capsular distension |
| Splenomegaly (occasional) | Reactive lymphoid hyperplasia |
| Lymphadenopathy (occasional) | Reactive immune response |
| Urticarial rash / arthritis (immune complex-mediated) | Circulating immune complexes (HBsAg-anti-HBs) deposit in small vessels and joints — a serum sickness-like syndrome, typically in the preicteric phase |
Most patients with chronic HBV are asymptomatic for decades (especially during the immune tolerance and inactive carrier phases). Symptoms, when present, include:
| Symptom | Phase/Pathophysiology |
|---|---|
| Non-specific fatigue, malaise | Chronic low-grade immune activation; cytokines |
| RUQ discomfort | Hepatomegaly / capsular stretch from fibrosis or inflammation |
| Symptoms of acute flare (similar to acute hepatitis) | Occurs during immune clearance phase or reactivation |
| Symptoms of decompensated cirrhosis | Late: jaundice, ascites (abdominal distension), variceal bleeding (haematemesis/melaena), confusion (hepatic encephalopathy) |
| Constitutional symptoms | Weight loss, anorexia — particularly concerning for HCC |
Depend on the stage of disease:
Compensated cirrhosis (may have NO signs):
| Sign | Pathophysiology |
|---|---|
| Spider naevi (> 5, upper body distribution) | Hyperestrogenism — impaired hepatic metabolism of oestrogen → arteriolar vasodilation |
| Palmar erythema | Same mechanism — oestrogen-mediated vasodilation of palmar arterioles |
| Gynaecomastia | Hyperestrogenism |
| Testicular atrophy | Hyperestrogenism + hypogonadism |
| Dupuytren's contracture | More common in alcoholic liver disease but can occur |
| Parotid enlargement | More common in alcoholic liver disease |
| Caput medusae | Portal hypertension → portosystemic shunting via periumbilical veins |
| Splenomegaly | Portal hypertension → splenic congestion |
| Hepatomegaly (early) / shrunken liver (late) | Early: inflammation and regeneration. Late: fibrosis and volume loss |
Decompensated cirrhosis:
| Sign | Pathophysiology |
|---|---|
| Jaundice | Insufficient functioning hepatocytes to conjugate and excrete bilirubin |
| Ascites | Portal hypertension + hypoalbuminaemia (reduced oncotic pressure) + RAAS activation (sodium/water retention) |
| Peripheral oedema | Hypoalbuminaemia + RAAS activation |
| Hepatic encephalopathy (confusion, asterixis, fetor hepaticus) | Impaired hepatic clearance of ammonia and other neurotoxins → accumulation → cerebral oedema and neurotransmitter disturbance |
| Bruising / bleeding tendency | Impaired hepatic synthesis of clotting factors (especially Factor VII — shortest half-life) |
These are immune complex-mediated or related to chronic immune stimulation:
| Manifestation | Mechanism |
|---|---|
| Polyarteritis nodosa (PAN) | HBsAg-anti-HBs immune complex deposition in medium-sized vessel walls → necrotising vasculitis |
| Membranous nephropathy (most common renal manifestation) | Immune complex deposition in glomerular basement membrane (HBeAg-anti-HBe complexes) |
| Membranoproliferative glomerulonephritis (MPGN) | Immune complex deposition |
| Serum sickness-like syndrome | Circulating immune complexes → urticaria, arthralgia, fever (preicteric phase of acute infection) |
| Aplastic anaemia | HBV infection of haematopoietic stem cells or immune-mediated destruction — hepatitis is well known to precede aplastic anaemia [15] |
| Mixed cryoglobulinaemia | Less common than in HCV |
Hepatitis episodes (acute flares) often complicate the course of chronic hepatitis B [12]. Causes include:
| Cause | Mechanism |
|---|---|
| "Spontaneous" reactivation | IgM anti-HBc levels rise but not as high as in acute hepatitis B [12] |
| Clearance of HBeAg (spontaneous or during therapy) | Immune flare during e-seroconversion |
| e-Seroreversion (HBeAg neg/anti-HBe → HBeAg pos) | Loss of immune control |
| Emergence of resistant variants / non-compliance during NUC therapy | Drug-resistant mutants replicate unchecked |
| Corticosteroid or other immunosuppressant withdrawal, especially anti-CD20 | During steroid treatment the patient is actually fine — it is the WITHDRAWAL that activates a massive immune response against a liver now full of virus [12] |
| Superinfection by hepatitis D | Very rare in Chinese [12] |
| Superinfection with other viral agents, especially HAV and HEV | More important than HDV; HEV more common now [12] |
| Drug-induced hepatic injury, including alcohol, TCM/herbal tea | Direct hepatotoxicity on already compromised liver [12] |
Steroid/Immunosuppressant Withdrawal — Classic Exam Scenario
A patient with resolved HBV (HBsAg−, anti-HBc+) or chronic HBV receives chemotherapy with rituximab (anti-CD20). During treatment, the immune system is suppressed → HBV replicates unchecked (reactivation of occult hepatitis B from cccDNA). When immunosuppression is withdrawn, the reconstituted immune system launches a massive attack on the now heavily infected liver → fulminant hepatic failure.
This is why anti-HBc screening is mandatory before immunosuppressive therapy, and prophylactic antivirals should be started.
10. Biochemical Features
| Parameter | Finding in Acute Hepatitis | Finding in Chronic Hepatitis | Pathophysiological Basis |
|---|---|---|---|
| ALT (SGPT) | 200-2000+ IU/L (sometimes up to 5000) | Normal to mildly elevated (or fluctuating during flares) | Released from damaged hepatocytes; ALT is more liver-specific than AST |
| AST (SGOT) | Elevated but usually lower than ALT | Similar to ALT | Less specific (also in muscle, heart, RBCs) |
| INR / PT | Best index for monitoring progress and prognosis [9] | Elevated in decompensated cirrhosis | Reflects synthetic function — Factor VII has shortest half-life (~6 hours), so INR changes most rapidly |
| Bilirubin | Elevated (predominantly direct/conjugated) | May be normal or elevated | Impaired hepatocyte excretory function; may remain elevated long after clinical recovery (cholestatic phase) [9] |
| ALP / GGT | Mildly elevated | May be elevated in cirrhosis | ALP from canalicular membrane; GGT from bile ductules |
| Albumin | Usually normal in acute | Low in cirrhosis | Impaired synthesis (half-life ~21 days, so slow to change) |
Fulminant Hepatitis — The Falling ALT Trap
In fulminant hepatitis, ALT may FALL as disease progresses [9] — not because the patient is improving, but because there are so few hepatocytes left to release enzymes. The clue is a falling ALT with a RISING INR/PT — this is ominous. If ALT falls AND INR improves, the patient is truly getting better.
- AFP is not always a tumour marker [7]
- High inflammation in the liver can cause marked elevation of AFP sometimes during acute flares
- Key: see whether AFP comes down after symptoms disappear. If it keeps rising, start worrying about HCC [7]
- However, 20-30% of HCC is non-secreting (no AFP elevation) [7]
- Normal AFP: < 6 ng/mL (some labs use < 12 ng/mL)
11. Diagnosis of Liver Fibrosis/Cirrhosis
- Liver biopsy is generally not done anymore, rarely performed due to invasiveness [7]
- Gold standard but has sampling error and risk of complications (bleeding, pain)
- Metavir fibrosis score: F0-F4
FibroScan (transient elastography) is the standard of care nowadays [7]:
Child-Pugh Score classifies cirrhosis severity [5]:
| Parameter | 1 point | 2 points | 3 points |
|---|---|---|---|
| Bilirubin (μmol/L) | < 34 | 34-50 | > 50 |
| Albumin (g/L) | > 35 | 28-35 | < 28 |
| INR | < 1.7 | 1.7-2.3 | > 2.3 |
| Ascites | None | Mild | Moderate-severe |
| Encephalopathy | None | Grade I-II | Grade III-IV |
- Child A (5-6 points) = Compensated cirrhosis
- Child B (7-9) or C (10-15) = Decompensated cirrhosis [5]
- Poor survival once decompensated [7]
12. Prevention
HBV vaccine is included in the CFB immunisation schedule [16]:
- Recombinant HBsAg vaccine (contains only HBsAg → this is why vaccinated individuals only develop anti-HBs, not anti-HBc)
- Universal neonatal vaccination in Hong Kong since 1988 [16]
- Schedule: 0, 1, 6 months (3 doses)
- Protective antibody: anti-HBs ≥ 10 mIU/mL [16]
- Non-responders (5-10%): may need booster doses or double-dose vaccine
- Duration of protection: at least 20+ years; immunological memory persists even when anti-HBs wanes below 10 mIU/mL
- Hepatitis B Immunoglobulin (HBIG) — provides immediate but temporary passive protection
- Indications:
- Neonates born to HBsAg+ mothers — HBIG + first dose of vaccine within 12 hours of birth (prevents vertical transmission; efficacy ~90-95% when combined)
- Post-exposure prophylaxis (needle-stick injury, sexual exposure) — within 24-48 hours
- Post-liver transplant for HBV — to prevent graft reinfection
- All pregnant women should be screened for HBsAg
- If HBsAg+:
- Check HBV DNA level
- If HBV DNA > 200,000 IU/mL (or > 10⁶ copies/mL): start tenofovir in 3rd trimester (week 28-32) to reduce viral load and decrease transmission risk
- Neonate receives HBIG + HBV vaccine within 12 hours of birth
- Can breastfeed (HBV in breast milk is not a significant transmission risk when neonate has been vaccinated/given HBIG)
Because HBV can cause HCC without cirrhosis (via direct DNA integration), surveillance criteria are more stringent [13]:
| Indication for HCC surveillance | |
|---|---|
| Male HBV carrier ≥ 40 years old | |
| Female HBV carrier ≥ 50 years old | |
| Any HBV carrier with cirrhosis (any age) | |
| Family history of HCC |
- Surveillance protocol: Ultrasound abdomen ± AFP every 6 months [13]
- For non-HBV causes of HCC (e.g., MAFLD, HCV), cirrhosis is required before HCC surveillance is indicated [13]
Occult HBV = HBsAg negative but HBV DNA detectable (in serum or more often in liver tissue) [7]
- Occurs after "functional cure" (HBsAg loss) — cccDNA persists in hepatocyte nuclei
- Usually has positive anti-HBc (total)
- Dangerous when prescribing steroids or immunosuppressants [7] → risk of reactivation
- Must screen for anti-HBc before starting immunosuppressive therapy (especially anti-CD20 agents like rituximab, which carry the highest risk)
High Yield Summary
Definition: HBV is an immune-mediated liver disease caused by a DNA hepadnavirus. Chronic HBV = HBsAg persistence > 6 months.
Epidemiology (HK): ~8% chronic carrier rate; most common cause of cirrhosis (~75%); universal vaccination since 1988.
Transmission: Vertical (most important in HK), parenteral, sexual, close contact. NOT airborne or faecal-oral.
Risk of Chronicity: 90% in neonates, 2% in adults — due to immature immune system + viral immune evasion (HBsAg decoy, HBx, polymerase suppression of TLR, HBeAg suppression of TLR-2/CD28/CD86).
Virology: dsDNA virus; cccDNA in nucleus = reason for incurability; DR-I/DR-II for genomic integration = direct carcinogenesis pathway; pre-core mutant (TAG stop codon) = false HBeAg negativity.
Natural History Phases: Immune tolerance → Immune clearance → Inactive carrier → ± HBeAg-negative hepatitis → ± Functional cure.
Key Serological Patterns: HBsAg (infection), anti-HBs (immunity/vaccination), HBeAg (replication), anti-HBc IgM (acute/flare), anti-HBc total (ever infected), HBV DNA (viral load). Vaccination = anti-HBs ONLY. Past infection = anti-HBs + anti-HBc.
