Diagnosis of hepatitis B virus infection
- Anna SF Lok, MD
Anna SF Lok, MD
- Professor of Medicine
- University of Michigan Medical School
The diagnosis of hepatitis B virus (HBV) infection was revolutionized by the discovery of Australia antigen, now called hepatitis B surface antigen (HBsAg). During the ensuing two decades, serologic assays were established for HBsAg and other HBV antigens and antibodies. Advances in molecular biology techniques led to the development of hybridization and polymerase chain reaction (PCR) assays for direct determination of hepatitis B virus DNA (HBV DNA). The diagnosis of HBV infection can also be made by the detection of HBsAg or hepatitis B core antigen (HBcAg) in liver tissues by immunohistochemical staining and of HBV DNA by Southern hybridization, in-situ hybridization, or PCR.
This topic review will focus on the changes in hepatitis B antigens, antibodies, and DNA levels that occur during acute and chronic infection and how these tests can be used clinically. A diagnostic algorithm will be presented for using these tests to diagnose acute hepatitis, past infection, and chronic infection.
WHO SHOULD BE TESTED OR SCREENED
We test for hepatitis B virus infection using HBsAg, hepatitis B core antibody (anti-HBc), and hepatitis B surface antibody (anti-HBs) in certain groups of patients (table 1). The interpretation of positive serologic test results is described below. (See 'Diagnostic algorithms' below.)
We evaluate the following groups of patients for HBV, regardless of their vaccination history:
●Individuals who have signs and symptoms of acute hepatitis (see "Clinical manifestations and natural history of hepatitis B virus infection")
- LeFevre ML, U.S. Preventive Services Task Force. Screening for hepatitis B virus infection in nonpregnant adolescents and adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014; 161:58.
- Schillie S, Murphy TV, Sawyer M, et al. CDC guidance for evaluating health-care personnel for hepatitis B virus protection and for administering postexposure management. MMWR Recomm Rep 2013; 62:1.
- Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep 2008; 57:1.
- Chou R, Dana T, Bougatsos C, et al. Screening for hepatitis B virus infection in adolescents and adults: a systematic review to update the U.S. Preventive Services Task Force recommendation. Ann Intern Med 2014; 161:31.
- Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50:661.
- Chu CM, Liaw YF, Pao CC, Huang MJ. The etiology of acute hepatitis superimposed upon previously unrecognized asymptomatic HBsAg carriers. Hepatology 1989; 9:452.
- Liaw YF, Sheen IS, Chen TJ, et al. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study. Hepatology 1991; 13:627.
- Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection. N Engl J Med 1982; 307:1481.
- Tsang TK, Blei AT, O'Reilly DJ, Decker R. Clinical significance of concurrent hepatitis B surface antigen and antibody positivity. Dig Dis Sci 1986; 31:620.
- Maruyama T, Schödel F, Iino S, et al. Distinguishing between acute and symptomatic chronic hepatitis B virus infection. Gastroenterology 1994; 106:1006.
- Tassopoulos NC, Papaevangelou GJ, Sjogren MH, et al. Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults. Gastroenterology 1987; 92:1844.
- Lok AS, Lai CL, Wu PC. Prevalence of isolated antibody to hepatitis B core antigen in an area endemic for hepatitis B virus infection: implications in hepatitis B vaccination programs. Hepatology 1988; 8:766.
- Chung HT, Lee JS, Lok AS. Prevention of posttransfusion hepatitis B and C by screening for antibody to hepatitis C virus and antibody to HBcAg. Hepatology 1993; 18:1045.
- McMahon BJ, Parkinson AJ, Helminiak C, et al. Response to hepatitis B vaccine of persons positive for antibody to hepatitis B core antigen. Gastroenterology 1992; 103:590.
- Hoofnagle JH, Seeff LB, Bales ZB, Zimmerman HJ. Type B hepatitis after transfusion with blood containing antibody to hepatitis B core antigen. N Engl J Med 1978; 298:1379.
- Dickson RC, Everhart JE, Lake JR, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Gastroenterology 1997; 113:1668.
- Bohorquez HE, Cohen AJ, Girgrah N, et al. Liver transplantation in hepatitis B core-negative recipients using livers from hepatitis B core-positive donors: a 13-year experience. Liver Transpl 2013; 19:611.
- Okada K, Kamiyama I, Inomata M, et al. e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N Engl J Med 1976; 294:746.
- Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 1977; 105:94.
