• Approximately 20 million new HEV infections per year worldwide, with > 55,000 deaths ^[4].
• Increased prevalence in developing countries — India, Burma (Myanmar), Nepal, Pakistan, China, Central Russia, Mexico ^[4].
• HEV is the most common cause of acute viral hepatitis globally when all genotypes are considered.

• HK seroprevalence: ~33.6% with an increasing trend (similar trend to hepatitis A seroprevalence) ^[4].
• HEV is a notifiable disease in Hong Kong ^[2].
• Demographics: usually occurs in adults in the 3rd decade of life ^[4].
• Important local risk: consumption of pork liver, pork blood, and undercooked pork products — a culturally relevant exposure in Hong Kong (e.g., pig liver congee / 豬潤粥) ^[3][4].
• Rat hepatitis E virus (rat-HEV) has been identified as a cause of human hepatitis in Hong Kong — a finding that gained international attention. Cases of chronic HEV caused by rat-HEV in immunosuppressed patients have been documented ^[1].

• Contact with contaminated food and water ^[5]
• Consumption of raw or undercooked meat or meat products derived from infected animals — especially pork liver, pork intestines, wild boar, deer ^[5]
• Consumption of raw or undercooked shellfish (filter-feeding bivalves concentrate the virus) ^[5]
• Blood transfusion — HEV can be transmitted parenterally (underappreciated route) ^[5]
• Poor sanitation — large waterborne outbreaks in endemic regions ^[5]
• Occupational exposure: pig farmers, slaughterhouse workers, veterinarians

• Pregnancy (especially 3rd trimester) — 20–25% maternal mortality ^[1]
• Patients with major underlying illness or chronic liver disease can develop severe liver consequences ^[1]
• Immunosuppression (organ transplant recipients, HIV, hematological malignancies on chemotherapy) — risk of chronicity
• Pre-existing chronic liver disease (especially chronic HBV — relevant in HK where ~8% population are HBV carriers) — superinfection with HEV can precipitate decompensation and acute-on-chronic liver failure

Why does pre-existing liver disease matter? The liver already has reduced functional reserve. When HEV causes additional hepatocyte necrosis on top of an already fibrotic/cirrhotic liver, the remaining hepatocytes cannot compensate → acute-on-chronic liver failure. This is particularly important in Hong Kong where chronic HBV is prevalent ^[6].

• Hepatocytes are arranged in plates radiating from the central vein, separated by hepatic sinusoids.
• Sinusoids are lined by fenestrated endothelial cells and contain Kupffer cells (resident macrophages).
• Bile canaliculi run between adjacent hepatocytes, draining bile into the canals of Hering → interlobular bile ducts → hepatic ducts → common bile duct.
• Glisson's capsule: the fibrous capsule surrounding the liver. It is innervated by the phrenic nerve and lower intercostal nerves — stretching of this capsule produces the dull RUQ ache characteristic of hepatitis.

HEV causes Kupffer cell damage → allows endotoxin damage to the liver. Pregnant women may be more sensitive to endotoxin effects ^[4]. This is one proposed mechanism for the disproportionately severe disease in pregnancy.

• The word "Hepeviridae" → "Hep-E" = hepatitis E virus family — the family was literally named after this virus.
• Non-enveloped viruses are generally more resistant to environmental degradation (bile salts, stomach acid, detergents) → this explains why it survives the fecal-oral route through the GI tract.
• The quasi-envelope in blood (membrane-wrapped virions in circulation) may help evade neutralizing antibodies during the viremic phase.

In Hong Kong, the relevant etiological considerations are:

1. Genotype 4 — commonest genotype causing autochthonous (locally acquired) HEV in HK and Southern China
2. Genotype 3 — also present, particularly in imported cases
3. Rat HEV (Orthohepevirus C) — Hong Kong was the first place in the world to document human infection with rat hepatitis E virus (2018). This is a distinct species that was previously thought unable to infect humans. Cases have since been identified in immunosuppressed patients ^[1].

Important local food sources of HEV in HK:

• Pork liver congee (豬潤粥) — HEV is concentrated in pig liver
• Pork blood products
• Raw/undercooked pork
• Raw shellfish (oysters, clams)
• Pig offal / viscera

HEV = "pork liver congee" in one word, as emphasized in the GC lecture ^[3]. This is the exam-friendly association for HK-based questions.

• Domestic pigs — primary reservoir worldwide and in HK
• Wild boar, deer — important in Japan, Europe
• Rats — Hong Kong rat-HEV cases
• Camels — genotype 7 (Middle East)
• Rabbits — genotype 3

1. Entry: HEV is ingested → survives gastric acid (non-enveloped, acid-resistant) → crosses intestinal mucosa → enters portal circulation.
2. Hepatotropism: HEV has tropism for hepatocytes. It enters hepatocytes, replicates in the cytoplasm using its RNA-dependent RNA polymerase.
3. Shedding: Progeny virions are released into bile canaliculi → excreted in feces (this is why stool HEV RNA can be detected). They also enter the bloodstream (viremia).
4. Immune-mediated injury: The liver damage in HEV is primarily immune-mediated, not due to direct cytopathic effect of the virus. CD8+ cytotoxic T lymphocytes recognize viral antigens on infected hepatocytes and kill them → hepatocyte necrosis → release of intracellular enzymes (ALT, AST) and bilirubin metabolism dysfunction.

This is a classic exam question. Several mechanisms have been proposed:

1. Kupffer cell damage: HEV damages Kupffer cells → impaired clearance of gut-derived endotoxins (lipopolysaccharide) from the portal blood → endotoxin-mediated hepatic injury ^[4]
2. Pregnant women may be more sensitive to endotoxin effects ^[4] — possibly because:
   • Pregnancy is an immunomodulated state (Th2-dominant) → reduced cell-mediated immunity → reduced viral clearance → higher viral load → more liver damage
   • Higher circulating estrogen and progesterone levels may modulate immune responses
   • Placental factors may amplify inflammatory cascades
3. Hormonal effects on HEV replication: Some evidence suggests that steroid hormones directly enhance HEV replication in hepatocytes.
4. Reduced hepatic blood flow in late pregnancy (due to IVC compression by gravid uterus) may worsen ischemic injury to already-damaged hepatocytes.

• In immunocompetent individuals: robust T-cell response → viral clearance → self-limited infection.
• In immunosuppressed patients (especially solid organ transplant recipients on calcineurin inhibitors like tacrolimus/cyclosporine):
  • Impaired T-cell function → inability to clear the virus → persistent viral replication → chronic HEV (defined as HEV RNA detectable for > 3 months)
  • NEJM (2008) reported 14 cases of acute HEV in transplant patients with 8 becoming chronic with elevated ALT and positive HEV RNA ^[4]
  • Typically occurs with HEV genotype 3 infection ^[4]
  • Risk of chronicity limited to transplant recipients and immunosuppressed state (e.g., HIV) ^[4]
  • Chronic HEV can progress to cirrhosis within months to years if untreated.

This is fundamentally different from HAV, which NEVER causes chronicity. The reason is that HAV induces a very strong innate and adaptive immune response even in immunosuppressed individuals, whereas HEV's immune evasion strategies (quasi-envelope in blood, ORF3 protein that inhibits interferon signaling) can allow persistence when adaptive immunity is weakened.

• ~20% of HEV cases present with prominent cholestasis (cf < 5% in hepatitis A) ^[4]
• Mechanism: hepatocyte swelling from inflammation → compression of intracellular bile canaliculi → intrahepatic cholestasis → bile acid accumulation in blood → pruritus; reduced bile reaching the gut → pale stools; conjugated bilirubin refluxes into blood → filtered by kidneys → dark urine
• HEV may also directly affect bile duct epithelial cells (cholangiocytes), contributing to the cholestatic pattern

• Largely asymptomatic; but adults are more symptomatic than children ^[1]
• Self-limiting > 95%; but can result in acute liver failure in rare cases ^[1]
• Incubation period: 2–10 weeks; mean 5–6 weeks ^[1]

HEV has a wider range of extrahepatic manifestations than HAV. These are important and increasingly recognized ^[5]:

Neurological manifestations are the most important extrahepatic feature of HEV — particularly Guillain-Barré syndrome and neuralgic amyotrophy (Parsonage-Turner syndrome). In Europe, HEV genotype 3 has been identified as the most common infectious trigger for neuralgic amyotrophy.

• 20–25% maternal mortality if acute HEV during the 3rd trimester ^[1]
• Usually Genotype 1 ^[2]
• Mechanism: Kupffer cell damage → endotoxemia + immunomodulation of pregnancy (Th2 shift) → impaired viral clearance → massive hepatocyte necrosis
• Risk of DIC, fetal loss, premature delivery, stillbirth
• This is one of the few infections where pregnancy dramatically alters mortality

• Patients with major underlying illness or chronic liver disease can develop severe liver consequences ^[1]
• In HK context: chronic HBV carrier + HEV superinfection → high risk of decompensation and acute-on-chronic liver failure

• Solid organ transplant recipients (especially liver, kidney)
• HIV patients with low CD4 counts
• Patients on anti-CD20 therapy (rituximab), other immunosuppressants
• Cases of chronic HEV (caused by rat-HEV) in immunosuppressed patients ^[1]
• Can progress rapidly to cirrhosis if not recognized and treated

Why does HAV have a shorter incubation? HAV replicates more rapidly and reaches peak viral shedding faster. The immune response mounts earlier, so clinical illness appears sooner.

This is a critical distinction in Hong Kong, where chronic HBV affects ~8% of the population ^[6][8].

• Acute HBV: Incubation 4–20 weeks ^[2]. Can present identically to HEV with fever, jaundice, and markedly elevated ALT.
• Acute flare of chronic HBV: A patient with known chronic HBV carrier status may present with acute hepatitis. This can be caused by multiple triggers including superinfection with HEV ^[6]. The clinical picture is identical.

How to differentiate:

• HBsAg positive + anti-HBc IgM positive may indicate either acute HBV infection or acute flare of chronic HBV ^[8]
• HBsAg clearing in 6 months indicates acute infection with clearance ^[8]
• Anti-HEV IgM will be positive if HEV is the superinfecting agent
• In HK, always consider dual pathology: a chronic HBV carrier presenting with acute hepatitis may have HEV superinfection on top ^[6]

• Acute HCV is rarely diagnosed because it is usually asymptomatic in the acute phase.
• Anti-HCV may take 12 weeks to appear ^[8] — so in the very early acute phase, serology may be negative. HCV RNA by PCR is needed if clinical suspicion is high (e.g., needlestick injury).
• Chronic HCV can also present with acute flares.
• In HK, HCV accounts for ~5–10% of chronic liver disease ^[9].

• Requires co-infection with HBV (HDV is an incomplete/defective virus that needs HBsAg as its envelope).
• Very rare in Chinese ^[6]. Not a major differential in HK.
• Consider only in patients with HBsAg-positive status who have unusually severe hepatitis or who come from endemic areas (Mediterranean, Middle East, South America).

• Both EBV and CMV infection can present with liver function abnormalities as well as fever, fatigue and lymphadenopathy ^[5][10].
• EBV classically causes infectious mononucleosis: triad of fever + tonsillar pharyngitis + lymphadenopathy ^[11], with hepatomegaly (15–25%), splenomegaly (50–60%), and atypical lymphocytosis ^[11].
• CMV can cause a mononucleosis-like syndrome without the prominent pharyngitis.
• Key differentiator: atypical lymphocytosis on blood film is characteristic of EBV/CMV but not of HEV. Also, EBV/CMV rarely cause marked jaundice (LFT derangement is usually mild).

• HSV infection can cause hepatitis as a rare complication, occurring most commonly in immunocompromised patients ^[5][10].
• HSV hepatitis is rare but important because it can cause fulminant hepatic failure with very high mortality if not treated with IV acyclovir.
• Look for: mucocutaneous vesicles, immunosuppressed background.

• Patients with acute HIV infection can have nausea, anorexia and diarrhea ^[5][10].
• Acute HIV seroconversion illness (2–4 weeks after exposure) can present with fever, lymphadenopathy, pharyngitis, rash, and mildly deranged LFT — overlapping with viral hepatitis.
• Risk factor history (unprotected sexual intercourse, IVDU) is critical.

• Adenovirus typically involves respiratory and gastrointestinal tracts. Hepatitis can be a complication in immunocompromised hosts ^[10].

• Paracetamol overdose is a leading cause of acute liver failure ^[12].
• History of intentional overdose or accidental excess is key.
• Distinct pattern: ALT/AST can be extremely high (> 10,000 U/L), with a characteristic timeline — liver injury peaks 48–72 hours post-ingestion.
• Specific antidote: N-acetylcysteine (NAC).
• Paracetamol level and Rumack-Matthew nomogram help differentiate.

