Serum hepatitis B surface antigen quantification as a useful assessment for significant fibrosis in hepatitis B e antigen-positive hepatitis B virus carriers
Yun-hao Xun
Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
Department of Liver Diseases, The Sixth People's Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorCorresponding Author
Guo-qing Zang
Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
Correspondence
Professor Jun-ping Shi, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou 310015, Zhejiang Province, China. Email: [email protected] and Professor Guo-qing Zang, Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China. Email: [email protected]
Search for more papers by this authorJian-chun Guo
Department of Liver Diseases, The Sixth People's Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorXiu-li Yu
Department of Liver Diseases, The Sixth People's Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorHong Liu
Department of Liver Diseases, The Sixth People's Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorJing Xiang
Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorJing Liu
Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorCorresponding Author
Jun-ping Shi
Department of Liver Diseases, The Sixth People's Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Department of Liver Disease, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou, 310015 Zhejiang Province, China
Correspondence
Professor Jun-ping Shi, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou 310015, Zhejiang Province, China. Email: [email protected] and Professor Guo-qing Zang, Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China. Email: [email protected]
Search for more papers by this authorYun-hao Xun
Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
Department of Liver Diseases, The Sixth People's Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorCorresponding Author
Guo-qing Zang
Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
Correspondence
Professor Jun-ping Shi, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou 310015, Zhejiang Province, China. Email: [email protected] and Professor Guo-qing Zang, Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China. Email: [email protected]
Search for more papers by this authorJian-chun Guo
Department of Liver Diseases, The Sixth People's Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorXiu-li Yu
Department of Liver Diseases, The Sixth People's Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorHong Liu
Department of Liver Diseases, The Sixth People's Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorJing Xiang
Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorJing Liu
Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Search for more papers by this authorCorresponding Author
Jun-ping Shi
Department of Liver Diseases, The Sixth People's Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
Department of Liver Disease, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou, 310015 Zhejiang Province, China
Correspondence
Professor Jun-ping Shi, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou 310015, Zhejiang Province, China. Email: [email protected] and Professor Guo-qing Zang, Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China. Email: [email protected]
Search for more papers by this authorAbstract
Background and Aims
The role of serum quantitative hepatitis B surface antigen (qHBsAg) in identifying hepatitis B virus (HBV) carriers with significant fibrosis is unknown. This study aims to evaluate the diagnostic value of qHBsAg for hepatic fibrosis in hepatitis B e antigen (HBeAg)-positive HBV carriers.
Methods
Consecutive biopsy-proven HBeAg-positive HBV carriers were prospectively recruited in our center from 2009 to 2011 and were randomly divided into training and validation set. Area under receiver-operator curve (AUC) was used to determine the diagnostic accuracy of simple tests for significant fibrosis (Scheuer stage, F ≥ 2).
Results
Overall, a total of 197 eligible patients (median age 31 years; 149 males) were enrolled. The median qHBsAg was 4.20 (log10 IU/mL). Significant fibrosis was confirmed in 112 (56.9%) patients. By logistical regression analysis, qHBsAg and γ-glutamyl transpeptidase were identified as predictors for significant fibrosis in training set (n = 124). Thus, qHBsAg index and γ-glutamyl transpeptidase to qHBsAg ratio (GqHBsR) were selected for the subsequent analysis. In the training set, an AUC of 0.762, 0.826, 0.749, and 0.771 was observed for qHBsAg index, GqHBsR, FIB-4, and aspartate aminotransferase to platelet ratio index, respectively (all P < 0.05). GqHBsR yielded a higher AUC than aspartate aminotransferase to platelet ratio index and FIB-4 (both P < 0.05). Using the optimal cut-off of 7.78, GqHBsR showed a sensitivity of 78.9% and a specificity of 73.6%. About 80% of liver biopsy could be avoided in the entire cohort.
Conclusions
Serum qHBsAg-based simple tests, especially GqHBsR, can accurately and specifically identify significant fibrosis in treatment-naïve HBeAg-positive HBV carriers.
References
- 1 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: 1121–1131.
- 2 Liaw YF. Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review. Hepatology 2011; 53: 2121–2129.
- 3 Nguyen T, Thompson AJ, Bowden S et al. Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia. J. Hepatol. 2010; 52: 508–513.
