Pathophysiology

• Humans appear to be the only reservoir for the HAV.
• The incubation period usually lasts 2-6 weeks. The time to onset of symptoms may be dose-related.
• Viral replication depends on hepatocyte uptake.
• After uptake, the viral RNA is uncoated, and host ribosomes bind to form polysomes.
• Viral proteins can then be synthesised with the viral genome being copied by a viral RNA polymerase.
• Assembled virus particles are then shed through the biliary tree into the faeces.
• Shedding of the HAV is greatest during the anicteric prodrome of infection (between 14 and 21 days after infection). This corresponds to the time when transmission is highest.

Epidemiology^[3]

• There was a peak in incidence in the early 1990s in the UK.
• The incidence over the last 10 years has been very low.
• The mean age of HAV infection has increased in recent years in the UK. The highest incidence is between the ages of 5 and 34 years.
• In developing nations the disease is usually acquired before age 2 years.
• In Western societies, acquisition is generally most common between ages 5 and 17 years.
• In developed countries, reduced encounters with HAV in the young have resulted in a decline in herd immunity.
• There is therefore a potential for epidemics in the future. However, public health policies and immunisation should prevent such epidemics.
• Food handlers are an infrequent source of outbreaks in the United States, although cases have been documented. Any food can be contaminated with the HAV.

Risk factors

Most people acquiring HAV infection do not have risk factors but these include:

• Personal contact
• Certain occupations (for example, daycare)
• Travel to high-risk areas
• Male homosexuality
• Intravenous drug abuse

Clinical features

• The incubation period is 2-6 weeks with a mean of 4 weeks.
• There is a prodrome of mild flu-like symptoms (anorexia, nausea, fatigue, malaise, joint pain, and low-grade fever) preceding the jaundice. There may also be myalgia, and mild headache with the fever. Smokers often lose their taste for tobacco. Diarrhoea can occur, particularly in children.
• This can progress to the icteric phase with:
  • Dark urine (appears first).
  • Pale stools (not always).
  • Jaundice occurs in 70 to 85% of adults with acute HAV infection. Jaundice is less likely in children and uncommon in infants. The degree of icterus also increases with age.
  • Abdominal pain occurs in 40% of patients.
  • Itch or pruritus (usually with jaundice but can occur without).
  • Arthralgias and skin rash occur less often (lower limbs and with a vasculitic appearance).
• Tender hepatomegaly, splenomegaly, and lymphadenopathy may occur.
• 15% have prolonged or relapsing illness for 6-9 months:
  • This is more common in the elderly.
  • There is a relapse of symptoms and signs following apparent resolution.

Differential diagnosis

• Other forms of viral hepatitis
• Acute HIV infection
• Drugs (hypersensitivity and toxicity)
• Cytomegalovirus

Investigations

• Specific antibody tests:
  • IgM antibody to HAV is positive with onset of symptoms (usually about 3 to 4 weeks after exposure but up to 6 weeks). The test is sensitive and specific. It remains positive for between 3 and 6 months (up to 12 months). It remains positive in relapsing hepatitis.
  • IgG antibody to HAV appears soon after IgM and persists for many years. In the absence of IgM it indicates past infection or vaccination rather than acute infection. IgG remains detectable for life.
• Liver enzymes:
  • Alanine aminotransferase (ALT) rises more than aspartate aminotransferase (AST) again with onset of symptoms, about 4 weeks after exposure. Levels usually return to reference ranges over several weeks but can remain elevated for months.
  • Alkaline phosphatase rises with ALT and AST. Further increase may occur in the cholestatic phase of the illness.
• Other test results:
  • Bilirubin rises soon after rises in ALT and AST levels. Levels may be very high and remain elevated for several months. Persistence beyond 3 months signals cholestatic HAV infection. Older patients have higher bilirubin levels.
  • Modest falls in serum albumin level may occur.
  • Prothrombin time usually remains normal and estimation is necessary only in unusual cases or with complications.
  • Indices of low-grade haemolysis may be detected.
  • Mild lymphocytosis is not uncommon.
  • Pure red cell aplasia and pancytopenia may rarely occur.
• Imaging:
  • Ultrasound may rarely be needed to exclude other diseases and in fulminant hepatic failure.

Management

• Mainly supportive with treatment of symptoms (fluids, antiemetics, rest).
• Avoid alcohol until liver enzymes normal.
• Admit patients with severe systemic upset or intractable vomiting for rehydration and observation

Complications

These rarely occur but include:

• Death (mortality 0.2%)
• Cholestatic viral hepatitis A
• Autoimmune hepatitis
• Relapsing HAV infection (about 2% of cases)
• Other very rare complications (for example, acute renal failure, red cell aplasia, Guillain-Barré syndrome, pancreatitis)

Prevention

Hepatitis A is the most frequent vaccine-preventable disease in travellers. It also has the highest mortality and morbidity of any vaccine-preventable infection in travellers.
It can be a serious illness, particularly in the elderly. With proven means of prevention, it is important to pursue prevention actively. After infection and active immunisation, immunity is probably lifelong.

• Control of infection at source is needed. This requires notification and contact tracing.
• Good hygiene and sanitation are of fundamental importance. Tap water should be avoided in high-risk areas.
• Public education about transmission and prevention are needed, particularly in communities where HAV is endemic.
• Immunisation is effective and should be appropriately used:
  • Passive immunisation with normal human immunoglobulin (0.02 ml/kg IM) gives <3 months' passive immunity to those at risk (for example, travellers and household contacts) and during incubation.
  • Active immunisation is covered in the article on Hepatitis A Vaccination.

Prognosis

• Excellent. It is usually self-limiting with no long-term sequelae.
• There is no carrier state, and chronic liver disease does not occur.