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Distinct effects of hepatic steatosis and metabolic dysfunction on the risk of hepatocellular carcinoma in chronic hepatitis B

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Abstract

Objective

Chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) are the leading causes of hepatocellular carcinoma (HCC). We aim to explore the impact of concurrent MAFLD on the risk of HCC in CHB.

Methods

Patients with CHB were consecutively recruited from 2006 to 2021. MAFLD was defined by steatosis and either obesity, diabetes mellitus, or other metabolic abnormalities. The cumulative incidence of HCC and associated factors were compared between the MAFLD and non-MAFLD groups.

Results

10,546 treatment-naïve CHB patients were included with a median follow-up of 5.1 years. CHB patients with MAFLD (n = 2212) had fewer hepatitis B e antigen (HBeAg)-positivity, lower HBV DNA levels, and Fibrosis-4 index compared with the non-MAFLD group (n = 8334). MAFLD was independently associated with a 58% reduced risk of HCC (adjusted hazard ratio [aHR] 0.42, 95% confidence interval [CI] 0.25–0.68, p < 0.001). Furthermore, steatosis and metabolic dysfunction had distinct effects on HCC. Steatosis was protective against HCC (aHR 0.45, 95% CI 0.30–0.67, p < 0.001), while a greater burden of metabolic dysfunction increased the risk (aHR 1.40 per dysfunction increase, 95% CI 1.19–1.66, p < 0.001). The protective effect of MAFLD was further confirmed in analysis with inverse probability of treatment weighting (IPTW), patients who had undergone antiviral therapy, those with probable MAFLD, and after multiple imputation for missing data.

Conclusions

Concurrent hepatic steatosis is independently associated with a lower risk of HCC, whereas the increasing burden of metabolic dysfunction aggravates the risk of HCC in untreated CHB patients.

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Data availability

The data supporting this study’s findings are not publicly available due to patients’ privacy but are available from a reasonable request and approved by the Institutional Review Boards.

Abbreviations

AASLD:

The American Association for the Study of Liver Diseases

AFP:

Alpha-fetoprotein

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

aHR:

Adjusted hazard ratio

BMI:

Body Mass Index

CHB:

Chronic hepatitis B

CI:

Confidence interval

CAP:

Controlled Attenuation Parameter

DM:

Diabetes mellitus

FIB-4:

Fibrosis-4

HBcAg:

Hepatitis B core antigen

HBsAg:

Hepatitis B surface antigen

HBeAg:

Hepatitis B e antigen

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HCC:

Hepatocellular carcinoma

HIV:

Human immunodeficiency virus

HR:

Hazard ratio

IFN:

Interferon

IPTW:

Inverse probability of treatment weighting

IQR:

Interquartile range

MAFLD:

Metabolic dysfunction-associated fatty liver disease

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

NA:

Nucleos(t)ide analogue

References

  1. Li J, Zou B, Yeo YH, Feng Y, Xie X, Lee DH, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999–2019: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2019;4:389–398

    Article  PubMed  Google Scholar 

  2. Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol. 2017;67:862–873

    Article  PubMed  Google Scholar 

  3. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20

    Article  PubMed  Google Scholar 

  4. Orci LA, Sanduzzi-Zamparelli M, Caballol B, Sapena V, Colucci N, Torres F, et al. Incidence of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression. Clin Gastroenterol Hepatol. 2022;20:283-292.e210

    Article  PubMed  Google Scholar 

  5. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol. 2020;73:202–209

    Article  PubMed  Google Scholar 

  6. Lin S, Huang J, Wang M, Kumar R, Liu Y, Liu S, et al. Comparison of MAFLD and NAFLD diagnostic criteria in real world. Liver Int. 2020;40:2082–2089

    Article  PubMed  Google Scholar 

  7. Huang SC, Su HJ, Kao JH, Tseng TC, Yang HC, Su TH, et al. Clinical and histologic features of patients with biopsy-proven metabolic dysfunction-associated fatty liver disease. Gut Liver. 2021;15:451–458

