Clinical, Biochemical, Immunological and Virological Profiles of, and Differential Diagnosis Between, Patients With Acute Hepatitis B and Chronic Hepatitis B With Acute Flare

Yongnian Han; Qun Tang; Wei Zhu; Xiaoqing Zhang; Longying You


J Gastroenterol Hepatol. 2008;23(11):1728-1733. 

In This Article

Abstract and Introduction


Background and Aim: In areas with high or intermediate endemicity for chronic hepatitis B virus (HBV) infection, it is difficult to distinguish acute hepatitis B (AHB) from chronic hepatitis B with an acute flare (CHB-AF) in patients whose prior history of HBV infection has been unknown. The present study aimed to screen laboratory parameters other than immunoglobulin M antibody to hepatitis B core antigen (IgM anti-HBc) to discriminate between the two conditions.
Methods: A retrospective and prospective study was conducted in patients first presenting clinically as HBV-related acute hepatitis to sort out acute self-limited hepatitis B (ASL-HB). Then, clinical and laboratory profiles were compared between patients with ASL-HB and CHB-AF. Parameters closely associated with ASL-HB were chosen to evaluate sensitivity, specificity, accuracy, positive predictive values and negative predictive values for diagnosing AHB.
Results: There were significant differences between patients with ASL-HB and CHB-AF in relation to clinical and laboratory aspects, with many outstanding differences in levels of serum HBV-DNA, hepatitis B e antigen (HBeAg) and alpha-fetoprotein (AFP) as well as IgM anti-HBc. In particular, there was a greater difference between the two groups in low levels of HBeAg (ratio of the optical density of the sample to the cut-off value [S/CO] <20) than in negativity for HBeAg (42.7% and 13.5% vs 49.3% and 45.9%). 1:10 000 IgM anti-HBc had a sensitivity and specificity of 96.2% and 93.1%, respectively, for predicting ASL-HB. Combining it with AFP, HBeAg or HBV-DNA could improve diagnostic power. A combination of IgM anti-HBc, HBV-DNA and HBeAg had a predictive value of 98.9% and a negative predictive value of 100.0%, similar to that of a combination of IgM anti-HBc and HBV-DNA. Adding AFP to the combinations of IgM anti-HBc and HBV-DNA or HBeAg could further heighten the positive predictive value. The positive predictive value and negative predictive value of the combination of IgM anti-HBc, HBV-DNA and AFP were both 100.0%.
Conclusions: (i) There are significant differences with respect to clinical, biochemical, immunological and virological aspects between ASL-HB and CHB-AF. (ii) Of several diagnostic combinations, IgM anti-HBc jointing HBV-DNA is most effective and most practicable in distinguishing ASL-HB from CHB-AF. (iii) A low HBeAg level is more useful than negative HBeAg in differential diagnosis between ASL-HB and CHB-AF. (iv) In those patients with a high level of IgM anti-HBc, serum AFP level >10× upper reference limit could rule out a probability of ASL-HB.


Hepatitis B virus (HBV) is a peculiar virus, leading to both an acute infection and a chronic one. HBV-related acute hepatitis may be a true episode of acute hepatitis B (AHB) or an acute flare of chronic hepatitis B (CHB) hitherto unknown. It is important to distinguish AHB patients, a great number of whom will have a self-limited, benign course and not require intervention, from patients with CHB with an acute flare (CHB-AF) who will not have such a benign course and benefit from treatment with antiviral agents.[1]

The presence of serum hepatitis B surface antigen (HBsAg) with clinical and biochemical features of acute hepatitis usually suggests AHB in patients from low HBV infection endemic areas but not in patients from high or intermediate HBV endemic regions, where AHB and CHB-AF may be misdiagnosed mutually, especially if patients' antecedent HBV carrier status is unknown.

Immunoglobulin M antibody to hepatitis B core antigen (IgM anti-HBc) has been well recognized as a gold standard for diagnosis of acute HBV infection.[2,3] The commercially available enzyme immunoassays (EIA) for IgM anti-HBc have been designed to detect only higher titers of the antibody, but IgM anti-HBc is present in approximately 10-15% of patients with CHB, especially in those with CHB-AF.[2,3] IgM anti-HBc in high titers had a high sensitivity (90-100%) and specificity (90-100%) for the diagnosis of acute HBV infection.[4,5,6] The results, however, were obtained by comparison of acutely HBV-infected patients with those with common CHB without an acute flare, even with healthy individuals who were only positive for anti-HBc. When CHB-AF was compared, IgM anti-HBc in a titer of 1:1000 had a sensitivity of only 77.6% and a specificity of 70.0% for diagnosing AHB.[7] Although a fully automated microparticle chemiluminescent immunoassay in which significant specimen dilution and multiple steps are avoided, has recently been developed, an ideal cut-off value to differentiate AHB from CHB-AF seems not to be established, because a great range (1.5, 2.4-2.5 and 10) of cut-off index values have been reported in patients from Greece, Taiwan and Italy; 90-85% and 100%, respectively, regarding sensitivity and 86-90% and 99%, respectively, regarding specificity for diagnosing acute hepatitis B were shown in the two latter studies.[8,9,10] However, the nearly perfect diagnostic power from Italy's study also resulted from comparison of AHB with common CHB without acute exacerbation.[10]

Therefore, it is necessary to seek other parameters to assist IgM anti-HBc to distinguish AHB from CHB-AF in patients with no prior HBV infection history information whose diagnosis could not be made by IgM anti-HBc alone during hospitalization. It has been reported that HBV-DNA <0.5 pg/mL at initial presentation had a sensitivity of 95.9% and a specificity of 86.6% for predicting AHB in a recent study.[7] Unfortunately, there were only 49 patients with AHB in the study and the diagnostic performance of a combination of IgM anti-HBc and HBV-DNA was not displayed. The present large study is intended to find better methods to discriminate the two diseases by comparison of the characteristics of patients with ASL-HB and CHB-AF with regard to clinical, biochemical, immunological and virological aspects.


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