• Approximately 1.4 million new cases per year worldwide ^[4]
• More common in developing countries due to overcrowding and poor sanitation, where it occurs in an endemic or epidemic pattern ^[4]
• In highly endemic areas (sub-Saharan Africa, South/Southeast Asia), most children are infected by age 10 — infections are largely asymptomatic, and nearly all adults have natural immunity
• In low-endemicity areas (Western Europe, Australasia), infection shifts to older age groups, paradoxically leading to more symptomatic and more severe disease when it does occur

• Decreasing incidence over the last decades ^[3][4]
  • Why? Improved sanitation, clean water supply, and food safety measures mean fewer people are exposed in childhood
  • Paradox of declining endemicity: As fewer young people are exposed, the pool of susceptible adults grows. When these susceptible adults eventually encounter HAV (e.g. travel, contaminated shellfish outbreaks), they present with more symptomatic and potentially severe disease
• By age 55, approximately 61.7% of the Hong Kong population has serological evidence of prior HAV infection (anti-HAV IgG positivity) ^[4]
• Mortality increases with age ^[3][4]:
  • 0.1% in ≤ 14 years old
  • 0.4% in 15–39 years old
  • 1.1% in ≥ 40 years old

• Household contacts of an infected individual ^[3]
• Sexual transmission — particularly men who have sex with men (MSM) due to oro-anal contact ^[1][3][4]
• Residential institutions (e.g. care homes, prisons) ^[3]
• Daycare centres — young children are often asymptomatic shedders ^[3]
• Healthcare workers — exposure to faecal material ^[4]

• Consumption of raw or undercooked shellfish — especially bivalve molluscs (clams, oysters, mussels) harvested from sewage-contaminated waters ^[4][5]
  • Why shellfish? Bivalves are filter feeders — they concentrate viral particles from surrounding water as they filter large volumes through their gills
• Uncooked vegetables washed with contaminated water ^[3][4]
• Contaminated food prepared by infected food handlers ^[3]
• Travel to areas of poor sanitation ^[3]

• Blood transfusion — rare because viraemia is transient and low-titre ^[3][4]
• Acupuncture, tattooing ^[3][4]
• Illicit drug use (both injection and non-injection routes) ^[3]

• The liver is composed of ~1 million lobules, each centred on a central vein (draining into hepatic veins → IVC)
• At the periphery of each lobule lie the portal triads (hepatic artery, portal vein, bile duct)
• Hepatocytes are arranged in plates radiating from the central vein, bathed by sinusoidal blood flowing from portal triad → central vein
• Kupffer cells (resident macrophages) line the sinusoids and serve as the liver's first-line immune defence, filtering gut-derived pathogens and endotoxins from portal blood
• Bile canaliculi run between hepatocytes, collecting bile and draining into bile ductules → interlobular bile ducts → common hepatic duct

• HAV is ingested (contaminated food/water)
• Survives gastric acid (non-enveloped, acid-resistant)
• Reaches the small intestinal epithelium → crosses the mucosa into the portal circulation

• HAV travels via the portal vein to the liver
• Binds to HAV cellular receptor 1 (HAVcr-1/TIM-1) on hepatocyte surfaces
• Enters hepatocytes by receptor-mediated endocytosis
• Replicates within hepatocytes using the host cell's translational machinery
• Newly synthesised viral particles are released into bile canaliculi → shed into the gut → excreted in faeces
• Also released into the bloodstream (transient, low-level viraemia)

Critical concept: HAV is not directly cytopathic (or only minimally so). The liver damage in hepatitis A is primarily immune-mediated — it is the host's immune response attacking infected hepatocytes that causes hepatitis ^[4].

