Association between Hepatitis B Surface Antigen Levels and the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Infection: Systematic Review and Meta-Analysis

Thu Thi Vo, Kittiyod Poovorawan, Pimphen Charoen, Ngamphol Soonthornworasiri, Apichart Nontprasert, Chatporn Kittitrakul, Weerapong Phumratanaprapin, Pisit Tangkijvanich, Thu Thi Vo, Kittiyod Poovorawan, Pimphen Charoen, Ngamphol Soonthornworasiri, Apichart Nontprasert, Chatporn Kittitrakul, Weerapong Phumratanaprapin, Pisit Tangkijvanich

Abstract

Background: The role of hepatitis B surface antigen (HBsAg) levels in predicting the risk of developing hepatocellular carcinoma (HCC) has remained unclear. The aim of this study was to obtain the most up-to-date estimated measure of the association between HBsAg levels and the development of HCC in patients. Methods: We performed a systematic review by searching for relevant studies on PubMed, Scopus, ProQuest and the Cochrane Central Register of Controlled Trials from January 2002 to November 2017. We presented the effects of HBsAg levels at each cut-off value as the odds ratios (ORs) at 95% confidence interval (CI). We also investigated HCC and its potential risk factors including HBeAg, and HBV DNA. We registered our protocol with the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42018081138. Results: We selected 10 studies representing 12 541 cases. At the 100 IU/ml cut-off, the OR for HCC at the high HBsAg level versus the low level was 4.99 (95% CI, 3.01–8.29) with high inconsistency (I2=79%). At the 1,000 IU/ml threshold, the pooled OR for HCC at the high HBsAg versus the low level was 2.46 (95% CI, 2.15–2.83) with low variance. We also found correlations between the risk of HCC and male gender (OR=2.12), hepatitis B e-antigen positivity (OR=2.99), or hepatitis B (HBV) viral load ≥ 2,000 IU/ml (OR=4.37). Conclusion: Our study revealed that HBsAg levels ≥ 100 IU/ml, and notably >1,000 IU/ ml, are associated with an increased risk of HCC development.

Keywords: Hepatitis B surface antigens; Hepatocellular carcinoma; Meta-analysis; chronic hepatitis B infections.

Figures

Figure 1
Figure 1
Flow Dagram of Study Inclusion
Figure 2
Figure 2
Risk of Bias and Applicability Concerns Graph of 10 Included Studies
Figure 3
Figure 3
Risk of Bias and Applicability Concerns Summary of 10 Included Studies
Figure 4
Figure 4
Comparison of High and Low HBsAg Level (at 100 IU/ml Cut-Off) and Risk of HCC in Patients with Chronic HBV Infection
Figure 5
Figure 5
Comparison of High and Low HBsAg Level (at 1,000 IU/ml Cut-Off) and Risk of HCC in Patients with Chronic HBV Infection
Figure 6
Figure 6
Funnel Plot for the Incidence of HCC at High HBsAg Level versus Low HBsAg Level (100 IU/ml)
Figure 7
Figure 7
Funnel Plot for the Incidence of HCC of High HBsAg Level (1,000 IU/ml) versus Low HBsAg Level

References

    1. Ahn JM, Sinn DH, Gwak GY, et al. Prediction of clinical outcomes in Hepatitis B E antigen negative chronic Hepatitis B patients with elevated Hepatitis B virus DNA levels. PLoS One. 2015;10:e0144777.
    1. 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;295:65–73.
    1. Chien J, Liu J, Lee MH, et al. Risk and predictors of hepatocellular carcinoma for chronic hepatitis B patients with newly developed cirrhosis. J Gastroenterol Hepatol. 2016;31:1971–7.
    1. Fernandez-Rodriguez CM, Gutierrez-Garcia ML. Prevention of hepatocellular carcinoma in patients with chronic hepatitis B. World J Gastrointest Pharmacol Ther. 2014;5:175–82.
    1. Guo JT, Guo H. Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA-targeting antiviral therapeutics. Antiviral Res. 2015;122:91–100.
    1. Kawanaka M, Nishino K, Nakamura J, et al. Quantitative levels of Hepatitis B virus DNA and surface antigen and the risk of Hepatocellular Carcinoma in patients with Hepatitis B receiving long-term nucleos(t)ide analogue therapy. Liver Cancer. 2014;3:41–52.
    1. Kumar R, Testoni B, Fresquet J, et al. Development of hepatocellular carcinoma in chronic hepatitis B patients with advanced fibrosis is independent of viral genotype. J Med Virol. 2017;89:845–8.
    1. Lee MH, Yang HI, Liu J, et al. Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles. Hepatology. 2013;58:546–54.
    1. Lee P-L, Chen J-J, Tung H-D, et al. Serum hepatitis B surface antigen level might predict cirrhosis and hepatocellular carcinoma in older patients with chronic hepatitis B. Adv Dig Med. 2015;2:102–7.
    1. Liu J, Hu HH, Lee MH, et al. Serum levels of M2BPGi as short-term predictors of Hepatocellular Carcinoma in untreated Chronic Hepatitis B patients. Sci Rep. 2017;7:14352.
    1. Liu J, Yang HI, Lee MH, et al. Serum levels of Hepatitis B surface antigen and DNA can predict inactive carriers with low risk of disease progression. Hepatology. 2016;64:381–9.
    1. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095–128.
    1. Poh Z, Goh BB, Chang PE, et al. Rates of cirrhosis and hepatocellular carcinoma in chronic hepatitis B and the role of surveillance: a 10-year follow-up of 673 patients. Eur J Gastroenterol Hepatol. 2015;27:638–43.
    1. Qu L-S, Liu J-X, Zhang H-F, et al. Effect of serum hepatitis B surface antigen levels on predicting the clinical outcomes of chronic hepatitis B infection: A meta-analysis. Hepatol Res. 2015;45:1004–13.
    1. Tseng T-C, Liu C-J, Su T-H, et al. Fibrosis-4 index helps identify HBV carriers with the lowest risk of Hepatocellular Carcinoma. Am J Gastroenterol. 2017;112:1564.
    1. 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;142:1140–9.
    1. Valaydon ZS, Locarnini SA. The virological aspects of hepatitis B. Best Pract Res Clin Gastroenterol. 2017;31:257–64.
    1. Werle-Lapostolle B, Bowden S, Locarnini S, et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology. 2004;126:1750–8.
    1. Whiting PF, Rutjes AS, Westwood ME, et al. Quadas-2: A revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529–36.
    1. WHO. Global hepatitis report. WHO. 2017. 978-92-4-156545-5.
    1. WHO. Hepatitis B. 2019. [Accessed 15 July 2019].
    1. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347:168–74.
    1. Yang HI, Tseng TC, Liu J, et al. Incorporating serum level of Hepatitis B surface antigen or omitting level of Hepatitis B virus DNA does not affect calculation of risk for Hepatocellular Carcinoma in patients without cirrhosis. Clin Gastroenterol Hepatol. 2016;14:461–8.
    1. Yang Y, Gao J, Tan YT, et al. Individual and combined effects of hepatitis B surface antigen level and viral load on liver cancer risk. J Gastroenterol Hepatol. 2017;33:1131–7.
    1. Zheng B, Zhu YJ, Wang HY, et al. Gender disparity in hepatocellular carcinoma (HCC): multiple underlying mechanisms. Sci China Life Sci. 2017;60:575–84.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi