Global Alert and Response (GAR)

Hepatitis A


The disease

- Diagnosis
- Host immune response
- Prevalence
- Pathogenesis
- Transmission
- Risk groups

The course of hepatitis A may be extremely variable.18

Patients with inapparent or subclinical hepatitis have neither symptoms nor jaundice. Children generally belong to this group. These asymptomatic cases can only be recognized by detecting biochemical or serologic alterations in the blood.18, 22, 40

Patients may develop anicteric or icteric hepatitis and have symptoms ranging from mild and transient to severe and prolonged, from which they recover completely or develop fulminant hepatitis and die (see below). The severity of the disease increases with age at time of infection.18, 23

The course of acute hepatitis A can be divided into four clinical phases:18,21-23, 40

  • an incubation or preclinical period, ranging from 10 to 50 days, during which the patient remains asymptomatic despite active replication of the virus. In this phase, transmissibility is of greatest concern.

  • a prodromal or preicteric phase ranging from several days to more than a week, characterised by the appearance of symptoms like loss of appetite, fatigue, abdominal pain, nausea and vomiting, fever, diarrhoea, dark urine and pale stools, followed by

  • an icteric phase, during which jaundice develops at total bilirubin levels exceeding 20 - 40 mg/l. Patients often seek medical help at this stage of their illness. The icteric phase generally begins within 10 days of the initial symptoms. Fever usually improves after the first few days of jaundice. Viremia terminates shortly after hepatitis develops, although faeces remain infectious for another 1 - 2 weeks. Extrahepatic manifestations of hepatitis A are unusual. Physical examination of the patient by percussion can help to determine the size of the liver and possibly reveal massive necrosis. The mortality rate is low (0.2% of icteric cases) and the disease ultimately resolves. Occasionally, extensive necrosis of the liver occurs during the first 6 - 8 weeks of illness. In this case, high fever, marked abdominal pain, vomiting, jaundice and the development of hepatic encephalopathy associated with coma and seizures, are the signs of fulminant hepatitis, leading to death in 70 - 90% of the patients. In these cases mortality is highly correlated with increasing age, and survival is uncommon over 50 years of age. Among patients with chronic hepatitis B or C or underlying liver disease, who are superinfected with HAV, the mortality rate increases considerably.

  • a convalescent period, where resolution of the disease is slow, but patient recovery uneventful and complete. Relapsing hepatitis occurs in 3 - 20% of patients 4 to 15 weeks after the initial symptoms have resolved. Cholestatic hepatitis with high bilirubin levels persisting for months is also occasionally observed. Chronic sequelae with persistence of HAV infection for more than 12 months are not observed.

Click here for: Predicted outcome of infection (table)

Diagnosis
Since both clinically and biochemically, acute hepatitis due to HAV cannot be distinguished from that due to the other hepatitis viruses, serologic tests are necessary for a virus-specific diagnosis.18, 21

Diagnosis of hepatitis is made by biochemical assessment of liver function (laboratory evaluation of: urine bilirubin and urobilinogen, total and direct serum bilirubin, ALT and/or AST, alkaline phosphatase, prothrombin time, total protein, albumin, IgG, IgA, IgM, complete blood count).18, 21-23, 40

The specific routine diagnosis of acute hepatitis A is made by finding anti-HAV IgM in the serum of patients. A second option is the detection of virus and/or antigen in the faeces.21, 23

Virus and antibody can be detected by commercially available RIA, EIA or ELISA kits. These commercially available assays for anti-HAV IgM and total anti-HAV (IgM and IgG) for assessment of immunity to HAV are not influenced by the passive administration of IG, because the prophylactic doses are below detection level.23

At the onset of disease, the presence of IgG anti-HAV is always accompanied by the presence of IgM anti-HAV. As IgG anti-HAV persists lifelong after acute infection, detection of IgG anti-HAV alone indicates past infection.18, 21, 40

Virus may still be present in the absence of detectable HAV antigen, as demonstrated by the use of more sensitive methods.18

If laboratory tests are not available, epidemiologic evidence can help in establishing a diagnosis.

Host immune response
In acute hepatitis A, the presence of anti-HAV IgM is detectable about 3 weeks after exposure, its titre increases over 4 to 6 weeks, then declines to nondetectable levels generally within 6 months of infection.18, 21-23, 40

Anti-HAV IgA and IgG are detectable within a few days of the onset of symptoms. IgG antibodies persist for years after infection and provide lifelong immunity.18, 21-23, 39, 40

The development of antibody to HAV coincides with a decrease in quantity of viremia and faecal shedding of virus.

Saliva and faeces generally do not contain neutralizing antibodies.22, 40

Click here for: Typical serologic course

Prevalence
The highest prevalence of faecal-oral infection occurs in regions where low standards of sanitation promote the transmission of the virus.22

In most industrialized nations, where hepatitis A is no longer considered a childhood disease, infections with HAV are increasingly contracted by adults.31, 40

Despite the high prevalence of antibody in highly endemic populations, the virus perpetuates in the region due to its high physical stability.