• Innate immunity: Kupffer cells and NK cells recognise infected hepatocytes → initial inflammatory response
• Adaptive immunity:
  • CD8+ cytotoxic T lymphocytes (CTLs) are the main effectors → they recognise HAV antigens presented on MHC class I on infected hepatocytes and kill them
  • CD4+ T-helper cells activate B cells → antibody production
  • Anti-HAV IgM appears early (coincides with symptom onset) → marker of acute infection
  • Anti-HAV IgG appears later → confers lifelong protective immunity

The immune-mediated destruction of hepatocytes leads to:

1. Release of intracellular enzymes → elevated ALT and AST (typically 200–2000 IU/L) ^[2][4]

   • ALT is more specific for hepatocytes than AST
   • In fulminant hepatitis, paradoxically, transaminases may be low because there are insufficient viable hepatocytes left to release enzymes — this is an ominous sign ^[2][4]

2. Impaired bilirubin metabolism:

   • Swollen, damaged hepatocytes compress bile canaliculi → intrahepatic cholestasis
   • Reduced conjugation capacity
   • Result: predominantly conjugated (direct) hyperbilirubinaemia ^[4]
   • Dark/tea-coloured urine (conjugated bilirubin is water-soluble → filtered by kidneys)
   • Pale stools (less bilirubin reaching the gut → less stercobilinogen)
   • Pruritus (retained bile salts deposited in skin → this mimics obstructive jaundice and is due to hepatocyte swelling compressing canaliculi) ^[5]

3. Impaired synthetic function (in severe cases):

   • PT/INR is the best index for liver function and prognosis because Factor VII has the shortest half-life (~6 hours) among clotting factors ^[2][4]
   • Reduced albumin synthesis (though albumin has a long half-life of ~20 days, so may not drop acutely)

4. Inflammatory cytokine release → fever, malaise, myalgia, anorexia ^[1][5]

5. Hepatocyte swelling → stretching of Glisson's capsule → right upper quadrant dull ache ^[5]

• In > 95% of cases, the immune system successfully clears HAV
• Hepatocytes regenerate; liver architecture is restored
• Anti-HAV IgM wanes over 3–6 months; anti-HAV IgG persists for life
• No chronic infection develops — this is fundamentally different from HBV and HCV

Hong Kong sits in the low endemicity zone — most infections occur in adolescents/adults rather than in early childhood.

• Inactivated whole-virus vaccine
• Given as 2 doses (0 and 6–12 months apart)
• Highly effective (> 95% seroconversion after 1 dose; near 100% after 2 doses)
• Indicated for: travellers to endemic areas, MSM, chronic liver disease patients (especially chronic HBV carriers), food handlers, healthcare workers, IVDU

• Pooled human immunoglobulin containing anti-HAV antibodies
• Provides immediate but temporary protection (~3 months)
• Used for post-exposure prophylaxis within 2 weeks of exposure, especially in those who cannot receive vaccine (e.g. < 12 months old, immunocompromised, allergy to vaccine components)

These viruses are not primarily "hepatitis viruses" but can cause hepatitis as part of systemic infection:

Teaching point: Both EBV and CMV infection can present with liver function abnormalities as well as fever, fatigue and lymphadenopathy ^[3]. The presence of atypical lymphocytes on peripheral blood film is a hallmark of these infections and helps differentiate them from HAV (where WCC is usually normal with only relative lymphocytosis).

Drug-induced hepatitis is one of the top 4 differentials for markedly elevated transaminases ^[7].

Ischaemic hepatitis is a critical differential, especially in the acute setting ^[7][11].

• Mechanism: Hepatic hypoperfusion (cardiogenic shock, septic shock, hypovolaemia) → centrilobular hepatocyte necrosis
• LFT pattern: Brisk rise and rapid resolution of LDH; ALT/AST strikingly elevated, peak within 1–3 days, then fall rapidly; ALT/LDH ratio < 1.5 early in course ^[7]
• How to differentiate from HAV:
  • Clinical context of haemodynamic instability / shock
  • Other evidence of end-organ damage (e.g. acute renal failure) ^[7]
  • No viral prodrome; no exposure history
  • Diagnosis based on clinical features — no specific serological test ^[7]
  • LDH is massively elevated (much more than in viral hepatitis)

Immunoglobulin pattern in liver diseases: ↑ IgG = Autoimmune hepatitis; ↑ IgM = Primary biliary cholangitis (PBC); ↑ IgA = Alcoholic hepatitis ^[12]. This is a classic exam question.

