Discussion

Normal Formation of Hepatitis B Core Antibody (Anti-HBc)

Hepatitis B core antibody (anti-HBc) is directed against the hepatitis B core antigen (HBcAg) peptides (Figure 1). The anti-HBc is the earliest antibody to develop in response to acute hepatitis B virus (HBV) infection, appearing predominantly as IgM anti-HBc at about 6 to 8 weeks after infection (Figure 2). The anti-HBc typically persists for life, but after about 6 months the total anti-HBc mainly consists of IgG anti-HBc[1]. For patients with resolved acute HBV infection, the IgM anti-HBc is not usually detectable after 6 months. With chronic HBV infection, the IgM anti-HBc can remain detectable at very low levels, even years after infection[1]. Isolated anti-HBc is defined as the presence of anti-HBc in the absence of detectable h epatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs). When routine HBV serology is requested, most laboratories report total levels of anti-HBc, which can consist of a combination of IgM and IgG antibodies. Accordingly, providers must specifically request measurement of IgM anti-HBc if they suspect acute HBV infection. In addition, some patients with isolated anti-HBc will have detectable hepatitis B e antibody (anti-HBe), but most routine hepatitis testing does not include anti-HBe. For a more detailed discussion of serologic responses with acute and chronic HBV, see the case Serologic and Virologic Markers of Hepatitis B Virus Infection.

Potential Causes of Isolated Hepatitis B Core Antibody Test

The finding of isolated anti-HBc may result from a (1) a false positive test, (2) the presence of IgM anti-HBc during the "window period" following acute HBV infection, (3) remote infection with HBV without persistent viremia, and (4) remote infection with persistent "occult" infection[1].These possibilities are discussed in more detail below.

  1. False positive anti-HBc results may occur when nonspecific IgM binds to the HBcAg peptides used as a probe in the assay (Figure 3). As with any screening assay, the anti-HBc assay has greater specificity in high-risk populations. Thus, if a patient with risk factors for hepatitis B infection demonstrates isolated anti-HBc in serum, a false positive result would be less likely than in a patient without risk factors[2].
  2. Anti-HBc is the earliest antibody to develop in response to acute HBV infection, appearing in IgM form as early as 12 weeks after infection (Figure 4). The IgM anti-HBc may be the only marker present during the "window period," when antigenemia with HBsAg has resolved and anti-HBs has not yet developed. Such patients often have other laboratory evidence of acute hepatitis B infection, including increased hepatic aminotransferase levels or hyperbilirubinemia.
  3. The most common scenario for detecting isolated anti-HBc is probably that of resolved hepatitis B infection with waning titers of anti-HBs, particularly in populations at high risk for HBV infection (Figure 5). This conclusion is largely derived from the observation that many individuals with isolated anti-HBc do not develop evidence of new hepatitis B infection despite repeated exposures[2]. Because most such patients will also a have negative HBV DNA test[3], it is difficult to firmly establish this diagnosis of prior infection. In this scenario, the detection of anti-HBe would support the diagnosis of prior infection.
  4. In rare patients with hepatitis B infection, the patient has actively replicating HBV (at low-levels, typically less than 10,000 IU/ml), but without the production of detectable HBsAg[4]. This is an unusual clinical situation, and the biological basis for occult HBV infection remains poorly understood[25]. This situation occurs with or without detectable anti-HBs and anti-HBc; tests for HBeAg and anti-HBe are typically negative. Many patients with occult HBV will have anti-HBc as the only serologic marker to suggest HBV infection (Figure 6). The diagnosis requires measurement of detectable HBV DNA and the infection is considered chronic, since HBV is actively produced and detectable in serum.

Frequency of Isolated Hepatitis B Core Antibody

The frequency of isolated anti-HBc relates directly to the prevalence of HBV infection in the population being tested. For example, among blood donors in geographic areas with low HBV prevalence, it occurs in 0.4 to 1.7%[4,5,6,7,8,9], but in persons from HBV-endemic areas, 10 to 20% of persons tested will have isolated anti-HBc[10,11]. In areas non-endemic for HBV, certain subpopulations with high HBV prevalence, such as persons with chronic hepatitis C virus infection[12,26], HIV infection[11,13,14,15], or injection drug use (IDU)[1,11], also have a relatively higher prevalence of isolated anti-HBc.

Evaluation and Management of Patient with Isolated Hepatitis B Core Antibody

The clinical approach to the evaluation and management of isolated anti-HBc varies depending on the clinical situation. We recommend the following approach:

  • For patients with no history of risk factors for hepatitis B, the isolated anti-HBc should be considered a false positive test and the patient considered non-immune.
  • For patients with risk factors for HBV infection, such as the patient in this case, there are several options. These patients may be treated as non-immune and vaccinated with the 3-vaccine series. Alternatively, some experts recommend repeating the measurement of total anti-HBc. If the repeat test is negative (thus suggesting the initial test was a false-positive result), the patient should receive the complete HBV immunization series. If the repeat anti-HBc test is positive, the patient most likely has resolved infection with gradually waning anti-HBs titers. There is a lack of consensus regarding whether these patients should receive HBV vaccination. The options in this situation include (1) do not give any doses of vaccine, (2) give one dose and check the anti-HBs titer to see if patient has a "booster" anamnestic response (anti-HBs titer greater than 10 IU/L), or (3) give the complete vaccine series, particularly if they are HIV-coinfected[27].
  • For patients with markedly increased hepatic aminotransferase levels (greater than 10-fold increase) and a history of potential recent exposure to HBV, the isolated HBcAb may represent acute HBV infection diagnosed during the window period. A HBV DNA level (with or without an IgM anti-HBc) should be ordered to confirm this diagnosis. Providers should keep in mind that detection of IgM anti-HBc is variable, but if positive, would suggest recent infection. In addition, repeat serologic testing several weeks later should yield a positive anti-HBs result.
  • In an uncommon situation, patients may have unexplained persistently elevated hepatic aminotransferase levels caused by occult HBV infection. In this scenario, an HBV DNA level should be checked and a positive test strongly suggests the diagnosis of chronic HBV infection with an HBsAg-negative variant.

