WikiJournal of Medicine/Hepatitis E

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, though the majority of HEV infections are asymptomatic. The symptomatic phase coincides with elevated hepatic aminotransferase levels.

Viral RNA becomes detectable in stool and blood serum during the incubation period. Serum IgM and IgG antibodies against HEV appear just before the 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 transplant patients—hepatitis E may cause a chronic infection. Occasionally this may cause a life threatening complication such as fulminant liver failure or liver cirrhosis.

Other organs
Infection with hepatitis E virus can also lead to problems in other organs. For some of these reported conditions the relationship is tenuous, but for several neurological and blood conditions the relationship appears causal:
 * Acute pancreatitis
 * Neurological complications include Guillain-Barré syndrome (acute limb weakness due to nerve involvement), neuralgic amyotrophy (arm and shoulder weakness, also known as Parsonage-Turner syndrome), acute transverse myelitis and acute meningoencephalitis.
 * Glomerulonephritis with nephrotic syndrome and/or cryoglobulinemia
 * Mixed cryoglobulinemia, where antibodies in the bloodstream react inappropriately at low temperatures
 * Severe thrombocytopenia (low platelet count in the blood) which confers a risk of dangerous bleeding

Infection in pregnancy
Pregnant women show a more severe course of infection than other populations. Mortality rates of 20% to 25% and hepatic failure have been reported from outbreaks of genotype 1 and 2 HEV in developing countries. Besides signs of an acute infections, adverse maternal and fetal outcomes may include preterm delivery, abortion, stillbirth, and intrauterine fetal and neonatal death.

The pathologic and biologic mechanisms behind the adverse outcomes of pregnancy infections remain largely unclear so far. Mainly, increased viral replication and influence of hormonal changes on the immune system have been discussed lately. Furthermore, studies showing evidence for viral replication in the placenta or reporting the full viral life cycle in placental-derived cells in vitro implicate the human placenta as site of extra-hepatic replication.

Classification
HEV is classified into the family Hepeviridae, which is divided in two genera, Orthohepevirus (all mammalian and avian HEV isolates) and Piscihepevirus (cutthroat trout HEV). Only one serotype of the virus is known, and classification is based on the nucleotide sequences of the genome. Genotype 1 has been classified into five subtypes, genotype 2 into two subtypes, pg 10 and genotypes 3 and 4 have been divided into 10 and seven subtypes. Additionally there are genotypes 5, 6, 7 and 8. Rat HEV was first isolated from Norway rats in Germany, a 2018 CDC article indicated the detection of rat HEV RNA in a transplant recipient.

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, and North and South America.
 * Genotype 4 appears to be limited to Asia and indigenous cases from Europe.

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 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. Genotypes 1 and 2 cause outbreaks, while the other genotypes cause sporadic cases.

As mentioned, the incubation period following exposure to the hepatitis E virus ranges from 3 to 8 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 (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). According to Rein et al., HEV genotypes 1 and 2 caused some 20.1 million Hepatitis E infections, along with 3.4 million cases of symptomatic disease, and 70,000 deaths in 2005; however the aforementioned paper  did not estimate the burden of genotypes 3 and 4.

According to the Department for Environment, Food and Rural Affairs, evidence indicated the increase in hepatitis E in the U.K. was due to food-borne zoonoses, citing a study that found in the U.K. that 10% of pork sausages contained the Hepatitis E virus. Some research suggests that food must reach a temperature of 70 °C for 20 minutes to eliminate the risk of infection. The Animal Health and Veterinary Laboratories Agency discovered hepatitis E in almost half of all pigs in Scotland.

Hepatitis E infection appeared to be more common in people on hemodialysis, although the specific risk factors for transmission are not clear.

Animal reservoir
The disease is thought to be a zoonosis in that animals are thought to be the source. Both deer and swine have been implicated. 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 (Bandicota bengalensis), the black rat (Rattus rattus brunneusculus) and the Asian house shrew (Suncus murinus). A new virus designated rat hepatitis E virus has been isolated.

Genomics
HEV has three open reading frames (ORFs) encoding two polyproteins (O1 and O2 protein). ORF2 encodes three capsid proteins whereas O1 encodes seven fragments involved in viral replication, among others.

The smallest ORF of the HEV genome, ORF3 is translated from a subgenomic RNA into O3, a protein of 113–115 amino acids. ORF3 is proposed to play critical roles in immune evasion by HEV. Previous studies showed that ORF3 is bound to viral particles found in patient sera and produced in cell culture. Although in cultured cells ORF3 has not appeared essential for HEV RNA replication, viral assembly, or infection, it is required for particle release.