A diagnosis of acute hepatitis A is established when:

• There is clinical and/or biochemical evidence of acute hepatitis (elevated ALT/AST, ± jaundice)
• Anti-HAV IgM is positive ^[1][2][5]

That's it. No biopsy needed. No imaging needed to make the diagnosis (imaging is for exclusion of other causes).

As per the GC diagnostic algorithm ^[1]:

Liver biopsy is NOT routinely required for the diagnosis of hepatitis A ^[7].

Indications for liver biopsy in the context of acute hepatitis:

• When the diagnosis remains unclear after full serological and biochemical workup ^[7]
• When autoimmune hepatitis is suspected but autoantibodies are inconclusive (AIH can be a diagnosis of exclusion; autoantibodies are not specific, require diagnostic criteria) ^[8]
• Atypical clinical course (e.g. prolonged cholestasis, failure to improve)
• When liver transplant is being considered → transjugular liver biopsy (percutaneous is contraindicated due to coagulopathy in fulminant cases) ^[4]

"Determining the final diagnosis requires: history (drug history), clinical presentation, other investigations. Liver biopsy may be required" — but it is "only useful" when the above non-invasive methods fail ^[7].

If performed, histological findings in acute hepatitis A:

• Lobular disarray: loss of normal hepatocyte plate architecture
• Hepatocyte ballooning and necrosis: primarily periportal and centrilobular
• Councilman bodies (acidophilic bodies): eosinophilic remnants of apoptotic hepatocytes
• Portal and lobular inflammation: predominantly lymphocytic infiltrate (CD8+ T cells)
• Kupffer cell hyperplasia: activated macrophages clearing debris
• Cholestasis: bile plugs in canaliculi (especially in cholestatic variant)
• NO fibrosis (unlike chronic hepatitis)
• NO plasma cell infiltrate (if plasma cells are prominent → think autoimmune hepatitis) ^[13]

This is a classic DI exam question ^[16]:

For patients admitted with acute hepatitis (including HAV), the initial management/monitoring workup includes ^[2]:

• If extremely tired, rest — but rest does not shorten the course of hepatitis ^[5]
• The evidence for this comes from studies on US soldiers in the Vietnam War who developed hepatitis — soldiers who rested and soldiers who continued active duty had the same prognosis and disease duration ^[5]
• So rest is for symptom relief, not disease modification

• No solid diet modifications needed — eat anything ^[5]
• Glucose drip does NOT help — in fact, excessive IV dextrose may induce fatty liver ^[5]
• Fatty diet is harmless ^[5]
• The only dietary modification is:

• No alcohol for 6 months for acute hepatitis ^[2][4][5]
• No alcohol for life for chronic hepatitis ^[4]
• Why? Alcohol is directly hepatotoxic (metabolised to acetaldehyde → oxidative stress, lipid peroxidation, mitochondrial injury). Adding alcohol to an already inflamed liver compounds the injury and impairs hepatocyte regeneration. The 6-month period allows full resolution of hepatic inflammation and normalisation of liver function.

• No known drugs or herbs hasten the recovery of acute hepatitis ^[5]
• "Definitely do not try TCM" ^[5] — there are no double-blind, placebo-controlled trials demonstrating any herbal remedy accelerates recovery from acute viral hepatitis. TCM/herbal remedies carry the additional risk of drug-induced liver injury (DILI), which would be catastrophic in a patient with active hepatitis
• Steroids are specifically NOT recommended even in cholestatic or relapsing variants (see complications section later): steroids may quickly "whitewash" the cholestatic picture but increase relapse rate ^[4]

• Avoid elective surgery — risk of post-operative liver failure when hepatocytes are already compromised ^[4]
• Avoid or minimise hepatotoxic drugs (paracetamol at high doses, certain antibiotics, statins)
• Avoid alcohol (as above)
• Review all current medications for hepatotoxic potential

The King's College Criteria are the most widely used criteria to predict poor prognosis in acute liver failure and guide transplant listing ^[4]:

For Non-Paracetamol Causes (including HAV):

• INR > 6.5 (PT > 100 seconds)
• OR any 3 of the following 5:
  1. Age < 10 or > 40 years
  2. Aetiology: non-A, non-B hepatitis, drug-induced, or halothane
  3. Duration of jaundice before encephalopathy > 7 days
  4. INR > 3.5 (PT > 50 seconds)
  5. Serum bilirubin > 300 µmol/L

