A lesson in the ABCs of hepatitis.

The more laboratorians know about the various hepatitis viruses that plague our society, the more guidance they can offer their client-physicians regarding the ordering of "ideal hepatitis profiles" to enhance patient care and cut laboratory costs.

Quite frequently, liver disease in the U.S. is the result of acute viral hepatitis. While it is true a variety of viruses can cause hepatitis, only five are believed to cause most infectious cases: hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV) (see Table 1, "Hepatitis types and their characteristics").[1] In addition, four more viruses associated with acute viral hepatitis recently have been identified: hepatitis GBV (GBV-A, GBV-B, and GBV-C)[2] and hepatitis G (HGV).[3]

Hepatitis A and E are transmitted via the fecal-oral route, while hepatitis B, C, D, GBV, and G are transmitted most often through receipt of contaminated blood products, intravenous drug use, and sexual contact with an infected partner.[1-3] It is impossible to distinguish between the different types of acute vital hepatitis based solely on clinical presentation.

Following are some pertinent facts about each virus named above.

Hepatitis A

Hepatitis A, caused by a picornavirus, accounts for up to 35% of all cases of acute viral hepatitis in developed countries. In underdeveloped countries, HAV is endemic, and nearly 90% of these adults demonstrate immunity to HAV from childhood exposure. Patients with HAV are most contagious when they are asymptomatic; by the onset of jaundice, however, they usually are no longer infectious. HAV should be suspected if infection occurs following the ingestion of contaminated food (e.g., shellfish), following a natural disaster, in institutionalized children, or in children who attend day care centers. Diagnosis of HAV is confirmed by the presence of the IgM antibody directed against HAV (IgM anti-HAV) in serum during the acute illness. After several months, the IgM anti-HAV titer decreases, while the IgG anti-HAV rises and persists indefinitely.[14]

Immunoglobulin is recommended for all household and sexual contacts of people with HAV. It also should be administered to all staff and attendees of day care centers and homes (e.g., retirement homes, orphanages) if a child or employee is diagnosed with HAV. Typically, contact with infected individuals of elementary and secondary schools is not a significant means of HAV transmission.[4]

A new HAV vaccine approved by the Food and Drug Administration (FDA) is now available.

Hepatitis B

Hepatitis B is caused by a DNA virus of the class hepadnaviridae. In this country, approximately 200,000-300,000 people become infected with HBV each year. Most of them remain asymptomatic; however, more than 10,000 hospital admissions and 250-300 deaths per year are due to this virus.[4]

Based on estimates from the Centers for Disease Control and Prevention (CDC), there are approximately 1.25 million "chronic carriers" (people with chronic HBV infection) in the U.S. Of these people, nearly 5,000 die from cirrhosis or hepatocellular carcinoma (primary liver cancer) each year.[1,4] The "chronic carrier" is defined as a person who either is HBV surface antigen (HBsAg) positive on at least two separate occasions (at least six months apart), or HBsAg positive, IgM antibody to HBV core (IgM anti-HBc) negative, and IgG anti-HBc positive when a single serum specimen is tested. An estimated 40% of patients with chronic HBV acquired early in life will develop hepatocellular carcinoma.[4]

The frequency of symptomatic acute HBV is directly related to age. Thus, fewer than 5% of infants infected with HBV will develop symptoms.[1] Further, the likelihood of developing chronic HBV infection is inversely proportional to age. For instance, the risk of developing a chronic HBV infection is 70%-90% if the infection is acquired during the perinatal period and 6%-10% if the infection is acquired as an adult.[4]

Although heterosexual contact with an infected partner is the most frequently identified source of HBV infection, the virus also can be transmitted parenterally, by homosexual contact with an infected partner, and perinatally.[1] Transmission of HBV from mother to infant during the perinatal period is one of the most efficient modes of HBV infection and often leads to severe long-term sequelae.[4] Infants born to HBV-e antigen (HBeAg)-positive mothers are at highest risk for the infection. Nearly one-third of individuals infected with HBV deny all known risk factors.[1]

Despite the introduction in 1982 of a safe and effective HBV vaccine, the Heptavax, Ricombivax, and Engerix-B vaccines have had little effect on the incidence of this infection. Most vaccine recipients have been at risk of acquiring HBV infection through occupational exposure, a group that accounts for about only 4% of cases. Further, many high-risk people already were infected with HBV before the vaccine was recommended.[1,4]