• Idiosyncratic drug reactions ^[12] — unpredictable, not dose-dependent.
• Common offenders: antibiotics (amoxicillin-clavulanate, isoniazid, rifampicin), NSAIDs, statins, anti-epileptics (phenytoin, carbamazepine, valproate), anti-TB drugs.
• Temporal relationship between drug initiation and hepatitis onset is the most important diagnostic clue.
• Drug history (including over-the-counter medications and supplements) is essential.

• Herbal-related hepatotoxicity ^[12] — very relevant in HK where traditional Chinese medicine (TCM) use is common.
• TCM and herbal teas can cause hepatocellular or cholestatic patterns of liver injury.
• Always ask about TCM intake in any patient with unexplained hepatitis in HK.

• Alcoholic hepatitis has a distinctive LFT pattern: AST > ALT (typically 2:1 ratio), and AST will usually not exceed 500 U/L ^[13].
• History of heavy alcohol use is essential.
• Signs: hepatomegaly (mild, soft), parotid enlargement, Dupuytren's contracture, spider naevi ^[13].
• Important: anyone presenting with chronic liver disease and a history of alcoholism must exclude other causes ^[8] — don't assume it's purely alcoholic.

• Presents as acute hepatitis with jaundice, abdominal pain and deranged LFT ^[10].
• Can mimic Parkinson's — extrapyramidal deposition of copper ^[14].
• Fulminant hepatic failure due to Wilson's has a very specific feature: young patients with no reason for fulminant liver failure, exclusion of all other common causes → only finding is low hemoglobin. Coombs-negative hemolytic anemia ^[14].
• Kayser-Fleischer rings on slit-lamp examination, low ceruloplasmin, elevated 24-hour urinary copper.
• Important differential in any young patient (< 40 years) with unexplained acute hepatitis, especially if hemolytic anemia is present.

• Usually presents insidiously with chronic liver disease, not as acute hepatitis.
• Skin pigmentation ("bronze diabetes"), diabetes, arthropathy, cardiomyopathy.
• Elevated ferritin and transferrin saturation.
• Less relevant as an acute HEV mimic but should be on the broader DDx of chronic hepatitis.

• More relevant in Caucasian populations; rare in Chinese.
• Can present with neonatal cholestasis or adult-onset liver disease.
• Low serum α1-antitrypsin level, PiZZ phenotype.

• Brisk rise and rapid resolution of LDH; ALT/AST strikingly elevated, peak within 1–3 days, then fall rapidly ^[7].
• ALT/LDH ratio < 1.5 early in course of hepatitis ^[7].
• Other evidence of end-organ damage, e.g., acute renal failure ^[7].
• Diagnosis based on clinical features ^[7] — typically a patient with preceding hypotension/shock (cardiogenic, septic, hemorrhagic).
• Key differentiator from HEV: the context (ICU patient, post-cardiac arrest, post-cardiac surgery, decompensated heart failure) and the LDH pattern (massively elevated in ischaemic hepatitis but not typically in viral hepatitis).

No other conditions can give this rapid improvement (along with cholangiohepatitis and paracetamol overdose) → no imaging required ^[13]. If the ALT/AST drops by ~50% per day, think ischaemic hepatitis, not viral.

• Hepatic venous outflow tract obstruction ^[10].
• Presents with acute or subacute liver disease or acute liver failure ^[10].
• Classic triad: abdominal pain, hepatomegaly, ascites.
• Risk factors: hypercoagulable states (myeloproliferative neoplasms, antiphospholipid syndrome, OCP use).
• Doppler ultrasound of hepatic veins is diagnostic.

• Presents with fever and jaundice due to hemolysis ^[10] — the jaundice is predominantly unconjugated (pre-hepatic), not hepatocellular.
• Travel history to endemic areas is critical.
• Thick and thin blood films, rapid diagnostic test for malaria antigens.
• Important DDx in HK for returned travelers from Southeast Asia or Africa.

• Weil's disease: jaundice, renal failure, hemorrhagic tendency.
• Exposure history: contact with contaminated water, animal urine (rats).
• Conjunctival suffusion is a characteristic sign.

• HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelets) ^[12].
• Occurs in the context of pre-eclampsia/eclampsia, typically 3rd trimester.
• Overlap with HEV: both occur in pregnancy, both cause elevated liver enzymes, both can cause fulminant liver failure.
• Differentiators: HELLP has hypertension, proteinuria, thrombocytopenia, evidence of microangiopathic hemolytic anemia (schistocytes on blood film, elevated LDH, low haptoglobin).

• Acute fatty liver of pregnancy ^[12] — rare but life-threatening.
• 3rd trimester, presents with nausea, vomiting, abdominal pain, jaundice, hypoglycemia.
• Differentiator from HEV: AFLP characteristically causes hypoglycemia (impaired gluconeogenesis from fatty infiltration) and DIC, with imaging showing fatty liver.

A diagnosis of acute HEV infection can be made when:

• Detection of HEV RNA in serum or stool for > 6 months ^[2] (some sources use > 3 months)
• Persistent elevation of ALT
• Almost exclusively in immunosuppressed patients (transplant recipients, HIV)
• Typically HEV genotype 3 ^[4]

• Anti-HEV IgG positive ^[3]
• Anti-HEV IgM negative
• HEV RNA negative
• Normal ALT
• Note: anti-HEV IgG can persist for several years ^[3] but does not confer permanent immunity — reinfection is possible ^[3]

Why H'stix BD? Because liver failure can cause hypoglycemia ^[2]. The liver is responsible for gluconeogenesis and glycogenolysis. In massive hepatocyte necrosis (fulminant hepatitis), these functions fail → dangerous hypoglycemia. Monitoring capillary blood glucose twice daily catches this early.

As emphasized in the GC slides, diagnosis of HEV requires exclusion of other causes ^[17]. The standard panel:

Recall: IgM reflects acute reaction ^[8]. This is the fundamental immunological principle — IgM is the first antibody produced in a primary immune response (it's a pentamer, large, doesn't cross the placenta). IgG appears later, is smaller, crosses the placenta, and indicates past exposure or chronic infection.

Interpretation of viral hepatitis markers ^[19]:

Urgent imaging may not be necessary ^[7] for conditions like acute hepatitis E where the diagnosis is serological. Imaging is primarily to exclude biliary obstruction ^[17].

• Liver biopsy may be required ^[7] — but only in specific scenarios:
  • Diagnostic uncertainty after full serological workup
  • Suspected autoimmune hepatitis (histological features support diagnosis)
  • Suspected chronic HEV with unclear etiology of liver disease
  • Assessment of fibrosis stage in chronic HEV
• NOT routinely needed for straightforward acute HEV
• Histological findings in HEV (if performed):
  • Lobular hepatitis with spotty necrosis
  • Portal and periportal inflammation (lymphocytic)
  • Cholestatic features (bile plugs in canaliculi) — more prominent than in HAV
  • In chronic HEV: progressive fibrosis

In Hong Kong, a common clinical scenario is a known chronic HBV carrier presenting with acute hepatitis flare. The investigation approach:

1. Check anti-HEV IgM — if positive, HEV superinfection confirmed ^[6]
2. Simultaneously check anti-HBc IgM (to assess for HBV reactivation) and HBV DNA (to quantify viral load)
3. If both anti-HEV IgM and anti-HBc IgM are positive → dual etiology possible
4. Remember: AFP can be elevated in acute inflammation — key is whether it comes down after symptoms disappear ^[8]

• Anti-HEV IgM may be negative (impaired humoral immunity)
• HEV RNA in serum or stool is the essential diagnostic test — must be positive for > 3–6 months to define chronicity ^[2]
• HEV genotyping should be performed (usually genotype 3)
• Liver biopsy may show progressive fibrosis

• Standard anti-HEV IgM assays may not detect rat-HEV (different species: Orthohepevirus C)
• Specialized RT-PCR targeting rat-HEV genome is required
• Consider in immunosuppressed patients in HK with unexplained hepatitis and negative standard HEV serology ^[3]

The GC 239 lecture slide states clearly: No specific treatment. Supportive measures: maintaining hydration, electrolyte balance, nutritional balance ^[1].

No drugs to be administered — no known drugs or herbs that hasten recovery of acute hepatitis ^[3]. This is a critical exam point: students often feel they should "do something" for acute viral hepatitis. The answer is: supportive care only.

