Hepatitis E is a viral 
hepatitis (liver inflammation) caused by 
infection with a 
virus called 
hepatitis E virus (
HEV).
 HEV is a positive-sense single-stranded RNA icosahedral virus with a 
7.5 kilobase genome. HEV has a fecal-oral transmission route. It is one 
of five known 
hepatitis viruses: 
A, 
B, 
C, 
D, and E. Infection with this virus was first documented in 1955 during an outbreak in 
New Delhi, India.
[1] A 
preventative vaccine (HEV 239) is approved for use in China.
The incidence of hepatitis E is highest in juveniles and adults 
between the ages of 15 and 40. Though children often contract this 
infection as well, they less frequently become symptomatic. Mortality 
rates are generally low, for hepatitis E is a "self-limiting" disease, 
in that it usually goes away by itself and the patient recovers. 
However, during the duration of the 
infection
 (usually several weeks), 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 hepatic failure. Pregnant women, especially those in the third trimester, suffer an elevated 
mortality rate from the disease of around 20%.
[2]
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.
[3]
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.
[3]
Chronic infection
While usually an acute disease, in immunocompromised 
subjects—particularly in solid organ transplanted patients—hepatitis E 
may cause a chronic infection.
[4] 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.
[5]
 Genotype 1 has been classified into five subtypes. The number of 
genotype 2 can be classified into two subtypes. 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%.
[6]
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 (DEFRA) said that the number of human hepatitis E cases increased by 39% between 2011 and 2012.
[7]
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 through 
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.
[8] 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 (30,000 cases in 1955–1956), 
Burma (20,000 cases in 1976–1977), 
Kashmir, 
India (52,000 cases in 1978), 
Kanpur, 
India (79,000 cases in 1991), and 
China (100,000 cases between 1986 and 1988).
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.
[7]
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.
[9] 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.
[10] The rate of transmission to humans by this route and the public health importance of this are, however, still unclear.
[11]
A number of other small mammals have been identified as potential reservoirs: the lesser bandicoot rat (
Bandicota bengalensis), the black rat (
Rattus rattus brunneusculus) and the Asian house shrew (
Suncus murinus).
[12] A new virus designated rat hepatitis E virus has been isolated.
[13]
A rabbit hepatitis E virus has also been described.
[14]
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 
Hepevirus, 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 (ORFs) along with 5' and 3' 
cis-acting elements, which have important roles in HEV replication and transcription. ORF1 encode a 
methyltransferase, 
protease, 
helicase and 
replicase; ORF2 encode 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.
[15] 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.
[16]
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 (military personnel of Nepal)
 in 2001.
[17]
 The vaccine appeared to be effective and safe, but development stopped 
for economical reasons, since hepatitis E is rare in developed 
countries.
[18] 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 (SFDA), 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.
[19] The first vaccine batches came out of Innovax' factory in late October 2012, and will be sold to Chinese distributors.
[18]
Treatment
Although 
prednisolone
 has been used in the treatment of this condition, because large scale 
studies have not yet been reported the role of this drug in treatment is
 not yet clear.
[citation needed]
Chronic infection
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 one thirds of 
patients with solid-organ transplantation viral clearance can be 
achieved by temporal reduction of the level of 
immunosuppression.
[3]
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.
[20]
 It is particularly dangerous for pregnant women, who can develop an 
acute form of the disease that is lethal in 20 per cent of cases. The 
virus (HEV) is a major cause of illness and of death in the developing 
world and disproportionate cause of deaths among pregnant women.
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.
[21]
In 2011, a minor outbreak was reported in Tangail, a neighborhood of Dhaka, Bangladesh.
[22]
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.
[23]
 and 3 died in Shirol taluka of Kolhapur Maharashtra, India in June 
2012. Officials in the Indian state of Maharashtra India 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.
[24]
 Progressing further, as of February 2, 2013, 88 have died due to the 
outbreak. The "Medical charity Medecins Sans Frontieres (MSF) said it 
had treated almost 4,000 patients."
[25]
History
The most recent common ancestor of Hepatitis E evolved between 536 and 1344 years ago.
[16]
 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 (genotype 1 and 2) 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 (range 
0.23 million years ago to 
2.6 million years ago).
[16]
 The use of a rat sequence also confirmed this topology and estimated 
date of divergence from the swine/human strains was 7.44×10
4 years ago (range 2.1×10
4 to 1.4×10
5
 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.
[16]
 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 substitutions/site/year.
[16]