Which Patients With Chronic Hepatitis B Require a Liver Biopsy?
Hepatitis B virus (HBV) infection is a significant global health issue that affects over 2 billion persons worldwide. In the United States, approximately 1.25 million persons have chronic infection and approximately 150,000 new infections are recorded each year. Individuals infected with HBV go through a series of serologic steps, which either results in spontaneous resolution of this virus and the development of protective hepatitis B surface antibodies (anti-HBs) or chronic HBV infection where hepatitis B surface antigen (HBsAg) persists in serum. Almost immediately after becoming infected, antibodies to hepatitis B core (anti-HBc) appear in serum, followed soon thereafter by HBsAg and then E-antigen. The E-antigen of HBV has traditionally been thought of as a marker of active viral replication. Over several weeks or months, the host immune response inactivates HBV and E-antigen becomes undetectable and is replaced by antibody (anti-E). This is followed by loss of HBsAg and the development of anti-HBs (Figure 9-1). The likelihood of spontaneously resolving HBV is directly related to patient age and whether jaundice occurred at the time of the acute infection. Thus, infants exposed to HBV vertically at birth rarely become jaundiced, only about 10% resolve the acute infection, and nearly 90% develop chronic HBV. In contrast, most adults develop acute icteric HBV and over 95% resolve this infection spontaneously.
Figure 9-1. Pattern of serum aminotransferse activity (AT) and serologic testing in a patients with acute HBV who develops spontaneous resolution.
Individuals who resolve acute HBV spontaneously and develop anti-HBs are immune and protected against reinfection from HBV. Over many decades, the level of anti-HBs in serum may decline below the level of detection. However, such persons typically remain positive for anti-HBc and anti-E. Administering a single dose of HBV vaccine acts like a booster in such individuals and results in the production of high-titer anti-HBs in serum.
Patients who develop chronic infection do not mount an appropriate immune response against HBV and remain HBsAg, E-antigen, and anti-HBc antibody positive (Figure 9‑2). Such patients continue to have elevated serum liver aminotransaminases (AT), high levels of HBV DNA in serum, and active hepatitis on liver biopsy. After a variable period of time, many of these patients with chronic active HBV resolve E-antigen and produce anti-E, a step referred to as seroconversion. This process is typically preceded by an acute elevation in serum ALT and, in some cases, symptoms of acute hepatitis. Some patients may even become icteric. Patients who have had active HBV for many decades and developed cirrhosis prior to seroconversion are at risk of decompensation and liver failure when they serconvert. Following seroconversion, HBV becomes “inactive,” replication of HBV DNA declines to very low levels, serum AT declines to the normal range, and liver inflammation resolves. Patients with inactive HBV may remain in this dormant state for decades. However, these patients remain at risk to “reactivate.” This is why all patients with inactive HBV should be monitored at periodic intervals. Reactivation may occur spontaneously or in response to any process that suppresses the immune response, including chemotherapy, the use of immune suppressive agents, or coinfection with the human immune deficiency virus (see Question 16).
Figure 9-2. Pattern of serum aminotransferse activity (AT) and serologic tests in a patient with acute HBV who develops chronic active infection and then seroconverts to a chronic inactive.
Viruses are prone to developing mutations and many variants of HBV are known to exist.1 Mutations may alter specific proteins (antigens) produced by HBV in such a way that they are unrecognizable by current serologic tests. In some cases, antibodies produced by the host in response to mutant antigens may also not be recognized by current assays. A common mutant form of HBV is the “precore” mutant, where a single nucleotide substitution results in the formation of a stop codon along the open reading fame of the precore gene. This causes the E-protein to be shortened, no longer functional, and unrecognized by the E-antigen assay. However, patients with the precore mutant form of HBV have all other features of active HBV, including HBsAg, anti-HBc, elevated serum AT, high levels of HBV DNA in serum, and active hepatitis on liver biopsy. These patients should be referred to as having E-antigen–negative chronic active HBV. On average the level of HBV DNA in the serum of these patients is approximately 10-fold lower than observed in patients with E-antigen–positive chronic active HBV.
As outlined in Table 9-1, mutations may also occur in the surface and core genes of HBV. Although the hallmark of chronic infection with HBV is surface antigen, a mutation in this gene may yield a surface protein that cannot be recognized by the current assay. These patients are positive for anti-HBV core, have an elevation in serum AT, detectable HBV DNA in serum, and active hepatitis on liver biopsy but are HBsAg negative. Recognizing patients with active HBV and mutations in the surface gene may therefore be a formidable challenge. In some cases, these patients may have anti-s, produced in response to a previous “wild-type” HBV infection. Mutations of the HBV core gene have also been reported. Such patients produce an abnormal core protein. In turn, the host either fails to produce an antibody against this protein or produces an antibody against HBcore that is not recognized by the current anti-HBcore assay. Such patients are recognized because they are positive for HBsAg and may have either active or inactive HBV.
