eMedicine Specialties > Gastroenterology > Liver

Hepatitis D

Sean R Lacey, MD, Consulting Staff, Department of Medicine, Division of Gastroenterology, Gastroenterology Associates, Ltd, Lehigh Valley Hospital

Updated: Oct 31, 2006

Introduction

Background

Hepatitis D virus (HDV) is an RNA virus that is structurally unrelated to hepatitis A, B, or C virus. It was discovered in 1977. HDV causes a unique infection that requires the assistance of viral particles from hepatitis B virus (HBV) to replicate and infect other hepatocytes. Its clinical course is varied and ranges from acute self-limited infection to acute fulminant liver failure. Chronic liver infection can lead to end-stage liver disease and associated complications.

Pathophysiology

HDV infection is an acute and chronic inflammatory process involving the liver. Three known genotypes are described. Genotype I has a worldwide distribution. Genotype 2 has been discovered in Taiwan, Japan, and northern Asia. Genotype 3 is found in South America. HDV can replicate independently within the hepatocyte, but it requires hepatitis B surface antigen (HBsAg) for propagation. Hepatic cell death may occur due to the direct cytotoxic effect of HDV or via a host-mediated immune response.

Frequency

United States

HDV infection occurs more commonly among adults than children. It is observed more commonly among patients with a history of intravenous drug use and in persons from the Mediterranean basin.

International

Approximately 15 million people are infected worldwide. Areas with the highest prevalence include southern Italy; North Africa; the Middle East; the Amazon Basin; and the American South Pacific islands of Samoa, Hauru, and Hiue. China, Japan, Taiwan, and Myanmar (formerly Burma) have a high prevalence of HBV infection but a low rate of HDV infection.

Mortality/Morbidity

• Simultaneous infection with HBV and HDV is known as co-infection and results in fulminant liver failure in 1% of patients. Complete clinical recovery and clearance of HBV and HDV co-infection is the most common outcome. Chronic infection with HBV and HDV occurs in less than 5% of patients.
• Infection with HDV in a patient already HBsAg-positive is known as superinfection and results in fulminant liver failure in 5% of patients. Approximately 80-90% develop chronic HDV infection. These patients progress more rapidly to develop cirrhosis and may develop hepatocellular carcinoma.

Sex

• HDV infection is not associated with a sex predilection.

Age

• HDV infection is more common among adults than children. However, children from underdeveloped, HDV-endemic countries are more likely to contract HDV infection through breaks in the skin due to the presence of skin lesions.

Clinical

History

• HDV infection is clinically indistinguishable from other forms of viral hepatitis.
• As many as 90% of patients are asymptomatic.
• The incubation period is 21-45 days but may be shorter in cases of superinfection.
• Symptoms include the following:
  • Jaundice
  • Dark urine
  • Abdominal pain
  • Nausea with vomiting
  • Confusion, bruising, and bleeding (rare)
  • Pruritus

Physical

• Symptoms upon presentation include the following:
  • Scleral icterus
  • Fever
  • Abdominal pain, usually right upper quadrant
  • Tea-colored urine
  • Encephalopathy (rare)
  • Petechia with bruising (rare)

Causes

• HDV is transmitted parenterally.
• Risk factors include intravenous drug use and multiple blood transfusions.
• Sexual transmission is less efficient than with HBV.
• Perinatal transmission is rare; no such cases have been reported in the United States.

Differential Diagnoses

Other Problems to Be Considered

Acetaminophen poisoning
Drug-induced hepatitis
Fatty liver of pregnancy
HELLP (hemolysis, elevated liver enzymes, and low platelet) syndrome in pregnant patients
Ischemic liver injury
Mushroom toxicity

Workup

Laboratory Studies

• The following serum test results are present in patients with co-infection with HDV and HBV:
  • Results are positive for HDV antigen in 20%.
  • Results are positive for HDV RNA in 90%. Reverse transcriptase polymerase chain reaction is currently the most sensitive assay for the detection of HDV viremia.
  • Results for anti-HDV immunoglobulin M (IgM) are positive initially and then are positive for anti-HDV immunoglobulin G. The finding of antigen A antibody to HDV is almost exclusively associated with chronic HDV infections.
  • Results for anti-HB core IgM are positive, except with superinfection, in which anti-HB core IgM is absent.
  • A hepatic panel may show alanine aminotransferase and aspartate aminotransferase levels greater than 500 IU/L.
  • For synthetic liver function markers, an international normalized ratio greater than 1.5 or a prothrombin time greater than 17 seconds may be the first evidence of fulminant liver failure.
• HBsAg is required for HDV replication but may be suppressed to undetectable levels with active HDV replication.

Imaging Studies

• Right upper quadrant ultrasound helps evaluate for biliary obstruction and hepatocellular carcinoma.
• Perform cholescintigraphy (hydroxy iminodiacetic acid) to exclude acute cholecystitis, if clinically indicated.
• Perform CT scanning or MRI if hepatocellular carcinoma is suggested. An alpha-fetoprotein level greater than 250 ng/mL is highly suggestive of hepatocellular carcinoma.

Procedures

• Results from liver biopsy in patients with acute disease are consistent with acute hepatitis, and, generally, a biopsy is not indicated. In patients with chronic liver disease, liver biopsy is indicated to evaluate for the presence of fibrosis and cirrhosis.
• HDV antigen immunohistochemical analysis of liver tissue is the criterion standard for establishing a diagnosis of persistent HDV infection.

Histologic Findings

Features are very similar to those observed in patients with HBV infection. Acidophilic bodies and degeneration of hepatocytes with acidophilic cytoplasm are present. The few inflammatory cells (lymphocytes) likely represent the direct cytotoxicity of HDV. Results of immunohistochemical staining for HDV antigen are positive. With superinfection, staining reveals that HBsAg is often suppressed.