Clinical Features: Often asymptomatic. Preicteric → icteric → convalescent phases. Extrahepatic: PAN, membranous nephropathy, aplastic anaemia. Flares: spontaneous, immunosuppressant withdrawal, superinfection.
Monitoring: INR is best prognostic marker in acute hepatitis. FibroScan (> 12 kPa = cirrhosis). AFP can be elevated in inflammation, not just HCC.
HCC Surveillance: Male ≥ 40, Female ≥ 50, any cirrhosis, family history → USG + AFP q6 months. HBV is unique — causes HCC WITHOUT cirrhosis.
Prevention: Vaccine (0, 1, 6 months); HBIG for neonates of HBsAg+ mothers; tenofovir in pregnancy if HBV DNA > 200,000 IU/mL; screen anti-HBc before immunosuppression.
Active Recall - Hepatitis B (Overview, Epidemiology, Pathophysiology, Clinical Features)
[1] Lecture slides: GC 239. Viral hepatitis HAV_HBV_HCV_HEV.pdf [2] Lecture slides: Block A - I am a hepatitis B carrier.pdf [3] Senior notes: Maksim Medicine Notes.pdf (GI & Hepatology — Viral Hepatitis section) [4] Senior notes: Ryan Ho GI.pdf (Hepatitis B section, pp.220-232) [5] Senior notes: Block A - Abdominal distension_ ascites and cirrhosis.pdf (Cirrhosis & Decompensation) [6] Senior notes: Maksim Surgery Notes.pdf (HCC section, p.124) [7] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (pp.3-4) [8] Senior notes: Block A - I am a hepatitis B carrier.pdf (pp.5, 16) [9] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (pp.1-2) [10] Senior notes: Block A - I am a hepatitis B carrier.pdf (p.5 — HBV genome) [11] AOS material: AOS - Pathology.pdf (p.8 — HBV DNA and complications MCQ) [12] Senior notes: Block A - I am a hepatitis B carrier.pdf (pp.25, 28) [13] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (p.2 — dual liver disease, HCC surveillance) [14] Lecture slides: Molecular Pathology Seminar 3_HBV lecture 2025_Prof IOL Ng.pdf (pp.8-9) [15] Senior notes: Block A - Hematology Data Interpretation.pdf (p.1 — hepatitis preceding aplastic anaemia) [16] Lecture slides: CFB (PAE03) Immunization.pdf
The clinical challenge with hepatitis B is not "Does this patient have HBV?" — serology answers that. The real differential diagnosis question in exams and clinical practice comes in two flavours:
- A patient presents with acute hepatitis (elevated transaminases ± jaundice) — what is the cause? (i.e., HBV vs. other causes of hepatitis)
- A known HBV carrier presents with deranged LFT — is this an acute flare of chronic HBV, a new acute infection, or a different superimposed pathology?
Both questions demand a systematic approach. Let's build it from first principles.
When a patient presents with a hepatitic pattern on LFT (ALT/AST rise >> ALP/GGT), you are dealing with hepatocyte injury. The differential is broad but can be categorised systematically.
The GI/Hepatology investigations lecture (GC) teaches that different liver diseases have different patterns of LFT abnormalities [17]. Determining the final diagnosis requires history (especially drug history), clinical presentation, other investigations, and sometimes liver biopsy [17].
1.1 Systematic Differential Diagnosis of Hepatitis
The mnemonic "All Medical Doctors Aren't Very Happy" covers the hepatic causes of jaundice, which are essentially the causes of hepatitis [18]:
| Category | Causes | Key Distinguishing Features |
|---|---|---|
| A — Alcohol | Alcoholic hepatitis | AST > ALT (typically 2:1 ratio); AST usually < 500 IU/L [19]; history of heavy alcohol use; elevated GGT |
| M — Metabolic | MASLD/MAFLD | Common co-existence with HBV in HK (dual liver disease) [13]; BMI ↑, metabolic syndrome; ALT mildly elevated; CAP score ↑ on FibroScan |
| Wilson disease | Young patients (5-35 y/o); Coombs-negative haemolytic anaemia; Kayser-Fleischer rings; low ceruloplasmin [20][21]. Can mimic acute viral hepatitis. Fulminant hepatic failure due to Wilson's has a very specific feature: young patient with unexplained liver failure + low Hb + Coombs-negative haemolytic anaemia [21] | |
| Haemochromatosis | Iron overload; raised ferritin and transferrin saturation; bronze diabetes; HFE gene mutation | |
| α1-antitrypsin deficiency | Young patient; emphysema + liver disease; low serum α1-antitrypsin | |
| D — Drugs | Drug-induced liver injury (DILI) | Temporal relationship to new drug; paracetamol overdose: acute toxic dose > 150 mg/kg [22]; TCM/herbal tea; antibiotics (augmentin, anti-TB drugs) |
| A — Autoimmune | Autoimmune hepatitis (AIH) | Bimodal age: young and middle-aged females; ↑total IgG; ANA, ASMA (Type 1) or anti-LKM1 (Type 2); diagnosis by exclusion of viral and other causes [22]. Autoimmune hepatitis is very difficult to diagnose, sometimes becomes a diagnosis of exclusion [7]. HCC is rare in AIH [21] |
| V — Viral | HAV, HBV, HCV, HDV, HEV | Serology (see below). HAV = shellfish; HEV = pork liver congee [9] |
| EBV, CMV | Both can present with LFT abnormalities + fever, fatigue, lymphadenopathy [23]; atypical lymphocytosis on blood film; heterophile antibodies (EBV) | |
| HSV | Rare; mostly in immunocompromised patients [23] | |
| HIV | Acute seroconversion illness; nausea, anorexia, diarrhoea [23] | |
| Adenovirus | Typically respiratory/GI; hepatitis can be a complication in immunocompromised [23] | |
| H — HCC / Hepatic | Hepatocellular carcinoma | Late presentation; 80% of HCC in HK are HBsAg+ [24]; AFP ↑; imaging |
| Ischaemic hepatitis | Very rapid rise and fall of transaminases (fall of ~1000 units/day); ALP typically normal; massive LDH elevation (high cell turnover but LDH is non-specific) [19]; occurs in context of haemodynamic compromise (shock, heart failure, sepsis) | |
| Other | Budd-Chiari syndrome | Hepatic venous outflow obstruction; acute/subacute liver disease; ascites; tender hepatomegaly [23] |
| HELLP syndrome | Pregnancy; Haemolysis, Elevated Liver enzymes, Low Platelets [23] |
GC High Yield — The 4 Differentials to Consider with Acutely Deranged LFT
The GC Introduction to GI/Hepatology Investigations lecture (workshop cases) teaches four key differentials for a markedly elevated ALT/AST [17]:
- Acute viral hepatitis
- Ischaemic hepatitis
- Drug-induced hepatitis
- Hepatitis B reactivation
These are the "big four" to consider when you see transaminases in the thousands. A second case framework also includes alcoholic hepatitis and CBD stone [17].
This is the most common exam scenario: a patient has acute hepatitis — which virus is it?
| Feature | HAV | HBV | HCV | HDV | HEV |
|---|---|---|---|---|---|
| Genome | ssRNA | dsDNA | ssRNA | ssRNA | ssRNA |
| Family | Picornaviridae | Hepadnaviridae | Flaviviridae | (Incomplete virus) | Hepeviridae |
| Transmission | Faecal-oral | Parenteral (vertical, blood, sexual) | Parenteral (IVDU, blood) | Parenteral (needs HBV) | Faecal-oral + zoonotic |
| Incubation | 2-4 weeks | 4-20 weeks | 2-26 weeks | 6-9 weeks | 3-8 weeks |
| Chronicity | Never | Yes (90% neonates, 2% adults) | Yes (70-85%) | Yes (depends on HBV) | No (except transplant recipients) |
| Key serology | Anti-HAV IgM | HBsAg + anti-HBc IgM | Anti-HCV ± HCV RNA | Anti-HDV IgM | Anti-HEV IgM |
| Vaccine | Yes | Yes | No | HBV vaccine (prevents HDV) | No |
| Immunoglobulin | Yes | Yes | No | No | No |
| Fulminant risk | Rare (mortality ↑ with age) | ~1% | Very rare | High (co/superinfection) | Rare, except pregnant women (20% mortality) |
High Yield — How History Helps Differentiate
- Raw shellfish / oysters → HAV [9]
- Pork liver congee / pig offal → HEV [9]
- Travel to endemic area with poor sanitation → HAV or HEV
- IVDU / blood transfusion / needle-stick → HBV or HCV
- Sexual contact / MSM → HBV (>> HCV)
- Mother HBsAg+ → HBV
- Pregnant woman with fulminant hepatitis → HEV (up to 20% mortality; HEV causes Kupffer cell damage → allows endotoxin damage to liver, and pregnant women are more sensitive to endotoxin) [4]
- Immunosuppressed transplant recipient with chronic hepatitis → HEV genotype 3 (uniquely can cause chronicity in transplant) [4]
3. The Critical DDx: Acute HBV Infection vs. Acute Flare of Chronic HBV
This is a favourite exam topic because it has genuine clinical uncertainty.
Both acute HBV infection and acute flare (reactivation) of chronic HBV present with elevated transaminases and positive HBsAg [7]. The question is: is this the first time the patient encountered HBV (acute), or has the patient been a chronic carrier who is now flaring?
- Acute HBV in adults: 98% will clear spontaneously. Treatment is supportive (antivirals NOT required unless fulminant). You monitor and recheck HBsAg at 6 months [22].
- Acute flare of chronic HBV: The patient already has chronic infection. They need antiviral treatment and long-term follow-up. Flares can precipitate decompensation in cirrhotic patients.
| Feature | Acute HBV | Acute Flare of Chronic HBV |
|---|---|---|
| Anti-HBc IgM | Very high titre | Positive but lower titre [7] |
| Anti-HBc IgG | Negative (or low) early on | Positive (has been infected for months/years) |
| HBeAg | May be positive | If negative → likely acute flare of chronic infection, since patient has already e-seroconverted [7] |
| HBV DNA | High | Very high |
| Prior HBsAg | Not previously documented | Previously positive (if known) |
| Risk factors | Recent exposure (sexual, needle-stick) | Known chronic carrier, immunosuppression |
Sometimes we simply cannot differentiate definitively [7]. The practical approach:
- Definition of chronic HBV = HBsAg persistence > 6 months
- If the patient doesn't die, recheck HBsAg at 6 months: if HBsAg clears → it was acute infection with clearance [7]
- Adults with acute hepatitis B are unlikely to become chronic carriers (2%), since the big immune reaction generally clears the virus [7]
Exam Pearl
Anti-HBc IgG helps here: in acute HBV infection, anti-HBc IgG is negative (not enough time to develop). In acute flare of chronic HBV, anti-HBc IgG is positive (has been present from prior infection). This is explicitly taught in the GI Data Interpretation tutorial [7] and Maksim Medicine Notes [3].