The primary deterrents to vaccinating high-risk groups include the public's lack of knowledge regarding the risk of disease and its consequences, the cost of the vaccine, and the inability of experts to access most high-risk populations. Nevertheless, the present strategy for HBV prevention is to vaccinate high-risk candidates. Currently, many areas of the country that can afford it are routinely screening pregnant women and treating infants born to infected women, as well as routinely administering HBV immunizations to infants.[1]

When given in the deltoid muscle, the HBV vaccine produces protective antibody in more than 90% of healthy individuals.[1] Post-vaccination testing for anti-HBsAg is advisable for people for whom a suboptimal response may be anticipated, such as those who have received a vaccine in the buttock, people beyond 50 years of age, people known to be HIV infected, and those at occupational risk who may have had needle-stick exposures necessitating post-exposure prophylaxis. Post-vaccination testing should be done one to six months following completion of the vaccine series.[4] Note that the reason for post-testing is to ensure vaccinations are effective, not to check if immunity has been lost.

About 30%-50% of people who develop adequate antibody after three doses of the vaccine will lose detectable antibody within seven years, yet protection against viremic infection and clinical disease seems to persist.[4] There are no universally accepted guidelines for nonresponders.[1] Some clinicians administer a. fourth dose, while others repeat the entire series. Revaccination of people who fail to respond to the primary series produces adequate antibody in 15%-25% of cases following one additional dose and in 30%-50% of cases after three additional doses. The HBV vaccine produces neither therapeutic nor adverse effects for HBV carriers.[4]

Patients with HBV who respond to antiviral therapy have a marked decrease in their HBV DNA levels.[5] HBV DNA assays are available for investigational use only and are relatively expensive. Studies have shown that following HBeAg levels in the blood reveals virus replication and that this procedure may be a cost-effective alternative to monitoring HBV DNA levels to determine patient response.[6]

Hepatitis C

Most hepatitis cases that were once referred to as "non-A, non-B" are now known to be due to hepatitis C (HCV).[1] Today one of the more common reasons for liver transplantation is the presence of hepatitis, cirrhosis, and/or hepatocellular carcinoma due to HCV. (David Crosby, Larry Hagman, and Mickey Mantle are good examples of this.)[7] Many "flower children" of the 1960s who practiced free love and abundant intravenous drug usage (e.g., the fictitious character Jenny in the movie "Forrest Gump") are now being diagnosed with HCV.

The clinical features of HCV infection are variable. The most common presentation is that of a chronic, asymptomatic increase of aminotransferases. Frequently, the first time patients learn they are anti-HCV positive is after they have donated blood and received a letter back from the blood bank informing them of their seropositive status. Patients with HCV infection occasionally present with symptomatic hepatitis and only rarely present with fulminant hepatic failure.[1]

The clinical outcome of patients with HCV can be quite variable, ranging from an acute infection of viral hepatitis to a slowly progressive chronic infection that may cause only a few symptoms but that may result in cirrhosis or hepatocellular carcinoma. Approximately 75% of patients who become infected with HCV develop chronic liver disease.[8]

In addition to blood transfusions, HCV infection can be acquired by parenteral drug abuse and needlestick exposure. Studies suggest an average of 5% of infants born to anti-HCV-positive mothers become infected. Whether transmission occurs in utero or during delivery is unknown. Recent data also suggest transmission of HCV by breast feeding. Patients who have acquired HCV infection by sexual and household contact show a higher seropositive rate than the general population, as do patients receiving hemodialysis. The risk of developing hepatitis following needlestick exposure to an infected patient is lower for HCV than for HBV. Approximately 50% of those infected with HCV deny all risk factors.[1]

We frequently make the diagnosis of HCV in our county hospital. Although about only 1% of our blood donors are seropositive for anti-HCV, approximately 40 new cases of HCV are diagnosed each month among our patients who present with elevated aminotransferases and symptomatic liver disease. Currently, the only test available for HCV detection is the IgG antibody to HCV (IgG anti-HCV). At this time, no commercial HCV antigen test has been approved by the FDA.