Treatment

Medical Care

Treatment consists primarily of support. Observe synthetic liver function markers and mental status closely. Deterioration of either should prompt early consultation with hospital personnel capable of performing liver transplantation.

Surgical Care

Liver transplantation is indicated in patients with fulminant liver failure.

Consultations

Early notification of a hepatologist or gastroenterologist is warranted.

Diet

• Diet need not be restricted.
• If enteral intake is poor, intravenous fluids can be administered.
• Total parental nutrition is seldom needed.

Activity

No restrictions are necessary.

Medication

Antiviral therapy with interferon alfa can be considered in patients with chronic infection. The treatment course is usually at least one year. Treating children with interferon alfa seems to be safe but is relatively ineffective. Treatment is not needed for patients with co-infection, given the high spontaneous clearance rates. Lamivudine, ribavirin, and corticosteroids have not been effective in treatment.

Interferons

Naturally produced proteins with antiviral, antitumor, and immunomodulatory actions.

Interferon alfa (Roferon)

Has been used in several small studies to treat HDV infection. Dosages varying from 3-10 mU three times/wk (tiw) for as long as 12 mo have been used. At the end of therapy, loss of HDV RNA and normalization of liver enzymes was seen in 50% of patients treated with 9 mU tiw and 21% in those treated with 3 mU . Half the responders remained in biochemical remission after cessation of therapy, while no patients maintained a virologic response after cessation. Histologic improvement was observed in patients treated with interferon.

Dosing

Adult

10 million U SC tiw
Reduce dose by 50% if platelet count falls to <50,000/µL or granulocyte count falls to <750/µL; discontinue use if platelet count drops to <30,000/µL or granulocyte count falls to <500/µL

Pediatric

<18 years: Not established
>18 years: Administer as in adults

Interactions

Decreases clearance of theophylline, which may increase theophylline levels 100%; caution when other potentially myelosuppressive drugs are used; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity

Contraindications

Documented hypersensitivity; psychiatric illness; uncontrolled depression; immunosuppression; thrombocytopenia ( <70,000/µL); concurrent alcohol use; severely compensated liver disease; autoimmune hepatitis when chronic HBV, HCV, or HDV infection present

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Fertility rates may be lowered in men and women; may cause abortion; not known if excreted in human breast milk, but is excreted in lactating mice; not known to be mutagenic; some adverse effects include fever, myalgia, anorexia, headache, bone marrow suppression, fatigue, anxiety, irritability, nervousness, thyroid abnormalities, autoimmune abnormalities, retinal hemorrhages, and hair loss; 50% dose reduction is suggested if platelet count falls to <50,000/µL or granulocyte count falls to <750/µL; discontinue use if platelet count drops to <30,000/µL or granulocyte count falls to <500/µL; caution in heart disease or arrhythmias

Follow-up

Further Inpatient Care

• Observe synthetic liver function and mental status for signs of deterioration.
• Consider liver biopsy if the serologic diagnosis of hepatitis is inconclusive.

Further Outpatient Care

• Follow-up is recommended for at least 6 months to determine if chronic HBV and HDV infection develop.
• Perform a liver biopsy to stage liver disease prior to beginning interferon alfa therapy.

Transfer

• Patients with evidence of decompensated liver disease or fulminant liver failure should be immediately transferred to a center capable of performing a liver transplantation.

Deterrence/Prevention

• No vaccine is available for HDV, but the HBV vaccination is effective against HDV.

Complications

• Liver failure
• Hepatocellular carcinoma
• Autoimmune manifestations, often including antinuclear antibodies and smooth muscle antibodies

Prognosis

• Prognosis is excellent for those with co-infection in whom treatment eradicates both viruses.
• Prognosis is variable for those who are superinfected. It depends on the duration and severity of HBV infection, alcohol consumption, comorbid illnesses, and age.
• In patients who undergo liver transplantation for chronic liver disease secondary to HBV and HDV infection, HDV seems to suppress the replication of HBV in the transplanted liver and may help prolong graft survival. However, fulminant hepatitis from recurrent HBV and HDV infection in the transplanted liver has resulted in patient death or the need to retransplant.

Patient Education

• Modify high-risk behaviors, including intravenous drug use or unsafe sexual practices.
• Promote the use of universal precautions for health care workers.
• Patients with chronic HDV and HBV infection should not donate blood, share toothbrushes or razors, or consume alcohol. Precautions should be observed.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize HDV in the setting of acute HBV co-infection
• Failure to closely monitor synthetic liver function
• Failure to transfer patient to a medical center capable of performing a liver transplantation early in the course of disease
• Failure to inform patients with alcoholism to abstain from alcohol consumption and to seek professional counseling in order to be considered a transplantation candidate, a prerequisite in some centers

Special Concerns

• Additional information regarding chronic viral hepatitis is available from the American Liver Foundation, 75 Maiden Lane, Suite 603, New York, NY 10038 USA; (800) 465-4837, toll-free.

References

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Keywords

HDV, HDV infection, viral hepatitis, delta hepatitis, delta virus, hepatitis delta, hepatitis B virus, HBV, hepatitis B surface antigen, HBsAg, liver failure, liver infection, acute fulminant liver failure, chronic liver infection, end-stage liver disease, end-stage liver disease, ESLD, cirrhosis, hepatocellular carcinoma, HCC, liver transplantation, hepatic transplantation

Contributor Information and Disclosures

Author

Sean R Lacey, MD, Consulting Staff, Department of Medicine, Division of Gastroenterology, Gastroenterology Associates, Ltd, Lehigh Valley Hospital
Sean R Lacey, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, and American Gastroenterological Association
Disclosure: astra zenaca Honoraria Speaking and teaching

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, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal 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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