Diagnostic Dilemma for Low Viremia with Significant Fibrosis; is Hepatitis B Virus DNA Threshold Level a Good Indicator for Predicting Liver Damage?

Abstract

Background: The most important difficulties about management of hepatitis B are still determining the liver damage and the right time to start antiviral therapy. Aims: To reveal the role of hepatitis B virus DNA threshold level for prediction of liver fibrosis and inflammation in young-aged hepatitis B e-antigen negative chronic hepatitis B patients. Study Design: Diagnostic accuracy study. Methods: A total of 273 hepatitis B e-antigen negative young chronic hepatitis B patients with any hepatitis B virus DNA levels between 2008 and 2016, who had liver biopsy after at least 6 months follow up period, enrolled in this retrospective study. We created two groups as case and control, cases with hepatitis B virus DNA levels below 2000 IU/mL and controls with hepatitis B virus DNA levels over 2000 IU/mL. Having histological activity index ≥4 or/and fibrosis scores ≥2 were defined as significant histological abnormality. Then, we analyzed the relationship between these groups. Results: We showed that significant fibrosis may occur in one third of young chronic hepatitis B patients with low viremia (30.2%, n=42/139 in cases, 55.2%, n=74/134 in controls). Among the 42 cases with low viremia and significant fibrosis, 21.4% had alanine aminotransferase level between 40-59 U/L, 42.8% had alanine aminotransferase level between 60-79 U/L, and 35.7% had alanine aminotransferase level over 80 U/L. There was weak correlation between hepatitis B virus DNA threshold level and fibrosis score (p<0.001, rho=0.253). The optimum serum hepatitis B virus DNA threshold level in our study for predicting significant fibrosis was 1293 IU/mL (p<0.001, AUC: 0.657±0.034). The optimum alanine aminotransferase threshold level for predicting significant histological activity index and fibrosis was 64.5 and 59.5 U/L, respectively. The sensitivity and the specificity of 1293 vs 2000 IU/mL hepatitis B virus DNA threshold with 60 U/L alanine aminotransferase threshold level for predicting F≥2 fibrosis score were similar (sensitivity: 0.43 and 0.38, specificity: 0.76 and 0.77, respectively).Conclusion: Significant fibrosis may occur even in young cases with low viremia. It is not possible to define a single threshold hepatitis B virus DNA level for differentiating inactive carriers from patients with hepatitis B e-antigen-negative chronic hepatitis. Diagnostic accuracy of hepatitis B virus DNA with alanine aminotransferase thresholds for the prediction of significant fibrosis is weak.

Keywords

• Chronic hepatitis B, fibrosis, HBV DNA, prediction, viremia

References

1. 1. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016;10:1-98.
2. 2. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016;63:261- 83.
3. 3. European Association for the Study of the Liver. Electronic address: easloffice@ easloffice.eu; European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-98.
4. 4. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva: World Health Organization; 2015 Mar. WHO Guidelines Approved by the Guidelines Review Committee 2015.
5. 5. Eren M, Reyhanioglu S, Ciftci E, Dundar E, Us T, Dinleyici CE, et al. Correlation of Liver Enzymes and Liver Histology in Chronic Hepatitis B Virus Infection. J Clin Anal Med 2016;7:639-42.
6. 6. Shafaei S, Soleimani Amiri S, Hajiahmadi M, Sadeghi-Haddad-Zavareh M, Bayani M. Histological grading and staging of liver and its relation to viral loads in chronic anti-HBe positive hepatitis. Caspian J Intern Med 2013;4:681-5.
7. 7. Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, et al. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology 2008;134:1376-84.
8. 8. Bruden DJT, McMahon BJ, Townshend-Bulson L, Gounder P, Gove J, Plotnik J, et al. Risk of end-stage liver disease, hepatocellular carcinoma, and liver-related death by fibrosis stage in the hepatitis C Alaska Cohort. Hepatology 2017;66:37-45.

9. 9. Can A, Dogan E, Bayoglu IV, Tatli AM, Besiroglu M, Kocer M, et al. Multicenter epidemiologic study on hepatocellular carcinoma in Turkey. Asian Pac J Cancer Prev 2014;15:2923-7.
10. 10. Kao JH. Risk stratification of HBV infection in Asia-Pacific region. Clin Mol Hepatol 2014;20:223-7.
11. 11. Charatcharoenwitthaya P, Phisalprapa P, Pausawasdi N, Rungkaew P, Kajornvuthidej S, Bandidniyamanon W, et al. Alanine aminotransferase course, serum hepatitis B virus DNA, and liver stiffness measurement for therapeutic decisions in hepatitis B e antigen-negative chronic hepatitis B. Hepatol Res 2016;46:1347-57.
12. 12. Papatheodoridis GV, Manolakopoulos S, Liaw YF, Lok A. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol 2012;57:196-202.
13. 13. Seto WK, Lai CL, Ip PP, Fung J, Wong DK, Yuen JC, 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.
14. 14. Nguyen LH, Chao D, Lim JK, Ayoub W, Nguyen MH. Histologic changes in liver tissue from patients with chronic hepatitis B and minimal increases in levels of alanine aminotransferase: a meta-analysis and systematic review. Clin Gastroenterol Hepatol 2014;12:1262-6.
15. 15. Barut S, Gemici Ü, Güneş F, Demir O, Duygu F. Predictors of histological indication for treatment in HBeAg negative chronic HBV infection. J Med Virol 2017;89:1952-7.
16. 16. Sanai FM, Babatin MA, Bzeizi KI, Alsohaibani F, Al-Hamoudi W, Alsaad KO, et al. Accuracy of international guidelines for identifying significant fibrosis in hepatitis B e antigen--negative patients with chronic hepatitis. Clin Gastroenterol Hepatol 2013;11:1493-9.