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nguyen VH, Le MH, Cheung RC, Nguyen MH. Differential clinical characteristics and mortality outcomes in persons with NAFLD and/or MAFLD. Clin Gastroenterol Hepatol. 2021;19:2172-2181.e2176

    Article  PubMed  Google Scholar 

  9. Su HJ, Kao JH, Tseng TC, Yang HC, Su TH, Chen PJ, et al. Pathologic findings of patients with nonalcoholic fatty liver disease and the impact of concurrent hepatitis B virus infection in Taiwan. J Formos Med Assoc. 2020;119:1476–1482

    Article  PubMed  Google Scholar 

  10. Yang M, Wei L. Impact of NAFLD on the outcome of patients with chronic hepatitis B in Asia. Liver Int. 2022;42:1981–1990

    Article  CAS  PubMed  Google Scholar 

  11. Huang SC, Kao JH. Metabolic dysfunction-associated fatty liver disease and chronic hepatitis B. J Formos Med Assoc. 2022;121:2148–2151

    Article  CAS  PubMed  Google Scholar 

  12. Joo EJ, Chang Y, Yeom JS, Ryu S. Hepatitis B virus infection and decreased risk of nonalcoholic fatty liver disease: a cohort study. Hepatology. 2017;65:828–835

    Article  CAS  PubMed  Google Scholar 

  13. Shi JP, Fan JG, Wu R, Gao XQ, Zhang L, Wang H, et al. Prevalence and risk factors of hepatic steatosis and its impact on liver injury in Chinese patients with chronic hepatitis B infection. J Gastroenterol Hepatol. 2008;23:1419–1425

    Article  PubMed  Google Scholar 

  14. Mak LY, Hui RW, Fung J, Liu F, Wong DK, Li B, et al. Reduced hepatic steatosis is associated with higher risk of hepatocellular carcinoma in chronic hepatitis B infection. Hepatol Int. 2021;15:901–911

    Article  PubMed  Google Scholar 

  15. Oh JH, Lee HW, Sinn DH, Park JY, Kim BK, Kim SU, et al. Controlled attenuation parameter value and the risk of hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy. Hepatol Int. 2021;15:892–900

    Article  PubMed  Google Scholar 

  16. Zheng Q, Zou B, Wu Y, Yeo Y, Wu H, Stave CD, et al. Systematic review with meta-analysis: prevalence of hepatic steatosis, fibrosis and associated factors in chronic hepatitis B. Aliment Pharmacol Ther. 2021;54:1100–1109

    Article  CAS  PubMed  Google Scholar 

  17. Chan AW, Wong GL, Chan HY, Tong JH, Yu YH, Choi PC, et al. Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B. J Gastroenterol Hepatol. 2017;32:667–676

    Article  CAS  PubMed  Google Scholar 

  18. Choi HSJ, Brouwer WP, Zanjir WMR, de Man RA, Feld JJ, Hansen BE, et al. Nonalcoholic steatohepatitis is associated with liver-related outcomes and all-cause mortality in chronic hepatitis B. Hepatology. 2020;71:539–548

    Article  CAS  PubMed  Google Scholar 

  19. van Kleef LA, Choi HSJ, Brouwer WP, Hansen BE, Patel K, de Man RA, et al. Metabolic dysfunction-associated fatty liver disease increases risk of adverse outcomes in patients with chronic hepatitis B. JHEP Rep. 2021;3: 100350

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lee YC, Chao YT, Lin PJ, Yang YY, Yang YC, Chu CC, et al. Quality assurance of integrative big data for medical research within a multihospital system. J Formos Med Assoc. 2022;121:1728–1738

    Article  PubMed  Google Scholar 

  21. Tchelepi H, Ralls PW, Radin R, Grant E. Sonography of diffuse liver disease. J Ultrasound Med. 2002;21:1023–1032 (quiz 1033-1024)

    Article  PubMed  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. EASL. Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;2017(67):370–398

