Hepatitis E 

Updated: Mar 13, 2019
Author: Prospere Remy, MD; Chief Editor: BS Anand, MD 

Overview

Background

Hepatitis E is an enterically transmitted infection that is typically self-limited.[1, 2] 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.[3, 4, 5] Outbreaks can be epidemic and individual. Hepatitis E has many similarities with hepatitis A. Hepatitis E has been associated with chronic hepatitis in solid-organ transplant recipients, patients infected by human immunodeficiency virus (HIV), and in an individual on rituximab treatment for non-Hodgkin lymphoma.[6, 7, 8, 9] A study has shown that among patients receiving hemodialysis, the seroprevalence of anti-HEV immunoglobulin G (IgG) was found to be high. However, no evidence of chronic infection was found.[10]

The course of infection has two phases, the prodromal phase and the icteric phase. The infection is self-limited. Whether protective immunoglobulins develop against future reinfection remains unknown. The overall case fatality rate is 4%, although pregnant women and liver transplant recipients may be at substantially higher risk.

Therapy should be predominantly preventive, relying on clean drinking water, good sanitation, and proper personal hygiene. A successful recombinant hepatitis E vaccine has been developed.[11, 12]

Etiopathophysiology

The hepatitis E virus (HEV) genome contains three 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.

Hepatitis E results from HEV infection and is spread by fecally contaminated water within endemic areas. However, in nonendemic areas, the major mode of the spread of HEV is foodborne, especially consumption of undercooked pork, raw liver, and sausages.[13, 14]

HEV is an RNA virus of the genus Hepevirus. It was discovered during electron microscopy of feces contaminated with enteric non-A, non-B hepatitis. The virus is icosahedral and nonenveloped. It has a diameter of approximately 34 nanometers, and it contains a single strand of RNA approximately 7.5 kilobases in length. 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 (eg, pigs, boars, deer), and genotype 7 primarily infects dromedaries.[14, 15]

Epidemiology

United States statistics

Population-based surveys from 1988-1994 indicate that 21% of US adults had anti–hepatitis E virus (HEV) antibody, a rate lower than that of anti–hepatitis A virus antibody (38.3%) but higher than that of antibodies against hepatitis B (5.7%) or hepatitis C (2%).[16]

Anti-HEV antibody rates increased markedly with age, from less than 10% among persons aged 6-19 years to more than 40% among those older than 60 years. Age-adjusted rates of anti-HEV antibody were lower among blacks (14.5%) than among non-Hispanic whites (22.1%); among men who had sex with men (23.1%) than among those who did not (23.9%); among cocaine users (16.8%) than among nonusers (23.6%); and among people living in the southern United States (14.7%) than among people living in the Northeast (20.8%), Midwest (26.6%), or West (25%). Rates of anti-HEV antibody were minimally higher among men than among women (21.6% vs 20.4%). Among men who had sex with men, the rates of anti-HEV antibody were lower among men with HIV infection (12.8%) than among men without HIV infection (19.2%).[17]

The route of exposure is unknown but is generally attributed to travel in endemic areas such as China, Nepal, India, Southwest France, North African countries, and Borneo. Exposure to pigs and consumption of undercooked pork are other methods of spread in autochthonous (nonendemic) areas, as testing of samples of pig liver and sausage from commercial groceries in the United States identified HEV RNA in a high percentage of samples.[18]

International statistics

The global disease burden of hepatitis E has been reported to be at least 20 million cases/year with 70,000 fatalities and 3,000 stillbirths.[19] Hepatitis E has worldwide distribution, but predominating factors include tropical climates, inadequate sanitation, and poor personal hygiene. It is found most often in developing countries near the equator, in both the Eastern and Western hemispheres. Regions with a prevalence rate of more than 25% include Central America, the Middle East, and large parts of Africa and Asia.[20]  Outbreaks are associated with rainy seasons, floods, and overcrowding.

Water supply contamination with human feces is a frequent source of epidemics. The largest outbreak was reported in Northeast China, with 100,000 people affected between 1986 and 1988.[21] The reservoir of HEV is unknown, but it is believed that the virus may be transmitted by animals. Waterborne epidemics of hepatitis E mainly affect young adults, the clinical attack rate being highest among those aged 15-35 years.[22] Men are clinically infected 2-5 times more commonly than women in most outbreaks.[21, 23] However, no sex difference exists in exposure to HEV.[24, 25]

Prognosis

No chronic cases of acute hepatitis E have been reported. The infection is self-limited. Whether protective immunoglobulins develop against future reinfection remains unknown. The overall case fatality rate is 4%.

Among pregnant women, the case fatality rate is 20%, and this rate increases during the second and third trimesters. Reported causes of death include encephalopathy and disseminated intravascular coagulation. The rate of fulminant hepatic failure in infected pregnant women is high.

In a 3-year (2010-2013) prospective observational study of 55 symptomatic anti-HEV IgM-positive Indian women, the overall maternal mortality was 5%, including one antenatal death. The most common fetal complications were prematurity (80%) and premature rupture of membranes (11%), with a 28% rate of vertical transmission.[26]

Liver transplant recipients may be at a greater risk for hepatitis E virus (HEV) infection, which can lead to chronic hepatitis and rapid progression of liver fibrosis.[27, 28] The presence of anti-HEV-IgG titer in pretransplantation measurements do not lead to protection of hepatitis E in posttransplantation patients.[29]

 

Presentation

History

The incubation period ranges from 15-60 days. The course of infection has two phases, the prodromal phase and the icteric phase. The prodromal phase usually is of short duration.

Prodromal-phase symptoms include the following:

  • Myalgia

  • Arthralgia

  • Fever with mild temperature elevations (25%-97%)

  • Anorexia (66%-100%)

  • Nausea/vomiting (30%-100%)

  • Weight loss (typically 2-4 kg)

  • Dehydration

  • Right upper quadrant pain that increases with physical activity (abdominal pain is reported in 35%-80% of patients)

Icteric-phase symptoms may last days to several weeks and include the following:

  • Jaundice - May be difficult to see with some patients’ natural skin color; serum bilirubin level is usually higher than 3 mg/dL; scleral icterus is present; usually occurs between the fifth and eighth week after infection

  • Dark urine

  • Light-colored stools (20%-40%)

  • Pruritus (50%)

Other features include the following[30, 31] :

  • Malaise (most common)

  • Arthritis

  • Pancreatitis

  • Aplastic anemia

  • Thrombocytopenia

  • Neurologic symptoms of polyradiculopathy, Guillain–Barré syndrome, Bell palsy, peripheral neuropathy, ataxia, and mental confusion

  • Membranoproliferative glomerulonephritis and membranous glomerulonephritis

In nonendemic (autochthonous) type of acute hepatitis E infection, the majority of patients have subclinical manifestations and mild symptoms, especially in women and young persons.[13] One report of an outbreak of hepatitis E on a cruise ship revealed only 7 of 33 patients had jaundice (21%) and most cases occurred in elderly men.[32]

Autochthonous hepatitis E also has a striking spectrum of serious complications, including “acute-on-chronic” liver failure, neurologic disorders, and chronic hepatitis. Acute-on-chronic disease refers to hepatitis with a rapid appearance of signs of liver failure ascites and encephalopathy in a person with preexisting liver disease.[13]

When or how long the patient is infectious cannot be determined, but infectivity may relate to the presence of the virus in the stool.

Physical Examination

Physical examination should focus on the following:

  • Icteric sclera

  • Right upper quadrant tenderness

  • Possible enlarged liver (palpable edges; hepatomegaly is noted in 10%-85% of patients)

  • Possible signs of advanced chronic liver disease - Spider angiomata, splenomegaly, ascites, prominent collateral veins over the abdominal wall, palmar erythema

 

DDx

Diagnostic Considerations

Autoimmune hepatitis

Acute hepatitis E presents with histologic and biochemical features of autoimmune hepatitis and, thus, acute HEV infection may be misclassified as de novo onset of autoimmune hepatitis—treatment with immunosuppressants in acutely HEV-infected patients may accelerate histologic progression.[33] Therefore, in patients with autoimmune hepatitis who will be treated with low doses of steroids with or without azathioprine, routine serologic testing of HEV infection should be strongly recommended in the initial work-up. Patients with autoimmune hepatitis who develop unexplained elevated liver enzyme levels should also be tested for HEV RNA.[33]

Differential Diagnoses

 

Workup

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.

