Hepatitis E

Introduction

Like hepatitis A, the hepatitis E virus is a non-enveloped single stranded RNA virus
of an icosahedral shape, measuring 27-34 nm in diameter. It is the sole member of
the genus Hepevirus in the family of Hepeviridiea (Emerson 2004). Its existence
was hypothesised when a retrospective analysis of clinical samples collected during
hepatitis outbreaks in India in 1955 with newly developed essays for hepatitis A
and B showed a high prevalence of close to 100% for anti-HAV-IgG but no sign of
acute hepatitis A or B. Thus the conclusion was that there must be another infectious
agent for enterically transmitted non-A non-B hepatitis (ET-NANB) (Khuroo
1980; Wong 1980). HEV was first visualised in 1983. It was transmitted to a human
volunteer in Russia and to cynomolgus monkeys, causing acute hepatitis in both,
and thus establishing its etiologic role in ET-NANB hepatitis (Balayan 1983).
Three large open reading frames (ORFs) of the positive-sense RNA of HEV have
been described. While the largest ORF consisting of 1693 codons encodes for nonstructural
proteins responsible for the processing and replication of the virus, the
other two ORFs (660 and 123 condons, respectively) encode for structural polypeptides
(Koonin 1992). Four genotypes and 24 subtypes of HEV have been identified
by phylogenetic analysis of stored HEV sequences. Each genotype has a distinct
geographical distribution and while genotype 1 and 2 appear to be confined to humans
only, genotype 3 and 4 have also been found in swine and wild animals (Lu
2006). Only one serotype of HEV is known.

Epidemiology and Transmission
The characteristics of hepatitis E epidemiology are similar to those of the hepatitis
A virus. Areas with endemic infections and high incidence are in Asia, Africa,
Central America and the Middle East (Belabbes 1985; Gupta 1957; Arankalle 1988;
Tsega 1991; Velazquez 1990). Here the predominant mode of infection is faecaloral
via contaminated water (Belabbes 1985; Naik 1992). Large outbreaks of HEV
have been described. The largest documented incident was in China between 1986
and 1988 involving over 100,000 individuals (Zhuang 1992). Parenteral transmission
by blood transfusion seems to occur especially in areas where HEV occurs
endemically (Matsubayashi 2004; Khuroo 2004).
In industrialised countries the disease occurs sporadically. Most of the infections
are diagnosed in individuals who travel to countries where HEV is endemic. It has
however been questioned if all cases are imported, for example when high rates of
hepatitis E antibodies were found in drug users in Denmark and Sweden (Sylvan
1998; Christensen 2002). This may indicate parenteral transmission by needle
sharing in this group. Furthermore, HEV was present in sewage samples collected
in France, Spain and the United States (Buti 2003). One could conclude from these
findings that the incidence of HEV in industrialised countries may currently be underestimated.
Zoonotic transmission is also being discussed. People with occupational contact
with swine in the United States (veterinarians and farmers) show high seroprevalence
of anti-HEV-antibodies (Meng 2002; Karetnyi 1999). Also rodents may function
as a reservoir in some regions (He 2006). Two case studies from Japan demonstrated
transmission by undercooked wild boar and deer meat to humans (Tei 2003;
Li 2005). To this day the extent of endemic or zoonotic transmission is not fully
understood.
Vertical transmission of HEV infection from mother to child has been identified. In
one study of eight pregnant women with acute hepatitis E, five blood specimens
collected from their babies at birth tested positive for HEV RNA (Khuroo 1995).
Clinical features
The disease may range in severity from sub-clinical to fulminant liver failure. Especially
pregnant women are at high risk with the death rate approaching 20%. Overall
fulminant fatal hepatitis E occurs in 0.5-3% (Herrera 1993).
After an incubation period of 15 to 60 days (Khuroo 1980; Bayalan 1983) the infected
patient develops symptoms and clinical signs that resemble those seen with
other forms of acute viral hepatitis. The most prominent feature is jaundice accompanied
by general symptoms such as malaise, anorexia and fever as well as abdominal
pain, nausea, vomiting and hepatomegaly. Other clinical symptoms are
diarrhoea, prutitus, arthralgia and rash. In biochemical analyses elevated serum
concentrations of bilirubin, alanin aminotransferase and aspartate aminotransferase
can be seen. Laboratory and clinical symptoms usually resolve within a few weeks
to two months. Compared to hepatitis A the disease appears to be more severe with
protracted coagulopathy and cholestasis in more than half of the patients (Chau
2006).
A study from Japan compared the clinical features of patients infected with genotype
3 and 4 and indicated that genotype 4 tends to have more severe clinical manifestations
than genotype 3 (Ohnishi 2006). It was observed that genotype 4 infected
individuals had significantly higher alanin aminotransferase peak levels (median
3430 IU/L versus 1052 IU/L) and a lower trough prothrombin time (61 versus 84%)
and that the median time in the hospital was longer (26.5 versus 18 days).
Liver histology in a study of eleven patients with sporadic acute hepatitis E showed
acute hepatic lesions in all cases. Nine samples displayed marked necroinflammatory
activity and in five confluent necrosis was present. Siderosis and
cholestasis were diagnosed in eleven and nine patients, respectively (Peron 2007).
The sero-epidemiology of hepatitis E suggests that people previously infected with
HEV are protected during epidemics of the disease, indicating that immunity to
HEV is induced and prevents re-infection (Bryan 1994).
Hepatitis E is widely accepted not to progress to a chronic infection. However, two
recent reports describe patients that underwent organ transplant (liver, kidney, pancreas)
and subsequent immunosuppressive therapy in which detectable levels of
HEV RNA were found over an extended period of time. In 10 of the 16 patients
Diagnosis 51
chronic hepatitis was found and attributed to hepatitis E virus (Haagsma 2008; Kamar
2008). It remains to be determined if there is a risk for immunosuppressed patients
of developing chronic HEV infection.
Diagnosis
Diagnosis of acute hepatitis E is based upon the detection of antibodies directed
against HEV or detection of HEV RNA in serum or faeces. HEV RNA may be
found very early in faeces and serum. It usually becomes undetectable within one to
six weeks after the onset of symptoms (Takahashi 2005). Anti-HEV-IgM antibodies
are also present early in the infection and remain positive for months. Formation of
anti-HEV-IgG can be detectable as early as in the second week of clinical symptoms.
Combined testing for anti-HEV-IgG and either anti-HEV-IgA or HEV RNA may be
helpful in areas of higher HEV prevalence to distinguish ongoing from remote infection
(Takahashi 2005), as anti-HEV-IgM (or anti-HEV-IgA) alone may be present
in individuals with previous HEV contact. Also IgM rheumatoid factor may
cause false positive results.
Pregnancy
Fulminant hepatic failure occurs more frequently in pregnant women, resulting in a
remarkably high mortality rate of 15 to 25%, primarily in women in the third trimester
(Khuroo 1981). The foetal and obstetric outcomes of pregnant women with
jaundice and acute viral hepatitis E appear to be worse compared to hepatitis due to
other causes (Patra 2007). In 220 consecutive pregnant women with icteric acute
hepatitis in a hospital in New Delhi fulminant hepatic failure was more common
and maternal mortality was higher (relative risk 2.7 and 6.0, respectively) in HEVinfected
women than in those with other aetiologies. The relative risks for obstetric
complications were: 4.1 for antepartum haemorrhage, 1.9 for intrauterine foetal
death, 1.2 for preterm delivery, and 1.8 for stillbirth.
Treatment
Specific treatment is not available for Hepatitis E infection and only supportive
therapy is possible. As in most cases the infection is self-limiting and is followed by
complete recovery without chronic sequelae, and no specific interventions are required.
Patients with hepatic failure should be transferred to a centre capable of
performing liver transplantation.