The World Health Organization (WHO) estimates that hepatitis E virus (HEV) causes 20 million new infections annually, with more than 3 million cases of acute hepatitis and over 55,000 deaths.(1) HEV infection has a global distribution.(2-16) Specific genotypes result in infection in different geographic areas.

  • Genotypes 1 and 2 have been reported mainly in Asia, India, and North Africa.
  • Genotype 2 has been identified in Mexico and West Africa.
  • Genotype 3 is prevalent in Western countries, as well as in Asia and North America.

Genotype 4 has been detected in Asian and European countries.

PATHOPHYSIOLOGY

Hepatitis E is an enterically transmitted infection that is typically self-limited.(17,18) It is caused by the hepatitis E virus (HEV) and is spread by fecally contaminated water within endemic areas or through the consumption of uncooked or undercooked meat.

HEV has an incubation period of 2-10 weeks.(1) Acute HEV infection is generally less severe than acute HBV infection and is characterized by fluctuating aminotransferase levels. However, pregnant women, especially when infected during the third trimester, have a greater than 25% risk of mortality associated with acute HEV infection.(19)

Traditionally, HEV was not believed to cause chronic liver disease. However, several reports have described chronic hepatitis due to HEV in organ transplant recipients. Liver histology revealed dense lymphocytic portal infiltrates with interface hepatitis, similar to the findings seen with hepatitis C infection. Some cases have progressed to cirrhosis.(20,21)

The hepatitis E virus (HEV) genome contains 3 open reading frames (ORFs). The largest, ORF-1, codes for the nonstructural proteins responsible for viral replication. ORF-2 contains genes encoding the capsid. The function of ORF-3 is unknown, but the antibodies directed against ORF-3 epitopes have been identified.

Five HEV genotypes have been identified. Genotypes 1 and 2 are considered human viruses; genotypes 3 and 4 are zoonotic and have been isolated from humans and animals (e.g. pigs, boars, deer), and genotype 7 primarily infects dromedaries.(22,23)

TRANSMISSION

Transmission of hepatitis E virus (HEV) can occur through contaminated food and water, blood transfusions, and through mother-to-child transmission. Although person-to-person transmission is uncommon, patients are infectious during fecal shedding. Specific genotypes differ in their route of transmission.

Contaminated food and water

  • Waterborne infection: HEV genotype 1 and 2 infections are spread by fecally contaminated water in endemic areas.(24,25) Thus, in resource-limited countries where sanitation and water purification services are limited, there is a high rate of lifetime exposure to HEV associated with HEV genotype 1 and 2 (and possibly 4) infection.
  • Zoonotic transmission: HEV genotypes 3 and 4 usually cause infections due to consumption of contaminated food. Most cases are sporadic and unidentified as an acute viral hepatitis, although isolated outbreaks have occurred, including an HEV outbreak associated with consumption of shellfish that affected passengers on a cruise ship.(26)

Swine are most frequently implicated in transmission, followed by consumption of filter feeder shellfish.(27-30) However, many animal species (including rodents in some regions), have been identified as part of the viral reservoir of disease.(31)

There are limited data regarding food preparation to reduce/eliminate HEV transmission. In one study, cooking liver at 191°F for five minutes or boiling liver for five minutes reduced the risk of transmission by inactivating HEV.(32)

Blood transfusion:

HEV can be transmitted by blood transfusions, particularly in endemic areas.(33-36) In one study that evaluated the prevalence and transmission of HEV in 225,000 blood donations, 79 HEV genotype 3 RNA-positive donations were detected.(36) These donations were used to prepare 129 blood components and 62 were transfused. On follow-up testing of 43 recipients, 18 (42 percent) HEV infections were detected.

Perinatal transmission:

There are limited data regarding vertical transmission of HEV from infected mothers to their infants. Case series suggest that HEV infection can be transmitted from mother to newborn with substantial perinatal morbidity and mortality; however, its contribution to the overall disease burden appears to be small.(37-39)

Transmission in breast milk:

It is unclear if breastfeeding is a potential route of HEV transmission. However, there is sufficient concern to discourage breastfeeding among confirmed HEV-infected mothers until further data are available. In one case report, HEV was isolated in breast milk during the acute phase of HEV infection.(40) Milk and serum HEV titers were comparable.