Potential Transmission of HBV by Patient

Is the patient with isolated anti-HBc infectious? Surprisingly, the answer is not clear and no large-scale investigations using extensive methods to detect HBV have been performed to provide a precise estimate of the infectious risk in patients with isolated anti-HBc. Detectable serum HBV DNA has been reported in some patients, even those with high titers of anti-HBs. Although nucleic acid amplification assays detect HBV DNA in up to 14% of patients with isolated anti-HBc, the detectable HBV DNA generally occurs at relatively low levels[16,17]. In addition, several reports have documented HBV transmission from blood and organ donors who had isolated anti-HBc[5,19,20,21], but other relatively large studies have shown no risk of HBV transmission from donors with isolated anti-HBc to kidney allograft recipients[22,28]. Nevertheless, based on available data, it appears that most persons with isolated anti-HBc have very low risk of transmitting HBV, except in settings involving potential transfer to susceptible individuals of substantial quantities of virus, such as with blood transfusion or liver transplantation[1,29]. In the latter setting, the practice of perioperative administration of hepatitis B immune globulin and postoperative prophylactic antiviral therapy has reduced the risk of HBV transmission or reactivation[23,30]. Although the infectious risk posed by our patient is probably low, he should be advised not to donate blood or sperm, nor should he identify himself as a tissue or organ donor. Of particular concern to our patient is the question of whether he is infectious to sex partners. There are no data to inform an estimate of risk associated with unprotected sex with a person who has isolated anti-HBc; the safest course is to advise him to use barrier protection (condoms) with partners whose immunization status for HBV is unknown or uncertain.

Follow-Up of Patients with Isolated Anti-HBc

The clinical implications of an isolated anti-HBc particularly the occult HBV variant remain controversial. Because patients with isolated anti-HBc generally have low or absent evidence of HBV replication, they are considered at low risk to develop the adverse sequelae of chronic hepatitis B, including cirrhosis and hepatocellular carcinoma[24]. Routine screening of this population for hepatocellular carcinoma is not recommended. Closer follow-up however may be indicated for patients with isolated anti-HBc who undergo immunosuppressive therapy with either chemotherapeutic agents for cancer or biologics like rituximab (Rituxan) for immune-mediated diseases since such patients are at risk for HBV reactivation[31,32]. Because this reactivation can manifest as fulminant hepatitis, patients with isolated anti-HBc may benefit from HBV DNA testing and preventive HBV-active therapy for those found to have occult HBV infection[25].

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    Figure 1 - Total Hepatitis B Core Antibody Response to Infection with HBV

    Total hepatitis B Core antibody (anti-HBc) is the first detectable host response to acute HBV infection. The anti-HBc appear as a response to HBcAg peptides (smaller fragments of the HBcAg). During acute infection, anti-HBc predominantly consists of IgM antibodies. The total anti-HBc generally persists with resolved infection and with chronic infection. Six months or longer after infection, the antibodies predominantly consist of IgG anti-HBc.

    Figure 1
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    Figure 2 - IgM Hepatitis B Core Antibody Response to Infection with HBV

    These IgM hepatitis B core antibodies (IgM anti-HBc) make up most of the total anti-HBc in the initial host response to acute infection. The IgM anti-HBc are produced as a response to HBcAg peptides (smaller fragments of the HBcAg). The IgM anti-HBc antibodies typically become undetectable after approximately 6 months.

    Figure 2
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    Figure 3 - False-Positive Isolated Anti-HBc Caused by Cross-Reactive Antibodies

    In some instances, patients will generate antibodies that cross react with HBcAg peptides and thus can generate a false-positive anti-HBc serologic response.

    Figure 3
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    Figure 4 - Isolated Anti-HBc During Window Period Following Acute Infection

    With acute HBV infection, many patients resolve their infection and may have an early decline in HBsAg prior to development of detectable anti-HBs. If, as shown in this graph, testing occurred between weeks 20-24, the patient would have with an isolated positive anti-HBc test, since the HBsAg and anti-HBs tests would be below the threshold of detection during this “window” period.

    Figure 4
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    Figure 5 - Resolved HBV Infection with Waning Anti-HBs

    In some patients who resolve their HBV infection, anti-HBs titers may gradually wane, whereas their total anti-HBc remain detectable. Because these patients do not have chronic infection, the HBV DNA is not detectable.

    Figure 5
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    Figure 6 - Persistent HBV Infection with Absent HBsAg and Anti-HBs

    In an unusual situation, patients may have persistent HBV infection without the production of detectable HBsAg. These patients may have persistent increases in hepatic aminotransferase levels, but typically have low levels of HBV DNA.

    Figure 6