- 4 Jaroszewicz J, Calle Serrano B, Wursthorn K et al. Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: a European perspective. J. Hepatol. 2010; 52: 514–522.
- 5 Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012; 142: 1293–302 e4.
- 6 Sebastiani G, Castera L, Halfon P et al. The impact of liver disease aetiology and the stages of hepatic fibrosis on the performance of non-invasive fibrosis biomarkers: an international study of 2411 cases. Aliment. Pharmacol. Ther. 2011; 34: 1202–1216.
- 7 Chen CH, Lee CM, Wang JH, Tung HD, Hung CH, Lu SN. Correlation of quantitative assay of hepatitis B surface antigen and HBV DNA levels in asymptomatic hepatitis B virus carriers. Eur. J. Gastroenterol. Hepatol. 2004; 16: 1213–1218.
- 8 Sanai FM, Helmy A, Bzeizi KI et al. Discriminant value of serum HBV DNA levels as predictors of liver fibrosis in chronic hepatitis B. J. Viral Hepat. 2011; 18: e217–225.
- 9 Croagh CM, Bell SJ, Slavin J et al. Increasing hepatitis B viral load is associated with risk of significant liver fibrosis in HBeAg-negative but not HBeAg-positive chronic hepatitis B. Liver Int. 2010; 30: 1115–1122.
- 10 Park H, Lee JM, Seo JH et al. Predictive value of HBsAg quantification for determining the clinical course of genotype C HBeAg-negative carriers. Liver Int. 2012; 32: 796–802.
- 11 Tseng TC, Liu CJ, Yang HC et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 2012; 142: 1140–1193; quiz e13–4.
- 12 Tseng TC, Liu CJ, Yang HC et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology 2013; 57: 441–450.
- 13 Manesis EK, Papatheodoridis GV, Tiniakos DG et al. Hepatitis B surface antigen: relation to hepatitis B replication parameters in HBeAg-negative chronic hepatitis B. J. Hepatol. 2011; 55: 61–68.
- 14 Brunetto MR, Oliveri F, Colombatto P et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology 2010; 139: 483–490.
- 15 Feld JJ, Heathcote EJ. Hepatitis B e antigen-positive chronic hepatitis B: natural history and treatment. Semin. Liver Dis. 2006; 26: 116–129.
- 16 Locarnini S, Bowden S. Hepatitis B surface antigen quantification: not what it seems on the surface. Hepatology 2012; 56: 411–414.
- 17 Janssen HL, Sonneveld MJ, Brunetto MR. Quantification of serum hepatitis B surface antigen: is it useful for the management of chronic hepatitis B? Gut 2012; 61: 641–645.
- 18 Jang JW, Yoo SH, Kwon JH et al. Serum hepatitis B surface antigen levels in the natural history of chronic hepatitis B infection. Aliment. Pharmacol. Ther. 2011; 34: 1337–1346.
- 19 Brunetto MR, Moriconi F, Bonino F et al. Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 2009; 49: 1141–1150.
- 20 Lee JM, Ahn SH, Kim HS et al. Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir. Hepatology 2011; 53: 1486–1493.
- 21 Sonneveld MJ, Rijckborst V, Boucher CA, Hansen BE, Janssen HL. Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. Hepatology 2010; 52: 1251–1257.
- 22 Rijckborst V, Hansen BE, Ferenci P et al. Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a. J. Hepatol. 2012; 56: 1006–1011.
- 23 Zoutendijk R, Hansen BE, van Vuuren AJ, Boucher CA, Janssen HL. Serum HBsAg decline during long-term potent nucleos(t)ide analogue therapy for chronic hepatitis B and prediction of HBsAg loss. J. Infect. Dis. 2011; 204: 415–418.
- 24 Thompson AJ, Nguyen T, Iser D et al. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology 2010; 51: 1933–1944.
- 25 Wursthorn K, Jung M, Riva A et al. Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatology 2010; 52: 1611–1620.
- 26 Liang Y, Jiang J, Su M et al. Predictors of relapse in chronic hepatitis B after discontinuation of anti-viral therapy. Aliment. Pharmacol. Ther. 2011; 34: 344–352.
