Hepatitis E is a viral hepatitis caused by infection with a virus called
hepatitis E virus. It is one of five known human hepatitis viruses: A, B, C,
D, and E. HEV is a positive-sense single-stranded non-enveloped RNA
icosahedral virus with a 7.5 kilobase genome. HEV has a fecal-oral
transmission route. Infection with this virus was first documented in 1955
during an outbreak in New Delhi, India. A preventative vaccine is approved for
use in China. Although Hepatitis E often causes an
acute and self-limiting infection with low mortality rates in the western
world, it bears a high risk of developing chronic hepatitis in
immunocompromised patients with substantial mortality rates. Organ
transplant recipients who receive immunosuppressive medication to prevent
rejection are thought to be the main population at risk for chronic hepatitis
E. Furthermore, in healthy individuals during the duration of the infection,
the disease severely impairs a person’s ability to work, care for family
members, and obtain food. Hepatitis E occasionally develops into an acute,
severe liver disease, and is fatal in about 2% of all cases. Clinically, it is
comparable to hepatitis A, but in pregnant women the disease is more often
severe and is associated with a clinical syndrome called fulminant liver failure.
Pregnant women, especially those in the third trimester, suffer an elevated
mortality rate from the disease of around 20%.
Signs and symptoms = Acute infection=
The incubation period of hepatitis E varies from 3 to 8 weeks. After a short
prodromal phase symptoms lasting from days to weeks follow. They may include
jaundice, fatigue and nausea. The symptomatic phase coincides with
elevated hepatic aminotransferase levels.
Viral RNA becomes detectable in stool and blood serum during incubation
period. Serum IgM and IgG antibodies against HEV appear just before onset of
clinical symptoms. Recovery leads to virus clearance from the blood, while
the virus may persist in stool for much longer. Recovery is also marked by
disappearance of IgM antibodies and increase of levels of IgG antibodies.
= Chronic infection= While usually an acute disease, in
immunocompromised subjects—particularly in solid organ transplanted
patients—hepatitis E may cause a chronic infection. Occasionally this may cause
liver fibrosis and cirrhosis. Virology
= Classification= There is only one serotype of the virus
and classification is based on the nucleotide sequences of the genome.
Genotype 1 has been classified into five subtypes, genotype 2 into two subtypes
and genotypes 3 and 4 have been into ten and seven subtypes respectively.
Differences have been noted between the different genotypes. For genotype 1, the
age at which incidence peaks is between 15 and 35 years and mortality is about
1%. Genotype 3 and 4—the most common in Japan—are more common in people older
than 60 years and the mortality is between 5 and 10%.
= Distribution= Genotype 1 has been isolated from
tropical and several subtropical countries in Asia and Africa. Genotype 2
has been isolated from Mexico, Nigeria, and Chad. Genotype 3 has been isolated
almost worldwide including Asia, Europe, Oceania, North and South America.
Genotype 4 appears to be limited exclusively to Asia.
Genotypes 1 and 2 are restricted to humans and often associated with large
outbreaks and epidemics in developing countries with poor sanitation
conditions. Genotypes 3 and 4 infect humans, pigs and other animal species
and have been responsible for sporadic cases of hepatitis E in both developing
and industrialized countries. In the United Kingdom the Department for
Environment, Food and Rural Affairs said that the number of human hepatitis E
cases increased by 39% between 2011 and 2012.
= Transmission= Hepatitis E is prevalent in most
developing countries, and common in any country with a hot climate. It is
widespread in Southeast Asia, northern and central Africa, India, and Central
America. It is spread mainly by the fecal-oral route due to fecal
contamination of water supplies or food; person-to-person transmission is
uncommon. The incubation period following exposure
to the hepatitis E virus ranges from three to eight weeks, with a mean of 40
days. Outbreaks of epidemic hepatitis E most commonly occur after heavy
rainfalls and monsoons because of their disruption of water supplies. Major
outbreaks have occurred in New Delhi, India, Burma, Kashmir, India, Kanpur,
India, and China. DEFRA said that there was evidence that
the increase in hepatitis E in the UK was due to food-borne zoonoses, citing a
study that found 10% of pork sausages on sale in the UK contained the virus. Some
research suggests that food must reach a temperature of 70 °C for 20 minutes to
eliminate the risk of infection. An investigation by the Animal Health and
Veterinary Laboratories Agency found hepatitis E in 49% of pigs in Scotland.