Interferon is the only effective and approved treatment for chronic HCV. In the initial multicenter study of interferon alpha-2b, about 40% of patients treated with 3 million units three times a week for six months had normal serum alanine aminotransferases during therapy, although about half of these patients had a relapse six months later.[9]

Quantification of HCV RNA may become important for monitoring patients with active disease and in determining which patients are most likely to respond to interferon therapy. In several studies, patients with low levels of HCV RNA were likely to be long-term responders to interferon treatment.[10]

Hepatitis D

Hepatitis D is an unclassified RNA virus that requires coinfection with HBV for viral replication. HBsAg-positive patients are at risk of acquiring HDV infection. The seroprevalence of HDV in the U.S. is low except in intravenous drug users and multiply transfused individuals.[1] HDV should be suspected in a patient with fulminant hepatitis or in one known to be HBsAg positive with clinical deterioration. HDV infection may be diagnosed by detecting HDAg in serum during early infection and by the appearance of total or IgM-specific delta antibody (anti-HDV) during or after infection. A test to detect total anti-HDV is commercially available. Other tests (HDAg, IgM anti-HDV) are available in research labs only.[4]

Hepatitis E

Hepatitis E is an unclassified RNA virus that causes enterically transmitted non-A, non-B hepatitis. HEV occurs most frequently in children and young adults. The clinical course of HEV is similar to that of HAV; however, liver failure can occur, particularly during pregnancy. Mortality rates of more than 30% have been reported in women infected during the third trimester. HEV is difficult to diagnose since no tests are commercially available.[1]

Chronic hepatitis and new viruses

Chronic hepatitis is characterized by persistently elevated liver enzymes for at least six months. The danger associated with being a chronic carrier of any hepatitis virus is the increased risk of developing cirrhosis and hepatocellular carcinoma. The rate of chronicity for HBV is approximately 10% in adults and 90% in infants. The risk of becoming a chronic HCV carrier is 50%-75%. There is no known chronic carrier state for HAV or HEV.

Approximately 5%-20% of cases of acute and chronic hepatitis cannot be attributed to any known virus.[5] This form of hepatitis has been termed "hepatitis X" or "hepatitis non-A-E." According to the CDC, 26%-29% of patients with acute non-A-E develop chronic hepatitis.[11] Recently, researchers cloned four viruses that are candidates for the causative agents of non-A-E hepatitis: hepatitis G (HGV) and hepatitis GBV, which includes GBV-A, GBV-B, and GBV-C.

Hepatitis G

News concerning the characterization of a new human hepatitis virus (HGV) and its implication in post-transfusion hepatitis was first discussed at the national meeting of the American Association of Blood Banks (AABB) in New Orleans, in November 1995.[3,1214] HGV is a novel virus belonging to the Flaviviridae family and is associated with non-ABC acute/chronic hepatitis and persistent viremia. A reverse-transcription polymerase chain reaction (PCR) assay demonstrated this virus in patients with non-ABC posttransfusion hepatitis. HGV RNA has been demonstrated in the serum of 1.7% of U.S. blood donors.[3]

Hepatitis GBV

In June 1995, a new GB hepatitis virus (GBV) was described in The Lancet by A. J. Zuckerman for the World Health Organization (WHO) Collaborating Centre for Reference and Research on Viral Diseases in London. This RNA virus belongs to the Flaviviridae family as well. Studies show distinct species of the GBV virus, named GBV-A, GBV-B, and GBV-C. Further studies show these species are not genotypes of HCV and that GBV-A and GBV-C are closely related. Anti-GBV-A, -B, and -C have been found in the sera of a large percentage [TABULAR DATA FOR TABLE 1 OMITTED] of patients who were at high risk for hepatitis and who were negative for anti-A, -B, -C, -D, and -E hepatitis viruses. A reverse-transcription PCR assay has been designed to monitor viremia associated with GBV infection. A survey of a small sample of 200 blood donors from one region in the U.S. indicated positive anti-GBV reaction in 2% of donors.[2]

Lab testing

At University Hospital, laboratorians often "guide" physicians into ordering an appropriate battery for hepatitis testing. For patients suspected of having acute hepatitis, the lab offers an acute hepatitis profile that consists of IgM anti-HAV, HBsAg, and IgM anti-HBc. Lab professionals also allow physicians to order these tests individually. If only an HBsAg is ordered and it tests positive, the laboratory automatically performs an IgM anti-HBc to determine if the patient has an acute case of hepatitis B. If the IgM anti-HBc tests negative, the laboratory performs a total core HBV (IgM + IgG). If the total core tests positive, the patient is assumed to be a chronic carrier of HBV. Conversely, if the total core tests negative, the patient is presumed to be in the very early stages of HBV, before the IgM antibody to the core has formed [ILLUSTRATION FOR FIGURE 1 OMITTED].

A problem with diagnosing HCV is that currently available serologic tests only detect the IgG antibody against HCV (which fails to distinguish acute from chronic infection). At present, the second-generation EIA test that detects anti-HCV has a sensitivity of about 90%.[1] False positivity continues to be a problem.

