eMedicine Specialties > Gastroenterology > Liver

Hepatitis E

Jonathan M Schwartz, MD, Assistant Professor, Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health and Sciences University
Kenneth Ingram, PAC, Assistant Professor, Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health Sciences University; Kenneth D Flora, MD, Adjunct Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Oregon Health Sciences University; Consulting Staff, Department of Gastroenterology, The Oregon Clinic

Updated: Nov 11, 2008

Introduction

Background

Hepatitis E virus (HEV) is an enterically transmitted infection that is typically self-limited. It is spread by fecally contaminated water within endemic areas. Outbreaks can be epidemic and individual. Hepatitis E has many similarities with hepatitis A. Hepatitis E infection has recently been associated with chronic hepatitis in solid organ-transplant recipients.¹

HEV 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.

Hepatitis E is an RNA virus of the genus Hepevirus. Four hepatitis E genotypes exist, and genotype 1 causes human disease.

The most exciting recent advancement has been the development of a successful recombinant hepatitis E vaccine.²

Pathophysiology

The 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.

Frequency

United States

The prevalence rate of anti-HEV antibodies is less than 2%. The route of exposure is unknown but generally is attributed to travel in endemic areas.

International

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. 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. The reservoir of HEV is unknown, but it may be transmitted by animals.

Mortality/Morbidity

• The overall case fatality rate is 4%.
• The case fatality rate among pregnant women is 20%, which 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.

Race

• Infection has no apparent racial predilection.

Sex

• Although predilection is unknown, pregnant women are prone to complications.

Age

• Hepatitis E predominantly affects those aged 15-40 years.
• It may affect younger age groups but generally is not recognized and may be subclinical.
• No chronic cases have been described.

Clinical

History

The incubation period ranges from 15 days to 60 days, and the course of infection has 2 phases termed prodromal and icteric.

• 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
• Icteric-phase symptoms include the following:
  • Jaundice - May be difficult to see with some patients' natural skin color; serum bilirubin level is greater than 3 mg/dL; scleral icterus is present
  • Dark urine
  • Light-colored stools (20-40%)
  • Pruritus (50%)
• Other features include the following:
  • Urticarial rash
  • Diarrhea
  • Rapidly increasing serum amino transferase (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) levels that peak within 4-6 weeks of onset and gradually decrease to normal within 1-2 months
  • Viral excretion in stool persisting 14 days from onset
• Symptoms of HEV are similar to other hepatitides and include the following:
  • Abdominal pain (35-80% of patients)
  • Jaundice
  • Anorexia
  • Hepatomegaly (10-85%)
  • Malaise (95-100%)
  • Vomiting
• 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

• Right upper quadrant tenderness
• Possible enlarged liver (palpable edges)
• Possible splenomegaly
• Possible transient spider angiomata

Causes

• HEV is spread by fecally contaminated water within endemic areas. See Background.

Differential Diagnoses

Workup

Laboratory Studies

• A study involving human volunteers and nonhuman primates determined the typical serological course of HEV.
  • Two humans ingested the virus and demonstrated liver enzyme elevations within 4-6 weeks that persisted for as long as 90 days.
  • The virus was detectable in their stool approximately 1 month after ingestion and remained for another 2-4 weeks.
• Western blot and enzyme immunoassays detect anti-HEV antibodies by using the antigenic domains from ORF-2 and ORF-3. Assays of ORF-2 are more sensitive.
  • Testing to detect anti-HEV immunoglobulin M (IgM) and immunoglobulin G (IgG) differentiates acute and chronic infection.
  • The IgM titer falls rapidly after infection, becoming virtually undetectable within 6 months.
  • Anti-HEV IgG persists for longer than 6 months, although its actual duration of positivity is unknown.
  • IgG anti-HEV appears to afford protection against reinfection.
  • HEV IgG AB testing is available through the Centers for Disease Control and Prevention (CDC).
• Serum, liver, and stool samples can be tested for HEV RNA with a polymerase chain reaction assay. These tests are not available commercially.
• Aminotransferase levels (AST, ALT) are elevated several days before the onset of symptoms but generally return to normal within 1-2 months after the peak severity of the disease has passed.
  • Elevations can be associated with underlying liver disease or exposure to other hepatotoxins.
  • Whether the magnitude of elevation correlates with the histological severity is not clear.
• Serum bilirubin elevations occur in both the total and direct fractions.
  • Hemolysis is unusual.
  • In most cases, bilirubin levels take longer to return to normal than aminotransferase levels.
• Many patients develop a mild leukocytosis.
  • If associated with fever, bacteremia should be suspected.
  • More commonly, WBC counts are decreased. Differential counts may show atypical cells and lymphocytosis.