• No alcohol for 6 months for acute hepatitis ^[2][3]
• No alcohol for life for chronic hepatitis ^[3]

Why 6 months? The liver needs time to regenerate fully after acute hepatitis. During this recovery phase, the cytochrome P450 enzyme system (especially CYP2E1, which metabolizes ethanol) is already stressed. Adding alcohol during recovery imposes additional oxidative stress via acetaldehyde production and reactive oxygen species, potentially prolonging inflammation and risking progression to more severe liver injury.

• Avoid hepatotoxic medications during the acute phase (paracetamol in high doses, NSAIDs, statins, azole antifungals, etc.)
• Review all current medications for hepatotoxic potential
• Definitely do not try TCM ^[3] — herbal preparations are a recognized cause of drug-induced liver injury and may worsen hepatitis

As established in the diagnosis section ^[2]:

Five principles of management of acute liver failure ^[20]:

1. Supportive care → standard ICU care
2. Identifying and removing/treating the insult
3. Manage complications
4. High-volume plasma exchange
5. Liver transplantation

Role of antiviral therapy in fulminant HEV is not well established ^[5]. There are case reports of ribavirin use in severe acute HEV, but no randomized trial evidence. The management remains primarily supportive.

• Liver transplantation may be indicated in patients with acute HEV infection who develop fulminant liver failure ^[5]
• Decision guided by King's College criteria (for non-paracetamol ALF): INR > 6.5, OR any 3 of: age < 10 or > 40, etiology non-A non-B hepatitis, jaundice to encephalopathy interval > 7 days, INR > 3.5, bilirubin > 300 µmol/L
• Practical considerations: organ availability, patient fitness for surgery, contraindications

• Reduction of immunosuppression → facilitates clearance of chronic HEV infection ^[5]
• This is the first-line intervention
• In transplant recipients: reduce tacrolimus/cyclosporine dose, reduce or stop mycophenolate mofetil (MMF), reduce corticosteroid dose
• Rationale: the reason HEV becomes chronic is T-cell suppression from immunosuppressive drugs. By reducing immunosuppression, you restore T-cell-mediated viral clearance

Why reduce immunosuppression first before trying antivirals? Because approximately 30% of transplant patients with chronic HEV will achieve viral clearance with immunosuppression reduction alone — no antiviral needed. This avoids unnecessary drug side effects and simplifies management. However, this must be balanced against rejection risk.

• HEV RNA should be tested in blood and stool after 12 weeks to look for sustained virologic response (SVR) ^[5]
• SVR is defined by absence of HEV RNA by RT-PCR 12 weeks after cessation of treatment ^[5]

The critical irony: HEV is most dangerous in pregnancy (20–25% mortality in 3rd trimester), yet the only specific antiviral (ribavirin) is absolutely contraindicated in pregnancy due to teratogenicity. This means management of severe HEV in pregnancy is entirely supportive ± liver transplantation. There is no antiviral option.

Prevention measures ^[5]:

• Avoidance of water of unknown purity
• Avoidance of food from street vendors
• Avoidance of raw or undercooked seafood, meat or pork products and raw vegetables
• Avoid internal organs (especially pig liver) ^[2] — highly relevant in HK

In Hong Kong specifically: the most actionable advice is to avoid raw or undercooked pork liver (豬潤), pork blood products, and raw shellfish. Cooking to an internal temperature of ≥ 71°C for at least 20 minutes inactivates HEV.

• A recombinant vaccine to prevent hepatitis E virus infection called Hecolin® was developed in China ^[1]
• Licensed in China since 2011 ^[1]
• Licensed in Pakistan in 2020 ^[1]
• Has been used as an outbreak response measure (e.g., vaccination campaign in South Sudan) via MSF ^[1]
• Clinical trials in USA being conducted ^[1]
• NOT currently available in Hong Kong ^[3]
• NOT WHO-prequalified (though under review)
• Based on recombinant HEV genotype 1 capsid protein (p239)
• 3-dose schedule: 0, 1, and 6 months
• Efficacy: ~97% in preventing symptomatic HEV genotype 4 infection in clinical trials

• Pre- or post-exposure immunoglobulin prophylaxis for prevention of HEV has not been established ^[5]
• No passive prevention available for HEV ^[2]
• This is in contrast to HAV, where immunoglobulin can be given for post-exposure prophylaxis

Why no immunoglobulin prophylaxis for HEV? Because (1) anti-HEV antibodies in pooled human immunoglobulin preparations are present at variable and often low titers, (2) the protective titer of anti-HEV has not been well-defined, and (3) anti-HEV antibodies do not confer 100% immunity — reinfection is still possible ^[3].

