Hepatitis E

Hepatitis E
Hepatitis E virus.jpg
Hepatitis E virus
SpecialtyInfectious disease Edit this on Wikidata
SymptomsNausea, jaundice[1]
Diagnostic methodBlood test[1]
TreatmentRest, Ribavirin (if chronic)[1]
Frequency28 million worldwide (2013)[2]

Hepatitis E is inflammation of the liver caused by infection with the hepatitis E virus (HEV).[3] It is one of five known human hepatitis viruses: A, B, C, D, and E. HEV is a positive-sense, single-stranded, nonenveloped, RNA icosahedral virus.[4][5] It is spread mainly by the fecal-oral route due to fecal contamination of water supplies or food.[4][6] Infection with this virus was first documented in 1955 during an outbreak in New Delhi, India.[7] A preventive vaccine (HEV 239) is approved for use in China.[8]

Although hepatitis E often causes an acute and self-limiting infection (the viral infection is temporary and the individual recovers) with low death rates in the western world, it bears a high risk of developing chronic hepatitis in people with a weakened immune system with substantially higher death rates. Organ transplant recipients who receive medications to weaken the immune system and prevent organ rejection are thought to be the main population at risk for chronic hepatitis E.[9]

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, have a higher rate of death from the disease of around 20%.[10] In 2013, hepatitis E newly infected over 28 million people.[2]

Signs and symptoms

Acute infection

The incubation period of HEV varies from three to eight weeks. A short prodromal phase is followed by symptoms lasting from days to weeks. These may include jaundice, fatigue, and nausea. The symptomatic phase coincides with elevated hepatic aminotransferase levels.[11]

Viral RNA becomes detectable in stool and blood serum during the 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 IgG antibody levels.[5][11]

Chronic infection

While usually an acute disease, in immunocompromised subjects—particularly in solid organ transplant patients—hepatitis E may cause a chronic infection.[12] This may occasionally cause liver fibrosis and cirrhosis.[13]

Other organs

Infection with HEV 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:[14]

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 HEV in developing countries. Besides signs of an acute infection, adverse maternal and fetal outcomes may include preterm delivery, stillbirth, and intrauterine fetal and neonatal death.[15][16]

The pathologic and biologic mechanisms behind the adverse outcomes of pregnancy infections remain largely unclear. Increased viral replication and influence of hormonal changes on the immune system have been discussed lately.[17] Furthermore, studies showing evidence for viral replication in the placenta[18] or reporting the full viral life cycle in placental-derived cells in vitro implicate the human placenta as a site of extra-hepatic replication.

Virology

Classification

Only one serotype of the virus is known, and classification is based on the nucleotide sequences of the genome.[19] Genotype 1 has been classified into five subtypes,[20] genotype 2 into two subtypes[20]pg 10, and genotypes 3 and 4 have been into ten[21] and seven subtypes,[21] respectively.

Distribution

Genotypes 1 and 2 are restricted to humans and often associated with large outbreaks and epidemics in developing countries with poor sanitary conditions.[22] 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.[25]

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.[26]

Transmission

Hepatitis E virus in pork liver sausage

Hepatitis E is widespread in Southeast Asia, northern and central Africa, India, and Central America.[27] It is spread mainly by the fecal-oral route due to fecal contamination of water supplies or food. Person-to-person transmission is uncommon.[6]

The incubation period following exposure to HEV ranges from three to eight weeks, with an average of 40 days.[6] Outbreaks of epidemic hepatitis E most commonly occur after heavy rainfalls and monsoons because of their disruption of water supplies.[28] Major outbreaks have occurred in New Delhi, India (30,000 cases in 1955–1956),[29] Burma (20,000 cases in 1976–1977),[30] Kashmir, India (52,000 cases in 1978),[31] Kanpur, India (79,000 cases in 1991),[29] and China (100,000 cases between 1986 and 1988).[32]

DEFRA said that evidence indicated the increase in hepatitis E in the UK was due to food-borne zoonoses, citing a study that found in the UK that 10% of pork sausages contained HEV. 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.[26]

Hepatitis E infection appeared to be more common in people on hemodialysis, although specific risk factors for transmission are not clear.[33]

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.[34] Domestic animals have been reported as a reservoir for HEV, with some surveys showing infection rates exceeding 95% among domestic pigs.[35] 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 also been reported.[36] The rate of transmission to humans by this route and its public health importance are, however, still unclear.[37]

