Hospital Medicine

Hepatitis A

I. What every physician needs to know.

The hepatitis A virus (HAV) is a hepatotropic 27 nm, non-enveloped, positive-stranded RNA virus of Picornaviridae family, closely related to enterovirus and erbovirus genera. Since humans are the only known reservoir for HAV, theoretically HAV could be eradicated with widespread immunization and prevention of fecal contamination of water supplies.

HAV infection occurs worldwide and is the most common cause of acute viral hepatitis in both the developing and the developed world. While HAV incidence is declining dramatically in the developed world following the widespread introduction of vaccination, it remains highly prevalent in the developing world owing to the lack of adequate sanitation.

The incidence of acute hepatitis A in the United States was reported to be 0.4 per 100,000 in 2014. This incidence reflects a 90% drop since 1998 due to the implementation and expansion of vaccination for all children in the US.

HAV infection is primarily transmitted by the fecal-oral route, by either person-to-person contact or consumption of contaminated food or water. Blood borne transmission can occur during the acute viremic phase, but is uncommon.

The incubation period is approximately 28 days (range, 15–50 days). The virus replicates in the liver, is excreted in the bile, and is shed in high quantities in the stool. Highest concentrations of viral particles in stool are found 2 weeks before the onset of clinical illness (jaundice or liver enzyme elevation). As a result, this is also the period of peak infectivity. Concentrations of HAV in the stool declines soon after the onset of clinical illness but may persist for up to 2.5 months in children.

HAV infection is a self-limited disease and does not result in chronic infection. It can rarely lead to acute liver failure. IgG antibodies to HAV appear early in the course of infection and provide lifelong protection against the disease.

Clinical features

Hepatitis A infection can present with various clinical patterns:

  • Asymptomatic or non-specific viral syndrome symptoms (most common presentation in children)

  • Jaundice lasting up to 8 weeks (most common presentation in adults)

  • Jaundice with cholestasis lasting over 10 weeks

  • Fluctuating course with 2 or more presentations of symptomatic acute illness during a 6 month period (estimated to occur in 10-15% of patients)

  • Acute liver failure (greater incidence in patients with underlying chronic liver disease and advanced age)

  • Precipitation of autoimmune hepatitis (rare but with case reports developing after acute HAV infection)

Children under 2 years of age are typically minimally symptomatic with less than 20% developing jaundice. On the other hand, greater than 80% of adults will be symptomatic with jaundice.

The most common symptoms include fever, malaise and jaundice. Additional symptoms may include fatigue, weakness, nausea, vomiting, abdominal pain, dark-colored urine, light colored stools. Extrahepatic manifestations due to immune-complex disease are rare but may include rash, arthritis, leukocytoclastic vasculitis, glomerulosclerosis, and arthritis.

Prevention

Vaccination

Vaccination is highly effective in preventing symptomatic HAV infection. HAV vaccine has been licensed in the United States for use in persons 12 months of age and older. Hepatitis A vaccination is recommended for all children between the ages of 1 and 2 years, for persons who are at increased risk for infection, for persons who are at increased risk for complications from hepatitis A because of underlying chronic liver disease and for any person wishing to obtain immunity.

Immune globulin (IG) is available for short-term protection (approximately 3 months) against HAV, both pre- and post-exposure.

Hand hygiene

Handwashing or use of hand sanitizer is integral to HAV prevention, given that the virus is transmitted through the fecal–oral route.

Food hygiene

Outbreaks and sporadic cases have been reported in association with contaminated food or water. Heating food at a temperature of 185°F (85°C) or higher for 1 minute is needed to inactivate HAV. Waterborne outbreaks are more common in developing countries without proper sanitation to prevent fecal contamination of water supplies; therefore, travelers to developing countries should be vaccinated before departure and should use bottled water for drinking, cleaning fresh fruits and vegetables and making ice cubes. Food contamination, such as consumption of undercooked shellfish, is a common cause of hepatitis A outbreaks.

Environmental hygiene

HAV can live outside the body for months, depending on the environmental conditions. The virus is killed by heating to 185°F (85°C) for one minute or by disinfection with a 1:100 dilution of household bleach (sodium hypochlorite) in water. Adequate chlorination of water kills HAV that enters the water supply.

Who is at higher risk?

  • Unvaccinated travelers to countries with high or intermediate endemicity of HAV infection

  • Men who have sex with men

  • Users of injection and non-injection illegal drugs

  • Persons with chronic liver disease

  • Persons with clotting factor disorders

  • Persons working with nonhuman primates susceptible to HAV infection

Who should be vaccinated against Hepatitis A?