The Recombinant Immunoblot Assay (RIBA) is used in our laboratory to confirm the presence of HCV. Unfortunately, this test is very expensive; it costs us $215 per test to run. Right now, there is no FDA-approved test for the antigen to HCV. After initial exposure and subsequent infection with HCV, it takes an average of 26 weeks to seroconvert.[15]

Because HDV is a defective virus, it cannot infect by itself and requires the HBV to create a coinfection (sometimes referred to as a superinfection).[4] Physicians in our hospital, therefore, cannot order an HDV IgM antibody (IgM anti-HDV) unless a diagnosis of HBV has been previously confirmed.

More esoteric laboratory tests to diagnose hepatitis, such as HBV DNA ($150, our referral lab cost), HCV RNA ($160, our referral lab cost), and HEV, all have to be specifically written in on our laboratory slip. Because these tests are so costly, the requesting physician soon will be required to obtain approval from our laboratory director before we send these tests out to a referral laboratory.

Each laboratory should consider consulting with physicians in their facility to create the ideal hepatitis profiles. Guidance from the laboratory for appropriate test ordering will not only help to educate those who initiate the tests but also decrease costs for the laboratory.[11] (Please turn page for references)

References

1. American Medical Association. Prevention, diagnosis, and management of viral hepatitis: A guide for primary care physicians. Chicago, Ill: American Medical Association; 1995.

2. Zuckerman AJ. The new GB hepatitis virus. The Lancet. 1995;345:1453-1454.

3. Kim JP. Characterization of new human hepatitis virus (HGV) and its implication in PTH. Transfusion. 1995;35:S158.

4. Protection against viral hepatitis: Recommendations of the Immunization Practices Advisory Committee. MMWR. 1990;39:1-23.

5. Kuhns MC. Viral hepatitis. Lab Med. 1995;26:650-659.

6. Perrillo RP, Mimms L, Schechtman K, Robbins D, Campbell C. Monitoring of antiviral therapy with a quantitative evaluation of HBeAg: A comparison with HBV DNA testing. N Eng J Med. 1993;18:1306-1312.

7. Chazouilleres O, Michael K, Combs C, et al. Quantitation of hepatitis C virus RNA in liver transplant recipients. Gastroenterology. 1994;106:994-999.

8. Fried MW, Hoofnagle JH. Therapy of hepatitis C. Seminars in Liver Disease. 1995;15:82-91.

9. Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon alfa: A multicenter randomized, controlled trial. N Engl J Med. 1989;321:1501-1506.

10. Lau JY, Davis GL, Kniffen J, et al. Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. The Lancet. 1993;341:1501-1504.

11. Tassopoulos NC, Hatzakis A, Kuhns MC. Clinical and laboratory features of acute community-acquired non-A, non-B, non-C hepatitis. In: Nishiokak, Suzuki H, Mishiro S, Oday T, eds. Viral Hepatitis and Liver Disease. Tokyo, Japan: Springer Verlag; 1994: 80-84.

12. Fry KE, Linnen J, Zhang-Keck Z-Y, Fung K, Hoover C. Sequence analysis of hepatitis G virus (HGV) reveals a unique virus in the Flaviviridae family. Transfusion. 1995;35:S222.

13. Hess G, Horsch A, Hadziyannia S, et al. The prevalence of a new hepatitis virus (HGV) in patients with liver disease and in groups at high risk of exposure to blood and blood products. Transfusion. 1995;35:S224.

14. Linnen JM, Zhang-Keck Z-Y, Fung K, et al. Sequence variation of the hepatitis G virus. Transfusion. 1995;35:S223.

15. Hepatitis C: Improved options available for diagnosis and treatment. Mayo Clinical Update. 1993;9:7-8.

CE

To earn CEUs, see test on page 40.

Objectives of this article:

1. Name the causative agents and describe the routes of transmission for hepatitis A, B, C, D, E, and G.

2. Describe the clinical presentation of infection for the above viruses.

3. Identify hepatitis viruses for which vaccines are available and to whom they should be administered.

4. Identify and discuss laboratory tests used to diagnose and confirm cases of hepatitis A, B, C, D, E, and G.

CE test published through an educational grant from SB SmithKline Beecham Clinical Laboratories

Joyce G. Schwartz is the medical director for Corning Clinical Laboratories, Texas region. At the time of this writing, Schwartz was medical director of chemistry at University Hospital in San Antonio, Texas, where Kathy M. Stellato is the supervisor of immunology and serology.