Hepatitis E virus

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis and is widely under-recognised. It causes an estimated 20 million infections a year, of which around 3.3 million are symptomatic, but that burden falls unevenly across the world. The virus wears two very different faces. In much of Asia and Africa it is a waterborne infection, spread by drinking water contaminated with sewage, causing large epidemics of acute hepatitis and, distinctively, killing a substantial fraction of the pregnant women it infects in the third trimester. In higher-income countries it is instead a zoonosis, caught from undercooked pork and game, usually mild in healthy people but able to settle into a chronic infection in those whose immune systems are suppressed. Most infections need no more than supportive care and resolve on their own. The exceptions, acute liver failure in pregnancy and chronic hepatitis in transplant recipients and other immunocompromised patients, are where the clinical weight lies. A recombinant vaccine exists, but it is licensed and used only in China, so prevention elsewhere still depends on clean water, safe food, and recognising the people at greatest risk.

Discovery and historical significance

Hepatitis E announced itself through water. A massive epidemic of jaundice in New Delhi in 1955, traced to faecal contamination of the city’s drinking water, and a similar outbreak in Kashmir in the late 1970s, did not fit hepatitis A or B and were labelled enterically-transmitted non-A, non-B hepatitis. The decisive experiment came in 1983, when the Soviet virologist Mikhail Balayan swallowed a pooled stool extract from affected soldiers, developed hepatitis, and recovered virus particles from his own stool, proving that a single transmissible agent was responsible. The genome was cloned and sequenced in 1990, giving the virus its name and place. The later recognition that the same virus circulates in pigs and other animals in high-income countries, and can cause chronic disease in the immunosuppressed, transformed it from a problem of the developing world into a global one.

Classification, structure, and genome

Classification

Hepatitis E virus belongs to the family Hepeviridae. Under current taxonomy the human virus is the species Paslahepevirus balayani in the genus Paslahepevirus. Eight genotypes (HEV-1 to HEV-8) are described, of which genotypes 1 to 4 account for essentially all human disease, and they split into two epidemiological groups. Genotypes 1 and 2 infect only humans and drive the waterborne epidemics of Asia and Africa. Genotypes 3 and 4 are zoonotic, with pigs, wild boar and deer as their main reservoir, and cause sporadic infection in higher-income regions; other genotypes have been found in animals including camels. This division between human-restricted and zoonotic genotypes is the single most useful organising idea in hepatitis E.

Virion structure

The virion is a small, roughly 27 to 34 nanometre icosahedral particle. Its capsid is built from the ORF2 protein, with copies arranged in a lattice that also carries the sites antibodies recognise. The most unusual feature is that the virus exists in two physical states. The form shed in bile and faeces is naked and non-enveloped, which makes it robust in the environment and able to spread by the faecal-oral route. The form circulating in the blood is quasi-enveloped, wrapped in a layer of host membrane that hides it from circulating antibody. The same genome and capsid therefore present very differently depending on whether the virus is being transmitted or moving within the body.

Genome organisation

The genome is about 7.2 kilobases of positive-sense, single-stranded RNA, capped at the 5’ end and carrying a poly-A tail at the 3’ end. It is organised into three open reading frames. ORF1 encodes a single large non-structural polyprotein that contains the machinery for copying the genome, including a methyltransferase, a protease, a helicase, and the RNA-dependent RNA polymerase. ORF2 encodes the capsid protein. ORF3 encodes a small phosphoprotein that acts as an ion channel and is essential for the virus to be released from the cell. Genotype 1 carries an additional small reading frame, ORF4, that helps its replication under cellular stress.

Replication cycle

Hepatitis E is hepatotropic, replicating mainly in liver cells. The virus attaches to the cell surface, with heparan sulfate proteoglycans acting as initial attachment factors, and is taken inside. Once the genome is released into the cytoplasm, its positive-sense RNA is translated directly to produce the ORF1 non-structural polyprotein. That polyprotein then copies the genome through a negative-sense intermediate and generates a shorter subgenomic RNA, which is used to make the ORF2 capsid and ORF3 proteins.

New genomes are packaged into capsids, and the particles acquire their quasi-envelope as they exit: the ORF3 protein recruits the cell’s ESCRT machinery, the same membrane-budding system the cell uses to form internal vesicles, to wrap and release the virus. Virus delivered into bile is stripped of this membrane by bile salts, which is why the faecal form is non-enveloped while the blood form is quasi-enveloped.

Pathogenesis

Hepatitis E does not appear to kill liver cells directly; the damage is largely caused by the immune response clearing infected cells, which is why most acute infection is self-limited once that response succeeds. Two situations break this pattern.

In pregnancy, infection with the waterborne genotype 1 can be catastrophic. Several factors are thought to combine: pregnant women carry higher viral loads, the high oestrogen and progesterone levels of pregnancy influence viral replication and immune function, and the immune adaptation that protects the fetus shifts the response in a way that blunts antiviral defence. The result is a high rate of fulminant hepatic failure in the third trimester.

In the immunosuppressed, particularly organ-transplant recipients on calcineurin inhibitors such as tacrolimus, the zoonotic genotypes 3 and 4 can fail to be cleared. Clearance of hepatitis E depends on a strong, broad T-cell response against the virus; when that response is pharmacologically suppressed, the virus is not eliminated and establishes chronic infection that drives progressive fibrosis. Tacrolimus in particular has been linked to a higher risk of chronicity, which is why it is a prime target for dose reduction. The virus also helps itself to persist by dampening the innate interferon response: domains within the ORF1 polyprotein and the ORF3 protein interfere with the signalling that would otherwise trigger an antiviral state. Restoring the host response, by reducing immunosuppression, is often enough to clear the infection.

Epidemiology

Hepatitis E causes around 20 million infections and 3.3 million symptomatic cases each year, but the burden is distributed very unevenly, and its epidemiology follows the genotype split.

Genotypes 1 and 2 are human-restricted and spread by the faecal-oral route through water contaminated with human sewage. They cause the large, explosive epidemics seen in South Asia, sub-Saharan Africa and Central America, typically affecting young adults and flaring when sanitation fails, for example during floods or in displaced populations. Background seroprevalence in endemic regions is high.

Genotypes 3 and 4 are zoonotic. Their reservoir is pigs, wild boar and deer, and humans acquire them by eating undercooked meat. These genotypes cause sporadic, locally acquired (autochthonous) infection in Europe, North America and parts of Asia, generally in older people, often with little or no travel history. A further route matters in these settings: hepatitis E can be transmitted by transfusion of blood components from viraemic donors, which has prompted donor screening in several countries.

Most infection is silent, with only around a fifth of infected adults developing symptoms, but the sheer number infected makes hepatitis E a major cause of acute hepatitis: it accounted for an estimated 44,000 deaths in 2015, about 3.3 per cent of all deaths attributed to viral hepatitis. Seroprevalence rises steadily with age in both epidemic and zoonotic settings, reflecting cumulative lifetime exposure, and blood-donor surveys in some high-income countries show that silent genotype 3 infection is far more common than the number of recognised clinical cases would suggest.

Natural history

The incubation period is around two to ten weeks, with a mean of about five to six weeks. In most healthy people, hepatitis E is a self-limited acute hepatitis: the virus is cleared within weeks and immunity follows. Viraemia and faecal shedding subside as the antibody response matures. Two groups diverge from this benign course.

Pregnant women infected with genotype 1 in the third trimester face a high risk of acute liver failure, with maternal mortality in the order of 20 to 30 per cent in outbreak settings, along with high rates of miscarriage, stillbirth and premature delivery.

Immunosuppressed patients infected with genotype 3 or 4 may develop chronic infection, defined as persistence of HEV RNA beyond three months. Among solid-organ transplant recipients who become infected, roughly 60 per cent (reported at around 56 to 66 per cent) progress to chronicity if nothing is done. The other main groups at risk are people with haematological malignancy or on chemotherapy, and those with advanced HIV. Untreated chronic infection can advance to bridging fibrosis and cirrhosis within only a few years, far faster than the decades-long course of other chronic viral hepatitides, so it must not be left to run. This is why hepatitis E must be considered in any transplant or immunocompromised patient with unexplained, persistently abnormal liver enzymes, and why the diagnosis rests on viral RNA rather than antibody in this group.

Clinical presentations and complications

Most hepatitis E infection is asymptomatic or a mild acute hepatitis, with malaise, nausea, jaundice and raised transaminases that settle over a few weeks.

Acute liver failure is the feared presentation in pregnancy, and can also occur in people with pre-existing chronic liver disease, in whom hepatitis E can precipitate acute-on-chronic decompensation.

Chronic hepatitis E is the presentation in the immunosuppressed: often few symptoms, with the diagnosis suggested by persistently raised liver enzymes.

Extrahepatic disease is increasingly recognised, particularly with genotype 3, and may occur with little hepatitis to draw attention to the virus. The best-characterised are neurological: Guillain-Barre syndrome (an immune-mediated ascending paralysis) and neuralgic amyotrophy (Parsonage-Turner syndrome, causing severe shoulder-girdle pain followed by patchy upper-limb weakness, often bilateral in hepatitis E). Neurological involvement has been reported in a striking proportion of symptomatic cases in European series, of the order of 16 to 30 per cent in some cohorts, the great majority associated with genotype 3, and HEV RNA can occasionally be found in the cerebrospinal fluid. Renal disease includes acute kidney injury, reported in around 8 per cent of one series, and glomerulonephritis, sometimes with cryoglobulinaemia. Haematological associations (thrombocytopenia, aplastic anaemia) and acute pancreatitis are also described. Hepatitis E is therefore worth considering in a patient with one of these syndromes and abnormal liver enzymes, even without prominent hepatitis.

