Management of the HBsAg Positive Patient

By Coleman I. Smith, M.D.

This article is reprinted with permission of the Hepatitis B Coalition.

Introduction

The hepatitis B virus (HBV) is a DNA virus and a member of the hepadna family of viruses, and is a very common virus with an estimated 300 million carriers worldwide. Only 1 - 1.5 million of these are in the United States. Hepatitis B is much more prevalent in other areas of the world such as parts of Asia including Southeast Asia, sub-Saharan Africa, and some of the Mediterranean countries. It is in these areas that hepatitis B-induced liver cell cancer is such a common problem.

In those populations where hepatitis B is endemic, the virus is usually transmitted from the infected mother to her child during the birth process or sometimes between children, especially in areas where overcrowding is common.

This is in contrast to the situation in Western countries where infection is most often spread by the parenteral route, e.g., from needle stick, or by sexual contact. Thus in these areas, infection usually occurs in young adults. Because failure to clear the virus and development of chronicity is much more common in those infected at a very young age, chronic hepatitis B is much less common in Western countries than in areas where hepatitis B is endemic.

Serologic Data

The hepatitis B virus is a complex virus with a central core and a protein coat. A number of antigens are associated with this virus and each antigen may result in the production of a corresponding antibody. Some of these antigens and antibodies are detected in routine commercially available assays. Assays to detect the hepatitis B virus DNA are now also available.

When the hepatitis B virus infects the liver, it replicates and produces excess surface material, some of which reaches the blood. Only when there is a great deal of viral replication does a significant load of the virus reach the blood. When there is less viral replication, the virus core is only detected in the liver but not in the blood (when assayed by the routine commercially available tests). The marker for the surface is HBsAg (hepatitis B surface antigen) and the markers for the core are HBeAg (hepatitis B "e" antigen) and HBV-DNA.

There is a recently described mutant strain of HBV (pre-core mutant) in which the virus cannot manufacture HBeAg and thus the only marker for the presence of the virus core is HBV-DNA. These patients may have antibodies to HBeAg and often have very severe liver disease.

Natural History

Acute hepatitis B

When an individual is infected with hepatitis B virus, a typical acute hepatitis can result. A significant number of cases produce a sub-clinical and often unnoticed infection. Rarely (<1%) fulminant hepatitis may develop and this has a very high mortality rate. These people are often treated by urgent liver transplantation. Most people with an acute infection test positive for HBsAg and IgM-antiHBc. After a variable period of time, the HBsAg will disappear and anti-HBs will appear, signifying termination of the infection.

The presence of hepatitis B surface antigen (HBsAg) signifies infection with the virus but does not give any information concerning infectivity or the presence of ongoing liver damage. When the virus is cleared from an individual, the antibody to hepatitis B surface (anti-HBs) develops and confers immunity to further virus infection. Anti-HBs often remains for life.

The finding of hepatitis B "e" antigen (HBeAg), a marker of the core of the virus, usually means that there is a great deal of viral replication allowing the core to be present in the blood. The disappearance of HBeAg and the appearance of an antibody to HBeAg usually means that the level of viral replication and associated liver disease has lessened and this individual is less capable of infecting others.

At some stage during the acute infection, HBeAg will be present but is usually cleared as the virus replication and liver damage is reduced. This disappearance may be followed by the transient appearance of anti-HBe.

Hepatitis B core antigen (HBcAg) never appears freely in the blood. The corresponding antibody (anti-HBc) appears in the blood at about the same time as HBsAg and usually remains for life, even if HBsAg is cleared. Anti-HBc does not imply immunity but merely signifies that the individual has at some time been infected with the hepatitis B virus. If the anti-HBc is of the IgM class of antibodies (as detected by routine clinical assay) this signifies that the individual has recently been infected; but if only the IgG antibody is detected, then the infection probably occurred at least six months prior to the test.

Chronic hepatitis B

Most individuals infected with hepatitis B virus will clear the virus with the development of anti-HBs. Only about five percent of people will not clear HBsAg and will not develop anti-HBs. Anti-HBc will remain positive in these patients. Those infected at a very young age are more likely to develop chronic infection.

When an individual develops chronic hepatitis B, a variety of outcomes are possible, ranging from a chronic carrier state with very little, if any, liver damage to ongoing chronic hepatitis of varying degrees of severity. The latter may at times progress to cirrhosis with all its clinical sequelae.

During the early phase of chronic infection, there is often significant viral replication and ongoing liver damage as manifested by HBeAg positivity and elevated transaminases. This often disappears after a variable period of time although it may sometimes take some years for this to occur. When the HBeAg does disappear, the liver disease becomes more quiescent and the patient is less infectious. It is in this stage that the virus DNA may become integrated into the host liver cell DNA. Hepatocellular carcinoma may complicate long-standing chronic hepatitis B infection.

Even after the HBeAg has disappeared and the liver disease has become relatively inactive, the whole process may be reactivated. Multiple cycles of reactivation may occur. Episodes of reactivation may occur spontaneously or may be precipitated by a course of immunosuppressant therapy (such as steroids or chemotherapy given for an unrelated illness). Such an event may result in worsening of the liver disease with a potentially severe outcome. Thus, one has to watch closely any chronic hepatitis B carrier who requires immunosuppressant therapy.

