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Table of Contents

Published May 29, 2002

Talal Adhami, MD

Talal Adhami, MD

Department of
Gastroenterology
and Hepatology

Gavin
Levinthal, MD

Gavin Levinthal, MD

Department of
Gastroenterology
and Hepatology

Print Chapter

Copyright 2002
The Cleveland Clinic Foundation

  

Viral liver disease, particularly with the current hepatitis C epidemic, presents a challenging and frequently encountered problem for practicing physicians. The literature on this subject is vast and rapidly increasing and new and promising therapies are being offered to patients.

Five viruses designated hepatitis A, B, C, D and E infect the liver and produce hepatitis as their primary clinical manifestation. Hepatitis G virus has been identified more recently, but its role in causing liver disease is not clearly defined. Other viruses, such as Epstein-Barr (EBV) and cytomegalovirus (CMV), may cause hepatitis as part of their clinical presentation but the liver is usually not the primary target organ.

This chapter covers hepatitis A. The other hepatitis viruses are discussed in separate chapters and can be viewed by clicking on the hyperlinks on the right-hand side of this page.

 

Chapter Outline

Definition

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy
and Prevention

Outcomes

References

National Guidelines

Prevention of Hepatitis A Through
Active or Passive Immunization:
Recommendations of the Advisory Committee on
Immunization Practices (ACIP)

 

RELATED
CHAPTERS

Hepatitis B

Hepatitis C

Hepatitis D

Hepatitis E
and Hepatitis G/GBV-C

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
DEFINITION

The hepatitis A virus (HAV) is a 27nm-diameter, non-enveloped, RNA virus. It belongs to the family Picornaviridae, the genus Hepatovirus, and has characteristics of the enteroviruses.1 Viral transmission occurs in a fecal-oral fashion. The genome is a positive strand RNA, 7474 nucleotides long, 7.5 kb in length that encodes a polyprotein with both structural and non-structural components. Viral replication and assembly occur in the hepatocyte cytoplasm of humans and nonhuman primates, the exclusive natural hosts. The virus is then secreted into the bile and serum.2-4

The hepatitis A virus is found throughout the world and is the most common cause of symptomatic acute hepatitis in the United States (annual incidence is 9.1 per 100,000) occurring largely as sporadic, rather than epidemic cases. The virus is more prevalent in areas with poor sanitary conditions. The most common source of hepatitis A is direct person-to-person exposure and, to a lesser extent, direct fecal contamination of food or water. Consumption of raw or partially cooked shellfish raised in contaminated waterways is an uncommon but possible source of hepatitis A.5 Vertical transmission from mother to fetus and transmission from blood or blood products have been described on rare occasions. High-risk groups for acquiring hepatitis A include travelers to developing nations, children in day-care centers, sewage workers, cleaning personnel, male homosexuals, intravenous drug users, hemophiliacs given plasma products, and persons in institutions. Forty-two percent of all cases have no identifiable source.6,7
PATHOPHYSIOLOGY
The HAV is not directly cytopathic to the hepatocyte. Injury to the liver is secondary to the host's immune response. Replication of HAV occurs exclusively within the cytoplasm of the hepatocyte. Human leukocyte antigen (HLA)-restricted, HAV-specific CD8+ T lymphocytes and natural killer cells mediate hepatocellular damage and destruction of infected hepatocytes. Interferon gamma appears to have a central role in promoting clearance of infected hepatocytes. 8-10
SIGNS AND SYMPTOMS
The incubation period of the hepatitis A virus ranges from 15 to 49 days (mean = 25 days). The prodromal phase is characterized by non-specific symptoms, such as fatigue, weakness, anorexia, nausea, vomiting, abdominal pain, and, less commonly, fever. Headache, arthralgias, myalgias, rash and/or diarrhea may follow.11 Jaundice begins within 1 to 2 weeks from the onset of the prodrome. It occurs in 70% of adults infected with hepatitis A, with or without pruritus, and in a far smaller proportion of children. Mild hepatomegaly, splenomegaly and cervical lymphadenopathy are found in 85%, 15% and 14% of infected patients respectively. The host is infective from 14 to 21 days before the onset of jaundice to 7 to 8 days after jaundice has resolved.12 Host serum and saliva are not nearly as infectious as stool, and urine does not transmit the virus. Anti-HAV antibody (immunoglobulin M [IgM] followed by immunoglobulin G [IgG]) appears shortly before the onset of symptoms and rises to high titers 3 to 4 months after exposure. IgM-specific anti-HAV persists for 4 to 12 months, and IgG-specific anti-HAV persists for life (Figure 1). Extrahepatic manifestations are uncommon and include a leukocytoclastic vasculitis, glomerulonephritis, arthritis, immune complex disease, toxic epidermal necrolysis, myocarditis, optic neuritis, transverse myelitis, polyneuritis, thrombocytopenia, aplastic anemia and red cell aplasia.13
DIAGNOSIS
Detecting IgM anti-HAV in the serum of a patient with the clinical and biochemical features of acute hepatitis usually makes the diagnosis of acute hepatitis A.14 Figure 1 outlines the immune response to Hepatitis A infection. HAV antigen can be detected in the stool or body fluids but there is no commercially available assay. Detecting viral RNA is highly specific but expensive and rarely used to confirm the diagnosis. Liver biopsy is not indicated. Testing for anti-HAV IgG is not helpful in diagnosis but is a means of assessing immunity to hepatitis A.
THERAPY AND PREVENTION

Acute hepatitis A is usually a self-limited infection. Complete recovery is seen in most and chronic disease does not occur. In rare cases infection is complicated by fulminant disease and fatalities occur. Treatment is mainly supportive. Attempts should be made to prevent transmission of the virus within the household and to close contacts. Boiling contaminated water for 20 minutes or exposing the virus to chlorine, formalin or ultraviolet light reduces the risk of infection.15,16

A safe and effective hepatitis A vaccine is available and is recommended for patients at high risk of acquiring hepatitis A. Patients with chronic liver disease are more likely to develop severe or fulminant liver disease when infected with hepatitis A and should be vaccinated. Two formulations of the HAV vaccine are available in the United States; both consist of inactivated hepatitis A antigen purified from cell culture. Havrix is recommended as two injections 6 to 12 months apart in an adult dose of 1440 enzyme-linked immunosorbent assay (ELISA) units (1.0 mL) and a pediatric dose (ages 2 to 18 years) of 720 units (0.5 mL). A dose of 360 units administered 3 times over a 6-month period is an acceptable regimen in children. Travelers to high-risk areas should receive the first dose of vaccine at least 4 weeks prior to anticipated exposure. VAQTA is recommended as 2 injections at least 6 months apart in an adult dose of 50 units (1.0 mL) and a pediatric dose (2-17 years) of 25 units (0.5 mL). Protection lasts for approximately 15 years.

Hepatitis A vaccines have an excellent safety record, with serious complications in less than 0.1% of recipients. Sero-conversion rates after the HAV vaccine are greater than 90%, but are lower in patients with chronic liver disease (possibly as low as 50%). At least half the patients who are vaccinated post transplantation have titers below the protective level 2 years after receiving the vaccination. Patients with liver disease should therefore be vaccinated as early on in their illness as possible. Follow-up testing for anti-HAV antibody and booster inoculations are not currently recommended. Pooled human immune globulin, 2 mL in adults and 0.02 mL/kg in children, given intramuscularly, is recommended for post-exposure prophylaxis.17,18

These recommendations for the prevention of hepatitis A are advocated by the Centers for Disease control and Prevention (CDC) and can be accessed at www.cdc.gov.19
OUTCOMES