A chronic HBV carrier presenting with newly deranged LFT has a broader differential than just "HBV flare." You must consider concomitant / superimposed pathology — a concept strongly emphasised in HK teaching given the high prevalence of dual liver disease (HBV + MAFLD) [13].
| Differential | Key Features / Clues |
|---|---|
| HBV flare / reactivation | Rising HBV DNA; ± recent immunosuppressant withdrawal; IgM anti-HBc ± |
| Superinfection with HAV or HEV | More important than HDV; HEV more common now [12]; check anti-HAV IgM, anti-HEV IgM |
| HDV superinfection | Very rare in Chinese [12]; check anti-HDV |
| Concomitant MAFLD | Very common in HK [13]; obesity; metabolic syndrome; CAP score ↑ on FibroScan |
| Alcoholic liver disease | Alcohol history; AST > ALT (2:1); AST rarely > 500 [19]; elevated GGT |
| DILI | Recent new medication, TCM, supplements |
| HCC | Known cirrhotic; AFP ↑ (but 20-30% of HCC is non-secreting [7]); new mass on imaging |
| Autoimmune hepatitis | Young female; autoantibodies; elevated IgG |
| Ischaemic hepatitis | Haemodynamic compromise; very rapid rise and fall of transaminases; massive LDH [19] |
The following flowchart captures the systematic approach to a patient presenting with hepatitis (elevated transaminases ± jaundice), showing where HBV fits in the differential:
6. Key DDx Pitfalls and Teaching Points
AFP is not always a tumour marker [7]. High inflammation in the liver can also cause marked elevation of AFP during acute flares. The key difference is whether AFP comes down after symptoms disappear — if it keeps rising, start worrying about cancer [7]. However, 20-30% of HCC is non-secreting and will have no AFP elevation [7].
> 70% of HCC and cirrhosis complications occur in anti-HBe+ patients, even in patients with "normal" ALT [12]. This is because:
- Pre-core mutant viruses cause ongoing hepatocyte damage that may not be reflected by markedly elevated ALT
- Fibrosis/cirrhosis can progress insidiously with only mild or intermittent transaminase elevation
- ALT may be within "normal" laboratory range but still be abnormal for that individual
AST > ALT (typically 2:1 ratio) and AST rarely exceeds 500 IU/L [19]. If you see transaminases > 1000, alcoholic hepatitis alone is very unlikely — think viral, ischaemic, or drug-induced.
Very rapid rise and fall of transaminases (fall of ~1000 units/day) [19]. The ALP is typically normal. Massive LDH elevation is an ancillary clue [19]. This occurs in the context of haemodynamic compromise (cardiac arrest, severe heart failure, septic shock). It is NOT a primary liver disease — fixing the haemodynamics fixes the liver.
Wilson disease can present as acute hepatitis clinically indistinguishable from acute viral hepatitis [20]. The clue is the age (5-35 y/o), Coombs-negative haemolytic anaemia, and Kayser-Fleischer rings. Fulminant hepatic failure from Wilson disease characteristically occurs in young patients with unexplained liver failure and the only finding being low haemoglobin [21].
High Yield Summary — Differential Diagnosis of Hepatitis B
When to consider HBV: Any patient with hepatitic LFT pattern, especially with risk factors for parenteral/vertical transmission. In HK, HBV is the most common cause of chronic liver disease.
Key DDx for acute hepatitis: Viral (HAV, HBV, HCV, HEV + EBV/CMV), DILI, alcoholic, ischaemic, autoimmune, Wilson disease.
Acute HBV vs. acute flare of chronic HBV: Anti-HBc IgM titre (very high = acute; lower = flare), anti-HBc IgG (negative = acute; positive = chronic), definitive answer at 6 months (HBsAg clearance = acute).
Known HBV carrier with deranged LFT: Always consider superinfection (HAV, HEV >> HDV), concomitant MAFLD (very common in HK), DILI (including TCM), HCC, alcohol.
Distinct LFT patterns: Alcoholic (AST > ALT, < 500); Ischaemic (rapid rise/fall, ↑LDH, normal ALP); Viral (ALT > AST, 200-5000).
AFP trap: Elevated in inflammation, not just HCC. Watch the trend — falling with clinical recovery = benign; persistently rising = worrisome for HCC.
Active Recall - Differential Diagnosis of Hepatitis B
[3] Senior notes: Maksim Medicine Notes.pdf (GI & Hepatology — Viral Hepatitis section) [4] Senior notes: Ryan Ho GI.pdf (Hepatitis B and E sections) [7] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (pp.2-4) [9] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (pp.1-2, 13, 20) [12] Senior notes: Block A - I am a hepatitis B carrier.pdf (pp.25-26, 28) [13] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (p.2) [17] Lecture slides: Gastroenterology Hepatology Introduction to GI:Hepatology investigations from the abnormal.pdf (pp.30, 38, 49) [18] Senior notes: Ryan Ho Fundamentals.pdf (p.295 — approach to jaundice mnemonic) [19] Senior notes: Block A - Introduction to GI_Hepatology investigations (LFT, Endoscopy).pdf (p.16 — ischaemic hepatitis) [20] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.266 — Wilson disease) [21] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (p.2) [22] Senior notes: Maksim Medicine Notes.pdf (pp.148-150 — AIH, DILI, Gilbert) [23] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp.738, 767) [24] Lecture slides: WCS 064 - A large liver - by Prof R Poon.pdf (pp.2-3)
1. Diagnostic Criteria
Hepatitis B does not have a single set of "diagnostic criteria" like rheumatic diseases. Instead, diagnosis relies on serological markers interpreted in clinical context. The key definitions are straightforward:
- HBsAg positive — confirms current HBV infection
- Anti-HBc IgM positive (high titre) — confirms acute/recent infection
- Markedly elevated ALT and AST (typically 200–2000+ IU/L, can reach 5000) — reflects immune-mediated hepatocyte destruction
- HBsAg clearance within 6 months confirms it was indeed acute
The GC 239 Viral Hepatitis lecture slide lists the investigation panel for acute viral hepatitis [1]:
HBsAg, Anti-HAV IgM, Anti-HCV, Anti-HEV IgM, ANA/anti-smooth muscle/anti-LKM-1, Ultrasound, Toxicology screen if appropriate
The logic of this panel: you send all viral serologies simultaneously because the clinical presentation of acute hepatitis is identical regardless of the virus — you cannot tell which virus is responsible from symptoms alone [3][9].
Definition: HBsAg positive for ≥ 6 months [3][25]
Further classification requires [3][25]:
- HBeAg and anti-HBe status — determines the natural history phase
- HBV DNA level — the most important marker for treatment decisions; directly quantifies viral replication
- ALT level — reflects degree of liver inflammation
- Liver fibrosis assessment — FibroScan or (rarely) biopsy
- HBsAg negative, anti-HBs negative, anti-HBc IgM positive — the only positive marker during the window period [3]
- This occurs in the gap between HBsAg clearance and anti-HBs appearance
- If you only check HBsAg, you will miss the diagnosis
This is a commonly asked examination question [25]. The GC 239 lecture and the GI Data Interpretation (DI) lecture both explicitly teach this [1][26].
The GC 239 lecture presents a case with HBsAg positive, HBeAg positive, anti-HBc IgM positive, HBV DNA > 10⁸ IU/mL and asks: "Acute hepatitis B versus Chronic hepatitis B with flare — how to differentiate?" [1]
2.1 Step-by-Step Approach
| Step | Method | Interpretation |
|---|---|---|
| 1. History | Personal history of HBV; family history; sexual history up to 24 weeks | Known prior HBsAg+ = chronic; new risk exposure = favours acute [25] |
| 2. Anti-HBc IgM | If positive | Cannot differentiate alone — positive in BOTH acute infection AND acute flare of chronic [7][25] |
| If negative | Acute flare of chronic HBV (has been infected long enough that acute-phase IgM is no longer produced) [7] | |
| 3. Anti-HBc IgG | If positive | Acute flare of chronic HBV — has had infection long enough to develop IgG [25] |
| If negative | Acute HBV infection — not enough time to develop IgG yet [25] | |
| 4. HBsAg at 6 months | If clears | Acute HBV infection with spontaneous clearance [7][25] |
| If persists | Chronic HBV infection [7][25] |
GC High Yield — Differentiating Acute vs. Chronic Flare
From GC 239 lecture and the GI DI lecture [1][26]:
Anti-HBc IgG is the most useful acute differentiator:
- Positive IgG anti-HBc = chronic infection with flare (IgG has had time to develop)
- Negative IgG anti-HBc = acute HBV infection (too early for IgG class switching)
Definitive answer: recheck HBsAg at 6 months.
Adults with acute HBV are unlikely to become chronic carriers (2%) because the vigorous immune reaction generally clears the virus [7].
3. Investigation Modalities — Systematic Approach
The investigations for hepatitis B serve four distinct purposes, each answering a different clinical question. Think of them as four pillars [27][3]:
| Clinical Question | Investigations |
|---|---|
| Is HBV active? (Viral activity) | HBV DNA, HBeAg/anti-HBe, HBsAg quantification |
| Is the liver inflamed? (Hepatocyte injury) | LFT: ALT, AST, bilirubin |
| Is there cirrhosis? (Fibrosis staging) | FibroScan, ± OGD for varices, ± liver biopsy |
| Is there HCC? (Cancer surveillance) | USG abdomen + AFP every 6 months |
Adapted from Maksim Medicine Notes disease monitoring framework [27].
3.1 Serology — The Foundation
| Marker | What it represents | When to order | Key interpretation |
|---|---|---|---|
| HBsAg | Hallmark of current HBV infection; appears 1-10 weeks after exposure, before ALT rises [3] | Always first-line | < 6 months = acute; ≥ 6 months = chronic. Quantification of HBsAg now available: predicts risk of HCC and risk of viral rebound after stopping treatment [3] |
| Anti-HBs | Marker of long-term immunity: post-vaccination or post-infection [3] | Follow-up, post-vaccination | ≥ 10 mIU/mL = protective. Co-existence of HBsAg + anti-HBs: antibodies unable to neutralise all virions → regard as HBV carriers [3] |
| Anti-HBc IgM | Acute infection marker | Acute presentation | Only marker positive during "window period" [3]. Positive in acute flares but at lower titre |
| Anti-HBc IgG | Marker of natural infection; differentiates past infection (+ve) from vaccination (-ve) [3] | Differentiating acute vs. chronic flare | Differentiates acute HBV (-ve) from acute exacerbation of chronic HBV (+ve) [3] |
| HBeAg | Marker of replication and infectivity — secretory protein from HBV [3] | Classification of chronic HBV | Current role: if seroconverted, consider stopping antiviral after 1 more year of treatment (30% recurrence) [3] |
| Anti-HBe | Marker of HBeAg seroconversion [3] | Follow-up | Seroconversion does NOT mean end of disease [3] — beware pre-core mutants |
| HBV DNA | Marker of replication and infectivity — assess candidacy for antiviral and response to antiviral [3] | Always in chronic HBV | Most important single test for treatment decisions. Measured in IU/mL by real-time PCR |
This master table is extremely high yield for exams [25][28]:
| Interpretation | HBsAg | Anti-HBs | HBeAg | Anti-HBe | Anti-HBc IgM | Anti-HBc IgG | HBV DNA |
|---|---|---|---|---|---|---|---|
| Acute HBV — early | + | − | + | − | + | − | +++ |
| Acute HBV — window | − | − | − | − | + | − | ± |
| Acute HBV — recovery | − | + | − | + | − | + | − |
| Chronic — HBeAg+ hepatitis | + | − | + | − | − | + | +++ |
| Chronic — HBeAg− hepatitis | + | − | − | + | − | + | ++ |
| Chronic — inactive carrier | + | − | − | + | − | + | ± |
| Exacerbation/flare of chronic | + | − | ± | ± | + | + | + |
| Occult HBV | − | ± | − | ± | − | ± | + |
| Immune — past infection | − | + | − | − | − | + | − |
| Immune — vaccination | − | + | − | − | − | − | − |
The One-Liner Differentiator
Vaccination = anti-HBs ONLY (no anti-HBc). Past infection = anti-HBs + anti-HBc (both present). The vaccine contains only HBsAg → you only make anti-HBs. You need actual viral exposure to make anti-HBc (the core antigen is not in the vaccine).
