Liver infections

Hepatitis A and E

Whats new?

Nikolai V Naoumov

Active immunization has replaced passive

immunoprophylaxis with human globulin for hepatitis A
Non-travel associated hepatitis E has been diagnosed
in indigenous patients in England and Wales. In the
majority of cases it is due to genotype 3
The clinical course of hepatitis E is usually more severe
than hepatitis A, frequently complicated by protracted
coagulopathy and cholestasis

Abstract
Infections with hepatitis A virus (HAV) or hepatitis E virus (HEV) cause
acute, self-limited hepatitis with no progression to chronic liver disease.
Hepatitis A and E are enterically transmitted diseases which share several common features such as faecaloral route of transmission, no chronic
carrier state for these two infections, the infection is asymptomatic in a
proportion of cases, resulting in virus-specific immunity. However, there
are important differences between HAV and HEV with respect to their
biology, epidemiology, their impact on morbidity and mortality of humans in different parts of the world. Hepatitis E is usually associated
with more severe liver damage than hepatitis A, frequently complicated
by coagulopathy and cholestasis. HEV is the primary cause of enterically
transmitted non A, non B hepatitis in Asia, Africa, the Middle East and
Central America with 20% mortality in HEV-infected pregnant women.
Non-travel associated hepatitis E has been diagnosed in indigenous patients in England and Wales, in the majority of cases it was due to HEV
genotype 3. Active immunization with attenuated HAV is highly effective,
resulting in rapid and long lasting immunity. The prophylaxis of hepatitis
E depends primarily on clean water supply and stringent sanitary measures. A vaccine against HEV is undergoing evaluation in clinical trials.

Immunity to hepatitis E virus (HEV) (unlike hepatitis A

virus) is not lifelong
A vaccine against HEV is being evaluated in clinical trials

Hepatitis A
Viral characteristics and epidemiology: HAV is a member of
the Picornaviridae (Table 1). The virus has several characteristics that make it unique among the picornaviridae, particularly
in terms of its mechanisms of polyprotein processing and virion
production.2 Unlike other human hepatitis viruses, HAV can
establish productive replication in vitro in various cultured cells.
HAV infection is enteric and associated with poor sanitation;
it usually occurs in children. Importantly, 90% of HAV infections

Characteristics of hepatitis A virus and hepatitis E

virus

Keywords acute hepatitis; fulminant hepatitis; hepatitis A; hepatitis E;

vaccines; viral hepatitis; zoonosis

Hepatitis A and E are enterically transmitted diseases with several common features.
The aetiological agents hepatitis A virus (HAV) and hepatitis
E virus (HEV) are RNA viruses.1
The route of transmission is mainly faecaloral.
The clinical course is acute, self-limiting hepatitis with no
progression to chronic liver disease. Clinically, HAV and HEV
infections are indistinguishable.
In some patients, the infection is asymptomatic, resulting in
virus-specific immunity. There is no chronic carrier state.
HAV and HEV infections show important geographical differences in biology, epidemiology, morbidity and mortality.

Family
Virion

Viral genome

Viral proteins

HAV

HEV

Picornaviridae
Non-enveloped,
spherical particles
2728 nm diameter
Single-stranded,
linear RNA
About 7500
nucleotides
5 and 3 non-coding
regions
Four capsid proteins

Caliciviridae
Non-enveloped,
spherical particles
3234 nm diameter
Single-stranded,
linear RNA
About 7500
nucleotides
5 and 3 non-coding
regions
ORF1 non-structural
proteins (helicase,
viral polymerase)
ORF2 structural,
capsid proteins
ORF3 small protein
(123 amino acids),
unknown function

Viral polymerase and

proteases
Nikolai V Naoumov DSc FRCP FRCPath is Professor of Hepatology at
University College London and Consultant Hepatologist at UCL
Hospitals, London, UK. His research interests are focused on
studying the mechanisms of host-immune control of viral replication,
pathogenesis of liver damage, and development of new therapies for
patients with chronic hepatitis B and hepatitis C. Competing interests:
none declared.

MEDICINE 35:1

ORF, open reading frame.