Serologic Testing

Acute hepatitis E virus (HEV) infection is diagnosed in immunocompetent individuals based on the detection of anti-HEV immunoglobulin M (IgM). The anti-HEV IgM usually starts rising 4 weeks after infection and remains detectable for 2 months after the onset of illness.[34]

The test for the presence of anti-HEV IgM is performed by detection of specific IgM antibodies directed against a range of recombinant viral antigens by enzyme immunoassay or rapid immunochromatography kits.[35] However, comparative studies show that these tests differ substantially in their accuracy.[36, 37] Therefore, users should ensure that a test is used that has been validated in their population.[34] Confirmation of acute cases detected in this way is either by molecular techniques, detecting rising reactivity in a specific immunoglobulin G (IgG) assay, or positivity in immunoblot IgM assays.[38]

A study comparing two rapid immunochromatography kits with three commercial anti-HEV ELISA assays and one real-time polymerase chain reaction (RT-PCR) assay showed that the sensitivity of Wantai Rapid and Assure Rapid tests was 96.1% and 92.6%, respectively; the specificity of both rapid tests was 100%.[39] Therefore, anti-HEV IgM rapid assays may be used as a first-line test in primary healthcare settings, particularly for patients with chronic liver disease or pregnant women who urgently need an antiviral treatment.[39]

After exposure, viral RNA can be detected just before the onset of clinical symptoms in both blood and stool samples. HEV RNA does not persist for long, becoming undetectable in blood about 3 weeks after the onset of symptoms. The virus is shed in stool for a further 2 weeks.[40, 41] The window of detectable RNA is, therefore, narrow, and if patients present late in their illness, an undetectable HEV RNA result does not exclude recent infection.[34] However, immunocompromised individuals (such as patients with autoimmune hepatitis who receive immunosuppressant agents) should always be tested for HEV RNA if there is suspicion that they are infected because seroconversion could be delayed in these patients.[42]

Detection of elevated reactivity in a specific IgG assay indicates the presence of acute hepatitis E. (The worldwide population seroprevalence of HEV IgG ranges between 5% and 50%.[43] ) However, the determination of immunity or previous exposure to HEV by detection of IgG antibodies is problematic. Available enzyme immunoassays use different antigens and vary in their effectiveness.[44, 45] The detection cutoff for some commercial assays may be close to the protective antibody concentration[46, 47] ; therefore, they might not reliably detect protective concentrations of anti-HEV IgG.

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.[48]

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.[49] 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

Medical Management

Prevention

Management should be predominantly preventive, relying on clean drinking water, good sanitation, and proper personal hygiene. Travelers to endemic areas should avoid drinking water or other beverages that may be contaminated and should avoid eating uncooked shellfish. Heating pork to an internal temperature of 71°C for 20 minutes is necessary to completely inactivate the hepatitis E virus (HEV).[50] Care should be taken in the preparation of uncooked fruits or vegetables. Boiling water may prevent infection, but the effectiveness of chlorination is unknown.

Hepatitis E is preventable by vaccination. Studies in Nepal and China have shown 95% efficacy of a recombinant genotype 1 HEV vaccine in preventing infection and clinical disease.[11, 12] Not only did the vaccine prevent the genotype 1 (Hecolin) HEV infection, genotype 4 HEV was also prevented with the vaccination, indicating cross-protection against different HEV genotypes. At this time, the vaccine efficacy against HEV genotype 3 is not known. A vaccine developed from HEV genotype 1 HEV vaccine was approved in China in December 2011. A study showed long-term efficacy of this vaccine, as it induced a sustained level of antibodies and protection against hepatitis E for up to 4.5 years.[51]  

However, further evaluation of these vaccines is required to determine their efficacy in special risk groups, such as patients with end-stage liver disease or immunosuppressed individuals, to define the anti-HEV titers that can be considered protective, and to know the duration of their protective effect.[52]