NATURAL HISTORY

In an acute infection the incubation period ranges from 15 to 60 days, through which viremia arises. Anti-HEV antibody (IgM) appears soon after the onset of the clinical infection. Anti-HEV IgG appears soon after that and can remain detectable for as long as 20 months (Figure 1). HEV RNA is detected in stool as early as 1 week before the onset of clinical illness and persists for 1 to 2 weeks afterward, during which stools are highly infectious.(41)

Similar to hepatitis A, HEV is most often a self-limited disease; immunity develops, and no second attack occurs. The disease is often cholestatic, with elevated bilirubin and alkaline phosphatase levels. On average, it occurs more commonly in the older population and severe disease, including fulminant hepatitis and death, occur more often in HEV than in other types of hepatitis.(42) Mortality rates range from 0% to 10%, but it is usually less than 1%. In pregnant women, infection has been associated with development fulminant liver failure and mortality can reach 25%.(43,44)

SIGN AND SYMPTOMS

Acute Hepatitis E:

Hepatitis E virus (HEV) generally causes a self-limited acute infection, although acute hepatic failure can develop in a small proportion of patients.

Clinical features: The vast majority of patients with acute HEV are asymptomatic or mildly symptomatic.(45) The proportion of people who develop clinical features following acute infection varies based upon age and prior HEV exposure.(46)

In symptomatic patients, jaundice is usually accompanied by malaise, anorexia, nausea, vomiting, abdominal pain, fever, and hepatomegaly.(47) Other less common features include diarrhea, arthralgia, pruritus, and urticarial rash.(48-51)

In addition, patients occasionally have extrahepatic findings. These include:(52)

  • Hematologic abnormalities including thrombocytopenia, hemolysis, and aplastic anaemia
  • Acute thyroiditis
  • Membranous glomerulonephritis
  • Acute pancreatitis
  • Neurological diseases including:
    • Acute transverse myelitis
    • Acute meningoencephalitis
    • Aseptic meningitis
    • Neuralgic amyotrophy
    • Pseudotumor cerebri
    • Bilateral pyramidal syndrome
    • Guillain–Barré syndrome
    • Cranial nerve palsies
    • Peripheral neuropathy

Laboratory findings: Laboratory findings include elevated serum concentrations of bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase.(48,53) Symptoms coincide with a sharp rise in serum ALT levels, which may rise up into the thousands and return to normal during convalescence.(54) Resolution of the abnormal biochemical tests generally occurs within one to six weeks after the onset of the illness (figure 1).

Hepatitis E virus (HEV) infection typical serologic course (courtesy Uptodate)

ALT: alanine aminotransferase; IgG: immunoglobulin G.

Liver histology: Morphological features of HEV include those noted with cholestatic and classic types of acute viral hepatitis. Cholestatic forms are characterized by bile stasis in canaliculi and gland-like transformation of hepatocytes. Other histologic findings include focal necrosis, ballooned hepatocytes, and acidophilic degeneration of hepatocytes.(55,56) In fatal cases, submassive or massive hepatic necrosis is present.(3,49)

In immunosuppressed patients, development of chronic hepatitis leads to inflammation and progressive fibrosis, which can lead to cirrhosis. In patients who have undergone organ transplantation, this process may be mistaken for rejection.(57)

Complications: The majority of patients who acquire HEV spontaneously clear the virus. However, patients may develop complications such as acute hepatic failure, cholestatic hepatitis, or chronic HEV.

  • Acute hepatic failure: A small proportion (0.5 to 4 percent) of HEV-infected persons develop acute hepatic failure.(58) As an example, in the United States Acute Liver Failure Study, only 3 of 681 adults demonstrated anti-HEV IgM antibodies, but none were HEV RNA positive, indicating that acute HEV is not a common cause of acute hepatic failure in the United States.(59) When it does occur, acute hepatic failure is more likely in those who are pregnant and in those who are malnourished or have preexisting liver disease.