- 27 Chen J, Wang Z, Zhou B, Wang Y, Hou J. Factors associated with serum hepatitis B surface antigen levels and its on-treatment changes in patients under lamivudine therapy. Antivir. Ther. 2012; 17: 71–79.
- 28 Gramenzi A, Loggi E, Micco L et al. Serum hepatitis B surface antigen monitoring in long-term lamivudine-treated hepatitis B virus patients. J. Viral Hepat. 2011; 18: e468–474.
- 29 Kim YJ, Cho HC, Choi MS et al. The change of the quantitative HBsAg level during the natural course of chronic hepatitis B. Liver Int. 2011; 31: 817–823.
- 30 Chan HL, Wong VW, Wong GL, Tse CH, Chan HY, Sung JJ. A longitudinal study on the natural history of serum hepatitis B surface antigen changes in chronic hepatitis B. Hepatology 2010; 52: 1232–1241.
- 31 Seto WK, Wong DK, Fung J et al. High hepatitis B surface antigen levels predict insignificant fibrosis in hepatitis B e antigen positive chronic hepatitis B. PLoS ONE 2012; 7: e43087.
- 32 Martinot-Peignoux M, Carvalho-Filho R, Lapalus M et al. Hepatitis B surface antigen serum level is associated with fibrosis severity in treatment-naïve, e antigen-positive patients. J. Hepatol. 2013; 58: 1089–1095.
- 33 Chinese Society of Hepatology, Chinese Medical Association and Chinese Society of Infectious Diseases, Chinese Medical Association. Guideline on prevention and treatment of chronic hepatitis B in China (2005). Chin. Med. J. 2007; 120: 2159–2173.
- 34 Deguchi M, Yamashita N, Kagita M et al. Quantitation of hepatitis B surface antigen by an automated chemiluminescent microparticle immunoassay. J. Virol. Methods 2004; 115: 217–222.
- 35 Wai CT, Greenson JK, Fontana RJ et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003; 38: 518–526.
- 36 Sterling RK, Lissen E, Clumeck N et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006; 43: 1317–1325.
- 37 Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J. Hepatol. 1991; 13: 372–374.
- 38 Zeng MD, Lu LG, Mao YM et al. Prediction of significant fibrosis in HBeAg-positive patients with chronic hepatitis B by a noninvasive model. Hepatology 2005; 42: 1437–1445.
- 39 Rosenberg WM, Voelker M, Thiel R et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004; 127: 1704–1713.
- 40 Hui AY, Chan HL, Wong VW et al. Identification of chronic hepatitis B patients without significant liver fibrosis by a simple noninvasive predictive model. Am. J. Gastroenterol. 2005; 100: 616–623.
- 41 DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988; 44: 837–845.
- 42 European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J. Hepatol. 2012; 57: 167–185.
- 43 Zhu X, Wang LC, Chen EQ et al. Prospective evaluation of FibroScan for the diagnosis of hepatic fibrosis compared with liver biopsy/AST platelet ratio index and FIB-4 in patients with chronic HBV infection. Dig. Dis. Sci. 2011; 56: 2742–2749.
- 44 Jin W, Lin Z, Xin Y, Jiang X, Dong Q, Xuan S. Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of hepatitis B-related fibrosis: a leading meta-analysis. BMC Gastroenterol. 2012; 12: 14.
- 45 Wu SD, Wang JY, Li L. Staging of liver fibrosis in chronic hepatitis B patients with a composite predictive model: a comparative study. World J. Gastroenterol. 2010; 16: 501–507.
- 46 Myers RP, Tainturier MH, Ratziu V et al. Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B. J. Hepatol. 2003; 39: 222–230.
- 47 Seto WK, Lai CL, Ip PP et al. A large population histology study showing the lack of association between ALT elevation and significant fibrosis in chronic hepatitis B. PLoS ONE 2012; 7: e32622.
- 48 Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. Liver biopsy. Hepatology 2009; 49: 1017–1044.
- 49 Fung J, Lai CL, Young J et al. Stability of hepatitis B surface antigen over time: implications for studies using stored sera. J. Med. Virol. 2011; 83: 1900–1904.
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