Hepatitis A

Genomic Organisation

The hepatitis A virus was identified in 1973 (Feinstone 1973). It is a 27 nm, positive-
stranded RNA, non-enveloped, icosahedral virus of the heparnavirus genus of
the Picornaviridiae. Its viral genome contains 7474 nucleotides that are grouped
into three regions: a 5’ and a 3’ non-coding region and a 6681 nucleotide open
reading frame. The polypeptide encoded by the open reading frame is processed by
a viral protease, resulting in eleven proteins of which four are structural and seven
are non-structural. Four distinct HAV genotypes in humans have been identified,
although significant biological differences have not been found (Lemon 1992).

Epidemiology

Hepatitis A infection occurs worldwide sporadically or in epidemic outbreaks.
There is an estimated caseload of 1.4 million cases per year (Viral Hepatitis Prevention
Board 1997). As it is transmitted and spread via the faecal-oral route
(Hollinger 1996), it shows higher prevalence in areas with low socio-economic
status where adequate sanitation or adequate hygienic practices are lacking. The
incidence of 1.5 per 100,000 in industrialised countries, e.g., the United States or
Germany (Wasley 2007; RKI 2006), is low compared to developing countries (parts
of Africa, Asia, Central and South America) where it may reach up to 150 per
100,000 per year (WHO).

Transmission

HAV is generally acquired via the faecal-oral route either by person-to-person
contact or ingestion of contaminated food or water, as well as other types of sex like
analingus. Hepatitis A is an enteric infection spread by contaminated excreta. High
concentrations of virus are shed in the stools of patients 3 to 10 days prior to the
onset of illness and until one to two weeks after the onset of jaundice. Faecal excretion
of HAV persists longer in children and in immunocompromised persons (up to
4 to 5 months after infection) than in otherwise healthy adults (Hollinger 1996).
Persons in psychiatric institutions, day-care centres, health care providers, military
personnel, and men who have sex with men (especially when practicing anal intercourse)
are at higher risk of infection. Parenteral transmission via IV drug use or
transfusion of blood products is rare because of the short viraemia of HAV during
acute infection. Mother-to-foetus transmission has not been reported.

Clinical course

Hepatitis A infection can take a wide spectrum of clinical courses ranging from
asymptomatic or subclinical infection to cholestatic presentation or even to fulmi
nant liver failure. In children most infections are asymptomatic, while in adults 70%
show clinical illness. Anicteric symptomatic HAV is more frequent than icteric disease,
as only 30% of patients develop jaundice.
The incubation time averages 30 days (15 to 49 days). The illness begins with the
abrupt onset of unspecific prodromal symptoms including fatigue, malaise, nausea,
vomiting, anorexia, fever, abdominal discomfort, and right upper quadrant pain
(Lednar 1985). Within one week, patients with an icteric course note darkened
urine, light-coloured acholic stool, jaundice, and often pruritus. The prodromal
symptoms usually diminish when jaundice appears. The jaundice is typically most
intense within the first two weeks. Decrease and subsequent normalisation of serum
aminotransferases occurs rapidly and before a decrease or normalisation of serum
bilirubin.
A biphasic or relapsing form of viral hepatitis A occurs in 6–10% of cases. The
initial episode lasts 3-5 weeks and is followed by a period of remission characterised
by normal liver chemistries lasting 4-5 weeks. Relapse may mimic the initial
episode of the acute hepatitis. The full duration of the illness ranges from 16-40
weeks from the onset, and HAV-IgM antibodies persist throughout the clinical
course (Schiff 1992).
Severe fulminant courses of HAV with hepatic failure are found more often in patients
with underlying liver disease. Patients with chronic Hepatitis C have a greatly
increased risk of hepatic failure, while HBV coinfection is less perilous (Vento
1989). Other risk factors are old age, malnutrition and immunosuppression.
The available data on HAV in pregnant women is not conclusive. Some data show a
risk of gestational complications and premature birth (Elinav 2006; Zhang 1990)
while others have not observed such complications (Tong 1981).
Hepatitis A infection has been reported as a trigger for autoimmune chronic active
hepatitis (CAH) in genetically susceptible individuals (Vento 1991). In 58 monitored
relatives of patients with CAH, three cases of subclinical HAV occurred. Two
of these developed CAH within 5 months of HAV infection. Both showed a defective
T-cell control of immune responses to the asialoglycoprotein receptor with ongoing
T helper cell activation after the clearance of HAV.
Overall, a lethal course of HAV occurs in 0.1% of children, in 0.4% of persons
aged 15-39 years, and in 1.1% in persons older than 40 years (Lemon 1985). Although
a relapsing form of HAV (see above) is known, the infection does not progress
to a chronic state.