Acute hepatic failure is characterized by hepatic encephalopathy, elevated aminotransferases (often with abnormal bilirubin and alkaline phosphatase levels), and impaired synthetic function (international normalized ratio ≥1.5). Acute hepatic failure carries a high mortality if intensive care support and liver transplantation are not available, resulting in an overall case fatality rate of 0.5 to 3 percent.(60)

  • Cholestatic hepatitis: Prolonged cholestasis, characterized by a protracted period of jaundice (lasting >3 months), has been described in up to 60 percent of patients with acute HEV.(61) Patients may be asymptomatic or have symptoms of pruritus due to cholestasis. In general, cholestatic hepatitis resolves spontaneously within weeks to months with no sequelae.(62) Recovery is marked by viral clearance, an increase in IgG anti-HEV titers, and a decrease in IgM anti-HEV levels.(63)
  • Chronic hepatitis E: Chronic HEV infection is defined empirically as detection of HEV RNA in serum or stool for longer than six months. Chronic HEV almost exclusively occurs in immunosuppressed patients (e.g. those with HIV infection, following solid organ or bone marrow transplantation).(64-67) Chronic infection is typically with HEV genotype 3 infection, although chronic infection with genotype 4 has been documented in a transplant recipient.(68,69) Chronic HEV infection with genotypes 1 and 2 have not been reported.

As with most chronic viral hepatitis patients, symptoms are minimal and include fatigue and nonspecific findings until progression to decompensated cirrhosis occurs. Patients with chronic HEV have persistently elevated aminotransferase levels, detectable serum HEV RNA, and histologic findings compatible with chronic viral hepatitis.

SCREENING

According to EASL 2018 guidelines on hepatitis E, several countries have introduced universal, targeted or partial screening for HEV in donors, including Ireland, the UK, France, the Netherlands and Japan. In Germany, some blood transfusion companies have introduced voluntary HEV screening. In many other countries donor screening is being considered.

DIAGNOSTIC TESTS

General approach:

The diagnosis of hepatitis E virus (HEV) should be considered in patients who present with acute or chronic hepatitis that cannot be explained by other causes. This includes putative cases of drug-induced liver injury which have been misclassified because HEV testing was not performed. It is particularly important that the diagnosis of HEV infection be considered in groups that are at risk for developing rapidly progressive liver disease, such as pregnant women, patients with underlying liver disease, solid organ transplant recipients, and those with hematologic malignancies.(71)

  • Acute HEV: The diagnosis of acute HEV is complicated by the lack of a standardized assay. Multiple commercial enzyme immunoassay (EIA) kits have been developed and have high variability in terms of test performance; both false positives and negatives are common with available assays.
    • In general, the initial test method is an anti-HEV IgM assay. The presence of IgM anti-HEV antibodies is suggestive of recent HEV infection.
    • If the initial test is positive, confirmatory testing should be performed when available since no single EIA method achieves high specificity. Confirmatory testing may include an alternate anti-HEV IgM, evidence of rising anti-HEV IgG titers (greater than fivefold change over two weeks), or detection of HEV RNA in serum or stool.(72)
    • If initial EIA testing is negative, and there is still a high suspicion for HEV infection, repeat testing should be performed, preferably with an HEV RNA assay. The use of RNA testing is particularly important in immunocompromised hosts with suspected HEV due to a high rate of false-negative antibody testing.(54,73,74)
  • Chronic HEV: In patients with suspected chronic HEV infection, detection of HEV RNA in serum is the mainstay of diagnosis. Chronic HEV infection is defined as detection of HEV RNA in serum or stool for longer than six months.

Testing for IgG anti-HEV antibodies is of limited utility in the diagnosis of chronic HEV infection. The presence of IgG (or total) anti-HEV antibodies is a marker of exposure to HEV, which can be either recent or remote. In addition, the decline in IgG anti-HEV titers with time might adversely affect its sensitivity for detecting remote infection (figure 1).

Diagnostic tests:

Antibody testing: The timing of appearance of HEV markers is important for interpreting results of serologic testing in the setting of acute hepatitis (figure 1).

  • IgM anti-HEV appears during the early phase of clinical illness and disappears rapidly over four to five months (figure 1).(53) Although IgM anti-HEV has been detected in the serum by EIA in more than 90 percent of patients in some outbreak settings when samples were obtained within one week to two months after the onset of illness, serology may be negative in a substantial proportion of patients with acute infection.(75)
  • The IgG response appears shortly after the IgM response, and its titer increases throughout the acute phase into the convalescent phase. It is unclear how long IgG anti-HEV antibodies persist. In one report, antibodies were detected as long as 14 years after the acute phase of illness; however, a booster effect due to reinfection could not be excluded.(53,76-79)

HEV RNA assay: HEV can be detected in stool approximately one week before the onset of illness and can persist for as long as two weeks thereafter.(2,80-82) In serum, HEV may be detected two to six weeks after infection and can persist for two to four weeks in those who resolve acute infection. Although HEV viremia is short-lived in most patients with acute infection, it can persist for years in those who develop chronic infection (figure 1).(83,84)

Imaging Studies

Abdominal radiography has no role in evaluating acute viral hepatitis unless clinically indicated.

Abdominal ultrasonography is recommended. It helps to rule out extra hepatic causes of biliary obstruction, which may coexist with the presence of hepatitis E virus (HEV) infection. It may also demonstrate the presence of an enlarged liver and the presence of advanced liver disease, such as splenomegaly, ascites, or hepatofugal flow of the portal venous system.

Basic Laboratory Studies

Elevation in the serum aminotransferase levels is the laboratory hallmark of acute viral hepatitis. Serum alanine aminotransferase (ALT) level is usually higher than the serum aspartate aminotransferase (AST) level. The levels of aminotransferases may range from 10 times the upper limit of normal to more than 20 times the upper limit of normal. They increase rapidly and peak within 4-6 weeks of onset but generally return to normal within 1-2 months after the peak severity of the disease has passed. The serum alkaline phosphatase level may be normal or slightly increased (<3 times upper limit of normal). Serum bilirubin level usually ranges from 5-20 mg/dL, depending on the extent of hepatocyte damage. The patient may develop leukopenia with neutropenia or lymphopenia. Prolonged prothrombin time, decreased serum albumin, and very high bilirubin are signs of impending hepatic failure requiring referral to a liver transplantation center.

Perform blood cultures if the patient is febrile and hypotensive with an elevated white blood cell (WBC) count.

Obtain serum acetaminophen levels if overdose is suspected.

Tissue Analysis and Histologic Findings

Liver biopsy usually is not necessary.

Biopsies from acute fulminant hepatitis E show varying degrees of hepatocyte necrosis and mixed portal and lobular inflammation, accompanied by bile ductular proliferation, lymphocytic cholangitis, Kupffer cell prominence, cholestasis, apoptotic bodies, pseudo-rosette formation, steatosis, and plasma cells in the portal tracts.

Compared with the epidemic type of acute hepatitis E virus (HEV) infection, liver biopsy from patients with autochthonous HEV infection show preferential localization of polymorphs at the portal-hepatocyte interface, and that of lymphocytes and plasma cells centrally in portal tracts. Hepatocyte necrosis is reported to be located in the perivenular acinar zone 3 in patients with autochthonous HEV infection. The histology of epidemic cases of HEV infection show less intense portal and acinar inflammation, no cholangiolitis, and no geographical distribution of the portal inflammatory infiltrate. Significant steatosis, megamitochondria, and Mallory bodies are not present in autochthonous cases.

TREATMENT OPTIONS

Management of hepatitis E virus (HEV) depends upon the immune status of the patient and the stage of disease (e.g. acute versus chronic).

Acute hepatitis E:

For most patients, the management of acute HEV infection is supportive, as the disease appears to be mild and self-limited in immunocompetent patients. However, patients with acute HEV infection who develop fulminant hepatic failure may require liver transplantation.(85)

The role of antiviral therapy in immunocompromised patients with acute HEV has not been established. Ribavirin should not be used in pregnant women as it is a potent teratogen. In addition, although small retrospective studies have suggested that patients with chronic liver disease and those receiving immunosuppressive therapy may benefit from ribavirin monotherapy,(86-92) it is unclear if improvement was spontaneous or due to ribavirin in the absence of controls.