For Paracetamol Causes (for comparison):

• Arterial pH < 7.3 (after resuscitation)
• OR all of: INR > 6.5 AND creatinine > 300 µmol/L AND grade III/IV encephalopathy

Post-Exposure Prophylaxis Strategy:

• Presentation: Prolonged, marked jaundice, pruritus for up to 12–24 weeks; high bilirubin (10× ULN) but with decreasing AST/ALT
• Management: ALWAYS complete resolution ^[4]
  • Symptomatic management of pruritus (cholestyramine, ursodeoxycholic acid, antihistamines)
  • Steroids are NOT used — they quickly "whitewash" the cholestatic picture but increase relapse rate ^[4]

• Presentation: Apparent clinical recovery followed by biochemical ± clinical relapse; can be biphasic or polyphasic, lasting 3–12 months
• Key findings: AST/ALT > 1000 IU/L again; IgM anti-HAV remains positive; HAV identified in stools and HAV RNA in serum
• Management: ALWAYS complete resolution — steroids can increase relapse ^[4]
• Reassurance and monitoring; no specific treatment required

• Increased risk of fulminant hepatic failure
• Management: supportive care with heightened vigilance; early hepatology/transplant team involvement
• Prevention is key: vaccinate all chronic HBV carriers against HAV ^[2]

Prolonged cholestasis occurring in < 5% of acute HAV infections ^[4].

• Prolonged, marked jaundice and pruritus for up to 12–24 weeks ^[4]
• Fever, weight loss, diarrhoea and malaise ^[3]
• Patients appear deeply jaundiced for weeks to months — can be alarming for both patient and clinician

• Characterised by very high bilirubin (up to 10× ULN) but with decreasing AST/ALT ^[4]
• This pattern is the key to recognising it: the "damage" markers (transaminases) are resolving, but bilirubin remains stubbornly elevated. Why? The hepatocytes are recovering from the acute injury, but the intrahepatic cholestasis (from hepatocyte swelling compressing canaliculi and from bile duct inflammation) takes much longer to resolve. Think of it as: the fire is going out, but the smoke lingers.

• Centrilobular cholestasis with periportal inflammation ^[4]
• May mimic chronic active hepatitis histologically — important not to be misled ^[4]

• ALWAYS achieves complete resolution ^[4][3]
• Steroids are NOT used — they may quickly "whitewash" the cholestatic picture (i.e. make the jaundice improve transiently) but increase the relapse rate ^[4]
• Symptomatic management of pruritus: cholestyramine (bile acid sequestrant), ursodeoxycholic acid, antihistamines
• Reassurance is the most important intervention — patients and families may panic at weeks of persistent jaundice

• Occurs in 6–10% of patients ^[4][3]
• Apparent clinical recovery followed by biochemical ± clinical relapse ^[4]

• Can be biphasic or polyphasic ^[4]
• Duration may last 3–12 months ^[4]
• Typically, the patient recovers from the initial episode (transaminases normalise, symptoms resolve), then weeks later develops a second (or occasionally third) episode of transaminase elevation ± recurrence of jaundice and symptoms

• Related to immune reaction towards HAV ^[4]
• The virus is not completely cleared during the initial immune response. Residual viral antigens trigger a second wave of immune-mediated hepatocyte destruction. The patient remains infectious during relapse because:

• AST/ALT > 1000 IU/L during relapse ^[4]
• IgM anti-HAV remains positive throughout ^[4][3]
• HAV identified in stools and HAV RNA in serum ^[4] — the patient is still shedding virus and is therefore infectious during the relapse

• ALWAYS achieves complete resolution ^[4]
• Steroids can increase relapse — do NOT use ^[4]
• The duration of clinical relapse is usually less than 3 weeks ^[3]
• Management: supportive care, reassurance, monitor LFTs

• Development of severe acute liver injury with hepatic encephalopathy and impaired synthetic function with INR ≥ 1.5 ^[3][18]
• In the absence of pre-existing liver disease
• Onset of encephalopathy within 8 weeks (some define up to 26 weeks) of symptom onset

