Hepatitis E Virus

Classification

General Characteristics

Structure

• RNA virus: genus Hepevirus
• 27–34 nm in diameter
• Linear, single-stranded, positive-sense RNA (resembles norovirus)
• Nonenveloped
• Icosahedral capsule
• 5 identified genotypes (only genotypes 1 and 2 affect humans)

Basic features

• Viable for years 
• Elimination: Boiling water, chlorine, and iodine can effectively destroy the virus. 
• Primary reservoir: animals (zoonotic virus)
• Acute versus chronic:
  • Causes acute hepatitis
  • Chronic cases of hepatitis E virus (HEV) have been reported in immunosuppressed patients but are very rare.

Epidemiology

• Prevalence:
  • Antibodies can be found in 21% of U.S. adults. 
  • Antibody rates ↑ with age, with those > 60 years old having the highest prevalence.
• Incidence:
  • At least 20 million cases worldwide each year
  • Most affected:
    • East and South Asia
    • Resource-poor areas with frequent water contamination
    • Areas with unsafe drinking water supplies
• Mortality rate: 4% overall, but 20% for pregnant patients

Pathogenesis

Transmission

• Fecal–oral route
• Foodborne outbreaks are common (e.g., shellfish cultivated in contaminated water).
• Highest transmission: greatest viral shedding during the anicteric prodrome (14–21 days)

Host risk factors

• Institutionalization (e.g., nursing homes)
• Occupation (e.g., daycare)
• Foreign travel
• Contaminated blood products
• IV or other illicit drug users
• Men who have sex with men (MSM)
• Homeless population
• Liver transplant recipients

Pathophysiology

Primary replication:

• Ingestion of contaminated food/fecal–oral transmission → replicates in the oropharynx/intestines → bloodstream = 1st viremia
• Reaches the liver because of tissue tropism (hepatotropic)
• Hepatocytes take up the virus by a receptor on the plasma membrane.
• Replication occurs in hepatocytes and Kupffer cells (hepatic macrophages):
  • After cell entry, viral RNA is uncoated and the host ribosomes bind to form polysomes. 
  • Viral proteins are synthesized, and the viral genome is copied by a viral RNA polymerase.
• Virus particles shed into the biliary tree → excreted in the feces

Clinical Presentation

• Causes acute viral hepatitis
• Incubation period: 2–6 weeks 
• Infectious period: 2 weeks before to 1 week after the onset of symptoms
• HEV can be asymptomatic or very mild in children.
• Prodromal symptoms:
  • Fever
  • Malaise
  • Abdominal pain (RUQ)
  • Myalgia and arthralgia
• Icteric-phase symptoms:
  • May last days to several weeks
  • Jaundice
  • Dark urine
  • Grayish stools 
  • Itching
• Relapsing hepatitis occurs in 15% of cases (but only for a year at most).

Diagnosis and Management

Diagnosis

• Abdominal ultrasonography: Rule out extrahepatic causes of biliary obstruction.
• Serologic testing: 
  • Anti-HEV IgM antibodies:
    • Positive in current or recent infection
    • Starts rising 4 weeks after infection and remains detectable for 2 months after
  • Anti-HEV IgG antibodies: previous infection
  • HEV RNA: tested in stool or serum 
• During acute infection, the liver enzyme ALT is elevated.

Management

• Acute, uncomplicated cases: supportive care sufficient
• Severe cases: Reduce immunosuppressive therapy, if possible.
• Antiviral options:
  • Ribavirin (contraindicated in pregnancy)
  • Sofosbuvir: in combination with ribavirin
  • Pegylated interferon alfa (PEG-IFN-α)

Prevention

• Sanitation: 
  • Chlorine treatment of water and sewage and regular handwashing
  • Avoidance of possibly contaminated food, such as uncooked shellfish
• To date, there is no FDA-approved vaccine.

Comparison of Hepatitis Viruses

Table: Comparison of hepatitis viruses A–E

Differential Diagnosis

• Alcoholic liver disease (ALD): liver pathology that occurs because of prolonged excessive alcohol consumption. The 1st stage is an asymptomatic fatty liver, which is reversible. The 2nd stage is alcoholic hepatitis, which most commonly presents with jaundice, fever, and RUQ pain. The 3rd stage is cirrhosis of the liver. Diagnosis is established by history, liver-function tests, and imaging studies. 
• Drug-induced liver injury (DILI): occurs when drugs ingested cause injury to the hepatocytes directly in a predictable dose-dependent way or through idiosyncratic reactions. The presentation of DILI can be acute or chronic, with severe toxicity manifesting as fulminant liver failure. The diagnosis of DILI requires a thorough history and laboratory tests. Management consists of early diagnosis and discontinuing the drug, as well as supportive therapy.
• Autoimmune hepatitis (AIH): liver inflammation that occurs when the body’s immune system attacks its own liver cells. Clinical presentation ranges from asymptomatic to symptoms of acute liver failure. Diagnosis is established via testing the blood for characteristic autoantibodies (especially, anti–smooth muscle antibodies) and liver biopsy. Management includes corticosteroids and azathioprine. 
• Wilson disease: autosomal recessive disorder from a mutation in the ATP7B gene, which regulates copper transport within hepatocytes. Neuropsychiatric manifestations of Wilson disease help differentiate it from other causes of hepatitis. In early stages, Wilson disease may be confused with hepatic encephalopathy. Kayser-Fleischer rings, low ceruloplasmin levels help separate Wilson disease from other causes of hepatitis.
• Nonalcoholic fatty liver disease (NAFLD): spectrum of liver pathology that arises due to accumulation of triglycerides in hepatocytes. Nonalcoholic fatty liver disease ranges from fatty liver or hepatic steatosis but can lead to nonalcoholic steatohepatitis which has fatty deposits and inflammation. Progressive liver injury and fibrosis irreversibly develop into cirrhosis and possibly, primary liver cancer. Management is with lifestyle modifications (diet and exercise).