- Hwang LY, Roggendorf M, Beasley RP, Deinhardt F. Perinatal transmission of hepatitis B virus: role of maternal HBeAg and anti-HBc IgM. J Med Virol 1985; 15:265.
- Alter HJ, Seeff LB, Kaplan PM, et al. Type B hepatitis: the infectivity of blood positive for e antigen and DNA polymerase after accidental needlestick exposure. N Engl J Med 1976; 295:909.
- Lok AS, Lai CL. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive Chinese children. Hepatology 1988; 8:1130.
- Chang MH, Hwang LY, Hsu HC, et al. Prospective study of asymptomatic HBsAg carrier children infected in the perinatal period: clinical and liver histologic studies. Hepatology 1988; 8:374.
- Hoofnagle JH, Dusheiko GM, Seeff LB, et al. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981; 94:744.
- Realdi G, Alberti A, Rugge M, et al. Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection. Gastroenterology 1980; 79:195.
- Bonino F, Rosina F, Rizzetto M, et al. Chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe. Gastroenterology 1986; 90:1268.
- Lieberman HM, LaBrecque DR, Kew MC, et al. Detection of hepatitis B virus DNA directly in human serum by a simplified molecular hybridization test: comparison to HBeAg/anti-HBe status in HBsAg carriers. Hepatology 1983; 3:285.
- Lok AS, Hadziyannis SJ, Weller IV, et al. Contribution of low level HBV replication to continuing inflammatory activity in patients with anti-HBe positive chronic hepatitis B virus infection. Gut 1984; 25:1283.
- Carman WF, Jacyna MR, Hadziyannis S, et al. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989; 2:588.
- Michalak TI, Pasquinelli C, Guilhot S, Chisari FV. Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 1994; 93:230.
- Lok AS, Chung HT, Liu VW, Ma OC. Long-term follow-up of chronic hepatitis B patients treated with interferon alfa. Gastroenterology 1993; 105:1833.
- Chu CJ, Hussain M, Lok AS. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology 2002; 36:1408.
- Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000--summary of a workshop. Gastroenterology 2001; 120:1828.
- Martinot-Peignoux M, Boyer N, Colombat M, et al. Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers. J Hepatol 2002; 36:543.
- Cornberg M, Wong VW, Locarnini S, et al. The role of quantitative hepatitis B surface antigen revisited. J Hepatol 2017; 66:398.
- Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295:65.
- Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130:678.
- Perrillo RP, Schiff ER, Davis GL, et al. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med 1990; 323:295.
- Buster EH, Hansen BE, Lau GK, et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology 2009; 137:2002.
- Hoofnagle JH, Doo E, Liang TJ, et al. Management of hepatitis B: summary of a clinical research workshop. Hepatology 2007; 45:1056.
- Bréchot C, Degos F, Lugassy C, et al. Hepatitis B virus DNA in patients with chronic liver disease and negative tests for hepatitis B surface antigen. N Engl J Med 1985; 312:270.
- Wright TL, Mamish D, Combs C, et al. Hepatitis B virus and apparent fulminant non-A, non-B hepatitis. Lancet 1992; 339:952.
- Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007; 45:507.
- Chan HL, Thompson A, Martinot-Peignoux M, et al. Hepatitis B surface antigen quantification: why and how to use it in 2011 - a core group report. J Hepatol 2011; 55:1121.
- Conjeevaram HS, Lok AS. Occult hepatitis B virus infection: a hidden menace? Hepatology 2001; 34:204.
- Bréchot C, Thiers V, Kremsdorf D, et al. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely "occult"? Hepatology 2001; 34:194.
- Minuk GY, Sun DF, Uhanova J, et al. Occult hepatitis B virus infection in a North American community-based population. J Hepatol 2005; 42:480.
- Raimondo G, Allain JP, Brunetto MR, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008; 49:652.
- Chaudhuri V, Tayal R, Nayak B, et al. Occult hepatitis B virus infection in chronic liver disease: full-length genome and analysis of mutant surface promoter. Gastroenterology 2004; 127:1356.
- WHO SHOULD BE TESTED OR SCREENED
- SEROLOGIC MARKERS
- Hepatitis B surface antigen and antibody
- Hepatitis B core antigen and antibody
- - Isolated anti-HBc
- Hepatitis B e antigen and antibody
- SERUM HBV DNA ASSAYS
- Clinical use
- DIAGNOSTIC ALGORITHMS
- Acute hepatitis
- Past HBV infection
- Chronic HBV infection
- Occult HBV infection
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS