Hepatitis E

Etiology

HEV is an icosahedral, nonenveloped, single-stranded ribonucleic acid virus with a diameter of approximately 27 to 34 nm. Four genotypes of HEV have been identified, 1 through 4.

Genotypes 1 and 2 

These genotypes are human viruses transmitted through the fecal-oral route via contaminated water and are predominantly found in developing countries, including regions in Africa, Asia, Central America, and the Middle East. During outbreaks, these genotypes typically affect young adults (15-40 years of age), causing a self-limited acute infection that generally does not progress to chronic infection. However, in pregnant patients or those with chronic liver disease, acute infections can be severe and may lead to fulminant liver failure.[5] 

Genotypes 3 and 4

These genotypes are primarily zoonotic, found in animals, and transmitted to humans through the consumption of undercooked meat such as pork and deer. These genotypes are more common in developed countries, including the United States, Australia, Japan, and China.[5] They generally cause sporadic cases, mainly affecting adults aged older than 40. While they can cause acute infections, there is a risk of progression to chronic infection, particularly in immunocompromised patients, such as recipients of immunosuppressives for solid organ transplants and individuals with human immunosupresive virus infection.[5]

Epidemiology

According to the World Health Organization (WHO), HEV causes approximately 20 million new infections and over 55,000 deaths annually.[WHO. Hepatitis E fact sheet. July 20, 2023. Accessed Jan 27, 2025. https://www.who.int/news-room/fact-sheets/detail/hepatitis-e] HEV infection has a global distribution but is most common in developing regions. The highest incidence is in Asia, Africa, the Middle East, and Central America.[6][7][8] HEV is the second most common cause of sporadic hepatitis in North Africa and the Middle East.[9] Sporadic cases have also been reported in Western countries, primarily among travelers returning from HEV-endemic regions.[10][11][12] 

In the United States (US), the overall seroprevalence of HEV was 6% between 2009 and 2010. The risk of HEV seropositivity is associated with increasing age, birth outside of the US, Hispanic ethnicity, and frequent meat consumption (>10 times per month).[13] While HEV was previously considered prevalent only in the developing regions of Asia and Africa, recent findings highlight its status as a zoonotic disease in high-income countries, particularly in Europe, where it is acquired from pigs.[14] 

Thus, there are 2 primary patterns of HEV infection: endemic and sporadic. The endemic form is common in developing countries, while the sporadic form occurs more occasionally. HEV1 is endemic in Asia and certain regions of Africa, where it is primarily waterborne and transmitted through human hosts, often causing large outbreaks. HEV2 shares similar epidemiological characteristics but is more geographically restricted to Africa and Latin America. HEV3 and HEV4, which are zoonotic, infect various mammals, particularly pigs. HEV3 is globally widespread, while HEV4 is predominantly found in East Asia.[15] Zoonotic genotypes typically result in sporadic cases of hepatitis E rather than widespread outbreaks. The epidemiology of hepatitis E varies by genotype and is influenced by factors such as transmission routes, geographic distribution, and diagnostic practices.

HEV infection during pregnancy, particularly in the third trimester, is associated with severe maternal and fetal outcomes.[16] Acute HEV infection in pregnant women can lead to fulminant hepatic failure, with maternal mortality rates ranging from 15% to 25%.[17] The risk of severe illness is significantly higher than in non pregnant women.[18] The fetus is also at considerable risk, with preterm birth, stillbirth, and neonatal death being more common than in non infected pregnancies. Although rare, vertical transmission of HEV from mother to child has been documented, leading to neonatal hepatitis E, which can further complicate postnatal care.[19][20] The mechanisms underlying this increased severity are not fully understood but may involve hormonal changes and immune modulation during pregnancy that exacerbate the infection.

Pathophysiology

HEV is most commonly transmitted through the fecal-oral route via contaminated water, leading to frequent large waterborne outbreaks, particularly in developing countries. Although rare, HEV can also be a fecally transmitted zoonotic infection.[21] Person-to-person transmission is uncommon, but HEV can be transmitted through blood transfusions, especially in endemic areas.[22] HEV can be transmitted vertically from infected mothers to their infants, potentially resulting in significant perinatal mortality and fetal loss.[23] While there is insufficient data regarding HEV transmission via breast milk, the virus has been isolated in breast milk, with serum titers found to be comparable.[24]

The incubation period of HEV infection ranges from 28 to 40 days. After ingestion, the virus is absorbed through the gastrointestinal mucosa into the portal circulation, eventually reaching the liver. In the liver, the HEV virion attaches to its receptor, likely mediated by heparan sulfate. This initial binding is followed by clathrin-mediated endocytosis, viral uncoating, and ribonucleic acid release.[25][26] 

Upon successful entry, the viral genome, a positive-sense single-stranded ribonucleic acid (RNA), is directly translated into the open reading frame 1 polyprotein.[15] The viral replication process involves the synthesis of negative-sense RNA intermediates, which serve as templates to produce both genomic and subgenomic positive-sense RNAs. HEV is eventually excreted in feces.