Note: Vaccination and other guidelines are frequently updated by CDC and the CDC website can be reviewed for the latest recommendations.

Two single-antigen HAV vaccines, (both inactivated vaccines) HAVRIX® (GlaxoSmithKline) and VAQTA® (Merck), are currently licensed in the United States (since 1995). Both vaccines are inactivated vaccines, given intramuscularly in two doses, with the second dose recommended to be given within 6 to 12 months with HAVRIX, and within 6 to 18 months, in case of VAQTA. These vaccines confer protective immunity (anti HAV titers >20 units/ml) for >20 years in nearly 100 percent cases.

A combination vaccine, TWINRIX® (GlaxoSmithKline), containing both HAV (in a lower dosage) and hepatitis B virus antigens, is also available only for persons greater than 18 years old. Studies have shown greater seroconversion rates for children given the monovalent vaccines.

The following groups are recommended to receive Hepatitis A vaccination (unless blood tests demonstrate prior immunity by a positive anti-HAV total antibody test):

  • All children at age 1 year (i.e., 12–23 months). Children who have not been vaccinated by age 2 can be vaccinated at subsequent visits.

  • Persons traveling to or working in countries that have high or intermediate rates of HAV endemicity.

  • Previously unvaccinated persons who anticipate close personal contact with international adoptee from a country of high or intermediate endemicity during the first 60 days following the arrival of the adoptee in the United States.

  • Men who have sex with men.

  • Users of illegal injection and non-injection drugs.

  • Persons who have occupational risk for infection i.e. persons who work with HAV-infected primates or with HAV in a research laboratory setting.

  • Persons who have chronic liver disease.

  • Persons who have clotting-factor disorders.

  • Anyone who desires to be vaccinated.

Additional motivating factors for people to be vaccinated include:

  • The economic impact on an individual can be substantial since the average time off work due to fatigue is 4-6 weeks.

  • Prevent the need for post-exposure immune globulin injection (a large volume injection in the buttocks).

Pre-vaccination testing with the anti-HAV total antibody test might be a cost-effective approach before vaccinating adults over 40 years of age, especially in individuals from areas with high endemicity of HAV infection.

Post-vaccination testing is not recommended because of the high rates of vaccine response among both adults and children. Moreover, the commercially available anti-HAV total antibody test is relatively insensitive and can be negative in one third to one half of HAV vaccinated people despite their protective antibody levels.

Post-exposure prophylaxis

The recommendations for post-exposure prophylaxis have recently evolved from reliance on immune globulin administration to vaccination based on clinical trial results demonstrating adequacy of vaccination alone in certain age groups. Immune globulin is derived from concentrated antibodies of pooled human plasma. When given prior to exposure, it can provide protection for 3-6 months, but this is unnecessary in most circumstances given the effectiveness of pre-exposure vaccination. If immune globulin is given within 2 weeks following exposure (i.e., during the incubation period), it can prevent clinical hepatitis A infection in 80-90% of cases. Post-exposure vaccination without immune globulin administration is adequate in immune competent individuals under the age of 40 years. Immune globulin should be administered to all the following groups whose age is more than 40 years or they are immunosuppressed:

  • Previously uninfected and unvaccinated person who has close personal contact (i.e., household members, sexual contact) to a person with serologically confirmed HAV.

  • Staff and attendees of child care centers or group homes if one or more cases identified in the children or employees or their households.

  • Exposed persons of a common-source outbreak if identified within the 2-week period.

  • Food handlers at an establishment that is identified as the location of a common source outbreak.

Hepatitis A and international travel

All susceptible persons traveling to or working in countries that have high or intermediate rates of HAV should be vaccinated or receive immune globulin before traveling.

The CDC guidelines state that one dose of single-antigen HAV vaccine administered at any time before departure will provide adequate short-term protection for most healthy persons. For optimal protection, immune globulin should also be administered to older adults, immunocompromised persons, and persons with chronic liver disease or other chronic medical conditions who will be traveling within 2 weeks. Completion of the vaccine series per schedule is needed for long term protection and should be done if possible.

No data is available regarding efficacy of combined HAV/HBV vaccine (Twinrix) for short-term protection. Thus, travelers should receive either of the monovalent vaccines.

Travelers who are allergic to a vaccine component or who elect not to receive a vaccine should receive a single dose of immune globulin (0.02mL/kg), which provides effective protection against HAV infection for up to 3 months. Such travelers whose travel period exceeds 2 months should be administered immune globulin at a higher dose (0.06 mL/kg). Administration must be repeated if the travel period exceeds 5 months.

