What is the comprehensive approach to hepatitis E, including transmission, symptoms, diagnosis, treatment, and prevention strategies?

Hepatitis E: Comprehensive Clinical Lecture

Epidemiology and Transmission

Hepatitis E virus (HEV) is now the most common cause of acute viral hepatitis in many developed countries, fundamentally changing how we approach patients with hepatitis. 1

Transmission Routes

• Fecal-oral transmission remains the primary route globally, occurring through contaminated water, food (particularly undercooked pork, wild boar, venison, and shellfish), or direct contact 1
• Zoonotic transmission from pigs, wild boar, and deer is the predominant pattern in developed countries, with genotypes 3 and 4 responsible for most infections 1, 2
• Transfusion-transmitted infection occurs at surprisingly high rates, with viraemic donor prevalence ranging from 1:600 in the Netherlands to 1:14,799 in Australia 1
  • 42% of recipients receiving infected blood components develop infection 1
  • Minimum infective dose is approximately 2 × 10⁴ IU HEV RNA 1
• Sexual transmission has been documented in men who have sex with men, though evidence is mixed 1
• Vertical transmission from mother to fetus can occur, leading to premature birth, increased fetal loss, and neonatal hepatitis 3

Genotype Distribution

• Genotypes 1 and 2: Obligate human pathogens causing epidemics in Asia, Africa, and Central America through contaminated water 2
• Genotypes 3 and 4: Zoonotic strains endemic in developed countries (Europe, Japan, North America) 1, 2
• Genotypes 5,6, and 8: Animal-restricted 4

Clinical Presentation

Acute Hepatitis E

Most immunocompetent individuals experience self-limiting infection, but specific populations face severe complications. 3

• Typical presentation: Flu-like febrile illness followed by nausea, vomiting, abdominal pain, jaundice, and tender hepatomegaly 1
• Asymptomatic infection: Most transfusion-transmitted cases remain asymptomatic 1
• Severe disease risk groups:
  • Pregnant women (particularly third trimester) with mortality rates up to 20-25% 3
  • Older men 1
  • Patients with pre-existing chronic liver disease who may develop acute-on-chronic liver failure 3, 5
  • Immunocompromised individuals 5

Chronic Hepatitis E

Chronic infection develops exclusively in immunosuppressed patients and is easily overlooked due to minimal symptoms. 1

• Definition: HEV RNA persistence beyond 3-6 months 1
• At-risk populations: Solid organ transplant recipients, HIV-infected patients, hematologic malignancy patients on chemotherapy 4, 2
• Clinical features: Minor persistent liver function abnormalities that may be delayed for months after infection 1
• Natural history: Without treatment, can progress to cirrhosis 2

Extrahepatic Manifestations

• Neurological: Neuralgic amyotrophy, Guillain-Barré syndrome, encephalitis 1, 5
• Renal: Glomerulonephritis, membranoproliferative glomerulonephritis 5
• Hematological: Thrombocytopenia, aplastic anemia 5
• Pancreatic: Acute pancreatitis 3
• Cholestatic hepatitis: One of the most devastating manifestations requiring specific management 6

Diagnosis

Critical Diagnostic Paradigm Shift

All patients presenting with biochemical evidence of hepatitis must be tested for HEV at initial presentation alongside HAV, HBV, and HCV—not as second-line testing. 1, 7

This represents a fundamental change from previous practice where HEV testing was reserved for travelers or performed only after negative HAV/HBV/HCV results 1

Recommended Testing Strategy

• Combination approach: Use both serology and nucleic acid testing (NAT) for optimal diagnostic accuracy 1, 7
• Acute infection:
  • Anti-HEV IgM antibody (appears 4-6 weeks after exposure, lasts 2-4 months) 7
  • HEV RNA by NAT (particularly important in early infection or immunosuppressed patients) 1, 7
• Chronic infection: NAT testing is essential as antibody responses may be absent or delayed in immunosuppressed patients 1
• Immunohistochemistry: HEV ORF2 protein detection can establish histopathologic diagnosis 1

Critical Differential Diagnosis

Drug-induced liver injury (DILI) is the most important differential diagnosis, and all suspected DILI cases must be tested for HEV. 1, 7

• In a UK cohort, 13% of patients with "criterion-referenced" DILI actually had acute hepatitis E (genotype 3) 1, 7
• This misdiagnosis is particularly common in elderly patients with polypharmacy 1

Complete differential diagnosis by infection status 1:

Acute infection (in order of frequency):

• Drug-induced liver injury
• Autoimmune hepatitis
• Acute hepatitis E
• Seronegative hepatitis
• EBV hepatitis
• Acute hepatitis B
• Acute hepatitis A
• Acute hepatitis C
• CMV hepatitis

Chronic infection in immunosuppressed:

• Graft rejection
• Drug-induced liver injury
• Recurrence of primary liver pathology
• Graft vs. host disease
• Intercurrent infections (sepsis)
• Chronic hepatitis E
• EBV and CMV reactivation

Treatment

Acute Hepatitis E in Immunocompetent Patients

Supportive care is the mainstay of treatment for acute infection in immunocompetent individuals. 6, 2

• No specific antiviral therapy is required for self-limiting disease 2
• Ribavirin may be considered in severe acute hepatitis E or acute-on-chronic liver failure, though evidence is limited 1, 6
• Supportive measures include vitamins, albumin, plasma, and symptomatic treatment 6

Chronic Hepatitis E in Immunosuppressed Patients

The treatment algorithm for chronic HEV in solid organ transplant recipients follows a stepwise approach: 1

Step 1: Reduction of immunosuppression

• Lower tacrolimus trough levels and reduce daily steroid dose 1
• Achieves sustained viral clearance in approximately one-third of chronically infected solid organ transplant recipients 1
• Consider switching from mTOR inhibitors (which upregulate HEV replication) to mycophenolate (which has suppressive effects in vitro) 1

Step 2: Ribavirin monotherapy if no clearance after Step 1

• 3-month course of ribavirin monotherapy is the standard treatment 1
• Monitor serum and stool HEV RNA for clearance 1
• Assess for relapse after ceasing ribavirin 1

Step 3: Pegylated interferon-α for treatment failures

• 3-month course of pegylated interferon-α in liver transplant patients who fail ribavirin 1
• No alternative therapy currently available for other transplant patients 1
• Associated with major side effects 6

Special Considerations

• Pregnant women: No approved treatments; supportive care only with active monitoring for liver failure 6
• Cholestatic hepatitis: Ursodeoxycholic acid, obeticholic acid, S-adenosylmethionine for jaundice removal; symptomatic treatment for pruritus 6
• Liver failure: Liver support devices as bridge to recovery or transplantation; liver transplantation is definitive treatment for those not improving with supportive measures 6

Unanswered Questions

• Optimal ribavirin dose and duration remain undefined 1
• Role of HEV RNA variants (including G1634R mutation) in treatment outcomes is uncertain 1
• Benefit of ribavirin in severe acute hepatitis E and acute liver failure is unclear 1

Prevention Strategies

Food Safety Recommendations

Immunocompromised individuals and those with chronic liver disease must avoid undercooked meat and shellfish. 1

• Specific recommendation: Consume meat only if thoroughly cooked to temperatures of at least 70°C for more than 2 minutes 1
  • 80°C required for 1-minute heating 1
  • HEV remains infectious at room temperature for 28 days 1
• High-risk foods: Undercooked pork, wild boar, venison, shellfish 1
• General population: Recommending avoidance of undercooked pork is not currently justified for immunocompetent individuals 1

Blood Safety

• Several countries (Ireland, UK, France, Netherlands, Japan, Germany) have introduced universal, targeted, or partial screening for HEV in blood donors 1
• Solvent/detergent-treated plasma has been tested for HEV by NAT in Europe since 2015 1
• No reports of HEV transmission by virally-inactivated fractionated blood products 1

Vaccination

An HEV vaccine (HEV 239) is licensed in China with 97% efficacy for preventing symptomatic acute hepatitis. 1

• Based on 239 amino acids of HEV ORF2 protein derived from genotype 1 1
• Prevents symptomatic genotype 4 infections, suggesting cross-genotype efficacy 1
• Does not provide sterilizing immunity; subclinical infections can still occur 1
• Limitations:
  • Only licensed in China 1
  • Long-term efficacy and safety in chronic liver disease and immunosuppressed patients remain undetermined 1
  • Efficacy against genotype 3 (predominant in developed countries) remains to be determined 1
• Potential role: Prevention of HEV outbreaks in refugee camps or emergency settings (WHO prequalification underway) 1

Infection Control

• Implement standard precautions to prevent spread by contaminated stool in hospitals and nursing homes 1
• HEV RNA detected in urine; unclear if transmissible via saliva, sweat, semen, or breast milk 1

Key Clinical Pitfalls to Avoid

1. Never defer HEV testing until HAV, HBV, and HCV results are negative—test all simultaneously at presentation 1, 7
2. Always test for HEV in suspected drug-induced liver injury, especially in elderly patients with polypharmacy 1, 7
3. Do not overlook chronic HEV in immunosuppressed patients with minor persistent liver function abnormalities 1
4. Remember that transfusion-transmitted HEV is common and mostly asymptomatic, but carries significant risk for chronic infection in immunosuppressed recipients 1
5. Recognize that anti-HEV IgG does not necessarily protect against reinfection, particularly with low antibody levels 1
6. In immunosuppressed patients, use NAT testing rather than relying solely on serology, as antibody responses may be absent 1