Clinical Presentation

Jaundice and hepatomegaly are the two main findings in a physical examination.
They are seen in 70 and 80% of symptomatic patients, respectively (Tong 1995).
Other findings are splenomegaly, evanescent rash, cervical and other lymphadenopathies.
Extrahepatic manifestations
Although less frequent than in HBV infection, extrahepatic manifestations have
been associated with acute HAV infection (Schiff 1992). Cutaneous vasculitis is
typically located on the legs and buttocks. Skin biopsies reveal the presence of anti-
HAV-IgM and components of the complement system in the blood vessel walls.
Also, arthritis appears to have a predilection for the lower extremities. Both arthritis
and vasculitis have been associated with cryoglobulinaemia. Manifestations in the
nervous system such as transverse myelitis, optic neuritis, and polyneuritis may also
be immunocomplex-related. Haematological complications include thrombocytopenia,
aplastic anaemia, and red cell aplasia. These conditions appear to be more
likely in patients with prolonged symptoms.

Laboratory findings

In symptomatic patients typical laboratory findings are marked elevations of serum
aminotransferases, alkaline phosphatase, and serum bilirubin (Tong 1995). Serum
alanine aminotransferase (ALT) usually shows higher values than serum aspartate
aminotransferase (AST) and concentrations exceeding 1000 IU/L are common.
The increase of serum aminotransferase precedes the elevation of serum bilirubin
and the peak of bilirubin concentration occurs after the peak of aminotransferase
concentration. Serum bilirubin often exceeds a concentration of 10 mg/dl. Other
laboratory abnormalities include elevations of acute phase reactants, an elevated
erythrocyte sedimentation rate, and increased immunoglobulins.

Diagnosis

The specific diagnosis of acute HAV infection is made by the detection of serum
anti-HAV-IgM antibodies in patients with symptoms of acute hepatitis. This antibody
is present in 99% of patients by the time of appearance of clinical symptoms.
Therefore, it is the gold standard for detection of acute HAV disease. Anti-HAVIgM
concentration peaks in the second month of infection and then gradually decreases
until it becomes undetectable, usually after 6 to 12 months. Sometimes anti-
HAV-IgM persists longer, and therefore, detection in asymptomatic individuals
does not necessarily indicate acute infection, as it could be an effect of previous
asymptomatic HAV contact (CDC 2005).
Detection of HAV in stool, body fluids, serum and liver tissue by either electron
microscopy or polymerase chain reaction (PCR) is more complicated and expensive.
Anti-HAV-IgG antibodies are formed in the early convalescent phase, remain
positive for decades, and provide long-lasting, if not lifetime immunity to reinfection.

Treatment

As acute hepatitis A is a self-limiting disease and in most cases resolves spontaneously
without residual damage or sequelea and no specific therapy is available, the
treatment is supportive. In 85% of cases, clinical symptoms and laboratory abnormalities
resolve within 3 months. After 6 months almost all patients have complete
recovery (Koff 1992). More severe courses require hospitalisation. In an outbreak
in Pennsylvania, USA, 20% of patients had to be admitted to hospital (Wheeler
2005). The rare cases that progress to fulminant hepatic failure (impaired synthetic
function, hepatic encephalopathy) require aggressive supportive therapy. These
patients should be transferred to a centre that is capable of performing liver transplantation.