For infants less than 12 months of age, immune globulin is recommended because HAV vaccine is currently not licensed for use in this age group.

B. History Part 2: Prevalence:

HAV infection occurs worldwide. Areas with highest prevalence include south Asia, and sub-Saharan Africa, followed by Mexico, Central and South America, Greenland, and the the Middle East. United States, Canada, Europe and Australia have the lowest prevalence.

The incidence of acute hepatitis A in the United States was reported to be 0.4 per 100,000 in 2014. The rates of infection have continued to decline ten-fold over the past decade due to the implementation of routine vaccination for all children in the country. Prior to the initiation of widespread vaccination in the United States, approximately one-third of the United States population had evidence of prior exposure of HAV.

D. Physical Examination Findings.

The two most common physical exam findings are jaundice (70%) and hepatomegaly (80%). Other less common findings include splenomegaly, cervical lymphadenopathy, arthritis, evanescent rash, and rarely a leukocytoclastic vasculitis. Other rare and atypical extrahepatic manifestations may include optic neuritis, transverse myelitis, Guillain-Barré syndrome, thrombocytopenia, aplastic anemia and red cell aplasia.

E. What diagnostic tests should be performed?

  • HAV serologies

    • Serum IgM anti-HAV is used to confirm acute HAV infection; it typically remains positive for at least 4 months and may persist up to 12 months.

    • Testing for IgM HAV (typically as part of a “hepatitis panel”) when evaluating patients with chronic liver disease is common but inappropriate and wasteful.

    • Total anti-HAV antibody: to confirm previous exposure or immunity, NOT for diagnosis.

    • HAV RNA (serum, stool, liver tissue): not used clinically but available for research purposes.

  • Tests to differentiate from other types of acute viral hepatitis: hepatitis B surface Ag (HBsAg), hepatitis B core antibody (HBcAb) IgM, antibody to hepatitis C virus (anti-HCV) (and Epstein Barr virus serologies in young patients).

  • Standard testing: ALT, AST, total and direct bilirubin, alkaline phosphatase, complete blood count, prothrombin time internationalized ratio (PT INR).

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted

Serological testing is necessary to diagnose HAV and to distinguish it from other forms of viral hepatitis. IgM anti-HAV typically becomes positive 5-10 days before onset of symptoms and declines to undetectable levels about 6 months after infection. Rarely, elevated liver enzymes are identified in the very early stages of infection before anti-HAV IgM is detectable; retesting 1-2 weeks later is recommended if testing is negative for other causes of acute hepatitis.

The presence of IgM anti-HAV in absence of clinical symptoms or an epidemiological link does not necessarily indicate acute infection; it may rather be a false positive test or protracted presence of IgM anti-HAV from an earlier acute infection.

IgG anti-HAV appears early in the convalescent phase of the disease and usually remains detectable by the total anti-HAV antibody test indefinitely. It is a reliable indicator of immunity to HAV resulting from infection (but it is not as reliable for detecting immunity from prior vaccination) and can be used to identify vaccination candidates.

Marked elevations of serum aminotransferases (usually >1000 IU/L) or total bilirubin (usually >10 mg/dL) are seen in the acute phase. The peak aminotransferase elevation is followed by the peak bilirubin concentrations with subsequent normalization over periods up to six months. Elevation of acute phase reactants, erythrocyte sedimentation rate, and increased immunoglobulins can be seen but are non-specific.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging is not typically required in evaluating patients with HAV infection. In atypical presentations, liver ultrasound can be used to exclude biliary obstruction and vascular thrombosis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

IgM anti-HAV serology is the test used for diagnosing acute HAV infection. Because some patients may have low levels of detectable IgM anti-HAV for over a year after initial infection, testing for IgM anti-HAV serology should be performed only in the presence of symptoms. If a patient's aminotransferases are not substantially elevated (i.e., < 250 U/L), checking the anti-HAV IgM has no clinical utility.

Testing for total anti-HAV antibodies (there is no commercially available tests for only anti-HAV IgG) can be done as it provides assurance of prior immunity when positive and the anti-HAV IgM is negative.

HAV RNA particles can be detected by electron microscopy or the virus can be detected by PCR in stool, serum, body fluids and liver tissue; however, this testing is not needed for clinical diagnosis and its utility is limited to research purposes.

Liver biopsy in not needed for diagnosis or management of acute hepatitis A but when done, there can be an abundance of plasma cells and thus share features with autoimmune hepatitis.

III. Default Management.

  • HAV is a self-limiting disease.

  • No antiviral therapy is available.

  • Management is supportive.

