GASTROENTEROLOGY 1994;106:1006-1016 Distinguishing Between Acute and Symptomatic Chronic Hepatitis B Virus Infection TOSHIYUKI MARUYAMA,” FLORIAN SCHODEL,’ SHIRO IINO,§ KAZUHIKO KOIKE,” KIYOMI YASUDA,” DARRELL PETERSON,n and DAVID R. MILICH* *Department of Molecular Biology, Scripps Research Institute, La Jolla, California; ‘Department of Bacterial Diseases, Walter Reed Army Institute of Research, Washington, D.C.; %stitute of Medical Science, St. Marianna University Medical School, Kanagawa, Japan; “First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan; and qDepartment of Biochemistry, Virginia Commonwealth University, Richmond, Virginia B~cIG%x&/A~~s: Differentiating between an acute hep atitis B (AH-B) infection and an acute exacerbation of a chronic hepatitis B (CH-B) infection can present a prob lem for the clinician. The only current serological method of distinguishing between acute and symptomatic chronic hepatitis B virus (HBV) infection is the immunoglobulin M antibody to hepatitis B core antigen (anti-HBc) assay, which can be problematic. Therefore, in an attempt to better distinguish between acute and chronic HBV infec- tion, sera from 26 patients with AH-B and 53 patients with CH-B were compared in a variety of experimental immunoassays. Methods: Experimental assays have been designed to detect free antibody to hepatitis B e antigen (anti-HBe), hepatitis B e antigen (HBeAg)/anti- HBe immune complexes (ICs), and hepatitis B surface antigen (HBsAg)/antibody to hepatitis B surface antigen (anti-HBs) in the presence of excess antigen. An addi- tional assay was developed to detect a novel anti-HBc specificity, designated antibody to woodchuck hepatitis virus (anti-HBcW), which cross-reacts with the core anti- gen of the woodchuck hepatitis virus. Results: Sera from patients with CH-B showed significantly higher levels of free anti-HBe, HBeAg/anti-HBe ICs, and HBsAg/anti-HBs ICs compared with AH-B patient sera. Furthermore, pa tients with CH-B consistently produced high titer anti- HBcw, whereas patients with AH-B produced little or no anti-HBcW antibody. Conclusions: The serology of AH-B infection and symptomatic CH-B infection can be distin- guished using a variety of experimental immunoassays in addition to the immunoglobulin M anti-HBc assay. I nfection with the hepatitis B virus (HBV) often results in subclinical or acute self-limited liver disease or long-term infection. Chronic HBV infection elicits a spectrum of disease entities ranging from the most severe form of chronic active hepatitis (CAH) to less severe chronic persistent hepatitis (CPH) to the asymptomatic carrier state. An array of diagnostic assays have recently been developed to aid the clinician in differentiating HBV infections from other forms of viral hepatitis (i.e., hepatitis A virus, hepatitis E virus, and hepatitis C virus). However, the ability to distinguish between acute hepa- titis B (AH-B) infection and symptomatic chronic hepa- titis B (CH-B) infection can still be problematic. This is especially true because patients with CAH and CPH often show a cyclic pattern of hepatitis characterized by acute exacerbations (AE) of liver injury alternating with normal liver function. During the symptomatic phases of infection, both patients with acute and chronic HBV are likely to show similar serologies as determined by the available commercial assays. For example, during symptomatic periods, patients with acute and chronic HBV have increased liver enzyme levels and the hepatitis B surface antigen (HBsAg) in their serum and produce antibodies to the hepatitis B core antigen (HBcAg), but antibodies specific for the HBsAg or the hepatitis B e antigen (HBeAg) are not detected. Antibody production to HBcAg occurs early in the course of the acute phase of HBV infection and can persist for many years,‘,* and chronically infected patients produce high titers of anti- body to hepatitis B core antigen (anti-HBc).j In contrast to most viral infections, patients with acute and chronic HBV often produce both immunoglobulin (Ig) M class and IgG class anti-HBc antibodies; therefore, the mere presence of IgM anti-HBc is not diagnostic of an acute infection. 4-7 However, higher levels of IgM anti-HBc are generally produced during the acute phase as compared with chronic infection, and this quantitative difference has become the only serological means of differentiating an acute HBV infection from an AE of a chronic infec- Abbreviations used in this paper: AE, acute exacerbation; AH-B, acute hepatitis B; anti-HBc”‘ , antibody to hepatitis B core antigen that cross-reacts with woodchuck core antigen; anti-WHc, antibody to woodchuck core antigen; ASC, asymptomatic carrier; CH-B, chronic hepatitis B; Cl, cutoff index; CPH, chronic persistent hepati- tis; EIA, enzyme immunoassay; IC, immune complexes; 2ME, 2-mer- captoethanol; P/N, positive/negative; Th, T helper cell; WHcAg, woodchuck core antigen. 0 1994 by the American Gastroenterological Association 00165065/94/$3.00
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