Table 1

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Liver infections

in children under 5 years of age are asymptomatic; the prevalence

of symptomatic anicteric or icteric hepatitis A increases with age.
Water-borne and food-borne transmission are responsible for
HAV endemicity in developing countries and occasionally cause
extensive outbreaks in countries in which the infection is at a
low prevalence. Shellfish are an important source of food-borne
HAV infection.
In developed countries, person-to-person transmission is the
most common source of HAV infection. Intrafamilial spread,
person-to-person contact at schools and day-care centres and
homosexual activity are most commonly involved. Travellers to
endemic areas, sewage workers and certain healthcare workers
are also high-risk groups. Humans are the only reservoir
ofHAV.
Studies of the seroprevalence of HAV antibody show that,
in the USA, Japan, Australia and some European countries,
4070% of the adult population has been exposed to HAV. In the
USA in 1992, the incidence of diagnosed hepatitis A was about
9/100,000 population (50% of all reported cases of acute viral
hepatitis). However, socioeconomic improvements and better
hygiene standards have reduced the prevalence of HAV antibody
in developed countries; as a result, the mean age of exposure to
HAV and the number of symptomatic cases may increase.
In developing countries, childhood exposure to HAV is almost
universal. The main route of transmission is faecaloral. Occasionally, HAV is transmitted by blood products or through illicit
use of injectable drugs.

(ALT) and/or aspartate aminotransferase, albumin, alkaline

phosphatase, prothrombin INR) and urinalysis.
Serum bilirubin (principally the conjugated fraction) is
elevated in icteric hepatitis.
Albumin may be reduced in severe cases.
ALT levels indicate the severity of hepatocyte lysis and can be
as high as 40005000 IU/litre.
Urinalysis for urobilinogen and bilirubin is important because
the presence of urobilinogen may be the first sign, even before
jaundice. During the acute phase, urobilinogen may be transiently undetectable in the urine; its reappearance and a decrease in
urine bilirubin signal the start of recovery.
Specific diagnosis of acute hepatitis A is based on the detection of IgM antibody to HAV, which is present in serum for
36 months from the onset of clinical symptoms (Figure 1).
A positive result for IgG anti-HAV, in the absence of IgM
anti-HAV, indicates past exposure to HAV and immunity to the
virus.
Detection of virus RNA or HAV antigen in faeces is not used
in routine clinical practice.
Management: there is no specific treatment for hepatitis A. Management is supportive (adequate fluid intake in the form of water
and fruit juices, bed-rest, avoidance of major physical exercise,
no alcohol) and patients at risk of complications are monitored
monthly. More frequent monitoring of liver function tests is
important in patients with very high ALT levels or deep jaundice,
particularly when prothrombin time is prolonged.

Pathogenesis: HAV replication in vivo occurs predominantly in

hepatocytes without cytopathic effect; large quantities of virus
are secreted into biliary canaliculi.1 In addition to faecal shedding
of the virus, there is sustained viraemia, which persists from the
earliest phase of HAV infection until onset of liver injury. Liver
injury is immune mediated by natural killer cells, virus-specific
CD8+ cytotoxic T lymphocytes and nonspecific cells recruited at
the site of inflammation.

Prophylaxis: improvement in hygiene and sanitation is the primary

preventive measure. In the UK, hepatitis A is a statutory notifiable
disease; this is important for monitoring the prevalence.
Historically, passive immunoprophylaxis with human immune
globulin was used; this provides short-term immunity for

Principal virological, serological and clinical events

in hepatitis A

Clinical features: the incubation period is 26 weeks; the duration appears to be related to the infecting dose. For a few days,
patients may have prodromal symptoms comprising malaise,
loss of appetite, nausea, vomiting and fever. The onset of dark
urine is usually the first clinical indication of disease, followed
by jaundice and pale stools. Colour returns to the stools after
23 weeks; this is a sign of disease resolution.
In most patients, HAV infection is benign the risk of fulminant hepatitis A is 0.140.35%. Age is the most important determinant of the severity of hepatitis A; the case fatality rate may
be as high as 2.7% in patients over 49 years of age and higher in
those with chronic liver disease.

HAV RNA in faeces

HAV RNA in serum
Jaundice
Alanine aminotransferase
Serum IgG anti-HAV

Complications include cholestatic hepatitis with itching and

jaundice lasting up to 18 weeks. In such cases, a short course
of rapidly tapered corticosteroids may accelerate resolution. The
disease may have a relapsing course with a second hepatitis flare
3090 days after the initial peak. This ultimately resolves without
chronic sequelae.

IgM anti-HAV

Time (months)

Diagnosis: the presence of acute hepatitis is established by routine

liver function tests (serum bilirubin, alanine aminotransferase

MEDICINE 35:1

Figure 1

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2006 Elsevier Ltd. All rights reserved.

Liver infections

26 months. With the availability of effective and safe vaccines

for hepatitis A (based on formaldehyde-inactivated HAV), this
approach has been replaced with active immunization. The vaccines induce a higher titre of antibodies to HAV than that achieved
with passive prophylaxis and provide long-lasting immunity.
Apart from individuals at high risk and travellers, hepatitis A
vaccination is recommended for patients with chronic hepatitis
C. A combined vaccine for hepatitis A and hepatitis B (Twinrix),
comprising the antigenic components used in the respective
monovaccines (Havrix and Engerix-B) has been approved. Studies investigating the early seroconversion following hepatitis A
vaccine found that in the majority of vaccine recipients, antibodies develop within two weeks of vaccination, some as early as
12 days after a single injection. Hepatitis A vaccine has been
proven effective in controlling outbreaks worldwide. Based on
these data, hepatitis A vaccine may be administered at any time
before departure because it will still provide travellers with
protection.3

genotype 3 sequences were unique and closely related to those

found in British pigs, suggesting that pigs might be a viral
reservoir.
In most outbreaks, the route of transmission is water contaminated with faeces. Food-borne transmission has been suggested
in some outbreaks.
Unlike HAV, HEV infection may be zoonotic. HEV RNA has
been found in the faeces of wild pigs, and serological evidence of
infection was found in pigs and sheep in endemic regions.4
Person-to-person transmission of HEV appears to be less common than for HAV. Nosocomial transmission has been reported
from a patient with proven hepatitis E to a doctor and two nurses; this emphasizes the importance of good standard procedures
for infection control.
Clinical course: the symptoms of hepatitis E are similar to those
of other forms of acute viral hepatitis. The average incubation
period is 40 days (range 1560 days, Figure 2). In most patients,
resolution of hyperbilirubinaemia and abnormal serum ALT
occurs within 3 weeks (range 16 weeks) and there is no clinical or histological evidence of chronic hepatitis. The severity of
hepatitis E is related to the dose of virus; low levels can infect
without causing disease. A cholestatic form of hepatitis E may
have a protracted course of 812 weeks, or occasionally up to
24 weeks.
Pregnant women are at greatest risk of a serious (complicated) course in hepatitis E. In the third trimester, fatality is 25%
and fetal morbidity and mortality are high.

Hepatitis E
Viral characteristics and epidemiology: HEV was discovered in
1983 and is now recognized as the agent responsible for enterically transmitted non-A, non-B hepatitis.1 The HEV genome
is a single-stranded, polyadenylated RNA molecule of 7500
nucleotides (Table 1).
Four genotypes of HEV have currently been identified. Geographically, genotype 1 has been isolated from tropical countries
in Asia and Africa, genotype 2 was found in Mexico, Nigeria and
Chad, whereas genotype 3 has worldwide distribution, including
Europe, Asia, North and South America. Genotype 4, in contrast,
was found exclusively in Asia. Genotypes 3 and 4 have been
identified in swine, but also in wild animals such as boar and
deer.4 With respect to vaccine development, it is important that
all HEV strains seem to constitute a single serotype.5
HEV infection is endemic in Asia, Africa, the Middle East and
Central America, particularly in areas with inadequate sanitation.
In countries endemic for HEV, seroprevalence studies demonstrate anti-HEV in only 5% of children under 10 years of age and
in 1040% of adults. In these areas, outbreaks of hepatitis E have
involved several thousand individuals; characteristic features of
such outbreaks include a higher rate of symptomatic hepatitis E in
1540-year-olds and a particularly high fatality rate (about 20%)
in HEV-infected pregnant women. A sero-epidemiological study
of antibody prevalence to hepatitis E virus from 11 countries has
shown that antibody to HEV increases with age. The rate of antibody positivity was over 20% in the 1630 year old group in most
participating countries, except Japan, USA and Spain. Of patients
with acute hepatitis of unknown aetiology from Nepal 56% were
positive for IgM anti-HEV.6 Unlike HAV, immunity to HEV is
not life-long. The large proportion of seronegative individuals in
the population probably accounts for the frequent epidemics of
hepatitis E in developing countries. The risk of epidemics is high
during the pre-monsoon and monsoon seasons.
Non-travel associated hepatitis E has been diagnosed in
England and Wales.7,8 Compared with patients with travelassociated disease, those with non-travel associated hepatitis E
were older, living in coastal areas, not of South Asian ethnicity
and were infected by genotype 3 strains of HEV.7 Importantly,

