What are the diagnosis, signs, and symptoms of Hepatitis E (HEV)?

Diagnosis, Signs, and Symptoms of Hepatitis E (HEV)

The diagnosis of hepatitis E requires a combination of serological and nucleic acid testing, with clinical presentation ranging from asymptomatic infection to acute hepatitis with jaundice, and in rare cases, chronic infection in immunocompromised patients.

Clinical Presentation

Signs and Symptoms

• Acute infection:
  • Incubation period: 15-60 days 1
  • Jaundice
  • Fatigue
  • Nausea/vomiting
  • Abdominal pain
  • Fever
  • Dark urine
  • Clay-colored stools

Special Populations

• Immunocompetent individuals: Usually self-limiting acute hepatitis
• Immunosuppressed patients: Risk of chronic infection (defined as HEV RNA detectable for ≥3 months) 1
• Pregnant women: Higher risk of severe disease with genotype 1 infection

Extrahepatic Manifestations

• Neurological disorders:
  • Guillain-Barré syndrome
  • Neuralgic amyotrophy
  • Encephalitis/myelitis 1
• Renal manifestations:
  • Glomerulonephritis (membranoproliferative or membranous) 1
  • Proteinuria
• Hematological disorders:
  • Severe thrombocytopenia
  • Hemolytic anemia
  • Aplastic anemia 1
• Other manifestations:
  • Myocarditis
  • Thyroiditis
  • Henoch-Schönlein purpura
  • Cryoglobulinemia 1

Laboratory Diagnosis

Diagnostic Algorithm

1. First-line testing for any patient with biochemical evidence of hepatitis:

   • HEV IgM antibody
   • HEV RNA testing
   • Consider HEV antigen testing 1

2. Interpretation of results:

   • Acute infection: Positive HEV IgM and/or HEV RNA
   • Chronic infection: HEV RNA detectable for ≥3 months (in immunosuppressed patients)
   • Past infection: Positive HEV IgG, negative HEV IgM and HEV RNA

Specific Tests

• Serological tests:

  • HEV IgM: Appears at symptom onset, lasts 3-4 months (may persist up to 1 year) 1
  • HEV IgG: Appears shortly after IgM, lasts >10 years 2

• Molecular tests:

  • HEV RNA: Detectable in blood and stool approximately 3 weeks post-infection
  • Viremia lasts 3-6 weeks
  • Viral shedding in stool lasts 4-6 weeks 1

• Antigen detection:

  • HEV antigen testing may be useful when RNA testing is unavailable
  • Higher positive predictive value than IgM testing 3

Timing of Markers

• HEV RNA appears shortly before symptom onset
• Biochemical markers (liver enzymes) become elevated at clinical onset
• Antibodies appear around clinical onset (IgM first, followed by IgG) 1

Diagnostic Pitfalls and Caveats

• False-positive IgM results: Cross-reactivity with EBV and CMV is common (33.3% and 24.2% respectively) 4
• Low positive predictive value of IgM: Only 13.3% of HEV IgM positive samples may be PCR positive 4
• Delayed antibody response: Immunosuppressed patients may have delayed or absent antibody response, making RNA testing essential 1
• Unexpectedly long IgM persistence: IgM can remain positive for over 3 years in some patients after acute infection 3

Differential Diagnosis

• Drug-induced liver injury (DILI)
• Autoimmune hepatitis
• Other viral hepatitis (A, B, C)
• EBV hepatitis
• CMV hepatitis 1

Important Recommendations

• All patients with hepatitis should be tested for HEV as part of first-line virological investigation, regardless of travel history 1
• Patients with suspected DILI should be tested for HEV (13% of suspected DILI cases may actually be HEV infection) 1
• Patients with neurological manifestations like Guillain-Barré syndrome or neuralgic amyotrophy should be tested for HEV, regardless of liver function test results 1
• Combination testing with both serology and nucleic acid testing provides the most accurate diagnosis 1
• HEV antigen testing may be particularly useful when RNA testing is unavailable 3

Management Considerations

• Acute hepatitis E: Usually self-limiting, supportive care
• Chronic hepatitis E: Consider ribavirin treatment in immunosuppressed patients 5
• Patients with HEV should avoid alcohol consumption to prevent accelerated disease progression 5