See article in J. Gastroenterol. Hepatol. 2006; 21: 859–862. Since the 1980s, assay of immunoglobulin class M (IgM) anti-HBc (antibody against hepatitis B core antigen [HBcAg]) has been applied for the differential diagnosis of acute viral hepatitis.1 Methods for detecting class-specific antibody are based on a different test principle than sandwich assays or competitive immunoassay. The tests use an IgM capture technique wherein a portion of the serum specimen IgM is captured by antibodies that are attached to a solid phase and are directed against human IgM. The captured IgM antibodies are then sequentially exposed in incubation with HBcAg particles and with labeled anti-HBc. This method is inherently very sensitive; so many commercial companies with tests of this type have intentionally reduced its sensitivity in order to make it capable of distinguishing acute from chronic hepatitis B virus (HBV) infection. Without this desensitization, IgM anti-HBc would be detectable in some patients for years after their acute infection. One method of desensitization is elevating the cut-off to a point at which specimens’ values are positive in most patients for 3–6 months after acute infection. Specimens that give values that are negative but not within the normal range (so called ‘borderline value’) can still be recognized in some cases of chronic hepatitis B patients. The results of IgM anti-HBc thus can be categorized into positive (for acute infection), borderline and non-reactive according to the product reference. The presence of serum hepatitis B surface antigen (HBsAg) in patients who present with clinical and biochemical evidence of acute hepatitis usually suggests acute type B hepatitis. This notion is generally true for patients from low HBV endemic areas but not for those from high or intermediate HBV endemic areas. In 1983, when testing for IgM anti-HBc had not yet become widely available, Liaw et al.2 first noted that 80% of HBsAg-positive patients with acute hepatitis in Taiwan were persistently HBsAg positive 6 months after the onset of acute hepatitis. Subsequent studies confirmed that 70-80% of HBsAg-positive patients with acute hepatitis in Taiwan indeed were non-reactive for IgM anti-HBc.3 These data indicated that a high proportion of HBsAg-positive patients with acute hepatitis in Taiwan were previously unrecognized HBsAg carriers with acute exacerbation of chronic hepatitis B or superinfection with other hepatitis viruses.4,5 Similar findings have been observed in other high or intermediate HBV endemic areas.6–9 IgM anti-HBc thus should be included for serodiagnosis of acute viral hepatitis. In this issue of the Journal, Huang et al.10 from Taiwan suggests that a higher cut-off index value of IgM anti-HBc than that suggested by product reference may be needed for discriminating acute from chronic HBV infection in high HBV endemic areas. Huang et al.’s conclusion was based on comparison of the index values of IgM anti-HBc between 20 patients with acute type B hepatitis and 22 chronic hepatitis B patients with acute flares using commercial kits. According to the product reference of this assay, an index value of greater than 1.2 is used to diagnose acute hepatitis B; an index value of 0.8–1.2 is stated as borderline value and a value less than 0.8 is considered non-reactive. In this study, only patients with an index value of IgM anti-HBc greater than borderline value were included. The results showed that all 20 patients with acute hepatitis B were IgM anti-HBc positive, as were 11 (50%) of 22 chronic hepatitis B patients with acute flare. The sensitivity and specificity of IgM anti-HBc for diagnosis of acute hepatitis B was estimated to be 100% (20/20) and 65% (20/31), respectively. The finding that 11 (35%) of the 31 patients with an index value of IgM anti-HBc greater than 1.2 indeed were HBsAg carriers with acute flare convinced the authors to elevate the cut-off value of IgM anti-HBc to 2.4 or 2.5 for diagnosis of acute type B hepatitis. Elevating the cut-off value to 2.4 increased the specificity by 21% (65% to 86%) for a cost of a loss in sensitivity by 10% (100% to 90%). Several studies have shown that up to 20% of chronic B hepatitis patients with acute flare may have an index value of IgM anti-HBc greater than the cut-off value for diagnosis of acute hepatitis B.11–13 It is not known if the 22 chronic hepatitis B patients in the Huang et al.’s series were selected from among how many chronic hepatitis B patients with acute flares. However, in our previous study, 14.5% of chronic hepatitis B patients with acute flare in Taiwan were reactive for IgM anti-HBc (greater than borderline value).14 The low specificity of IgM anti-HBc for the diagnosis of acute hepatitis