MEDICINE 35:1

Diagnosis of acute infection is usually based on detection of IgM

anti-HEV in serum, using assays with recombinant viral proteins.
These tests have not been standardized, however, and may give
negative results in cases in which HEV RNA is detectable by
reverse-transcription polymerase chain reaction analysis. The

Principal virological, serological and clinical events

in hepatitis E
HEV RNA in faeces
HEV RNA in serum
Jaundice
Alanine aminotransferase

Serum IgG anti-HEV

IgM anti-HEV

Time (months)
Figure 2

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Liver infections

latter method can be applied to serum, liver and faecal samples.

The IgG anti-HEV titre decreases with time and can disappear,
particularly in children.

5 Worm H C, Wirnsberger G. Hepatitis E vaccines: progress and

prospects. Drugs 2004; 64: 151731.
6 Abe K, Li T C, Ding X et al. International collaborative survey on
epidemiology of hepatitis E virus in 11 countries. Southeast Asian
J Trop Med Public Health 2006; 37: 905.
7 Ijaz S, Arnold E, Banks M et al. Non-travel-associated hepatitis
E in England and Wales: demographic, clinical, and molecular
epidemiological characteristics. J Infect Dis 2005; 192: 116672.
8 Lewis H, Morgan D, Ijaz S, Boxall E. Indigenous hepatitis E virus
infection in England and Wales. BMJ 2006; 332: 150910.

Prophylaxis: prevention of hepatitis E depends primarily on provision of clean drinking water and improved sanitation. Studies
of passive prophylaxis in macaques have shown that antibodies to HEV could be protective. However, attempts using pooled
human plasma were not successful because the antibody levels were too low to be effective. Development of an attentuated
vaccine is not possible because there is no cell culture system
for HEV. A candidate vaccine comprising baculovirus-expressed
recombinant HEV capsid protein was proved safe and immunogenic in a phase I trial and is being evaluated in phase II/III
clinical trials.

Practice points
References
1 Naoumov N V. Hepatitis viruses, including TTV. In: Warrell D, Cox T,
Firth J, Benz E, eds. Oxford textbook of medicine. 4th ed. Oxford:
Oxford University Press, 2003: 41419.
2 Martin A, Lemon S M. Hepatitis A virus: from discovery to vaccines.
Hepatology 2006; 43(Suppl. 1): S16472.
3 Connor B A. Hepatitis A vaccine in the last-minute traveler. Am J Med
2005; 118(Suppl. 10A): 58S62S.
4 Lu L, Li C, Hagedorn C H. Phylogenetic analysis of global hepatitis E
virus sequences: genetic diversity, subtypes and zoonosis. Rev Med
Virol 2006; 16: 536.

MEDICINE 35:1

HAV and HEV cause acute, self-limiting hepatitis with no

progression to chronic liver disease
HAV vaccines are highly effective; immunity is rapid and long
lasting
HEV is the main cause of enterically transmitted non-A, non-B
hepatitis in Asia, Africa, the Middle East and Central America;
mortality is 20% in HEV-infected pregnant women
Prevention of HEV depends primarily on the provision of a
clean water supply and stringent sanitary measures

38

2006 Elsevier Ltd. All rights reserved.