Chronic hepatitis E:

Chronic HEV occurs almost exclusively in immunocompromised patients.

The management of chronic infection involves reduction of immunosuppressive therapy and/or antiviral therapy.

Reduction of immunosuppression: A reduction in immunosuppressive therapy is the first step in the treatment of chronic HEV infection. There are no clear data to guide how immunosuppressive therapy should be reduced; however, for solid organ transplant recipients, typically reduce tacrolimus first, if possible, since there is an association of chronic infection with tacrolimus.

Clearance of chronic HEV infection has been reported after reducing or withdrawing immunosuppressive therapy.(93,94) As an example, in a retrospective series that evaluated 85 solid organ transplant recipients with chronic HEV, reduction of immunosuppressive therapy resulted in viral clearance in approximately 30 percent of patients.(93)

Antiviral therapy: Antiviral therapy is directed against genotype 3, since chronic infection is typically observed in patients with this genotype.(95)

Whom to treat: 12-week course of ribavirin monotherapy is recommended to certain nonpregnant patients with chronic HEV infection.(54)

  • In solid organ transplant recipients, ribavirin is administered in conjunction with reducing immunosuppressive therapy.
  • For others, antiviral therapy is administered if immunosuppressive therapy cannot be reduced, or if the patient has persistent HEV RNA despite a reduction in immunosuppressive therapy for 12 weeks.(85,95)

The dose of ribavirin is 600 to 1000 mg daily (administered in two divided doses).

Treatment failure: Patients who fail to achieve an SVR should continue to be followed for signs of progression of liver disease. There is no established alternative antiviral therapy with evidence of efficacy in this setting.

Therapies that have been considered for the management of treatment failure include pegylated interferon-alfa and sofosbuvir. However, concerns regarding toxicity and efficacy prevent these agents from being used in routine care.

GOAL OF THERAPY

The goal of treatment is to eradicate HEV RNA, which is predicted by achieving a sustained virologic response (SVR). An SVR is defined as the absence of HEV RNA by polymerase chain reaction 12 weeks after cessation of treatment. Patients with an SVR are considered cured since there is no viral reservoir, similar to hepatitis C virus; however, they remain at risk for reinfection.

GUIDELINES

To view, EASL Clinical Practice Guidelines on hepatitis E virus infection 2018, please click on below link:

https://www.journal-of-hepatology.eu/article/S0168-8278(18)30155-7/pdf

To view WHO guidance on Waterborne Outbreaks of Hepatitis E: recognition, investigation and control, please click on below link:

http://www.who.int/hiv/pub/hepatitis/HepE-manual/en/

To view British Transplantation Society (BTS) draft Guidelines for Hepatitis E & Solid Organ Transplantation, please click on below link:

https://bts.org.uk/wp-content/uploads/2017/05/BTS-HEV-Guideline-CONSULTATION_DRAFT.pdf

CONSULTATION AND COUNCELLING

The acute illness may result in anorexia, nausea, and vomiting, predisposing patients to dehydration. These symptoms tend to be worse in the afternoon or evening. Patients should attempt to ingest significant calories in the morning. As they improve, frequent small meals may be better tolerated. Hospitalization should be considered for patients with dehydration. Neither multivitamins nor specific dietary requirements are required.

Patients should be allowed to function at whatever activity levels they can tolerate. No evidence indicates that bed rest hastens recovery. It actually may retard recovery.

PREVENTION

General measures: Management should be predominantly preventive, relying on clean drinking water, good sanitation, and proper personal hygiene. Travelers to regions where hepatitis E virus (HEV) is endemic should follow the general precautions used for the prevention of travelers’ diarrhea. This includes avoidance of water of unknown purity, food from street vendors, raw or undercooked seafood, meat or pork products, and raw vegetables.

Vaccines – Recombinant vaccines have demonstrated efficacy against HEV.

Immune globulin: The efficacy of pre- or post-exposure immune globulin prophylaxis for the prevention of HEV has not been established.

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