Imaging Studies

• Abdominal radiographs have no role in evaluating acute viral hepatitis unless the physical examination suggests a perforated viscus.
• Abdominal ultrasonography is recommended.
  • It helps rule out biliary obstruction in cases with significant nausea, vomiting, or fever.
  • It can demonstrate the presence of an enlarged liver; echo texture is heterogeneous and coarsened.
  • It can demonstrate splenomegaly, if present.

Other Tests

• Perform blood cultures if the patient is febrile and hypotensive with an elevated WBC count.
• Determine serum acetaminophen levels if overdose is suspected.

Procedures

• Liver biopsy usually is not necessary.
• Typical pathological findings are included in Histological Findings.

Histologic Findings

The pathology picture is cholestatic, with stasis of canalicular bile and marked proliferation of intralobular bile ductules. The cholestasis is most notable within the centroacinar regions. Parenchymal changes are less severe and include swollen hepatocytes, foam cells, and acidophil bodies. Inflammatory infiltrate of mononuclear cells is present, resulting in expanded portal areas and possible piecemeal necrosis.

Treatment

Medical Care

• Therapy 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. Care should be taken while preparing uncooked fruits or vegetables. Boiling water may prevent infection, but the effectiveness of chlorination is unknown.
• No immunoprophylaxis is available. Immunoglobulin from infected patients is not effective in preventing outbreaks or sporadic cases.
• Prototype vaccines are being developed using animal models. To date, this is hindered by an inability to maintain the virus in cell cultures.
• Once infection occurs, therapy is limited to support. Provide patients with adequate hydration and electrolyte repletion. Hospitalization is indicated only for patients unable to maintain oral intake.

Diet

• 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.

Activity

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

Follow-up

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.

References

1. Kamar N, Selves J, Mansuy JM, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med. Feb 21 2008;358(8):811-7. [Medline].

2. Shrestha MP, Scott RM, Joshi DM, et al. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med. Mar 1 2007;356(9):895-903. [Medline].

3. Favorov MO, Fields HA, Purdy MA, et al. Serologic identification of hepatitis E virus infections in epidemic and endemic settings. J Med Virol. Apr 1992;36(4):246-50. [Medline].

4. Fields HA, Favorov MO, Margolis HS. Hepatitis E virus: a review. J Clin Immunoassay. 1993;16:215-23.

5. Ghabrah TM, Tsarev S, Yarbough PO, et al. Comparison of tests for antibody to hepatitis E virus. J Med Virol. Jun 1998;55(2):134-7. [Medline].

6. Harrison TJ. Hepatitis E virus -- an update. Liver. Jun 1999;19(3):171-6. [Medline].

7. Mast EE, Krawczynski K. Hepatitis E: an overview. Annu Rev Med. 1996;47:257-66. [Medline].

8. Purdy MA, Krawczynski K. Hepatitis E. Gastroenterol Clin North Am. Sep 1994;23(3):537-46. [Medline].

9. Skidmore SJ. Factors in spread of hepatitis E. Lancet. Sep 25 1999;354(9184):1049-50. [Medline].

Keywords

hepatitis E, hepatitis E virus, HEV, Caliciviridae family, anti-HEV antibodies

Contributor Information and Disclosures

Author

Jonathan M Schwartz, MD, Assistant Professor, Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health and Sciences University
Jonathan M Schwartz, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, and American Hepato-Pancreato-Biliary Association
Disclosure: Nothing to disclose.

Coauthor(s)

Kenneth Ingram, PAC, Assistant Professor, Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health Sciences University
Disclosure: Nothing to disclose.

Kenneth D Flora, MD, Adjunct Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Oregon Health Sciences University; Consulting Staff, Department of Gastroenterology, The Oregon Clinic
Kenneth D Flora, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, and American Gastroenterological Association
Disclosure: Nothing to disclose.

Medical Editor

David Eric Bernstein, MD, Chief, Section of Hepatology, North Shore University Hospital, Director, Associate Professor, Department of Internal Medicine, Division of Hepatology, New York University School of Medicine
David Eric Bernstein, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine, University of California at San Diego; Consulting Staff, Mecklenburg Medical Group
Oscar S Brann, MD, FACP is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

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