Treatment of acute HEV infection

Acute hepatitis E in immunocompetent persons usually only requires symptomatic treatment, as almost all of them are able to clear the virus spontaneously. A report showed significant improvement of liver enzymes and functions in a patient with severe acute hepatitis E who was treated with ribavirin for 21 days.[53] Although ribavirin therapy is contraindicated in pregnancy owing to teratogenicity, the risks of untreated HEV to the mother and fetus are high, and trials of antiviral therapy might be worthwhile.[34]

Treatment of chronic HEV infection

In transplant recipients with chronic HEV infection, viral clearance is desirable. The first step is to reduce the immunosuppressive therapy, as reduction of immunosuppression results in viral clearance in 30% of patients.[54, 55] Calcineurin inhibitor (cyclosporine A, tacrolimus) and mTOR inhibitors (rapamycin, everolimus) have an in vitro effect of stimulation of HEV replication.[56] However, mycophenolic acid (including prodrug mycophenolate mofetil) inhibits the HEV replication in vitro.[57] Steroids were found not to influence HEV replication in vitro.[57]

Antiviral therapy should be considered for patients for whom immunosuppressive therapy cannot be reduced and for those who do not achieve viral clearance after reducing immunosuppression. Although data are limited, ribavirin monotherapy (600–1000 mg/day) for at least 3 months seems to be the first treatment option for patients with chronic hepatitis E who are not able to clear HEV after immunosuppression is reduced.[58] However, the presence of G1634 mutation in the RdRp domain of HEV ORF1 protein was reported to be associated with ribavirin treatment failure.[59, 60]  In this situation, pegylated interferon alfa may be used as an alternative treatment option if there is no contraindication. It appears that ribavirin causes HEV mutagenesis in treated patients, and distinct mutants within the viral population occurs during ribavirin therapy.[60]

Treatment with pegylated interferon alfa for 3-12 months has led to sustained clearance of HEV RNA in patients with chronic hepatitis E who underwent liver transplantation.[61, 62] However, interferon therapy can cause significant adverse effects and organ rejection in transplant recipients, especially those who have undergone heart or kidney transplantation.

A study revealed that sofosbuvir, a nucleotide analogue, inhibits RNA replication of HEV genotype 3 in vitro. In addition, sofosbuvir has an additive antiviral effect when it is combined with ribavirin.[63] Although the data appear promising, more studies are needed to explore the antiviral potential of sofosbuvir in combination with ribavirin in chronic HEV infection, especially in patients in whom ribavirin monotherapy fails to achieve HEV elimination.[64]

Diet and Activity

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.

 

Guidelines

Guidelines Summary

European Association for the Study of the Liver

The European Association for the Study of the Liver (EASL) suggests testing for hepatitis E in patients with unexplained flares of chronic liver disease.

EASL recommends hepatitis E virus (HEV) testing in all immunosuppressed patients with unexplained abnormal liver function tests (LFTs).

Travelers with hepatitis returning from areas endemic for HEV genotype (gt) 1 or 2 should be tested for HEV.

Pregnant women with HEV gt 1 or 2 should be cared for in a high-dependency setting and transferred to a liver transplant unit if liver failure occurs.

EASL recommends HEV testing, irrespective of LFT results, in patients presenting with neuralgic amyotrophy (NA) and GBS (Guillain-Barré syndrome) and suggests HEV testing for patients with encephalitis/myelitis.

EASL suggests testing patients with HEV infection for proteinuria.

Patients with acute or chronic HEV infection who develop new-onset proteinuria may be considered for a renal biopsy.

EASL suggests antiviral treatment for patients with chronic HEV infection and associated glomerular disease.

EASL recommends using a combination of serology and nucleic acid amplification technique (NAT) testing to diagnose HEV infection.

EASL recommends NAT testing to diagnose chronic HEV infection.

All patients with hepatitis should be tested for HEV, as part of the first-line virological investigation, irrespective of travel history.

Patients presenting with suspected drug-induced liver injury (DILI) should be tested for HEV.

Patients with abnormal LFTs after receiving blood products should be tested for HEV.

EASL recommends that blood donor services screen blood donors for HEV by NAT, informed by local risk-assessment and cost-effectiveness studies, both of which may vary considerably by geographic location.

Ribavirin treatment may be considered in cases of severe acute hepatitis E or acute-on-chronic liver failure.

EASL recommends decreasing immunosuppression at diagnosis of chronic HEV infection in solid organ transplant recipients, if possible.