Histopathology

HEV can produce morphologic changes in the liver that resemble both cholestatic and classic acute hepatitis, but these features are not diagnostic for hepatitis E.[27] Generally, a spectrum of histopathologic findings is possible and may be influenced by the patient’s immune status or the presence of chronic liver disease. Observed changes include minimal portal or lobular hepatitis, steatohepatitis, bile duct damage, and varying stages of hepatocyte necrosis.[28]

History and Physical

HEV most commonly causes an acute illness that is typically indistinguishable from other forms of acute hepatitis. The vast majority of patients are asymptomatic or experience mild clinical disease. When clinical signs and symptoms develop, they resemble those of other forms of acute viral hepatitis. HEV should be considered in any patient with symptoms of acute hepatitis, particularly those from or recently traveling to a high-incidence or endemic region. The disease is more common in adults than in children, with pregnant individuals experiencing more severe symptoms. In immunocompetent individuals, HEV is typically self-limiting.

The clinical presentation of HEV infection encompasses a spectrum of symptoms, ranging from common manifestations to less frequent complications. Jaundice stands out as the most prevalent symptom, observed in two-thirds of cases. Malaise and lethargy affect one-third, but they usually occur before the onset of jaundice and are accompanied by fever, anorexia, and myalgia. Gastrointestinal disturbances such as nausea and vomiting are also reported. Of particular clinical significance are the neurologic complications, which, although less common, affect approximately 8% of patients and represent a crucial aspect of HEV's extrahepatic manifestations.[29] 

Chronic hepatitis does not develop after acute HEV infection, except in immunocompromised individuals such as transplant recipients. Due to their ongoing immunosuppression, those with a transplant are unable to clear the virus and develop chronic hepatitis, with a risk of eventually developing cirrhosis.[30] Clinical findings are nonspecific; patients may present with jaundice and appear acutely ill. Physical examination may reveal right upper quadrant tenderness and hepatomegaly. When fulminant hepatitis occurs, it can result in an overall case fatality rate of 0.5% to 3%.[31] Patients can also have extrahepatic manifestations such as thrombocytopenia, hemolysis, aplastic anemia, acute thyroiditis, membranous glomerulonephritis, and neurological diseases such as acute transverse myelitis and septic meningitis.[32]

Evaluation

Accurate diagnosis requires a high index of clinical suspicion. Serum biochemical markers follow patterns similar to other acute viral hepatitis. HEV viremia begins after 2 to 6 weeks of incubation, with viral particles detectable in both blood and feces. Testing for HEV virions in blood and feces can be crucial for diagnosing immunocompromised patients with an inadequate immune response. 

As viral replication progresses and the virus appears in the blood, serum transaminases rise, and specific antibodies become detectable. Laboratory diagnosis of HEV infection remains challenging due to the lack of standardized testing. Commercial kits have been developed to detect anti-HEV IgM and IgG, but the utility is limited due to a high rate of false positive and negative results. In most cases, acute HEV infection is diagnosed based on a positive serum HEV IgM in the appropriate clinical setting.[33] Patients should also be tested for other viral hepatitis infections such as A, B, and C.

A definitive diagnosis is made by detecting HEV RNA in serum or stool by polymerase chain reaction (PCR). However, HEV viremia can be short-lived, especially in immunocompetent patients, meaning a negative PCR result does not exclude a recent HEV infection. In such cases, serological testing may be more beneficial. Conversely, PCR testing should be the cornerstone of diagnosis in immunocompromised individuals who may not mount a sufficient antibody response.[34][35][36] 

Chronic HEV infection is diagnosed by the persistent isolation of HEV RNA in serum or stool for at least 6 months after the initial infection. In European countries, the 2018 European Association for the Study of the Liver (EASL) guidelines recommend both serology and nucleic acid amplification technique (NAT) tests for diagnosing acute HEV infection, while NAT alone is recommended for diagnosing chronic HEV infection.[14]

Treatment / Management

Acute HEV infection is generally self-limited and requires only supportive care. Abnormal biochemical markers typically resolve within 1 to 6 weeks after symptom onset. However, patients who develop fulminant liver failure may require liver transplantation. The role of antiviral therapy such as ribavirin in treating acute HEV infection in immunocompromised patients remains uncertain. Ribavirin is contraindicated during pregnancy due to its teratogenic risk and should not be used in pregnant individuals with acute HEV infection. Therefore, women of childbearing age and men who engage in sex with women of childbearing age should receive contraceptive counseling during treatment and for 6 months after therapy.

For chronic HEV infection, ribavirin has shown a good sustained virological response, though resistance mutations may reduce efficacy. In patients who are immunocompromised with chronic HEV, modifying immunosuppressive therapy and using antiviral agents such as ribavirin, peginterferon, or both should be considered.[36][37](B2)

Calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors might increase HEV replication, as evidenced by animal studies, whereas mycophenolate mofetil appears to be a safer alternative. Therefore, reducing the tacrolimus dose and optimizing immunosuppression by increasing mycophenolate mofetil or corticosteroids may be a reasonable approach, though no standardized guidelines exist. In patients with HIV with chronic hepatitis E, antiretroviral therapy-induced immune reconstitution may clear HEV viremia; if unsuccessful, ribavirin may be considered as an additional treatment. 

Differential Diagnosis

In the differential diagnosis of HEV infection, particularly in cases presenting with jaundice and elevated serum alanine aminotransferase (ALT) levels, a range of potential etiologies must be considered. Other forms of viral hepatitis should be ruled out, including hepatitis A, hepatitis B, hepatitis C (HCV; less common), as well as Ebstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. Additional causes include drug or toxic hepatitis and ischemic hepatitis, depending on the clinical context. Infectious diseases such as leptospirosis, dengue, yellow fever, and malaria should be considered in endemic regions.

In immunosuppressed transplant recipients in developed countries, an ALT elevation between 100 to 300 IU/L may be due to chronic HEV infection, graft rejection, recurrence of primary liver disease, graft-versus-host disease, or drug-induced liver injury. Additionally, refractory viral infections such as EBV or CMV and intercurrent infections like sepsis may contribute to liver dysfunction in this population.

Prognosis

The prognosis of HEV infection is excellent in most cases, as the condition is often asymptomatic and self-limiting. Rarely, acute liver failure with rapid onset of encephalopathy can progress to fulminant hepatic failure, which carries a poor prognosis. HEV infection in pregnant women, particularly with genotypes 1 and 2 in developing countries, is associated with a poor prognosis. When acquired in the third trimester, HEV infection can result in maternal mortality rates of up to 25% and severe complications, including coagulopathy, disseminated intravascular coagulation, and encephalopathy.

Fetal outcomes are also poor, with more than half of the infants dying in utero or shortly after birth.[38] In individuals with preexisting chronic liver disease, acute HEV infection can trigger acute-on-chronic liver failure, increasing mortality rates by up to 70%. In immunocompromised individuals, HEV replication can lead to chronic liver disease and, in rare cases, cirrhosis. 

Complications

HEV is typically a self-limited disease, but some patients may develop acute complications such as acute hepatic failure, cholestatic jaundice, or chronic HEV infection. In rare cases, HEV infection can also lead to extrahepatic manifestations affecting the neurological, renal, hematological, and cardiovascular systems. Acute hepatic failure is more common among pregnant women and has high mortality rates, as evidenced by multiple studies from developing countries. While the exact cause is unknown, it is likely due to hormonal and immunological changes in a high viral load setting. During pregnancy, immune tolerance mechanisms protect the fetus, leading to a suppressed immune response, which makes pregnant women more susceptible to viral infections. HEV infection during pregnancy is also linked to pregnancy losses and vertical transmission, with the highest mortality occurring in the third trimester.

In developed countries, those with preexisting chronic liver disease have the highest mortality rates from HEV infection. HEV genotype 3 has been associated with extrahepatic manifestations, primarily neurological complications, including inflammatory polyradiculopathy, Guillain-Barré syndrome, peripheral neuropathy, encephalitis, and ataxia.[39] Nephrological complications are primarily glomerular diseases, particularly membranoproliferative and membranous glomerulonephritis. Additionally, HEV infection has been linked to hematological disorders such as thrombocytopenia, lymphopenia, and aplastic anemia. Other reported associations include acute pancreatitis, arthritis, myocarditis, and autoimmune thyroiditis. 

In patients with preexisting chronic liver disease, HEV infection can precipitate acute-on-chronic liver failure, which carries a high mortality rate. Predictors of mortality in these patients include elevated serum bilirubin levels, prolonged prothrombin time, and renal dysfunction. Immunocompromised individuals, such as solid organ transplant recipients, are at risk for chronic HEV infection, most commonly caused by HEV genotype 3. Any transplant recipient with persistent viral replication beyond 3 months should be suspected of having chronic HEV infection. Reinfection can also occur in HEV-seropositive transplant patients, particularly in those with low anti-HEV immunoglobulin G concentrations.