The GI/Hepatology Investigations lecture (GC) teaches that LFTs assess three distinct aspects [19][29]:
| Aspect | Markers | What they reflect |
|---|---|---|
| Cellular integrity | ALT, AST | Hepatocyte damage — released when hepatocytes are destroyed by CTLs |
| Synthetic function | Albumin, PT/INR | Liver's manufacturing capacity — INR reflects Factor VII (half-life ~6 hours); albumin (half-life ~21 days) |
| Excretory function | Bilirubin, ALP, GGT | Cholestasis — ALP from canalicular membrane; GGT from bile ductules |
Key interpretations specific to HBV:
- ALT >> AST in primary liver pathology (most hepatitis). 4 liver pathologies where AST > ALT: alcoholic hepatitis, HCC, congestive heart failure, ischaemic hepatitis [19]
- In acute hepatitis, ALT typically 200-2000 IU/L [3], sometimes up to 5000
- INR is the best index for monitoring progress and prognosis in acute hepatitis [9]. Why? Because Factor VII has the shortest half-life (~6 hours) — it drops first when synthetic function fails and recovers first when function improves
- Falling ALT + improving INR = recovery. Falling ALT + worsening INR = fulminant hepatitis (catastrophic loss of hepatocytes → not enough cells to release ALT, but not enough cells to synthesise clotting factors either) [9]
- Bilirubin may remain elevated long after clinical and histological recovery — the cholestatic phase — so it is less helpful for monitoring acute progress [9]
- Albumin is usually normal in acute hepatitis (long half-life) but low in cirrhosis (chronic synthetic failure)
- AST/ALT do NOT reflect severity of cirrhosis [28] — a cirrhotic patient can have normal transaminases
GC High Yield — AST:ALT Ratio as Diagnostic Clue
From the GI Data Interpretation lecture [29]:
- AST:ALT > 2:1 → strongly suggests alcoholic hepatitis
- AST:ALT approaching 1:1 with markedly elevated transaminases + high LDH → ischaemic hepatitis
- AST almost never > 500 IU/L in alcoholic hepatitis [19]
- Isolated GGT rise with normal ALP → alcohol, drugs (phenytoin, carbamazepine), or fatty liver (GGT is an inducible enzyme) [19]
- Measured by real-time PCR (quantitative)
- Reported in IU/mL (1 IU ≈ 5 copies)
- The GC 239 case shows HBV DNA > 10⁸ IU/mL [1]; the DI lecture shows HBV DNA > 640 million copies/mL [26] — both indicating extremely high viral loads
- Clinical thresholds:
- Immune tolerance: typically > 10⁷–10⁸ IU/mL
- Threshold for treatment consideration: > 2000 IU/mL (HBeAg−) or > 20,000 IU/mL (HBeAg+) with elevated ALT (varies by guideline)
- Undetectable = successful viral suppression on treatment
- Very high HBV DNA titer → prone to develop cirrhosis and HCC [11]
| Feature | Detail |
|---|---|
| Normal | < 6 ng/mL (some labs < 10–12 ng/mL) |
| Diagnostic level for HCC | > 400–500 ng/mL (AFP > 400 ng/mL requires further investigation on HCC [25]) |
| Sensitivity | ~60-70% (30% of HCC is non-AFP-secreting) [25][27] |
| False positives | Pregnancy, germ cell tumours, acute/chronic hepatitis, liver cirrhosis, gastric cancer [25] |
| Monitoring tip | AFP can be elevated in active hepatitis (liver regeneration). Key: check if AFP comes down after flare resolves. If it keeps rising → concern for HCC [7] |
| Prognosis | AFP > 1000 ng/mL has higher risk of recurrent disease following liver transplantation regardless of tumour size [25] |
| Modality | Details | Interpretation |
|---|---|---|
| FibroScan (transient elastography) | Standard of care nowadays [7]. Non-invasive, done at bedside | Liver stiffness > 12 kPa suggestive of cirrhosis [13]. CAP score 248-280 dB/m = mild-moderate steatosis; > 280 = severe steatosis [13] |
| Liver biopsy | Gold standard but generally not done anymore, rarely performed due to invasiveness [7]. Risk: bleeding, pain, sampling error | Metavir F0-F4. ONLY method to distinguish steatosis from steatohepatitis [4]. Only useful here (as per GI Hepatology conclusions slide [17]) |
| Serum fibrosis markers | FIB-4 index, APRI score | Non-invasive calculators using age, AST, ALT, platelets. Useful for risk stratification |
| Modality | Role | Key Findings |
|---|---|---|
| Ultrasound abdomen | First-line imaging; HCC surveillance; assess liver parenchyma, spleen, ascites | Coarsened liver parenchyma in chronic hepatitis; nodular contour in cirrhosis; splenomegaly in portal hypertension; focal lesions suggesting HCC |
| Triphasic CT scan | Gold standard for HCC characterisation [6] | HCC: arterial phase hyperenhancement (rich hepatic artery supply) + portovenous/delayed phase washout (hypodense). Liver metastases: hypodense in all phases [6] |
| MRI with Primovist | If CT contraindicated or equivocal | HCC: high intensity T2, low intensity T1; hepatospecific contrast shows lack of hepatocyte uptake [6] |
| Contrast-enhanced USG | Alternative for lesion characterisation | Similar arterial enhancement pattern to CT |
HCC surveillance protocol [27]:
- USG + AFP every 6 months
- Mass ≥ 1 cm: triphasic CT
- Mass < 1 cm: repeat USG at 4 months
- Rationale: tumour doubling time of HCC ~140 days; if missed at initial scan (< 1 cm), will be ≤ 2 cm 6 months later and still operable [27]
GC High Yield — USG Findings in Acute Hepatitis
The GC 239 lecture investigation slide states the expected USG finding in acute viral hepatitis [1]: "No biliary obstruction / liver normal / no splenomegaly"
The purpose of the ultrasound is exclusion — you are ruling out biliary obstruction (which would suggest a surgical/cholestatic cause rather than hepatitis) and space-occupying lesions. A normal USG in the context of markedly elevated transaminases strongly supports a hepatitic (medical) cause.
From the approach framework [3]:
| Investigation | Purpose | Expected Findings |
|---|---|---|
| CBC | Baseline; WCC usually normal with relative lymphocytosis | Thrombocytopenia if hypersplenism from cirrhosis |
| Clotting profile / INR | Best for reflecting liver synthetic function (Factor VII half-life) [3] | Prolonged in severe hepatitis; critical in fulminant liver failure |
| Ammonia (NH₃) | Hepatic encephalopathy assessment | Elevated when liver fails to clear portal blood ammonia |
| Glucose (H'stix BD) | Liver failure can cause hypoglycaemia [3] — impaired gluconeogenesis and glycogenolysis | |
| Amylase | Exclude pancreatitis (differential for upper abdominal pain) | |
| Toxicology screen / paracetamol level | Exclude drug-induced cause | Paracetamol levels normal to exclude overdose [1] |
| ANA, anti-smooth muscle, anti-LKM-1 | Exclude autoimmune hepatitis [1] | Positive autoantibodies with elevated IgG suggest AIH |
Initial management monitoring [3]:
- DAT (diet as tolerated), Obs Q4h, H'stix BD
- Bloods: CBC, LRFT, INR, NH₃ daily
This framework from the Maksim Medicine Notes [27] is a clean way to remember what to monitor and why:
| Question | Investigation | Frequency |
|---|---|---|
| Is HBV active? | HBV DNA Q6-12 months (if active: Q3 months until undetectable × 2 visits) | |
| HBeAg and anti-HBe Q6-12 months until seroconversion | ||
| Is the liver inflamed? | LFT Q6-12 months (if active: Q3 months until normalised or undetectable HBV DNA) | |
| Is there cirrhosis? | FibroScan, OGD ± liver biopsy | Baseline + as needed |
| Is there HCC? | USG + AFP Q6 months | See surveillance criteria below |
Target patients for HCC surveillance [27][13]:
- Asian HBV carriers: male > 40 y/o; female > 50 y/o
- Any HBV carrier with cirrhosis
- Family history of HCC
- Not all patients benefit: e.g., Child C cirrhosis unless transplant candidate, limited life expectancy [27]
When a chronic HBV patient is being considered for antiviral therapy, additional baseline investigations include [28]:
| Investigation | Purpose |
|---|---|
| HBV DNA level | Baseline viral load; determines treatment threshold |
| HBeAg / anti-HBe | Determines whether treatment can potentially be finite (HBeAg+ → can stop after seroconversion + consolidation) vs. lifelong (HBeAg− → lifelong unless HBsAg loss) [7] |
| LFT including ALT | Treatment indicated when ALT elevated above threshold with significant viral load |
| FibroScan / liver biopsy | Fibrosis staging; significant fibrosis (≥ F2) generally warrants treatment regardless of ALT |
| Renal function | Baseline before tenofovir (nephrotoxic potential) |
| Bone density | Consider if tenofovir disoproxil fumarate (TDF) planned (risk of bone loss) |
| HBV genotype | Not routinely done in HK; genotype C has worse prognosis |
| Resistance testing | If prior NUC exposure with suspected resistance |
5. Putting It All Together — The Workup Sequence
Here is the practical, chronological order of investigations for a patient presenting with suspected hepatitis B:
- Bloods: CBC, LRFT, INR, ammonia, glucose, amylase
- Viral serology panel (all at once): HBsAg, anti-HAV IgM, anti-HCV, anti-HEV IgM [1]
- Autoimmune screen: ANA, anti-smooth muscle, anti-LKM-1 [1]
- Toxicology: Paracetamol level if appropriate [1]
- Imaging: USG abdomen (to exclude biliary obstruction) [1]
- If HBsAg positive: Add HBeAg, anti-HBc IgM/IgG, HBV DNA [1]
- Monitor: CBC, LRFT, INR, NH₃ daily; H'stix BD [3]
- At 6 months: Recheck HBsAg to determine if acute vs. chronic [7]
- Viral activity: HBV DNA, HBeAg/anti-HBe (Q6-12 months)
- Liver inflammation: LFT (Q6-12 months; Q3 months if active)
- Fibrosis staging: FibroScan (baseline + follow-up)
- HCC surveillance: USG + AFP Q6 months (if meets criteria)
- Complications screen: OGD for varices if cirrhosis; renal function if on tenofovir
High Yield Summary — Diagnostics for Hepatitis B
Acute HBV diagnosis: HBsAg + anti-HBc IgM (high titre). Window period: anti-HBc IgM is the only positive marker.
Chronic HBV diagnosis: HBsAg positive ≥ 6 months.
Acute vs. chronic flare: Anti-HBc IgG negative = acute; positive = chronic flare. Definitive: recheck HBsAg at 6 months.
Phase classification: HBeAg status + HBV DNA level + ALT → determines immune tolerance vs. clearance vs. inactive carrier vs. immune escape.
LFT interpretation: ALT/AST = cellular damage; INR = best prognostic marker (Factor VII half-life ~6h); falling ALT + rising INR = fulminant hepatitis (not recovery).
AFP: Elevated in inflammation AND HCC. Trend matters more than single value. 30% HCC is non-secreting.
FibroScan: Liver stiffness > 12 kPa = cirrhosis; CAP > 280 = severe steatosis.
HCC surveillance: USG + AFP Q6 months. Mass ≥ 1 cm → triphasic CT. Tumour doubling time ~140 days.
Vaccination vs. past infection: Anti-HBs only = vaccination. Anti-HBs + anti-HBc = past infection. Anti-HBc alone = distant past infection / occult HBV.