Management of HBsAg Positive Patients

Patients who are HBsAg positive should be assessed as follows:

1. Virologic and hepatic status
   
   Clinical history (including family history) should be taken, in particular looking for evidence of symptomatic liver disease in the patient, family, or household member.
   
   Physical examination to look for evidence of liver disease such as spider nevi, jaundice, ascites, etc.
   
   Biochemical tests to assess liver status (bilirubin, transaminases, albumin, prothrombin time.) All of these should be repeated every six months.
   
   Anti-HBc IgM should be measured for evidence of recent (less than six months) acquisition of the virus. This need only be done at initial presentation and only repeated if positive.
   
   HBeAg and/or HBV-DNA should be measured to assess if active viral replication is present.
   
   Individuals who have clinical and biochemical evidence of liver disease should be further assessed and consideration given to liver biopsy. In those with liver disease and active viral replication (HBeAg positivity) treatment with interferon should be considered. This treatment is FDA-approved. There are clinical trials underway involving other antivirals, e.g., lamivudine, which are showing promising results.
   
   All HBsAg carriers should be monitored for the development of hepatocellular carcinoma. Although there is much debate on the degree of frequency of such monitoring and the modalities to be used, a reasonable approach is to do ultrasound and alpha-fetoprotein estimation every six month, especially if the infection has been present for ten years or more.
   
   
2. Risks to others
   
   Sexual contacts of any person acutely infected with hepatitis B are at risk of acquiring hepatitis and should be vaccinated.
   
   Family members of chronically infected persons (including non-sexual contacts) are at risk of acquiring hepatitis B and, if not already infected or immune, should be vaccinated. This approach should also be adopted to newborn members of infected families, especially if the mother is infected. In this latter case, hepatitis B immune globulin (HBIG) should also be administered to provide immediate protection.

Conclusion

Hepatitis B virus infection is a complex virus which can produce a variety of clinical situations. It can produce subclinical or clinical acute hepatitis and it can go on to chronic hepatitis. This latter event is more common when infection occurs at a very young age and is therefore more frequent in areas of the world where the disease is highly prevalent and maternal-fetal spread is common.

Chronic hepatitis infection can produce a range of sequelae, from very little liver damage to chronic hepatitis varying from mild to more severe, or even cirrhosis with all its complications. Hepatocellular carcinoma is a risk of long-standing chronic hepatitis B infections.

This disease can now be prevented by vaccinating all at-risk persons. There is also some new data suggesting that suitable patients with chronic hepatitis B with significant liver damage and ongoing viral replication may benefit from treatment with interferon. Trials of other antivirals (e.g., lamivudine) are ongoing and appear to have promising results without significant side effects.

What the Physician Can Do to Help the Adult Hepatitis B Carrier

Coleman I. Smith, M.D.
Hepatologist
Minnesota Gastroenterology
Minneapolis, MN 55404
612-871-1145

1. A YEARLY PHYSICAL to ensure the patient is healthy without overt evidence of severe liver disease. This should include evaluation of routine liver biochemistry (AST, ALT, alkaline phosphatase) and liver function (bilirubin, albumin, prothrombin time) tests. Referral to a specialist gastroenterologist/hepatologist if there is evidence of deterioration in liver function.
   
   
2. ALPHA-FETOPROTEIN (AFP)* every six months. The AFP is a tumor marker which may become elevated when hepatocellular carcinoma is present.
   
   
3. AN ULTRASOUND OF THE LIVER* every six months. The ultrasound may show small cancers in the liver before the blood abnormalities develop and while the cancer is still treatable.
   
   
4. HBsAg TESTING. HBsAg should be checked every year to see if a person is still a carrier. Less than 1% of carriers clear HBsAg and develop anti-HBs each year.
   
   
5. HBeAg TESTING. If a person remains HBsAg positive, HBeAg should be checked every year. This latter test will demonstrate in most cases if the virus is actively replicating. A person who is HBeAg positive (+) or has an AST>200 should be referred to a gastroenterologist/hepatologist for evaluation of need for liver biopsy and anti-viral treatment. Indications for referral include any of the following:
   
   
   • HBeAg positivity
   • ALT >200
   • Deterioration in liver function
   • Suspicion of a liver tumor
     
     (The American Liver Foundation will provide names and phone numbers of gastroenterologists and hepatologists in various regions of the United States to whom patients may be referred. The phone number is 800-223-0179.)
     
     
6. TESTING OF HOUSEHOLD MEMBERS. All members of the carrier's household and his/her sexual partners should be tested for hepatitis B. If found susceptible or if they have an indeterminate pattern (an isolated anti-HBc +) they should be vaccinated against hepatitis B, even if pregnant.
   
   
7. HEPATITIS B EDUCATION. Each hepatitis B carrier should receive hepatitis B education, as should his/her household members and sexual partners. Brochures to assist with education are available in many languages and are free from the Hepatitis B Coalition, a program of the Immunization Action Coalition. (See the address and phone number below.)
   
   * especially if infection has been present for over ten years.

Dr. Smith is a consultant gastroenterologist/hepatologist at Minnesota Gastroenterology in Minneapolis. Smith has done extensive research on hepatitis and is the author of dozens of publications. He has written two articles for the Hepatitis B Coalition on the care of the adult hepatitis B carrier. Additionally, Smith is a member of the Advisory Board of the Hepatitis Coalition. This article is reprinted with permission of the Hepatitis B Coalition.