= Animal reservoir= Domestic animals have been reported as a
reservoir for the hepatitis E virus, with some surveys showing infection
rates exceeding 95% among domestic pigs. Replicative virus has been found in the
small intestine, lymph nodes, colon and liver of experimentally infected pigs.
Transmission after consumption of wild boar meat and uncooked deer meat has
been reported as well. The rate of transmission to humans by this route and
the public health importance of this are, however, still unclear.
A number of other small mammals have been identified as potential reservoirs:
the lesser bandicoot rat, the black rat and the Asian house shrew. A new virus
designated rat hepatitis E virus has been isolated.
A rabbit hepatitis E virus has also been described, with a study published in
2014 showing that research rabbits from two different American vendors showed
seroprevalences of 40% for Supplier A and 50% for Supplier B when testing for
antibodies against hepatitis E virus. Supplier A was a conventional rabbit
farm, and supplier B was a commercial vendor of specific pathogen free
research rabbits. The study remarks "HEV probably is widespread in research
rabbits, but effects on research remain unknown." Laboratory animal care
personnel, researchers, and support staff represent a new population at risk
for HEV infection, and research facilities should be diligent in
measures to prevention of this possibly zoonotic pathogen.
An avian virus has been described that is associated with
hepatitis-splenomegaly syndrome in chickens. This virus is genetically and
antigenically related to mammalian HEV, and probably represents a new genus in
the family. = Molecular biology=
Although it was originally classified in the Caliciviridae family, the virus has
since been classified into the genus Orthohepevirus, and has been reassigned
into the Hepeviridae family. The virus itself is a small non-enveloped
particle. The genome is approximately 7200 bases
in length, is a polyadenylated single-strand RNA molecule that contains
three discontinuous and partially overlapping open reading frames along
with 5' and 3' cis-acting elements, which have important roles in HEV
replication and transcription. ORF1 encodes a methyltransferase, protease,
helicase and replicase; ORF2 encodes the capsid protein and ORF3 encodes a
protein of undefined function. A three-dimensional, atomic-resolution
structure of the capsid protein in the context of a virus-like particle has
been described. An in vitro culture system is not yet available.
As of 2009 there are approximately 1,600 sequences of both human and animal
isolates of HEV available in open-access sequence databases.
Species of this genus infect humans, pigs, boars, deer, rats, rabbits and
birds. Prevention
= Sanitation= Improving sanitation is the most
important measure in prevention of hepatitis E; this consists of proper
treatment and disposal of human waste, higher standards for public water
supplies, improved personal hygiene procedures and sanitary food
preparation. Thus, prevention strategies of this disease are similar to those of
many others that plague developing nations, and they require large-scale
international financing of water supply and water treatment projects.
= Vaccines= A vaccine based on recombinant viral
proteins was developed in the 1990s and tested in a high-risk population in
2001. The vaccine appeared to be effective and safe, but development was
stopped for economic reasons, since hepatitis E is rare in developed
countries. There is no licensed hepatitis E vaccine for use in the US.
Although other HEV vaccine trials, including trials conducted in
populations in southern Asia, have shown candidate vaccines to be effective and
well-tolerated, these vaccines have not yet been produced or made available to
susceptible populations. The exception is China. After more than a year of
scrutiny and inspection by China's State Food and Drug Administration, a
hepatitis E vaccine developed by Chinese scientists was available at the end of
2012. This vaccine—called HEV 239 and sold as Hecolin by its developer Xiamen
Innovax Biotech—was approved for prevention of hepatitis E in 2012 by the
Chinese Ministry of Science and Technology, following a phase 3 trial on
two groups of 50,000 people each from Jiangsu Province where none of the
vaccinated became infected during a 12-month period, compared to 15 in the
group given placebo treatment. The first vaccine batches came out of Innovax'
factory in late October 2012, and will be sold to Chinese distributors.
Treatment Apart from supportive care, no specific
validated treatment exists for acute hepatis E infection. Although ribavirin
is not registered for Hepatitis E treatment, there is off-label experience
for treating chronic Hepatitis E with this compound. The use of low doses, 600
to 800 milligrams per day, of ribavirin over a three-month period has been
associated with viral clearance in about two-thirds of chronic cases. Other
possible treatments include peginterferon or a combination of
ribavirin and peginterferon. In general chronic HEV infection is associated with
immunosuppressive therapies, but remarkably little is known about how
different immunosuppressants affect HEV infection. In one third of patients with
solid-organ transplantation viral clearance can be achieved by temporal
reduction of the level of immunosuppression.
Epidemiology The hepatitis E virus causes around 20
million infections a year. These result in around three million acute illnesses
and as of 2010, 57,000 deaths annually. It is particularly dangerous for
pregnant women, who can develop an acute form of the disease that is lethal in 20
percent of cases. The virus is a major cause of illness and of death in the
developing world and disproportionate cause of deaths among pregnant women.
Among indigenous people, a significant prevalence of hepatitis E virus-specific
antibody has been reported in several amerindian Yupka tribes in South
America. = Recent outbreaks=
In 2004, there were two major outbreaks, both of them in sub-Saharan Africa.
There was an outbreak in Chad in which, as of September 27, there were 1,442
reported cases and 46 deaths. The second was in Sudan with, as of September 28,
6,861 cases and 87 deaths. Increasingly, hepatitis E is being seen in developed
nations, with reports of cases in the UK, US and Japan. The disease is thought
to be a zoonosis in that animals are thought to be the source. Both deer and
swine have been implicated. In October 2007, an epidemic of
hepatitis E was suspected in Kitgum District of northern Uganda where no
previous epidemics had been documented. This outbreak has progressed to become
one of the largest hepatitis E outbreaks in the world. By June 2009, the epidemic
had caused illness in 10,196 persons and 160 deaths.
In 2011, a minor outbreak was reported in Tangail, a neighborhood of Dhaka,
Bangladesh. In June 2012, an outbreak was reported
in city of Ichalkaranji, Maharashtra, India. As of June 14, 2012, 3232 cases
were reported and 18 died and another 3 died in Shirol taluka of Kolhapur
Maharashtra, India in June 2012. Officials in the Indian state of
Maharashtra suspect that contaminated water from the Panchganga river was
responsible for the hepatitis E outbreak in Ichalkaranji.
In July 2012, an outbreak was reported in South Sudanese refugee camps in Maban
County near the Sudan border. South Sudan's Ministry of Health reported over
400 cases and 16 fatalities as of September 13, 2012. Progressing further,
as of February 2, 2013, 88 have died due to the outbreak. The "Medical charity
Medecins Sans Frontieres said it had treated almost 4,000 patients."
In April 2014 there was an outbreak in Nepal, Biratnagar Municipality with over
6,000 locals infected and at least 9 dead.
History The most recent common ancestor of
Hepatitis E evolved between 536 and 1344 years ago. It diverged into two
clades—an anthropotropic and an enzootic form—which subsequently evolved into
genotypes 1 and 2 and genotypes 3 and 4 respectively. The divergence dates for
the various genotypes are as follows: Genotypes 1/2 367–656 years ago;
Genotypes 3/4 417–679 years ago. For the most recent common ancestor of the
various viruses themselves: Genotype 1 between 87 and 199 years ago; Genotype 3
between 265 and 342 years ago; and Genotype 4 between 131 and 266 years
ago. The anthropotropic strains have evolved more recently than the others
suggesting that this virus was originally a zooenosis.
The use of an avian strain confirmed the proposed topology of the genotypes 1–4
and suggested that the genus may have evolved 1.36 million years ago. The use
of a rat sequence also confirmed this topology and estimated date of
divergence from the swine/human strains was 7.44×104 years ago. Since this date
is approximately coincident with the advent of agriculture it may be that
this virus originally infected rats and subsequently spread to pigs and then to
humans. Additional work is required to support or refute this possibility as
very few sequences have been isolated from species other than humans and
suids. Genotypes 1, 3 and 4 all increased their
effective population sizes in the 20th century. The population size of genotype
1 increased noticeably in the last 30–35 years. Genotypes 3 and 4 population
sizes began to increase in the late 19th century up to 1940–1945. Genotype 3
underwent a subsequent increase in population size until the 1960s. Since
1990 both genotypes' population sizes have been reduced back to levels last
seen in the 19th century. The overall mutation rate for the genome
has been estimated at ~1.4×10−3 substitutionsyear.
References This article incorporates public domain
text from the CDC as cited External links
"Hepatitis E". Media centre: Fact sheet N°280. World Health Organization. July
2013. Virus Pathogen Database and Analysis
Resource: Hepeviridae Aggarwa, Rakesh; Gandhi, Sanjay. "A
systematic review on prevalence of hepatitis E disease and seroprevalence
of hepatitis E virus antibody". World Health Organization. WHO10.14.
Bjorn, Genevive. "The night my liver started running my life". New York
Times.