  • Medication review is important to identify possible hepatotoxic medications, including herbal supplements.

  • Most patients can be monitored at home. About 25% will require hospitalization for closer monitoring and intravenous fluids.

  • Patients who develop signs of liver failure, such as encephalopathy or coagulopathy, should be promptly transferred to centers with liver transplantation capabilities.

  • Return to school or work is not recommended until fever and jaundice have resolved.

  • About 85% will have a full clinical and biochemical recovery within 3 months, and nearly all have complete recovery in six months. Death or liver transplant from acute liver failure caused by HAV is rare (about 300 cases per year in the US). The risk of death is increased in the presence of underlying chronic liver disease.

A. Immediate management.

Treatment of acute hepatitis A is supportive. No specific antiviral therapy is available.

Contacts should be identified and vaccinated or given immune globulin.

Disease is usually self-limiting but careful monitoring and follow up is important to identify those who are at risk of acute liver failure.

Most HAV infections in children are minimally asymptomatic and can be confused by common viral syndromes. In adults, most will present with jaundice that typically recovers completely by 8 weeks. Rarely, a prolonged cholestatic jaundice lasting about 10 weeks can be seen. Some patients may show a relapsing pattern with two or more periods of increased symptoms and liver enzymes within a 6-10 week period.

Patients at higher risk for more severe clinical outcomes (i.e., advanced age, chronic liver diseases, co-infection with HIV) require admission. Other indications for hospitalization include persistent nausea and vomiting, progressive jaundice, altered mental status, coagulopathy. Development of acute liver failure is rare after 4 weeks. Liver transplantation should be considered for patients with acute liver failure.

Unlike hepatitis E, HAV infection in pregnant women is not associated with increased mortality.

B. Physical Examination Tips to Guide Management.

Presence of jaundice, right upper quadrant tenderness and hepatomegaly are common. Splenomegaly, lymphadenopathy, vascular rashes occur less commonly. Mental status should be monitored closely as any changes may indicate acute liver failure.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Patients should be monitored for the development of symptoms such as jaundice and encephalopathy. Laboratory tests to trend include liver chemistry panel (i.e., bilirubin and aminotransferases), blood counts, and coagulation panel (i.e., INR). Aminotransferase levels (ALT and AST) may rise to levels >1000 IU/mL before they start to trend down. The bilirubin rise and fall typically lags behind the aminotransferases by 5-7 days.

Prolongation of PT INR is an indicator of significant liver injury and requires hospitalization for close monitoring of mental status and laboratory parameters; furthermore, this should prompt consideration for transfer to a tertiary care center with liver transplant capabilities if clinical status deteriorates further.

D. Long-term management.

HAV does not cause chronic liver disease. Nearly all cases of acute HAV infections clear within 6 months. Natural infection confers lifelong immunity. Such immunity can be detected by measuring the HAV total antibody titer. Those who are vaccinated will have protective immunity within 1-2 weeks of the first dose that lasts at least 20-30 years. Booster doses are not recommended.

Since persons with pre-existing liver disease from other causes may develop acute liver failure from HAV infection, these patients should be checked for immunity by checking the HAV total antibody status and subsequently vaccinated if negative. This is often combined with hepatitis B vaccination series.

As can happen after many types of liver injury, HAV infections have been occasionally linked to subsequent development of autoimmune hepatitis. Autoimmune serologies (anti-nuclear antibody [ANA] and anti-smooth muscle antibody or anti-F-actin antibody should rechecked in evaluating any new elevations of the aminotransferases or bilirubin occurring after HAV infection.

What's the evidence?

"Prevention of hepatitis A after exposure to hepatitis A virus and in international travelers.". MMWR. vol. 56. 2007. pp. 1080.

Jacobsen, KH,, Wiersma, ST. "Hepatitis A virus seroprevalence by age and world region, 1990 and 2005.". Vaccine. vol. 28. 2010. pp. 6653.

Jacobsen, KH. "The global prevalence of hepatitis A virus infection and susceptibility: a systematic review.". World Health Organization. 2009.

Rezende, G,, Roque-Alsonso, M,, Samuel, D. "Viral and clinical factors associated with fulminant course of hepatitis A infection.". Hepatology. vol. 38. 2003. pp. 613.

Victor, JC,, Monto, AS,, Surdina, TY. "Hepatitis A vaccine versus immune globulin for postexposure prophylaxisis.". N Engl J Med. vol. 357. 2007. pp. 1685.

Martin, A,, Lemon, SM. "Hepatitis A virus: from discovery to vaccines.". Hepatology. vol. 43. 2006. pp. S164-72.

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