The course of hepatitis A infection is benign in the majority of those infected. It occasionally may be severe, or fulminant, in adults, particularly in those with chronic liver disease. Jaundice usually resolves in less than 2 weeks and full recovery usually occurs in 2 months. The illness occasionally may persist for several weeks or months, but never leads to a chronic infection, chronic hepatitis, or cirrhosis. A chronic relapsing hepatitis has been noted to last for as long as a year. Hepatitis A may cause a cholestatic hepatitis which usually responds to a short course of prednisolone 30 mg daily. Pregnancy does not affect the severity or outcome of acute hepatitis A infection. In the rare case of fulminant hepatitis, patients should be evaluated early for possible liver transplantation.20,21

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REFERENCES
  1. Feinstone SM. Hepatitis A: epidemiology and prevention. Eur J Gastroenterol Hepatol. 1996;8:300-305.

  2. Lemon SM, Jansen RW, Brown EA. Genetic, antigenic and biological differences between strains of hepatitis A virus. Vaccine. 1992; 10 ( Suppl 1):S40-44.

  3. Versalovic J. Hepatitis G virus. Clinical microbiol newsletter. 1997;19:161.

  4. Dienstag JL, Isselbacher KJ. Acute viral hepatitis. Fauci AS, Braunwald E, Isselbacher KJ, et al. eds. Harrison's Principles of Internal Medicine. New York: McGraw-Hill, 1998:1677-1692.

  5. Koff RS. Preventing hepatitis A infections in travelers to endemic areas. Am J Trop Med Hyg. 1995;53:586-590.

  6. Advisory Committee on Immunization Practices (ACIP). Prevention of hepatitis A through active or passive immunization. MMWR Morb Mortal Wkly Rep. 1999;48(RR-12):l-37.

  7. Bell BP, Shapiro CN, Alter MI, et al. The diverse patterns of hepatitis A epidemiology in the United States- implications for vaccination strategies. J Infect Dis. 1998;178:1579-1594.

  8. Vallbracht A, Fleischer B, Busch FW. Hepatitis A: hepatotropism and influence on myelopoiesis. Intervirology. 1993;35:133-139.

  9. Fleischer B, Fleischer S, Maier K, et al. Clonal analysis of infiltrating T lymphocytes in liver tissue in viral hepatitis A. Immunology. 1990; 69:14-19.

  10. Baba M, Hasegawa H, Nakayabu M, et al. Cytolytic activity of natural killer cells and lymphokine activated killer cells against hepatitis A virus infected fibroblasts. J Clin Lab Immunol. 1993; 40:47-60.

  11. Dentinger CM, Bower WA, Nainan OV, et al. An outbreak of hepatitis A associated with green onions. J Infect Dis. 2001; 183:1273-1276.

  12. Tong MJ, el-Farra NS, Grew MI. Clinical manifestations of hepatitis A: recent experience in a community teaching hospital. J Infect Dis. 1995; 171( Suppl 1): S15-18.

  13. Schiff ER. Atypical clinical manifestations of hepatitis A. Vaccine. 1992;10(Suppl 1):S18-20.

  14. Younossi ZM. Viral hepatitis guide for practicing physicians. Cleveland Clinic J Med. 2000;67(Suppl 1) SI:6-7.

  15. Koff RS. Clinical manifestations and diagnosis of hepatitis A virus infection. Vaccine. 1992;10( Suppl 1):S15-17.

  16. Mbithi JN, Springthorpe VS, Boulet JR, Sattar SA. Survival of hepatitis A virus on human hands and its transfer on contact with animate and inanimate surfaces. J Clin Microbiol. 1992;30:757-763.

  17. Younossi ZM. Viral hepatitis guide for practicing physicians. Cleveland Clinic J Med. 67:SI:13-14.

  18. Lemon SM, Thomas DL. Vaccines to prevent viral hepatitis. NEJM. 1997;336:196-204.

  19. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1999;48(RR12):1-37.

  20. Lemon SM. Type A viral hepatitis: epidemiology, diagnosis, and prevention. Clin Chem. 1997;43:1494-1499.

  21. Dusheiko GM. Review article: the management of hepatitis A, B, D and non-A non-B. Aliment Pharmacol Therap. 1989;3:1-20.
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