• All viral hepatitis are notifiable diseases ^[2] in Hong Kong
• Report to the Centre for Health Protection (CHP) upon diagnosis
• Contact tracing is not as critical as for HAV (since most HEV transmission is zoonotic in HK, not person-to-person)

As detailed in Section 4 above: reduce immunosuppression → ribavirin if needed → monitor for SVR.

Cholestatic hepatitis ^[5]:

• Characterized by marked jaundice, pruritus, fever, weight loss, diarrhea and malaise ^[5]
• Resolves spontaneously within weeks to months with no sequelae ^[5]
• Recovery is marked by viral clearance with an increase in IgG and decrease in IgM levels ^[5]

Pathophysiology: Hepatocyte swelling from inflammation compresses intrahepatic bile canaliculi → intrahepatic cholestasis → bile acids cannot be excreted into the gut → accumulate in blood → deposit in skin (pruritus), spill into urine (dark urine), fail to reach the colon (pale stools). Conjugated bilirubin refluxes into the bloodstream → deep jaundice.

HEV has a notably higher proportion with prominent cholestasis (~20%) compared to HAV (< 5%) ^[4]. This means a patient with HEV may have prolonged jaundice lasting weeks to months even after the transaminases have normalized — this is the "cholestatic phase" ^[3]. Bilirubin may be elevated for a long time even after clinical and essential histological recovery ^[3]. This can be alarming to patients and trainees but is benign and self-resolving — you do NOT need to investigate further if the clinical trajectory is otherwise improving.

Acute liver failure ^[5]:

• Characterized by hepatic encephalopathy, elevated AST, ALT, ALP and bilirubin, impaired synthetic function with INR ≥ 1.5 ^[5]
• Fulminant Hepatitis E is actually very rare ^[13], but when it occurs, it is devastating

Definition of ALF (from the HK internal medicine handbook) ^[21]:

• A severe liver injury (coagulopathy with INR ≥ 1.5)
• With onset of hepatic encephalopathy within 26 weeks of the first symptoms
• In the absence of pre-existing liver disease

Who is at risk of fulminant HEV?

Complications within ALF (these are the organ-specific complications that develop once fulminant hepatitis occurs) ^[20]:

The LFT in fulminant hepatitis shows a paradoxical finding: reductions in AST/ALT as disease progresses ^[3] — not because the liver is recovering, but because there are so few remaining viable hepatocytes to release enzymes. The "burnt-out liver" phenomenon. You differentiate this from true recovery by looking at synthetic function: if AST/ALT is falling along with a fall in PT/INR, the patient is probably improving. If AST/ALT is falling with worsening and prolongation of PT, keep fulminant hepatitis in mind ^[3].

• The patient's disease course was complicated with GI bleeding → fulminant hepatic failure ^[13]
• GI bleeding in acute HEV occurs due to:
  1. Coagulopathy — impaired clotting factor synthesis → cannot form adequate clots
  2. Portal hypertension (if underlying cirrhosis) → variceal bleeding
  3. Stress ulceration — critically ill patients in ICU develop stress-related mucosal disease
• GI bleeding accelerates liver failure by increasing ammonia load (blood protein in the gut is broken down by bacteria → ammonia absorbed → worsens encephalopathy)

Neurological complications are the most clinically significant extrahepatic manifestations of HEV. The key teaching point: if a patient develops GBS or neuralgic amyotrophy, check HEV serology — it may be the unrecognized trigger. This is frequently tested.

• Presents with proteinuria, hematuria, rising creatinine
• Usually resolves with viral clearance but may become chronic in immunosuppressed patients with persistent HEV viremia

Hepatitis is well known to precede aplastic anemia ^[22]. The mechanism: viral hepatitis (including HEV) triggers an aberrant T-cell response that cross-reacts with bone marrow hematopoietic stem cells → pancytopenia. This is not a direct cytopathic effect of the virus on the marrow but an immune-mediated phenomenon.

• Presents with epigastric pain radiating to back, elevated amylase/lipase
• Usually mild and self-limiting