B based on the product reference in Huang et al.’s series may have resulted from the inclusion of relatively more IgM anti-HBc-positive chronic hepatitis B patients with acute flare (n = 11) compared to the number of acute hepatitis B patients (n = 20). This phenomenon is a very unique feature in Taiwan. Previous epidemiological studies have shown that, among patients with acute hepatitis in Taiwan, the number of chronic hepatitis B patients with acute flare far exceed the number of acute hepatitis B patients (approximately 4:1).2–5 Given that about 10% to 20% of chronic hepatitis B patients with acute flare are reactive for IgM anti-HBc, it is estimated that there are 12.5 IgM anti-HBc-positive chronic hepatitis B patients with acute flare per 30 patients with acute hepatitis B (Table 1). These data suggest that up to 30% (12.5/12.5 + 30) of patients positive for IgM anti-HBc according to the product reference were previously unrecognized HBsAg carriers with acute flares, in keeping with the finding by Huang et al.10 that 11 of 31 IgM anti-HBc-positive patients were chronic hepatitis B patients with acute flare. Unfortunately, the number of patients enrolled in Huang et al.’s series was very small. Further studies of a larger series of patients are indicated to clarify whether or not a higher cut-off value of IgM anti-HBc than the product reference may increase the specificity without much loss of sensitivity for the diagnosis of acute hepatitis B in high HBV endemic areas. Conversely, several reports have revealed that a few acute hepatitis B patients (with transient HBsAg) might have only borderline values of IgM anti-HBc.3,15,16 Notably, in these patients, the first serum samples were usually taken at the relatively early phase of disease, and the index value of IgM anti-HBc was usually elevated above the cut-off value for acute hepatitis B 1–2 weeks later. These findings suggest that it is necessary to repeat testing for IgM anti-HBc 1–2 weeks later if the first serum samples were borderline for IgM anti-HBc. Taken together, testing for IgM anti-HBc has greatly improved the diagnostic accuracy of acute hepatitis B compared to testing for HBsAg alone. However, the presence of positive IgM anti-HBc does not necessarily indicate acute type B hepatitis, especially in high HBV endemic areas and vice versa. It is particularly important to document the disappearance of HBsAg after apparent clinical recovery from HBsAg-positive acute hepatitis. In the core window of acute stage, that is, between the loss of HBsAg and the appearance of anti-HBs, IgM anti-HBc can have particular diagnostic use, especially if the patients experience an early clearance of HBsAg prior to serological testing for the illness. This is true for 5–6% of acute hepatitis B and is encountered particularly in fulminant hepatitis.17–20 Negative testing for IgM anti-HBc in HBsAg-negative patients usually indicates acute non-B hepatitis. However, the possibility of acute non-B viral superinfection in previously unrecognized HBsAg carriers with suppression of HBsAg to undetectable levels cannot be excluded.21–23 HBsAg may reappear during the convalescent phase if the suppression of HBsAg is only transient.21,22 In general, testing for IgM anti-HBc is not necessary for serodiagnosis of acute hepatitis superimposed on chronic HBsAg carriers. Approximately 10-20% of chronic B hepatitis cases with acute flare were reactive for IgM anti-HBc, but significance of reactive IgM anti-HBc in HBsAg carriers with acute flares remained unclear. The clinical and laboratory features showed no significant difference between patients positive for and those with borderline values of IgM anti-HBc in Huang et al.’s series.10 It has not been shown that the index values of IgM anti-HBc, although usually below the borderline value in most cases, are significantly higher in HBsAg carriers with acute exacerbation of chronic hepatitis B, compared to those with hepatitis C or D virus superinfection.14,24 The presence of IgM anti-HBc in HBsAg carriers with acute flare thus may suggest an acute attack of hepatitis due to HBV rather than superinfection with another virus. However, the role of IgM anti-HBc in the differential diagnosis of acute hepatitis superimposed on chronic HBsAg carriers warrants further investigation. In summary, the diagnostic value of IgM anti-HBc is well known, but based on the product reference misdiagnosis between acute and chronic infection is still possible. These rare exceptions should be kept in mind, as summarized in Table 2, particularly in high HBV endemic areas.
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Chia‐Ming Chu (2006) studied this question.
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