• < 1% of all HAV infections ^[4]
• Occurs especially in patients > 50 years old and individuals with other liver diseases such as chronic hepatitis B or C ^[4][3]
• This is profoundly relevant in Hong Kong: a chronic HBV carrier who acquires HAV superinfection has a dramatically increased risk of fulminant failure

The immune response to HAV is the double-edged sword. In most patients, the immune attack on infected hepatocytes is measured and proportional — enough to clear the virus but not enough to destroy the entire liver. In fulminant failure, the immune response is excessively vigorous — massive hepatocyte necrosis occurs faster than the liver can regenerate. Contributing factors include:

• Age-related factors: older adults mount stronger but less well-regulated immune responses
• Pre-existing liver disease: fewer reserve hepatocytes → less capacity to withstand immune-mediated destruction + less regenerative capacity
• Genetic/host factors: likely variation in HLA types and cytokine responses

These are the complications OF the complication — multi-organ failure cascading from hepatic failure:

As covered in the management section, the King's College Criteria guide transplant listing:

• INR > 6.5
• OR any 3 of: age < 10 or > 40, non-A non-B/drug aetiology, jaundice-to-encephalopathy > 7 days, INR > 3.5, bilirubin > 300 µmol/L

Variceal bleeding is uncommon in acute liver failure ^[18]. If variceal bleeding is present, suspect Budd-Chiari syndrome as an alternative diagnosis rather than straightforward acute liver failure.

• Occur in < 15% of patients ^[4]
• More common in prolonged diseases, e.g. relapsing hepatitis, prolonged cholestasis ^[4]

• Characterised by immune complex-mediated disease ^[4]
• During active HAV infection, circulating immune complexes (HAV antigen + anti-HAV antibodies) deposit in various tissues → activate complement → tissue damage
• This is a type III hypersensitivity reaction (Arthus-type/serum sickness-like)

All extrahepatic manifestations of HAV are self-limiting and resolve with viral clearance. No specific treatment beyond supportive care is usually required.

Hepatitis is a well-known antecedent to aplastic anaemia ^[14]. This is sometimes called hepatitis-associated aplastic anaemia (HAAA).

• T-cell mediated destruction of haematopoietic stem cells ^[14]
• The hepatitis triggers an aberrant immune response where activated T cells (specifically CD8+ cytotoxic T cells and γδ T cells) attack not only infected hepatocytes but also haematopoietic stem cells in the bone marrow
• Interestingly, the responsible virus in most cases of HAAA is never identified — most are "seronegative" (all standard hepatitis viral markers are negative). HAV, HBV, and HCV are rarely the direct cause, but the association highlights the concept that viral hepatitis can trigger immune-mediated bone marrow failure

• Pancytopenia — anaemia, leukopenia, thrombocytopenia ^[14]
• Occurs weeks to months after the hepatitis episode
• Bone marrow biopsy shows: no abnormal cells, just the absence of normal cells (hypocellular marrow) ^[14]

• While most cases of HAAA are seronegative, HAV has been documented as a trigger in case reports
• If a patient develops pancytopenia after recovering from hepatitis A, think of aplastic anaemia
• This is important because aplastic anaemia requires urgent haematological management (immunosuppressive therapy with ATG + ciclosporin, or bone marrow transplant)

• HAV infection may act as a trigger for autoimmune hepatitis in genetically predisposed individuals
• The viral infection breaks immune tolerance to hepatocyte autoantigens through:
  • Molecular mimicry: HAV antigens share epitopes with hepatocyte surface proteins
  • Bystander activation: the intense immune response during HAV infection non-specifically activates autoreactive T cells
  • Epitope spreading: initial immune response to HAV antigens spreads to target self-antigens on damaged hepatocytes

• If transaminases fail to normalise after expected recovery from HAV, or if they worsen after an initial improvement, consider autoimmune hepatitis
• Investigate with: ANA, ASMA, anti-LKM-1, serum IgG levels, ± liver biopsy
• Management is that of autoimmune hepatitis: corticosteroids + azathioprine