In patients with persisting HEV replication 3 months after detection of HEV RNA, EASL recommends ribavirin monotherapy for a duration of 12 weeks.

At the end of the scheduled period of therapy, HEV RNA should be assessed in the serum and in the stool. If HEV RNA is undetectable in both, EASL suggests stopping ribavirin.

In patients in whom HEV RNA is still detectable in the serum and/or in the stool after 12 weeks, ribavirin monotherapy may be continued for an additional 3 months (6 months therapy overall).

Liver transplant recipients who show no response to ribavirin can be considered for treatment with PEGylated-interferon-α.

Immunocompromised individuals and those with chronic liver diseases should avoid consumption of undercooked meat (pork, wild boar, and venison) and shellfish.

EASL suggests that immunocompromised patients consume meat only if it has been thoroughly cooked to temperatures of at least 70 °C.

Reference

EASL clinical practice guidelines on hepatitis E virus infection. European Association for the Study of the Liver. J Hepatol. 2018 Jun;68(6):1256-71. https://www.journal-of-hepatology.eu/article/S0168-8278(18)30155-7/fulltext

 

Medication

Medication Summary

Medical therapy consists of electrolyte repletion and stabilization.

Ribavirin may be considered in severe acute hepatitis E or chronic hepatitis E of transplant recipients who are not able to clear HEV after immunosuppression is reduced (see "Treatment of chronic HEV infection" in Medical Management). Pegylated interferon alfa, if not contraindicated, is an alternate treatment option for patients with chronic hepatitis E infection who develop ribavirin-treatment failure. Sofosbuvir is a potential treatment option for HEV infection; however, to date, no data exist regarding its in-vivo effect.

Electrolytes

Class Summary

Electrolytes are necessary in patients with profound malnutrition or dehydration. They may be replaced orally or parenterally, depending on the clinical state of the patient.

Potassium chloride

Potassium is essential for the transmission of nerve impulses, contraction of cardiac muscle, maintenance of intracellular tonicity, skeletal and smooth muscles, and maintenance of normal renal function. Gradual potassium depletion occurs via renal excretion or GI loss or because of low intake. Depletion may result from severe diarrhea.

Potassium depletion sufficient to cause 1 mEq/L drop in the serum potassium level requires a loss of approximately 100-200 mEq of potassium from the total body store.

Calcium gluconate

Calcium moderates nerve and muscle performance and facilitates normal cardiac function. It can be given intravenously initially, and calcium levels can be maintained with a high calcium diet. Some patients require oral calcium supplementation. The 10% IV solution provides 100 mg/mL of calcium gluconate that equals 9 mg/mL (0.46 mEq/mL) of elemental calcium. One 10 mL ampule contains 93 mg of elemental calcium

Potassium phosphate

For severe hypophosphatemia (< 1 mg/dL), parenteral preparations of phosphate should be used for repletion. IV preparations are available as sodium or potassium phosphate (K2PO4). Response to IV serum phosphorus supplementation is highly variable and is associated with hyperphosphatemia, and hypocalcemia. The rate of infusion and choice of initial dosage should be based on severity of hypophosphatemia and presence of symptoms. Serum phosphate and calcium should be monitored closely.

For less severe hypophosphatemia (1-2 mg/dL), PO phosphate salt preparations can be used. PO preparations are available as sodium or potassium phosphate in capsule or liquid form. Neutra-Phos packets contain 250 mg of phosphorus/packet. Tablets contain either 250, 125.6, or 114 mg each. Liquid preparations are available as 250 mg/75 mL.

Antiviral Agent, Oral

Ribavirin

Ribavirin may improve liver enzymes and functions in severe acute hepatitis E. Ribavirin monotherapy for at least 3 months seems to be the first treatment option for patients with chronic hepatitis E who are not able to clear the hepatitis E virus (HEV) after immunosuppression is reduced.

Hepatitis B/Hepatitis C Agents

Peginterferon alfa 2a (Pegasys, Pegasys ProClick)

Pegylated interferon alfa monotherapy is an alternate treatment option for patients with chronic hepatitis E who experience ribavirin treatment failure. However, this medication is contraindicated in transplant patients.