Hepatitis A Virus

Classification

General Characteristics

Structure

• Family: Picornaviridae; genus: Hepatoviridae
• Icosahedral nonenveloped enterovirus with single-stranded, positive-sense linear RNA (ssRNA)
• Small (approximately 27 nm in diameter)
• Genome functions as mRNA
• Hepatotropic 
• 1 serotype and 7 different genetic groups have been described.
• Human genotypes are numbered I–III, with 6 subtypes (IA, IB, IIA, IIB, IIIA, IIIB)

Basic features

• Resistant to acid (can survive in GI tract and sewage), ether, drying, and temperatures as high as 56°C and as low as –20°C
• Reservoir: humans
• Found in stool and blood of acutely infected individuals
• Can be viable for years 
• Boiling water, chlorine, and iodine are effective means of destroying the hepatitis A virus.

Epidemiology

• Worldwide: 
  • Incidence: about 1.4 million per year
  • Around 7100 deaths (2016) → accounts for only 0.5% of deaths from viral hepatitis
• Incidence in the United States: 
  • Declined from 6 cases to 0.4 cases per 100,000 between 1999 and 2014, mainly because of updated vaccination recommendation for all children
  • Rising incidence since 2016, mainly because of large person-to-person outbreaks
• Highest prevalence: Africa, South Asia
• In areas with high endemicity: 90% of children will be infected before age 10

Pathogenesis

Transmission

• Fecal–oral:
  • Most common route of transmission
  • Human-to-human contact
  • Contaminated water or food (especially raw shellfish, vegetables)
• Other:
  • Contaminated blood products
  • (Illicit) drug injection
• Viral shedding:
  • HAV is replicated in the liver → excreted in stool
  • High concentrations: 2–3 weeks before to 1 week after onset of symptoms

Risk factors

• Institutionalization (e.g., in nursing homes, hospitals)
• Occupations in day care, health care
• International travel
• Age > 50 years
• Underlying liver disease (especially chronic hepatitis C)
• Blood transfusion recipients 
• Persons who inject drugs (PWIDs)
• Men who have sex with men (MSM)
• Homelessness
• Pregnancy

Pathophysiology

• Primary replication:
  • Ingestion of contaminated food/fecal–oral transmission → replicates in the oropharynx/intestines → bloodstream = first 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)
    • Cell entry → viral RNA uncoated; 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
  • There is no apparent viral cytotoxicity; hepatic injury is immune-related:
    • Immunologic response to infection
    • Accompanied by portal and periportal lymphocytic infiltration → varying degrees of necrosis
• Incubation period: 2–6 weeks before symptoms or anti-HAV IgM antibodies
• Infectious period: 2 weeks before to 1 week after the onset of illness

Clinical Presentation

General features

• Acute viral hepatitis
• Usually self-limiting, no chronification
• Lifelong immunity after infection
• Symptomatic illness: > 70% of infected adults
• Specific subgroups:
  • Children: asymptomatic or very mild symptoms
  • Pregnant women: increased risk of preterm labor and other complications 
• Acute hepatic failure: < 1% of cases 
• Recovery:
  • 85% of infected individuals recover after 2–3 months.
  • Relapsing hepatitis in up to 10% of cases (usually only during the 6 months after infection)

Specific symptoms

The presence of 1 of the following symptoms is a reason to suspect hepatitis A infection, especially in the presence of risk factors:

• Nausea
• Anorexia 
• Abdominal pain
• Fever
• Hepatomegaly
• Jaundice
• Discolored stool
• Dark urine
• Joint pain

Diagnosis and Management

Diagnosis

• Diagnosis of acute infection: 
  • Anti-HAV IgM antibodies in serum (detectable from 1–2 weeks after infection)
  • OR positive PCR for HAV RNA 
  • Supportive for diagnosis: ↑ serum transaminases
• Anti-HAV IgG without Anti-HAV IgM: past infection or vaccination

Management

• Management is supportive, as the infection is self-limiting.
• Use medications that can cause liver damage cautiously.
• In cases of fulminant liver failure: Consider liver transplantation.

Prevention

• In the United States (per the CDC):
  • Routine vaccination for all children > 12 months
  • Individuals at increased risk
• International (per the WHO):
  • Recommendation for vaccination depends on local endemicity of a country
  • Intermediate endemicity: greatest benefit from vaccinating children
  • Low endemicity: benefit from vaccinating high-risk adults 
  • High endemicity: limited benefit from vaccination → high rate of natural immunity
• Hygiene: sanitation (chlorine treatment) of water and sewage, regular handwashing
• Avoidance of possibly contaminated food, such as uncooked shellfish and vegetables in regions with high endemicity

Comparison of Hepatitis Viruses

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).