Virus lifecycle
The lifecycle of hepatitis E virus is unknown; the capsid protein obtains viral entry by binding to a cellular receptor. ORF2 (c-terminal) moderates viral entry by binding to HSC70.

Geldanamycin blocks the transport of HEV239 capsid protein, but not the binding/entry of the truncated capsid protein, which indicates that HSP90 plays an important part in HEV transport.

Diagnosis
In terms of the diagnosis of hepatitis E, only a laboratory test that confirms antibodies present for HEV RNA or HEV can be trusted as conclusive for the virus in any individual tested for it. In the United States no serologic tests for diagnosis of HEV infection have ever been authorized by the Food and Drug Administration. The World Health Organization has developed an international standard strain for detection and quantification of HEV RNA.

Virological markers
Assuming that vaccination has not occurred:
 * Positive Anti-HEV-IgM- with HEV-Ag and/or HEV-RNA positive indicates chronic infection, however if negative with Anti-HEV-Ag being 'positive' this indicates recent infection, if Anti-HEV-Ag is negative then there is cross reactivity.


 * Negative Anti-HEV-IgM- with HEV-Ag and/or HEV-RNA positive as well as Anti-HEV-Ag positive then it is acute infection, if the latter is negative then it is dependent on time taken for seroconversion. If HEV-Ag and/or HEV-RNA is negative with Anti-HEV-Ag being 'positive' it is a past infection, if the latter is negative then infection is not present.

Sanitation
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 other diseases that plague developing nations. Cooking meat at 71 degrees Celsius for 5 minutes kills the Hepatitis E virus.

Blood products
The amount of virus present in blood products required to cause transfunction-transmitted infection (TTI) appears variable. Transfusion transmission of Hepatitis E virus can be screened via minipool HEV NAT (Nucleic acid testing) screening. NAT is a technique used to screen blood molecularly, when blood donations are received; it screens for TTI.

Vaccines
A vaccine based on recombinant viral proteins was developed in the 1990s and tested in a high-risk population (in Nepal) in 2001. The vaccine appeared to be effective and safe, but development was stopped for lack of profitability, since hepatitis E is rare in developed countries. No hepatitis E vaccine is licensed for use in the United States.

Although other HEV vaccine trials have been successful, 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. The vaccine —called HEV 239 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 controlled trial on 100,000+ people from Jiangsu Province where none of those vaccinated became infected during a 12-month period, compared to 15 in the group given placebo. The first vaccine batches came out of Innovax' factory in late October 2012, to be sold to Chinese distributors.

Due to the lack of evidence, WHO as of 2015 did not make a recommendation regarding routine use of the HEV 239 vaccine. National authorities may however, decide to use the vaccine based on the local epidemiology.

Treatment
In terms of treatment, ribavirin is not registered for hepatitis E treatment, though off-label experience for treating chronic hepatitis E with this compound exists. The use of low doses of ribavirin over a three-month period has been associated with viral clearance in about two-thirds of chronic cases. Other possible treatments include pegylated interferon or a combination of ribavirin and pegylated interferon. In general, chronic HEV infection is associated with immunosuppressive therapies, but remarkably little is known about how different immunosuppressants affect HEV infection. In individuals 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 resulted in 44,000 deaths during 2015. Pregnant women are particularly at risk of complications due to HEV infection, who can develop an acute form of the disease that is fatal in 30% of cases or more. HEV is a major cause of illness and of death in the developing world and disproportionate cause of deaths among pregnant women. Hepatitis E is endemic in Central Asia, while Central America and the Middle East have reported outbreaks. Increasingly, hepatitis E is being seen in developed nations, with reports in 2015 of 848 cases of hepatitis E virus infection in England and Wales.

Recent outbreaks
In October 2007, an epidemic of hepatitis E occured in Kitgum District of northern Uganda. This outbreak progressed to become one of the largest known hepatitis E outbreaks in the world. By June 2009, it had resulted in illness in 10,196 persons and 160 deaths.

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 died due to the outbreak. The medical charity Medecins Sans Frontieres said it treated almost 4,000 people. In April 2014, an outbreak in the Biratnagar Municipality of Nepal resulted in infection of over 6,000 locals and at least 9 dead.

An outbreak was reported in Namibia which is located in Africa, in January 2018, the total infected is reported as 490. As of 14 April, 2019 according to the World Health Organization, there have been 5,014 cases and 42 deaths due to this Hepatitis E outbreak in the country of Namibia. The case fatality ratio for this outbreak is currently 0.8%.

History
The most recent common ancestor of hepatitis E evolved between 536 and 1344 years ago. It diverged into two clades — an anthropotropic form and an enzootic form — which subsequently evolved into genotypes 1 and 2 and genotypes 3 and 4, respectively.

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 roughly 1.4 substitutions/site/year.