Active Recall - HBV Diagnostic Criteria, Algorithm and Investigations
[1] Lecture slides: GC 239. Viral hepatitis HAV_HBV_HCV_HEV.pdf (pp.11, 20, 32) [3] Senior notes: Maksim Medicine Notes.pdf (GI & Hepatology — Viral Hepatitis, pp.141-143) [4] Senior notes: Ryan Ho GI.pdf (Hepatitis E section, p.235) [6] Senior notes: Maksim Surgery Notes.pdf (HCC section, p.124) [7] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (pp.2-4) [9] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (pp.2, 13) [11] AOS material: AOS - Pathology.pdf (p.8) [13] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (p.2) [17] Lecture slides: Gastroenterology Hepatology Introduction to GI:Hepatology investigations from the abnormal.pdf (p.49) [19] Senior notes: Block A - Introduction to GI_Hepatology investigations (LFT, Endoscopy).pdf (pp.5, 10) [25] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp.749, 828) [26] Lecture slides: Data Interpretation (M24 slides) LFT.pdf (pp.4, 9); 1213_DI_GI_Prof_WK_Leung.ppt.pdf (pp.14-15) [27] Senior notes: Maksim Medicine Notes.pdf (p.143 — disease monitoring) [28] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (pp.473, 484) [29] Senior notes: Learning_Points_All_Lectures.txt (GI/Hepatology learning points)
Management of hepatitis B is fundamentally different depending on whether you are dealing with acute or chronic infection, and within chronic infection, whether the patient is in an immune-active or immune-tolerant phase. Before diving into specifics, understand the overarching aims.
1.1 Aims of Treatment
Three ultimate aims of treatment for chronic hepatitis B [30][4]:
- Prevent / decrease cirrhotic complications AND HCC — the reason we treat at all
- Viral suppression and reduction of liver damage:
- Viral eradication:
Why Can't We Cure HBV?
The HBV genome persists as cccDNA in hepatocyte nuclei and as integrated DNA in the host genome. Current antivirals (nucleos(t)ide analogues) inhibit the viral polymerase (reverse transcriptase step), suppressing new virion production — but they do not eliminate cccDNA. When you stop the drug, cccDNA serves as the template for viral resurgence. This is why most patients need lifelong therapy and why "functional cure" (HBsAg loss) is the aspirational but rarely achieved endpoint.
2. Management of Acute Hepatitis B
No specific treatment is needed for uncomplicated acute hepatitis B [9]:
| Measure | Detail | Rationale |
|---|---|---|
| Rest | If extremely tired, rest — but rest does not shorten the course [9] | US soldiers in Vietnam with hepatitis: those who rested vs. those who fought had the same disease duration |
| Diet | No solid diet modifications needed — eat anything [9] | Glucose drip does not help (may induce fatty liver); fatty diet is harmless [9] |
| Alcohol | No alcohol for 6 months for acute hepatitis; no alcohol for life for chronic hepatitis [9] | Alcohol is directly hepatotoxic and synergistic with HBV |
| Drugs | No known drugs or herbs that hasten recovery [9]. "Definitely do not try TCM" [9] | No evidence base for any complementary therapy |
| Monitoring | DAT, Obs Q4h, H'stix BD [3]; Bloods: CBC, LRFT, INR, NH₃ daily [3] | H'stix (capillary glucose) because liver failure can cause hypoglycaemia (impaired gluconeogenesis) |
| Follow-up | Monitor HBsAg + anti-HBc IgM 6 months later [3] | Determines if acute (clears) vs. chronic (persists) |
Antivirals are NOT required in most cases, EXCEPT [31]:
| Indication | Rationale |
|---|---|
| Acute liver failure (INR ≥ 1.5) | Reduce viral load to prevent graft reinfection if liver transplant becomes necessary [31] |
| Protracted course (persistent symptoms or marked jaundice > 4 weeks) | Suggests immune system is not clearing the virus effectively [31] |
| Immunocompromised patients | Cannot mount adequate immune response to clear virus |
| Pre-existing liver disease | Additional insult on already compromised liver |
| Concomitant HCV or HDV infection | Dual infection worsens outcomes |
- Drug of choice: entecavir [3][30]
- IFN should be avoided in acute hepatitis — increased risk of hepatic necroinflammation (IFN augments immune killing of infected hepatocytes, which in the acute setting worsens liver damage) [31]
- Stop treatment after confirmed HBsAg clearance by 2 consecutive tests 4 weeks apart [31]
If acute HBV progresses to fulminant hepatic failure [32][4]:
Five principles [32]:
- Supportive → standard ICU care
- Identify and remove/treat the insult — antivirals (entecavir) for HBV
- Manage complications (encephalopathy, coagulopathy, renal failure, sepsis, raised ICP)
- High-volume plasma exchange — washes away cytokines causing liver failure; expensive but proven [32]
- Liver transplantation — the final line after exhausting all other treatments [32]
3. Management of Chronic Hepatitis B
Every chronic HBV carrier should receive comprehensive education [27]:
| Domain | Measure | Rationale |
|---|---|---|
| Alcohol | Avoid alcohol | Synergistic hepatotoxicity; accelerates fibrosis |
| Drugs | Avoid hepatotoxic drugs (including TCM, NSAIDs) | Direct liver injury on already compromised hepatocytes |
| Vaccination | Immunisation for hepatitis A | HAV superinfection on chronic HBV can cause devastating acute-on-chronic liver failure |
| Transmission prevention | Sexual: vaccination of spouse/steady partners, safe sex with barrier contraception | HBV is highly infectious sexually |
| MTCT: perinatal TDF, HBV vaccine + HBIG for newborn | Prevents vertical transmission | |
| Environmental: avoid sharing razors/toothbrushes/needles, avoid donating blood/organs | Prevents parenteral transmission |
This is the most clinically important and exam-relevant topic. The key principle: treat when there is both active viral replication AND active liver disease — this corresponds to the immune clearance (or immune escape) phase, not the immune tolerance phase [30][4].
HK Hospital Authority / Internal Medicine Handbook indications for oral antiviral therapy [33]:
1. ALT > ULN AND HBV DNA ≥ 2000 IU/mL (if HBeAg-positive, may consider observing 3-6 months for spontaneous e-seroconversion)
2. Significant fibrosis or cirrhosis with detectable HBV DNA
3. Hepatitis B infection with decompensated liver disease
4. HCC with detectable HBV DNA
5. Pre-emptive treatment before certain chemotherapy or immunosuppressive therapy
6. Hepatitis B reactivation during chemotherapy
7. Pregnant women with HBV DNA > 200,000 IU/mL (start at 3rd trimester and continue for up to 12 weeks after delivery) — use TDF
8. Transplant patient with hepatitis B infection
EASL 2017 guidelines (least restrictive — ensures more patients treated) [30]:
- All patients regardless of HBeAg status with: ALT > ULN + HBV DNA > 2000 IU/mL + moderate necroinflammation/fibrosis
Why NOT Treat During Immune Tolerance?
During immune tolerance, HBV DNA is extremely high but ALT is normal — meaning the virus is replicating freely but the immune system is not attacking hepatocytes, so there is minimal liver damage. Antivirals suppress viral replication but do not eliminate cccDNA. If you start antivirals in this phase, you commit the patient to lifelong therapy without clear short-term benefit (no hepatitis to suppress). Practically, treatment should start in the immune clearance phase, defined by elevated ALT [4]. However, HBV DNA levels for treatment indication are being increasingly lowered, and it is increasingly recognised that disease can be active even with low ALT levels [30].
HBeAg status is crucial for determining whether treatment can be finite or lifelong [7]:
| HBeAg Status at Treatment Start | Can You Stop Treatment? | Condition |
|---|---|---|
| HBeAg positive | Yes, potentially | Can stop antiviral treatment once quiescent (e-seroconverted + undetectable HBV DNA + normal ALT for at least 12 months of consolidation) [7]. However, still good practice to keep antivirals for a longer time to prevent flare-ups [7]. 30% recurrence [3] |
| HBeAg negative | No — need lifelong | Unless they lose their HBsAg [7] |
Current endpoints for stopping treatment [31]:
- Loss of HBsAg (ideal, rarely achieved)
- HBeAg seroconversion (for HBeAg+ patients → continue 12 more months then consider stopping)
- Undetectable HBV DNA by PCR
- Normalisation of ALT < 0.5 ULN
For immune-tolerant patients, management is monitoring [4]:
- ALT Q6 months
- HBsAg Q1 year
- HBeAg/anti-HBe Q6-12 months
- Consider treatment if evidence of progression to active disease (↑ ALT, biopsy showing activity)
- HCC screening: USG ± AFP Q6 months (even in immune tolerance, HCC can develop from DNA integration)
4. Pharmacological Treatment — Drug Classes
There are two major groups of pharmacological treatment for chronic hepatitis B [30]:
These are the mainstay of current treatment. The name tells you the mechanism: they are analogues (mimics) of nucleosides/nucleotides — the building blocks of DNA. They competitively inhibit the HBV polymerase (reverse transcriptase), blocking viral DNA synthesis.
The HA Handbook lists three first-line options [33]:
| Drug | Dose | Key Characteristics | When Preferred |
|---|---|---|---|
| Entecavir (ETV) | 0.5 mg daily PO (1 mg daily if lamivudine-refractory or decompensated liver disease) [33] | High genetic barrier to resistance; very low resistance rate (1.2% at 5 years in NUC-naïve) | General first-line |
| Tenofovir disoproxil fumarate (TDF) | 300 mg daily PO [33] | No resistance reported to date; nephrotoxic potential; bone density effects | Preferred when: resistance to prior NUC treatment; women of child-bearing age; pregnant women with HBV DNA > 200,000 IU/mL; underlying HIV infection [33] |
| Tenofovir alafenamide (TAF) | 25 mg daily PO [33] | Prodrug of tenofovir with less systemic exposure → better renal and bone safety | Preferred when: at risk of deteriorating renal function or low eGFR; bone disease, osteopenia, or osteoporosis [33]. Not recommended for decompensated (Child-Pugh B/C) hepatic impairment [33] |
Dose adjustments are needed in patients with renal dysfunction [33]
Older/inferior NUCs (important for context but NOT first-line):
| Drug | Problem |
|---|---|
| Lamivudine | High resistance rate (up to 70% at 5 years) — only use if nothing else available or for short-term prophylaxis in very low-risk patients. Still requires frequent monitoring of LFT and HBV DNA if used [30] |
| Adefovir | Lower resistance but nephrotoxic; superceded by tenofovir |
| Telbivudine | Moderate resistance; associated with myopathy |
Entecavir vs. Tenofovir — How to Choose
Both ETV and TDF/TAF have equivalently high efficacy and low resistance. The choice depends on patient factors:
- Renal impairment or osteoporosis → TAF preferred (less nephrotoxicity and bone loss than TDF)
- Pregnancy / women of child-bearing age → TDF preferred (most safety data in pregnancy)
- Prior lamivudine resistance → TDF/TAF preferred (cross-resistance with ETV if lamivudine-resistant mutations exist)
- Decompensated cirrhosis → ETV 1 mg or TDF (TAF not recommended)
- HIV co-infection → TDF preferred (also active against HIV; ETV monotherapy has suboptimal HIV activity and can select HIV resistance)
Interferons work by a completely different mechanism: they don't directly kill the virus but instead boost the immune system's ability to clear infected hepatocytes and have direct antiviral effects (degrade viral mRNA, inhibit viral protein synthesis).
| Type | Route | Duration | Key Features |
|---|---|---|---|
| Interferon-α | SC injection, 3× per week, 4-6 months [31] | Finite | Not commonly used nowadays [31] |
| Pegylated interferon-α (PEG-IFN) | SC injection, 1× per week, 12 months [31] | Finite | PEG = polyethylene glycol — no activity against virus itself; allows interferon to stay in body much longer [31] |
Advantages of IFN [31]:
- No resistant mutation (immune-mediated, not targeting viral polymerase)
- Finite period of treatment (partly related to side effects — you can't tolerate it indefinitely)
- More HBsAg seroconversion (higher chance of "functional cure")
- More HBeAg seroconversion
Disadvantages of IFN [31]:
- Moderate side effects (see below)
- Detectable HBV DNA by PCR despite HBeAg seroconversion (doesn't suppress virus as completely as NUCs)
- Unable to decrease incidence of liver cirrhosis (paradoxically, because it increases immune-mediated hepatocyte killing)
- Hepatotoxicity in cirrhosis (augmented immune attack on a liver already damaged)
Contraindications of IFN [31]:
- Pregnancy
- Children
- Liver cirrhosis / decompensated liver disease (risk of precipitating hepatic decompensation by enhanced immune killing)
Side Effects of IFN [31]:
| Category | Side Effects | Mechanism |
|---|---|---|
| Flu-like symptoms | Fever, fatigue, myalgia, headache | Direct interferon effect on cytokine release |
| Autoimmune reactivation | Autoimmune thyroiditis, autoimmune hepatitis | Immune stimulation can unmask latent autoimmunity |
| Hepatic decompensation | Decompensation of cirrhosis | Further killing of virus by destroying infected hepatocytes — too much collateral damage in a cirrhotic liver [31] |
| Neuropsychiatric | Depression (± suicidal), bipolar disorders, schizophrenia | Interferon-induced serotonin pathway disruption |
| Myelosuppression | Anaemia, neutropenia, leukopenia | Interferon inhibits haematopoietic progenitor proliferation |
| Others | Diarrhoea, alopecia, rapid tachyphylaxis |
IFN vs. NUCs — Summary
In modern HK practice, NUCs (entecavir, TDF/TAF) are the standard of care because they are oral, well-tolerated, potent, and safe even in cirrhosis. PEG-IFN is reserved for select patients — typically young, non-cirrhotic, with low viral load and high ALT (best chance of immune-mediated clearance), who strongly prefer a finite treatment course. Most hepatologists in HK use NUCs as first-line [30].
5. Special Situations
This is a critical clinical scenario and exam favourite [30]:
Screening before immunosuppression [30]:
- Check HBsAg, anti-HBs, anti-HBc for ALL patients planned for immunosuppressive therapy
- If HBsAg positive OR anti-HBc positive → check baseline HBV DNA + LFT
- For anti-CD20 (rituximab) / anti-CD52: if ANY HBV marker positive → check baseline HBV DNA + LFT [30]
Management of HBsAg+ patients requiring immunosuppression [30]:
- Start prophylactic antiviral therapy irrespective of baseline HBV DNA levels
- Superior and safer than monitoring for reactivation and treating when it occurs [30]
- Choice of agent: entecavir or TDF/TAF (low resistance profiles) [30]
- Duration:
For occult HBV (HBsAg−, anti-HBc+) [30]:
- Same principle — if in doubt, just start prophylactic antivirals. They are cheap drugs with not a lot of side effects [30]
From GC 239 lecture and HA Handbook [1][33]:
- All pregnant women: screen for HBsAg
- If HBV DNA > 200,000 IU/mL: start TDF in 3rd trimester, continue up to 12 weeks after delivery [33]
- Neonate: HBV vaccine + HBIG within 12 hours of birth
- Post-vaccination serologic testing: test baby for HBsAg and anti-HBs after completing 3-dose vaccination [1]
- Breastfeeding is safe if neonate has received vaccine + HBIG
Common in HK (dual liver disease) [13]:
- Weight loss of 5-7% sufficient to reduce liver fat in non-fibrosis patients; 10% in fibrosis patients [13]
- GLP-1 receptor agonists: emerging evidence for MAFLD, on top of DM and obesity [13]
- Coffee: beneficial for fatty liver [13]
- Treat HBV and MAFLD concurrently
| Parameter | Frequency | Purpose |
|---|---|---|
| HBV DNA | Q3 months until undetectable × 2 visits, then Q6-12 months [27] | Assess viral suppression; detect virological breakthrough |
| ALT | Q3 months until normalised, then Q6-12 months [27] | Assess biochemical response |
| HBeAg / anti-HBe | Q6-12 months until seroconversion [27] | Determines if treatment can be stopped |
| HBsAg (quantitative) | Q1 year | Declining HBsAg may predict eventual clearance |
| Renal function | Q6-12 months (especially TDF) | Detect nephrotoxicity (proximal tubular dysfunction) |
| Bone density | Baseline + as needed (TDF) | Detect TDF-related bone loss |
| HCC surveillance (USG + AFP) | Q6 months | Even on effective antiviral, HCC risk reduced but not eliminated |
| FibroScan | Annually or as needed | Monitor fibrosis regression (can occur with viral suppression) |
| Complication | Management (Brief) |
|---|---|
| Cirrhosis (compensated) | Antiviral if any detectable HBV DNA (lower threshold than non-cirrhotic); OGD for variceal screening; HCC surveillance |
| Cirrhosis (decompensated) | Entecavir 1 mg or TDF; refer for liver transplant assessment; manage ascites, SBP, HE, variceal bleeding |
| HCC | Curative: hepatectomy, RFA (< 2 cm), liver transplant (Milan criteria: single ≤ 5 cm or ≤ 3 lesions each ≤ 3 cm) [34]. Palliative: TACE, TARE, sorafenib/lenvatinib, immunotherapy [4] |
| Acute-on-chronic liver failure | ICU; antivirals; manage complications; high-volume plasma exchange; consider liver transplant [32]. HBV-related ACLF is most common in HK/Asia-Pacific [32] |
High Yield Summary — Management of Hepatitis B
Acute HBV: Supportive. No antivirals unless INR ≥ 1.5, jaundice > 4 weeks, immunocompromised, or fulminant. Drug of choice: entecavir. IFN is contraindicated. No alcohol × 6 months. Recheck HBsAg at 6 months.
Chronic HBV — when to treat: ALT > ULN + HBV DNA ≥ 2000 IU/mL; cirrhosis with detectable HBV DNA; decompensated liver disease; pre-immunosuppression; pregnancy with HBV DNA > 200,000.
First-line drugs: Entecavir 0.5 mg daily (1 mg if lamivudine-resistant or decompensated); TDF 300 mg daily (preferred in pregnancy, prior resistance, HIV); TAF 25 mg daily (preferred in renal/bone disease; avoid in decompensated cirrhosis).
Treatment duration: HBeAg+ → can stop after e-seroconversion + 12 months consolidation (30% recurrence). HBeAg− → lifelong unless HBsAg loss.
IFN: Finite course, higher HBsAg clearance, but contraindicated in cirrhosis, pregnancy, children. Many side effects. Rarely used as first-line in HK.
Reactivation prevention: Screen HBsAg + anti-HBc before immunosuppression. If positive, start prophylactic ETV or TDF. Continue 6-12 months after stopping immunosuppression.
Pregnancy PMTCT: TDF from 3rd trimester if HBV DNA > 200,000; HBIG + vaccine for neonate within 12 hours.
Active Recall - Management of Hepatitis B
[1] Lecture slides: GC 239. Viral hepatitis HAV_HBV_HCV_HEV.pdf (pp.57) [3] Senior notes: Maksim Medicine Notes.pdf (GI & Hepatology — Viral Hepatitis, pp.141-143) [4] Senior notes: Ryan Ho GI.pdf (pp.207, 226, 266) [7] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (p.4) [9] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (p.3) [13] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (p.2) [27] Senior notes: Maksim Medicine Notes.pdf (p.143 — disease monitoring) [30] Senior notes: Block A - I am a hepatitis B carrier.pdf (pp.38, 40, 70) [31] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp.750-751, 762) [32] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf (p.24) [33] Lecture slides: Handbook of Internal Medicine 2024.pdf (p.123 — G36) [34] Senior notes: Maksim Surgery Notes.pdf (pp.125-127)
The complications of hepatitis B span the full spectrum from acute liver failure to chronic cirrhosis, portal hypertension, and malignancy. Understanding them requires appreciating that HBV's damage is cumulative and immune-mediated — the longer you have inflammation, the more likely you get fibrosis/cirrhosis [7]. Every complication can ultimately be traced back to either ongoing hepatocyte destruction, loss of hepatic synthetic/excretory/metabolic function, or the unique ability of HBV to directly cause carcinogenesis.
Six associated complications of liver failure (and by extension, chronic HBV progressing to cirrhosis) [35]:
- Infections
- Variceal bleeding
- Ascites / Spontaneous bacterial peritonitis (SBP)
- Hepatorenal syndrome
- Hepatic encephalopathy
- (Coagulopathy)
- (Hepatocellular carcinoma — you must ask for this during history for any patient with cirrhosis) [35]
These complications essentially define the transition from compensated to decompensated cirrhosis. Poor survival once cirrhosis becomes decompensated [7].
2. Acute Complications
- Occurs in ~0.1-0.5% of acute HBV infections [4]
- Represents massive immune-mediated hepatocyte destruction outstripping the liver's regenerative capacity
- Defined by the development of hepatic encephalopathy within 8 weeks of onset of symptoms in a patient without pre-existing chronic liver disease
- Falling ALT with rising INR is the ominous sign — not enough hepatocytes left to release enzymes, and not enough to synthesise clotting factors [9]
Pathophysiology:
- Overwhelming cytotoxic T-cell attack on HBV-infected hepatocytes → massive necrosis → loss of all hepatic functions simultaneously (synthetic, metabolic, excretory, detoxification)
- Complications: cerebral oedema (failure to clear ammonia), coagulopathy (failure to synthesise factors), hypoglycaemia (failure of gluconeogenesis), infection (loss of reticuloendothelial function), renal failure (hepatorenal physiology)
Definition: acute liver insult manifesting as jaundice and INR > 1.5, complicating within 4 weeks by ascites and/or encephalopathy in patients with underlying chronic liver disease [35][4].
HBV-related ACLF is the most common cause in HK and the Asia-Pacific region (but is decreasing because the diagnostic rate of chronic HBV is increasing — fewer patients are going unnoticed) [35].
Causes of ACLF in HBV carriers [35]:
- Severe exacerbation of undiagnosed HBV
- Immunosuppressive agents (steroids, rituximab) — upon withdrawal
- Superimposed HAV/HEV
- Other systemic infections (pneumonia, UTI, soft tissue)
- Hepatotoxic drugs/herbs, alcoholic hepatitis
Prognosis of ACLF — assessed by 6 organ-specific factors [35]:
| Organ | Parameter |
|---|---|
| Cerebral | Hepatic encephalopathy grade |
| Respiration | SaO₂/FiO₂ |
| Circulation | Need for vasopressors |
| Liver | Bilirubin level |
| Coagulation | INR level |
| Kidney | Creatinine level |
All 3 components of the MELD score (bilirubin, INR, creatinine) are present in the ACLF prognostic criteria — so the MELD score is still useful for prognosticating ACLF [35]. 28-day mortality > 20% [35].
