What are the clinical presentation and laboratory characteristics of Hepatitis E (HEV)?

Clinical Presentation of Hepatitis E

Hepatitis E is clinically silent in the vast majority of patients, with less than 5% developing symptomatic acute hepatitis characterized by elevated liver enzymes, jaundice, and non-specific symptoms including fatigue, itching, and nausea. 1

Clinical Manifestations

Acute Infection in Immunocompetent Patients

• Most infections are asymptomatic – the vast majority of HEV infections produce no clinical symptoms 1

• When symptomatic, patients present with a flu-like febrile illness followed by:

  • Nausea and vomiting 1
  • Abdominal pain (right upper quadrant discomfort) 2
  • Jaundice (yellowing of skin and eyes) 1
  • Tender hepatomegaly 1
  • Fatigue 1, 2
  • Pruritus (itching) 1
  • Dark urine and light-colored stools 1
  • Fever 2, 3

• Demographic pattern: In developed countries (genotypes 3 and 4), symptomatic disease predominantly affects older males with a male-to-female ratio of 3:1 and median age of 63 years 1

High-Risk Populations with Severe Disease

Pregnant women with genotype 1 or 2 infection face approximately 25% mortality due to fulminant hepatic failure and obstetric complications including eclampsia and hemorrhage 1

Patients with underlying chronic liver disease are at significant risk for acute-on-chronic liver failure when infected with HEV, particularly elderly patients who may experience a more severe course 1

Acute liver failure is rare with genotype 3 infection but has been documented, with one German study finding HEV RNA in 10% of patients with acute liver failure 1

Chronic Infection in Immunosuppressed Patients

• Occurs only with genotypes 3 and 4 in immunosuppressed individuals including solid organ transplant recipients, HIV-infected patients, and those with hematological malignancies 1, 3

• Clinical presentation is often subtle: Only one-third of chronically infected transplant recipients are symptomatic, with fatigue as the main complaint 1

• Many patients have normal or only slightly elevated liver enzymes, making diagnosis challenging 1

• Chronic infection is defined as HEV RNA persistence for at least 3-6 months 1, 3

• Without treatment, approximately 60% of HEV infections in solid organ transplant recipients progress to chronic hepatitis E 3

Laboratory Characteristics

Liver Enzyme Patterns

Elevated aminotransferases are the hallmark finding:

• Alanine aminotransferase (ALT) elevation 1
• Aspartate aminotransferase (AST) elevation 1
• Median ALT in chronic infection: 260 ± 38 IU/L 1
• Median AST in chronic infection: 155 ± 25 IU/L 1

Other hepatic markers:

• Elevated bilirubin (correlates with jaundice severity) 1
• Elevated gamma-glutamyl transferase (GGT): median 308 ± 56 IU/L in chronic infection 1
• Alkaline phosphatase may be elevated 4

Severe jaundice cases show distinct patterns:

• Lower GGT levels (median 170.31 U/L vs 237.96 U/L in non-severe cases) 4
• Lower albumin levels (33.84 g/L vs 36.89 g/L) 4
• Lower acetylcholine esterase (4500.93 U/L vs 5815.28 U/L) 4
• Higher total bile acid (275.56 μmol/L vs 147.03 μmol/L) 4
• Higher viral load 4

Coagulation Parameters

INR monitoring is essential as coagulopathy indicates severe hepatic dysfunction and potential progression to acute liver failure 1

Prothrombin index is significantly different in patients with severe jaundice 4

Serological Markers

HEV IgM antibody:

• Appears 4-6 weeks after exposure 1
• Lasts 2-4 months (may persist up to one year) 1
• Indicates acute or recent infection 1

HEV IgG antibody:

• Detectable by 4 weeks after clinical presentation 1
• Persists long-term with increasing avidity 1
• Indicates past infection or immunity (though not sterilizing) 1

Critical caveat: In immunosuppressed patients with chronic HEV infection, both anti-HEV IgG and IgM may remain negative, making serology unreliable 1

Molecular Testing

HEV RNA detection is the gold standard, particularly in immunosuppressed patients:

• Detectable in blood approximately 3 weeks post-infection 1
• Viraemia lasts 3-6 weeks in acute infection 1
• Viral shedding in stool occurs for 4-6 weeks 1
• Nucleic acid amplification testing (NAAT) is mandatory for diagnosis in immunosuppressed patients where antibodies may be absent 1
• Quantitative HEV RNA monitoring is used to assess treatment response 1

Key Clinical Pitfalls

Do not rely on serology alone in immunosuppressed patients – some chronically infected patients have negative or weakly positive antibodies, requiring molecular testing for diagnosis 1

Consider HEV in all patients with unexplained hepatitis – EASL recommends testing all patients with symptoms consistent with acute hepatitis and those with unexplained flares of chronic liver disease 1

Recognize that normal liver enzymes do not exclude chronic HEV – some chronically infected patients have only minimal enzyme elevations 1

Higher viral loads correlate with severe jaundice and may predict worse outcomes 4