As noted in Question 3, when the role of liver biopsy was discussed, in patients with chronic hepatitis C virus (HCV), a liver biopsy is also only necessary in patients with chronic HBV if the information gained by this procedure will affect disease management and, in particular, the need for treatment. In the case of chronic HBV, it is therefore best to assess the need for liver biopsy in relation to the serologic and biochemical status of the HBV infection.
Chronic HBV infection can be divided into 2 states as summarized in Table 9-2: active and inactive disease.2 Patients with active HBV generally have an elevation in serum AT activity and serum levels of HBV DNA greater than 100 000 (1 × 105) IU/mL. On liver biopsy nearly all of these patients have active hepatitis with variable degrees of fibrosis. These patients may be either E-antigen positive or negative depending upon whether they are infected with wild-type HBV or the precore mutant form of this virus. Almost all experts would agree that these patients should be considered candidates for treatment. At the other end of the spectrum are patients with inactive HBV. These patients tend to have normal serum AT and undetectable or low levels (<105 IU/mL) of HBV DNA. They are almost always E-antigen negative, anti-E positive and on liver biopsy they have no evidence of inflammation and in most cases no fibrosis. As a result, there is no reason why these patients require treatment for HBV.
Between these two extremes lies a grey zone of patients who do not fit into either of these two categories with discordant levels for serum AT and HBV DNA. One form
of discordance is referred to as immune tolerant because the immune system does not appear to be mounting an effective immune response against HBV. On liver biopsy no inflammatory response against HBV-infected hepatocytes is apparent and as a result the serum AT is normal and serum HBV DNA is very high. It is unclear why the immune system appears to “tolerate” HBV in some patients. This phase of HBV may last for several months or decades. Treatment has not been advocated for patients with immune tolerance to HBV for several reasons. Without inflammation, fibrosis progression does not occur and as a result treatment yields no histologic benefit. However, a more important reason for not treating a patient in the immune-tolerant phase is that treatment is likely to be ineffective. It is currently believed that a viable immune response against HBV is required for treatment to be effective, and this appears to be true for both peginterferon and oral antiviral agents. Peginterferon works primarily by enhancing the immune response against HBV and if no immune response is present, peginterferon will be ineffective (see Question 10). Even very potent antiviral agents are unlikely to suppress HBV DNA to undetectable levels in patients without an immune response to HBV. As a result, the use of an oral antiviral agent in this setting is likely to promote resistance to the antiviral agent. For these reasons, all previous clinical trials evaluating either peginterferon or antiviral agents have excluded immune-tolerant patients. Performing a liver biopsy in these patients is often helpful to ensure that no ongoing inflammation is present and to confirm that the patient is indeed in an immune-tolerant state.
The other type of discordance is the patient with an elevated serum AT but low or undetectable HBV DNA. This pattern may be seen in patients with HCV or hepatitis D virus (HDV) coinfection because the coinfecting virus inhibits HBV replication (see Question 13). Alternatively, another cause for the elevation in serum AT, other than HBV, may be present histologically. Thus, liver biopsy is often essential in the patient with an elevated serum AT but low levels of HBV DNA.
Liver biopsy may also be helpful in many patients with mutations in the HBV genome. As noted above, the most common variant of HBV is the precore mutation. These patients cannot seroconvert to an inactive state either spontaneously or in response to treatment. The goal of HBV therapy in these patients is to suppress HBV DNA and this is typically a lifelong process (see Question 10). As a result, before committing a patient to lifelong treatment it is often important to document that treatment needs to be initiated at this time and should not be deferred. This is particularly true in young persons, where the lifelong risk of resistance needs to be balanced against the need to treat HBV. As a result, a liver biopsy may be useful in some patients with E-antigen–negative HBV. Performing a liver biopsy and confirming active HBV infection through immunohistochemical staining of liver tissue is also helpful in patients with atypical serologic HBV testing. This is most commonly observed in patients with mutations in the surface or core genes or in patients who are also infected with HCV, HDV, or human immunodeficiency virus (HIV).
In summary, a liver biopsy is not necessary in patients with classic E-antigen–positive or E-antigen–negative HBV as long as no absolute or relative contraindications to treatment exist. Similarly, a liver biopsy is not indicated for patients with inactive HBV since such patients do not require therapy. However, we find that a liver biopsy is extremely useful in those patients who fall outside these classic criteria and in patients with unusual mutations of the HBV genome. A liver biopsy is also useful in young patients with E-negative chronic active HBV since this carries with it a lifelong risk of resistance. These issues will be discussed in more detail in Questions 10 through 12.
1. Baumert TF, Barth H, Blum HE. Genetic variants of hepatitis B virus and their clinical relevance. Minerva Gastroenterol Dietol. 2005;51:95-108.
2. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936-962.