3. Hepatitis Flares (Acute Exacerbations)
Apart from malignancy, hepatitis episodes (acute flares) often complicate the course of chronic hepatitis B [12]. These can be with or without symptoms [12].
| Cause | Mechanism |
|---|---|
| "Spontaneous" reactivation | IgM anti-HBc levels rise but not as high as in acute hepatitis B [12] |
| Clearance of HBeAg (spontaneous or during therapy) — e-seroconversion | Immune flare as CTLs intensify attack; not always successful → repeated severe acute exacerbations [12][36] |
| e-Seroreversion (anti-HBe+ → HBeAg+) | Loss of immune control → resurgence of viral replication [12] |
| Emergence of resistant variants / non-compliance during NUC therapy | Drug-resistant mutants replicate unchecked [12] |
| Corticosteroid or immunosuppressant withdrawal, especially anti-CD20 | During steroid treatment actually fine — it is the WITHDRAWAL that activates a massive immune response [12]. Can be potentially dangerous and fatal, especially in decompensated liver disease, abnormal immune system (lymphoma, leukaemia), and occasionally even in "normal" patients [30] |
| Superinfection by hepatitis D | Very rare in Chinese [12] |
| Superinfection with other viral agents, especially HAV and HEV | More important than HDV; HEV more common now [12] |
| Drug-induced hepatic injury, including alcohol, TCM/herbal tea | Direct hepatotoxicity [12] |
Repeated flares are a major driver of disease progression. Cirrhosis occurs more frequently in [36]:
- Older age — more time for cumulative damage
- Hepatic decompensation during follow-up
- Repeated severe acute exacerbations characterised by:
- AFP > 100 ng/mL (AFP is produced by regenerating liver cells, not just tumours — so elevated AFP reflects regenerative nodule formation, a hallmark of cirrhosis) [36]
- Bridging necrosis — severe injury where necrosis extends zonally from one lobule to another (portal-portal, central-central, or portal-central) linking vasculature between lobules [36]
- Unsuccessful HBeAg seroconversion — multiple immune attacks without clearance [36]
- HBV reactivation with HBeAg seroreversion [36]
4. Cirrhosis
- Annual incidence of cirrhosis: 2.4% for HBeAg+ patients, 1.3% for anti-HBe+ patients [12]
- For chronic HBsAg carriers, 25% die of liver diseases (50% for males, 14% for females) [4]
- > 70% of HCC and cirrhosis complications occur in anti-HBe+ patients, even in patients with "normal" ALT [12] — this seems paradoxical but is explained by:
- The anti-HBe phase spans decades (much longer than the HBeAg+ phase)
- Pre-core mutant viruses continue causing damage without HBeAg production
- Cumulative fibrosis from prior immune clearance phase takes time to manifest clinically
Chronic immune-mediated hepatocyte destruction → hepatic stellate cell activation → collagen deposition → fibrosis → diffuse distortion of liver architecture with formation of regenerative nodules surrounded by fibrous bands = cirrhosis [5]. The fibrotic bands distort the hepatic vasculature, creating resistance to portal blood flow → portal hypertension → all downstream complications.
Probably — more and more evidence suggesting yes, to some extent [5]:
4.4 Complications of Cirrhosis (Portal Hypertension-Related)
Once cirrhosis develops, the complications are driven by portal hypertension and hepatic insufficiency:
Pathophysiology: Portal hypertension (portal pressure > 12 mmHg) → blood seeks alternative routes back to the systemic circulation via portosystemic collaterals → oesophageal and gastric varices dilate under high pressure → thin-walled veins prone to rupture → massive upper GI haemorrhage.
- Screening: OGD recommended Q2-3 years in cirrhotic patients [4]
- Prophylaxis: Non-selective beta-blockers (propranolol, carvedilol) or endoscopic variceal ligation (EVL)
- Acute management: Resuscitation + IV terlipressin (splanchnic vasoconstrictor) + IV antibiotics + urgent OGD with EVL ± glue injection for gastric varices
Pathophysiology: Portal hypertension → splanchnic vasodilation → effective arterial underfilling → RAAS and sympathetic nervous system activation → sodium and water retention → fluid transudation into the peritoneal cavity, exacerbated by low oncotic pressure (hypoalbuminaemia from impaired hepatic synthesis).
- Management: Sodium restriction, diuretics (spironolactone ± furosemide), therapeutic paracentesis for tense ascites (with albumin replacement), TIPS for refractory ascites
Pathophysiology: Bacterial translocation from the gut (portal hypertension impairs intestinal barrier function) → bacteria enter ascitic fluid which has low opsonic activity (protein < 10 g/L) → infection in the absence of an intra-abdominal surgical source.
Pathophysiology: Extreme splanchnic vasodilation → maximal RAAS activation → intense renal vasoconstriction → functional renal failure (kidneys are structurally normal). The kidneys are "innocent bystanders" — they are responding appropriately to what they perceive as hypovolaemia.
- Type 1 (acute): Rapid doubling of creatinine to > 226 μmol/L within 2 weeks; poor prognosis
- Type 2 (chronic): Gradual; often associated with refractory ascites
- Management: IV terlipressin + IV albumin; liver transplant is definitive
Pathophysiology: Failing liver cannot clear ammonia and other gut-derived neurotoxins from portal blood → these cross the blood-brain barrier → astrocyte swelling (ammonia is converted to glutamine in astrocytes, an osmolyte causing cellular oedema) → cerebral dysfunction.
- Precipitants: GI bleeding (protein load → ammonia production), infection/sepsis, constipation, electrolyte imbalance (hypokalaemia, alkalosis), medications (sedatives, diuretics), dehydration, portosystemic shunting
- Grading: Grade I (confusion, mood change) → Grade II (drowsy, asterixis) → Grade III (somnolent, responsive to stimuli) → Grade IV (coma)
- Management: Treat precipitant; lactulose (osmotic laxative — traps ammonia as NH₄⁺ in the colon for excretion); rifaximin (non-absorbable antibiotic — reduces ammonia-producing gut bacteria)
Pathophysiology: The liver synthesises virtually all clotting factors (except vWF and Factor VIII). Cirrhosis → impaired synthesis → bleeding tendency. Additionally, thrombocytopenia from hypersplenism (portal hypertension → splenomegaly → splenic sequestration of platelets).
- INR is the most sensitive early marker (Factor VII has shortest half-life ~6 hours) [9]
- Management: Vitamin K (if deficient — especially in cholestasis); FFP or prothrombin complex concentrate for active bleeding; platelet transfusion if < 50 with active bleeding
Infections in liver failure are very common [35]. Why?
- Reticuloendothelial dysfunction and reduced opsonisation — the failing liver cannot clear bacteria and toxins from portal blood [35]
- Impaired production of complement, fibronectin, and other opsonins [35]
- Gut bacterial translocation (portal hypertension disrupts gut mucosal barrier)
Causative organisms [35]:
- Bacteria: especially from respiratory and urinary tract — Staph, Strep, gram-negative rods
- Bacteraemia in up to 25% of fulminant hepatic failure patients [35]
- Fungal infection: especially Candida (but bacterial is still most common) [35]
5. Hepatocellular Carcinoma (HCC)
HCC is the most feared complication of chronic HBV and the primary reason we treat and surveil.
- Most common primary liver cancer (80%) [6][24]
- 80% of HCC in Hong Kong are HBsAg positive [24]
- M:F = 4:1; most in age > 50 years but can occur in young patients [24]
- 80% associated with liver cirrhosis in HK [24]
- 3rd leading cause of cancer mortality in Hong Kong [6]
The "80% tumour" mnemonic for HCC [6]:
80% of primary liver cancer; 80% due to HBV; 80% associated with liver cirrhosis; 80% treated non-surgically; 80% recur even with surgical resection
Two mechanisms (covered in Part 1, briefly recapped):
- Indirect (cirrhosis pathway): Chronic inflammation → cirrhosis → regenerative/dysplastic nodules → HCC
- Direct (DNA integration pathway): HBV DNA integrates via DR-I/DR-II → insertional mutagenesis → oncogene activation (HBx transactivation). This is why HBV can cause HCC without cirrhosis [13]
From the complications lecture [31]:
| Factor | Mechanism |
|---|---|
| High HBV DNA level | Associated with increased incidence of cirrhosis, HCC, and liver-related mortality (REVEAL study) [11][31] |
| HBeAg status | Prolonged HBeAg+ replication phase = worse prognosis due to ongoing immune-mediated destruction [31]. But > 70% of HCC occurs in anti-HBe+ phase [12] |
| HBsAg level | High HBsAg levels associated with increased risk of disease progression and HCC [31] |
| ALT 1-2× ULN | Paradoxically, highest risk of complications — higher ALT (2-6× ULN) actually carries less risk [30] |
Late presentation + absence of pathognomonic symptoms → difficult diagnosis [24][6]:
| Feature | Pathophysiology |
|---|---|
| RUQ pain ± right shoulder pain | Glisson's capsule distension. No nerve fibres in liver parenchyma → asymptomatic until > 8 cm when capsule stretches [31][24] |
| Hepatomegaly | Tumour mass effect |
| Decompensation of cirrhosis | Tumour replacing functioning hepatic parenchyma |
| Intraperitoneal haemorrhage (ruptured HCC) | HCC is a hypervascular tumour with propensity for capsular rupture → presents with severe abdominal pain, peritoneal signs, and shock [31]. Treatment: TAE; uncontrolled bleeding → laparotomy [31] |
| Paraneoplastic syndromes | Erythrocytosis (EPO), hypoglycaemia (IGF-2 + high metabolic demand), hypercalcaemia (PTHrP), hypercholesterolaemia (autonomous synthesis), watery diarrhoea (VIP) [6] |
| Metastasis | Intrahepatic (via portal vein), lung (most common distant), bone, brain, peritoneum [6] |
Four reasons for poor prognosis [31]:
- Present in the late stage — asymptomatic when tumour < 8 cm; no nerve fibres in the liver [31]
- Majority have underlying liver cirrhosis which limits scope for resection — 80% in HBV, 100% in HCV/alcohol [31]
- Early venous permeation (HBV is a vascular tumour with high propensity for venous invasion of portal and hepatic veins) → early metastasis and portal vein thrombosis [24]
- Field cancerisation effect — the whole liver is exposed to oncogenic influence of HBV/HCV or cirrhosis → multiple small tumours at sites not yet identified [31]
These are not caused by liver failure per se, but by chronic immune stimulation and circulating immune complexes:
| Complication | Mechanism | Details |
|---|---|---|
| Polyarteritis nodosa (PAN) | HBsAg-anti-HBs immune complex deposition in medium-vessel walls | Necrotising vasculitis; HBV is one of the few known causes of PAN |
| Membranous nephropathy | HBeAg-anti-HBe immune complex deposition in glomerular basement membrane | Most common renal manifestation of HBV; HBV-related membranous nephropathy is treatable with antivirals (e.g. lamivudine) [37] |
| Membranoproliferative GN | Immune complex deposition | Less common than membranous |
| Aplastic anaemia | Immune-mediated destruction of haematopoietic stem cells; hepatitis is well known to precede aplastic anaemia [15] | Typically occurs after acute hepatitis (seronegative or HBV-associated) |
| Mixed cryoglobulinaemia | Immune complexes precipitating in cold | Less common than in HCV |
7. Coinfection Complications
- Shortens duration of HBsAg antigenaemia and increases rate of HBsAg seroconversion
- Reduces peak serum aminotransferase and HBV DNA levels
- But increases risk of severe hepatitis, HCC, and fulminant hepatic failure [31]
- Treatment of HCV with DAAs may cause increased HBV replication and flare → fulminant liver failure [31]
- Must either give HBV antivirals together with DAAs for HCV, or monitor HBV DNA closely [31]
8. Drug-Related Complications
This has been discussed in management but is also a major complication category. The two highest-risk drugs [30]:
- Anti-CD20 (rituximab) — profound B-cell depletion → loss of immune surveillance → HBV replicates from cccDNA → immune reconstitution upon drug cessation → massive immune flare → fulminant hepatic failure [30]
- Reactivation can occur over 11 months after the last cycle of rituximab — because profound depletion of B cells takes 1 year to recover, and once they recover, these B cells prime T cells, which then damage the liver [30]
- Can be FATAL — Prof CL Lai's first case: 78-year-old lady treated with rituximab for lymphoma, recovered from lymphoma but died from fulminant liver failure 11 months after stopping rituximab [30]
- Anti-CD52 (alemtuzumab) — used in B-CLL and as 3rd line in relapsing-remitting MS in HA [30]
Rituximab and HBV Reactivation — Must-Know for Exams
The mnemonic RIT for rituximab [37b]:
- R = Reactivation (especially hepatitis B)
- I = Infusion reaction
- T = Thorax (PJP/PCP)
Presence of anti-HBs appears to have some protective benefit against HBV reactivation in lymphoma patients on rituximab (68.3% vs. 34.4%) [30] — but does NOT eliminate risk entirely.