Pathogenesis
Virus-induced cytopathology may not be responsible for the pathologic changes seen in HAV infection as liver disease may result primarily from immune mechanisms. Antigen-specific T-lymphocytes are responsible for the destruction of infected hepatocytes.18, 21-23, 39

Increased levels of interferon have been detected in the serum of HAV-infected patients and are presumably responsible for the reduction in virus burden seen in patients following the onset of clinical disease and in their symptoms.18

Rarely, patients with acute viral hepatitis A develop features of cholestasis.18

Confluent hepatic necrosis may lead to fulminant hepatitis and death in 30-60% of cases. Death appears to be inevitable when necrosis involves more than 65-80% of the total hepatocyte fraction. In patients who survive an episode of acute fulminant hepatic failure, neither functional nor pathologic sequelae are common, despite the widespread necrosis.18

During the recovery stage, cell regeneration is prominent. The damaged hepatic tissue is usually restored within 8 to 12 weeks.18

Transmission
HAV is generally acquired by the faecal-oral route by either person-to-person contact or ingestion of contaminated food or water. Hepatitis A is an enteric infection spread by contaminated excreta.9, 18, 23, 40

High concentrations of virus are shed in the stools of patients during 3 to 10 days prior to the onset of illness till one - two weeks after the onset of jaundice. Faecal excretion of HAV persists longer in children and in immunocompromised persons (up to 4 - 5 months after infection) than in otherwise healthy adults. Communicability is highest during this interval.18

Hepatitis A may be acquired from faecally contaminated food or water and from wastewater-contaminated drills or water supplies.18, 22

HAV present in sewage-contaminated fresh or salt water can be concentrated by mollusc-like oysters and clams, which can be an important source of infection if eaten raw or inadequately cooked. Cooked food may become recontaminated after cooking during inappropriate handling.18

Transmission by blood transfusion is rare: the donor must be in the viremic prodromal phase of infection at the time of blood donation. Current blood practices do not include screening of donors for evidence of active HAV infection.18, 22, 23, 40

Substantial viremia persisting for several weeks suggests the possible role of needle-borne transmission of virus among intravenous drug users, although HAV concentrations in blood are manifold lower than in faeces.

Outbreaks (1992) have occurred among haemophiliacs receiving factor VIII concentrates prepared by a solvent-detergent inactivation process which did not reduce the infectivity of nonenveloped viruses.18, 23, 38

HAV is not transmitted from infected mothers to newborn infants, as anti-HAV
IgG antibodies present during initial stages of HAV infection cross the placenta and provide protection to the infant after delivery.

Transmission by exposure to urine, nasopharyngeal secretions or aerosol of infected persons is improbable, regardless of the stage of infection. Transmission of HAV by biting insects is conceivable.18

Click here for: Role of non-human primates in the transmission of HAV

Risk groups
Certain groups can be defined as high risk for contracting HAV :18, 21, 23, 41, 45

  • people in household/sexual contact with infected persons
  • medical and paramedical personnel in hospitals
  • international travellers from developed countries to regions of the world where HAV is endemic (3/1000 to 20/1000 people per month's stay abroad)
  • persons living in regions with endemic hepatitis A
  • persons residing in areas where extended community outbreaks exist
  • preschool children attending day-care centres, their parents and siblings
  • day-care centre employees
  • residents and staff of closed communities (institutions)
  • refugees residing in temporary camps following catastrophes
  • homosexually active men
  • injecting drug users using unsterilized injection needles
  • persons with clotting factor disorders
  • persons with chronic liver disease
  • food-service establishments/food handlers
  • persons working with non-human primates

Risk factors remain unidentified in as much as 50% of hepatitis A cases.21, 45

Hepatitis A is contracted at least 100 times more frequently than typhoid fever or cholera.

Persons falling into any of the above mentioned categories should consider being vaccinated as a preventive measure.


Predicted outcome of HAV infection

 

Predicted outcome

Parameter

Children (<5 years)

       Adults

Inapparent infection

       80-95%

       10-25%

Anicteric or icteric disease

       5-20%       

       75-90%

Complete recovery

       99+%        

       98+%

Chronic disease

none

Mortality rate: <14 years

0.1%

                     15-39 years

0.3%

                     >40 years

2.1%


Typical serological course

From Stapleton JT and Lemon SM. Hepatitis A and hepatitis E. In: Hoeprich PD, Jordan MC, and Ronald AR, eds. Infectious Diseases, 5th ed. Philadephia, Lippincott Co, 1994:790-797, 40 with permission (http://lww.com).

Summary of clinical, virologic and serologic findings in uncomplicated acute hepatitis A.


Role of non-human primates in the transmission of HAV

Various monkey species such as chimpanzees, owl monkeys, cynomolgus monkeys, rhesus monkeys, stump-tailed monkeys, African green monkeys, tamarins, marmosets and squirrel monkeys are susceptible to HAV.8, 15, 18, 20, 22, 24, 29, 36

HAV-induced disease in non-human primates resembles human disease, but is usually milder, or subclinical, followed by complete recovery.8, 18, 20, 29

HAV can be transmitted experimentally to these animals, but the presence of anti-HAV antibody in the sera of newly captured monkeys shows that infection may also spread in the natural habitat of non-human primates. HAV isolates from several naturally infected monkeys were shown to represent strict simian HAV strains, closely related antigenically to human HAV strains.8, 14, 20, 22, 24

A molecular comparison of the human HM175 and the simian PA21 and PA33 strains of HAV has shown that, despite major divergence at the nucleotide level (>10%), the viruses share immunodominant neutralization epitopes. Infection of owl monkeys with either virus provides high, although incomplete (mild symptoms, relapsing hepatitis) protection against later intravenous challenge with the other virus.14, 24

Well documented is the natural transmission of human HAV from experimentally infected animals to humans. Still unknown is the susceptibility of humans to true simian HAV strains.

If it could be shown that simian strains do not induce disease in humans despite virus replication and subsequent seroconversion, simian strains might be used as live, attenuated vaccines.

If, on the other hand, HAV-immune people challenged with simian HAV strains developed signs of hepatitis, even a global immunization programme could never achieve the eradication of HAV, because monkeys would constantly represent a natural reservoir of virus.

Share