Diagnosis

Diagnosis combines serology and molecular testing, and the right choice depends on the patient’s immune status.

In the immunocompetent patient, serology comes first. Anti-HEV IgM indicates recent infection and is the usual front-line test, though its sensitivity and specificity vary considerably between commercial assays, so results may need cautious interpretation. Anti-HEV IgG seroconversion between paired samples supports recent infection, while a single positive IgG reflects past exposure. HEV RNA by reverse transcription polymerase chain reaction confirms active infection and is useful early or where serology is equivocal.

In the immunosuppressed patient, serology is unreliable because the patient may not mount an antibody response, so anti-HEV IgM and IgG can be falsely negative. Diagnosis here depends on HEV RNA in serum and stool, which is the reference test, and an HEV antigen assay is a useful alternative where available. Because chronic infection is defined by HEV RNA persisting beyond three months, repeat RNA testing both establishes chronicity and monitors the response to treatment.

Management

Acute hepatitis E in an otherwise healthy person needs only supportive care, as the infection clears on its own. Severe acute or fulminant disease, including in pregnancy, is managed with intensive supportive care and assessment for liver transplantation; ribavirin cannot be used in pregnancy because it is teratogenic.

Chronic hepatitis E in the immunosuppressed is managed in steps. The first move is to reduce immunosuppression where the graft allows, particularly calcineurin inhibitors; this alone clears the virus in roughly a third of patients. If infection persists, the next step is ribavirin monotherapy, typically around 600 mg daily for three months, which clears the great majority, in the region of three-quarters to four-fifths of treated patients, with the dose and duration extended guided by the response. Pegylated interferon alpha is an alternative with a high clearance rate, used mainly in liver-transplant recipients, but it carries a risk of rejection in other organ transplants and so is used cautiously. Treatment response is judged by HEV RNA in serum and stool: clearance must be confirmed and then re-checked after stopping, because relapse can occur if RNA was still present in stool when treatment ended.

Prevention and public health

Vaccination

A recombinant vaccine based on the ORF2 capsid protein has been developed and is licensed in China, given as three doses over six months. It is highly protective in trials, with efficacy of around 100 per cent at one year and still high several years later, but it is not yet registered or widely available outside China, and it is not recommended in pregnancy. Its potential role in outbreak control and in protecting high-risk groups in endemic regions is an active question for global public health.

Infection prevention and control

For the waterborne genotypes, prevention rests on safe drinking water and sanitation: protecting water supplies from faecal contamination is the single most effective measure. For the zoonotic genotypes, the key is food safety, thoroughly cooking pork, game and pork products, since the virus survives undercooking. Screening of blood donations for HEV RNA has been introduced in several countries to prevent transfusion-transmitted infection.

Outbreak response

Waterborne epidemics demand rapid restoration of clean water, sanitation and hygiene, identification of the contamination source, and protection of pregnant women, who bear the greatest risk of death. Vaccination has been considered as an outbreak-control tool where the vaccine is available.

South African context

Hepatitis E is present in South Africa, and the 2019 National Department of Health Viral Hepatitis Guideline recognises it as an endemic infection, with reported seroprevalence spanning a wide range across studied populations. Most infection is sporadic and self-limited, but the same two high-risk situations apply: severe disease in pregnancy and chronic infection in the immunosuppressed, a group that is large in South Africa given the size of the HIV-positive and transplant populations.

• Vaccine availability: the recombinant hepatitis E vaccine is not available in South Africa, so prevention relies on water, sanitation and food safety, and on clinical vigilance in high-risk patients.
• Diagnosis and referral: testing follows the serology-plus-RNA approach, with HEV RNA the reliable marker in immunosuppressed patients, and complex or chronic cases are managed at tertiary level.
• Notification: viral hepatitis is a notifiable medical condition in South Africa, so cases are reported through the national surveillance system, and clusters of acute hepatitis prompt outbreak investigation.

Detailed South African seroprevalence and the local evidence for zoonotic genotype 3 transmission are documented in the regional literature and would strengthen this section once added to the source registry.

References and recommended reading

• Luo Q, Chen J, Zhang Y, et al. Viral hepatitis E: clinical manifestations, treatment, and prevention. Liver Research 2024;8(1):11-21. A current clinical review of presentation, chronic and extrahepatic disease, treatment, and the vaccine.
• Dalton HR, Kamar N, Izopet J. Hepatitis E Virus. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition, Chapter 50. Washington: ASM Press; 2016. Foundational account of the virus, its structure, replication, and epidemiology.
• National Department of Health, South Africa. National Guidelines for the Management of Viral Hepatitis. December 2019. The South African programmatic source for testing and referral.