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.[38]

A rabbit hepatitis E virus has been described,[39] 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 HEV. While supplier A was a conventional rabbit farm, 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." Research facilities should implement preventive measures for this zoonotic pathogen to protect staff.[40]

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.[41]

Genomics

Geldanamycin

The virus has since been classified into the genus Orthohepevirus, and has been reassigned into the Hepeviridae family. The virus itself is a small nonenveloped particle.The genome is about 7,200 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. While ORF1 encodes a methyltransferase, protease, helicase and replicase, ORF2 and ORF3 respectively encode the capsid protein and 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.[42][43]

As of 2009, around 1,600 sequences of both human and animal isolates of HEV are available in open-access sequence databases. Species of this genus infect humans, pigs, boars, deer, rats, rabbits, and birds.[44]

Virus lifecycle

The lifecycle of HEV is unknown. The capsid protein obtains viral entry by binding to a cellular receptor. ORF2 (c-terminal) moderates viral entry by binding to HSC70.[42]

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.[42]

Diagnosis

Only a laboratory test that confirms antibodies present for HEV RNA or HEV can be trusted as conclusive to diagnose the viral infection.[45][46]

Prevention

Sanitation

Sanitation is the most important measure in the prevention of hepatitis E. This consists of proper disposal of human waste, higher standards for public water supplies, improved personal hygiene procedures, and sanitary food preparation. Thus, prevention strategies for this disease are similar to those of many others that plague developing nations.[6]

Vaccines

A vaccine based on recombinant viral proteins was developed in the 1990s and tested in a high-risk population (in Nepal) in 2001.[47] The vaccine appeared to be effective and safe, but development was stopped for lack of profitability, since hepatitis E is rare in developed countries.[48] No hepatitis E vaccine is licensed for use in the United States.[49]

Although other HEV vaccine trials have been successful, these vaccines have not yet been produced or made available to susceptible populations. The only 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 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 over 100,000 people from the province of Jiangsu where none of those vaccinated became infected during a 12-month period, compared to 15 in the group given placebo.[50] The first vaccine batches left Innovax's factory in late October 2012, to be sold to Chinese distributors.[48]

Due to the lack of evidence, the World Health Organization, as of 2015, did not make a recommendation regarding routine use of the HEV 239 vaccine.[51] National authorities may, however, decide to use the vaccine based on local epidemiology.[51]

Treatment

Ribavirin

Although ribavirin is not registered for hepatitis E treatment, 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.[52][53]

Epidemiology

HEV causes around 20 million infections per year. These result in around three million acute illnesses and, as of 2010, 57,000 deaths annually.[54] It is particularly dangerous for pregnant women, who can develop an acute form of the disease that is lethal in up to 25% of cases. 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.[55] Increasingly, hepatitis E is being seen in developed nations, with reports of 329 cases of hepatitis E virus infection in England and Wales in 2005.[56]

Recent outbreaks

In 2004, two outbreaks occurred in sub-Saharan Africa. Both outbreaks in Chad and Sudan had several fatalities.[57][58]

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 progressed to become one of the largest hepatitis E outbreaks in history. By June 2009, the epidemic had caused illness in 10,196 persons and 160 deaths.[59]

In 2011, a minor outbreak was reported in Tangail, a neighborhood of Dhaka, Bangladesh.[60]

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.[61] Progressing further, as of February 2, 2013, 88 had died due to the outbreak. The international humanitarian medical non-governmental organisation Médecins Sans Frontières said it treated almost 4,000 patients.[62]

In April 2014, an outbreak in the Biratnagar Municipality of Nepal resulted in infection of over 6,000 locals, resulting in at least 9 deaths.[63]

In January 2018, an outbreak was reported in Namibia. Two mothers died from a total of 490 infected persons.[64]

History

The most recent common ancestor of hepatitis E evolved between 536 and 1,344 years ago.[44] 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. 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. A study of genotype 3 has suggested that it evolved 320 years ago (95% HPD: 420 – 236 years ago) and that two main subtypes occur.[65]

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).[44]

Genotypes 1, 3, and 4 all increased their effective population sizes in the 20th century.[44] 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 1.4×10−3 substitutions/site/year.[44]

See also

References

This article incorporates public domain text from the CDC as cited

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Further reading

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