Key principle: if in doubt, just start prophylactic antivirals. They are cheap drugs with not a lot of side effects [30].
- Lamivudine: highest resistance (up to 70% at 5 years) — emergence of YMDD mutants
- Entecavir: very low resistance (1.2% at 5 years in NUC-naïve); higher if prior lamivudine resistance
- TDF/TAF: no resistance reported to date
- Resistance manifests as virological breakthrough (> 1 log rise in HBV DNA from nadir) followed by biochemical breakthrough (ALT rise)
| Phase | Key Complications |
|---|---|
| Acute HBV | Fulminant hepatic failure (~0.1-0.5%); serum sickness-like syndrome (immune complexes) |
| Chronic HBV — immune tolerance | Generally none (minimal liver damage); but HCC surveillance still needed (DNA integration) |
| Chronic HBV — immune clearance | Hepatitis flares; progressive fibrosis; ACLF |
| Chronic HBV — inactive carrier | Reactivation risk (spontaneous or immunosuppression-triggered); HCC (> 70% of complications occur in this phase) |
| Cirrhosis — compensated | Portal hypertension developing; variceal formation; HCC risk |
| Cirrhosis — decompensated | Variceal bleeding, ascites/SBP, hepatic encephalopathy, hepatorenal syndrome, coagulopathy, infections, HCC |
| Any phase | Extrahepatic: PAN, membranous nephropathy, aplastic anaemia, cryoglobulinaemia |
High Yield Summary — Complications of Hepatitis B
6 complications of liver failure: Infections, variceal bleeding, ascites/SBP, hepatorenal syndrome, hepatic encephalopathy, coagulopathy. Always ask about HCC in any cirrhotic patient.
Acute: Fulminant hepatic failure (0.1-0.5%); falling ALT + rising INR = ominous. ACLF most commonly HBV-related in HK.
Flares: Spontaneous, e-seroconversion, immunosuppressant withdrawal (anti-CD20 most dangerous), superinfection (HAV/HEV >> HDV), drugs/TCM/alcohol.
Cirrhosis progression: Annual incidence 2.4% (HBeAg+). Risk factors: older age, repeated flares, AFP > 100, bridging necrosis, unsuccessful e-seroconversion. Cirrhosis is probably reversible with long-term NUC therapy.
HCC — the "80% tumour": 80% primary liver cancer, 80% HBV, 80% cirrhosis, 80% non-surgical, 80% recur. Poor prognosis because late presentation, underlying cirrhosis, early venous invasion, field cancerisation. HBV unique: can cause HCC without cirrhosis.
Extrahepatic: PAN, membranous nephropathy, aplastic anaemia.
Reactivation: Rituximab is highest risk; screen anti-HBc before all immunosuppression; prophylactic antivirals are cheap and save lives.
Active Recall - Complications of Hepatitis B
[4] Senior notes: Ryan Ho GI.pdf (pp.208, 222, 224, 315) [5] Senior notes: Block A - Abdominal distension_ ascites and cirrhosis.pdf (pp.2-3, 16) [6] Senior notes: Maksim Surgery Notes.pdf (pp.124-125) [7] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (pp.3-4) [9] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (p.2) [11] AOS material: AOS - Pathology.pdf (p.8) [12] Senior notes: Block A - I am a hepatitis B carrier.pdf (pp.26-28) [13] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (p.2) [15] Senior notes: Block A - Hematology Data Interpretation.pdf (p.1) [24] Lecture slides: WCS 064 - A large liver - by Prof R Poon.pdf (p.3) [27] Senior notes: Maksim Medicine Notes.pdf (p.143) [30] Senior notes: Block A - I am a hepatitis B carrier.pdf (pp.38, 68-70) [31] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp.753, 840) [35] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf (p.12) [36] Senior notes: Block A - I am a hepatitis B carrier.pdf (p.27 — development of cirrhosis) [37] Senior notes: learning_points_output.txt (Nephrology — HBV membranous nephropathy) [37b] Senior notes: Ryan Ho Rheumatology.pdf (p.55 — rituximab RIT mnemonic)
High Yield Summary
Definition: HBV is an immune-mediated liver disease caused by a DNA hepadnavirus. Chronic HBV = HBsAg persistence > 6 months.
Epidemiology (HK): ~8% chronic carrier rate; most common cause of cirrhosis (~75%); universal vaccination since 1988.
Transmission: Vertical (most important in HK), parenteral, sexual, close contact. NOT airborne or faecal-oral.
Risk of Chronicity: 90% in neonates, 2% in adults — due to immature immune system + viral immune evasion (HBsAg decoy, HBx, polymerase suppression of TLR, HBeAg suppression of TLR-2/CD28/CD86).
Virology: dsDNA virus; cccDNA in nucleus = reason for incurability; DR-I/DR-II for genomic integration = direct carcinogenesis pathway; pre-core mutant (TAG stop codon) = false HBeAg negativity.
Natural History Phases: Immune tolerance → Immune clearance → Inactive carrier → ± HBeAg-negative hepatitis → ± Functional cure.
Key Serological Patterns: HBsAg (infection), anti-HBs (immunity/vaccination), HBeAg (replication), anti-HBc IgM (acute/flare), anti-HBc total (ever infected), HBV DNA (viral load). Vaccination = anti-HBs ONLY. Past infection = anti-HBs + anti-HBc.
Clinical Features: Often asymptomatic. Preicteric → icteric → convalescent phases. Extrahepatic: PAN, membranous nephropathy, aplastic anaemia. Flares: spontaneous, immunosuppressant withdrawal, superinfection.
Monitoring: INR is best prognostic marker in acute hepatitis. FibroScan (> 12 kPa = cirrhosis). AFP can be elevated in inflammation, not just HCC.
HCC Surveillance: Male ≥ 40, Female ≥ 50, any cirrhosis, family history → USG + AFP q6 months. HBV is unique — causes HCC WITHOUT cirrhosis.
Prevention: Vaccine (0, 1, 6 months); HBIG for neonates of HBsAg+ mothers; tenofovir in pregnancy if HBV DNA > 200,000 IU/mL; screen anti-HBc before immunosuppression.
High Yield Summary — Differential Diagnosis of Hepatitis B
When to consider HBV: Any patient with hepatitic LFT pattern, especially with risk factors for parenteral/vertical transmission. In HK, HBV is the most common cause of chronic liver disease.
Key DDx for acute hepatitis: Viral (HAV, HBV, HCV, HEV + EBV/CMV), DILI, alcoholic, ischaemic, autoimmune, Wilson disease.
Acute HBV vs. acute flare of chronic HBV: Anti-HBc IgM titre (very high = acute; lower = flare), anti-HBc IgG (negative = acute; positive = chronic), definitive answer at 6 months (HBsAg clearance = acute).
Known HBV carrier with deranged LFT: Always consider superinfection (HAV, HEV >> HDV), concomitant MAFLD (very common in HK), DILI (including TCM), HCC, alcohol.
Distinct LFT patterns: Alcoholic (AST > ALT, < 500); Ischaemic (rapid rise/fall, ↑LDH, normal ALP); Viral (ALT > AST, 200-5000).
AFP trap: Elevated in inflammation, not just HCC. Watch the trend — falling with clinical recovery = benign; persistently rising = worrisome for HCC.
High Yield Summary — Diagnostics for Hepatitis B
Acute HBV diagnosis: HBsAg + anti-HBc IgM (high titre). Window period: anti-HBc IgM is the only positive marker.
Chronic HBV diagnosis: HBsAg positive ≥ 6 months.
Acute vs. chronic flare: Anti-HBc IgG negative = acute; positive = chronic flare. Definitive: recheck HBsAg at 6 months.
Phase classification: HBeAg status + HBV DNA level + ALT → determines immune tolerance vs. clearance vs. inactive carrier vs. immune escape.
LFT interpretation: ALT/AST = cellular damage; INR = best prognostic marker (Factor VII half-life ~6h); falling ALT + rising INR = fulminant hepatitis (not recovery).
AFP: Elevated in inflammation AND HCC. Trend matters more than single value. 30% HCC is non-secreting.
FibroScan: Liver stiffness > 12 kPa = cirrhosis; CAP > 280 = severe steatosis.
HCC surveillance: USG + AFP Q6 months. Mass ≥ 1 cm → triphasic CT. Tumour doubling time ~140 days.
Vaccination vs. past infection: Anti-HBs only = vaccination. Anti-HBs + anti-HBc = past infection. Anti-HBc alone = distant past infection / occult HBV.
High Yield Summary — Management of Hepatitis B
Acute HBV: Supportive. No antivirals unless INR ≥ 1.5, jaundice > 4 weeks, immunocompromised, or fulminant. Drug of choice: entecavir. IFN is contraindicated. No alcohol × 6 months. Recheck HBsAg at 6 months.
Chronic HBV — when to treat: ALT > ULN + HBV DNA ≥ 2000 IU/mL; cirrhosis with detectable HBV DNA; decompensated liver disease; pre-immunosuppression; pregnancy with HBV DNA > 200,000.
First-line drugs: Entecavir 0.5 mg daily (1 mg if lamivudine-resistant or decompensated); TDF 300 mg daily (preferred in pregnancy, prior resistance, HIV); TAF 25 mg daily (preferred in renal/bone disease; avoid in decompensated cirrhosis).
Treatment duration: HBeAg+ → can stop after e-seroconversion + 12 months consolidation (30% recurrence). HBeAg− → lifelong unless HBsAg loss.
IFN: Finite course, higher HBsAg clearance, but contraindicated in cirrhosis, pregnancy, children. Many side effects. Rarely used as first-line in HK.
Reactivation prevention: Screen HBsAg + anti-HBc before immunosuppression. If positive, start prophylactic ETV or TDF. Continue 6-12 months after stopping immunosuppression.
Pregnancy PMTCT: TDF from 3rd trimester if HBV DNA > 200,000; HBIG + vaccine for neonate within 12 hours.
High Yield Summary — Complications of Hepatitis B
6 complications of liver failure: Infections, variceal bleeding, ascites/SBP, hepatorenal syndrome, hepatic encephalopathy, coagulopathy. Always ask about HCC in any cirrhotic patient.
Acute: Fulminant hepatic failure (0.1-0.5%); falling ALT + rising INR = ominous. ACLF most commonly HBV-related in HK.
Flares: Spontaneous, e-seroconversion, immunosuppressant withdrawal (anti-CD20 most dangerous), superinfection (HAV/HEV >> HDV), drugs/TCM/alcohol.
Cirrhosis progression: Annual incidence 2.4% (HBeAg+). Risk factors: older age, repeated flares, AFP > 100, bridging necrosis, unsuccessful e-seroconversion. Cirrhosis is probably reversible with long-term NUC therapy.
HCC — the "80% tumour": 80% primary liver cancer, 80% HBV, 80% cirrhosis, 80% non-surgical, 80% recur. Poor prognosis because late presentation, underlying cirrhosis, early venous invasion, field cancerisation. HBV unique: can cause HCC without cirrhosis.
Extrahepatic: PAN, membranous nephropathy, aplastic anaemia.
Reactivation: Rituximab is highest risk; screen anti-HBc before all immunosuppression; prophylactic antivirals are cheap and save lives.