    Google Scholar 

  24. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–1599

    Article  PubMed  Google Scholar 

  25. Su TH, Liao CH, Liu CH, Huang KW, Tseng TC, Yang HC, et al. Acoustic radiation force impulse US imaging: liver stiffness in patients with chronic hepatitis B with and without antiviral therapy. Radiology. 2018;288:293–299

    Article  PubMed  Google Scholar 

  26. Bruix J, Sherman M. American association for the study of liver D: management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022

    Article  PubMed  Google Scholar 

  27. van Buuren S, Groothuis-Oudshoorn K. Mice: multivariate imputation by chained equations in R. J Stat Softw. 2011;45:1–67

    Article  Google Scholar 

  28. Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat Med. 2014;33:1242–1258

    Article  PubMed  Google Scholar 

  29. Hui RWH, Seto WK, Cheung KS, Mak LY, Liu KSH, Fung J, et al. Inverse relationship between hepatic steatosis and hepatitis B viremia: results of a large case-control study. J Viral Hepat. 2018;25:97–104

    Article  CAS  PubMed  Google Scholar 

  30. Wang MM, Wang GS, Shen F, Chen GY, Pan Q, Fan JG. Hepatic steatosis is highly prevalent in hepatitis B patients and negatively associated with virological factors. Dig Dis Sci. 2014;59:2571–2579

    Article  CAS  PubMed  Google Scholar 

  31. Yu MW, Lin CL, Liu CJ, Huang YW, Hu JT, Wu WJ, et al. Hepatic steatosis and development of type 2 diabetes: impact of chronic hepatitis B and viral specific factors. J Formos Med Assoc. 2022;121:1478–1487

    Article  CAS  PubMed  Google Scholar 

  32. Hu D, Wang H, Wang H, Wang Y, Wan X, Yan W, et al. Non-alcoholic hepatic steatosis attenuates hepatitis B virus replication in an HBV-immunocompetent mouse model. Hepatol Int. 2018;12:438–446

    Article  PubMed  Google Scholar 

  33. Liu Q, Mu M, Chen H, Zhang G, Yang Y, Chu J, et al. Hepatocyte steatosis inhibits hepatitis B virus secretion via induction of endoplasmic reticulum stress. Mol Cell Biochem. 2022;477:2481–2491

    Article  CAS  PubMed  Google Scholar 

  34. Wong VW, Wong GL, Yu J, Choi PC, Chan AW, Chan HY, et al. Interaction of adipokines and hepatitis B virus on histological liver injury in the Chinese. Am J Gastroenterol. 2010;105:132–138

    Article  CAS  PubMed  Google Scholar 

  35. Yoon S, Jung J, Kim T, Park S, Chwae YJ, Shin HJ, et al. Adiponectin, a downstream target gene of peroxisome proliferator-activated receptor γ, controls hepatitis B virus replication. Virology. 2011;409:290–298

    Article  CAS  PubMed  Google Scholar 

  36. Seto WK, Hui RWH, Mak LY, Fung J, Cheung KS, Liu KSH, et al. Association between hepatic steatosis, measured by controlled attenuation parameter, and fibrosis burden in chronic hepatitis B. Clin Gastroenterol Hepatol. 2018;16:575-583.e572

    Article  PubMed  Google Scholar 

  37. Mak LY, Hui RW, Fung J, Liu F, Wong DK, Cheung KS, et al. Diverse effects of hepatic steatosis on fibrosis progression and functional cure in virologically quiescent chronic hepatitis B. J Hepatol. 2020;73:800–806

    Article  CAS  PubMed  Google Scholar 

  38. Huang SC, Liu CJ. Chronic hepatitis B with concurrent metabolic dysfunction-associated fatty liver disease: challenges and perspectives. Clin Mol Hepatol. 2023;29(2):320–331

    Article  PubMed  PubMed Central  Google Scholar 

  39. van der Poorten D, Samer CF, Ramezani-Moghadam M, Coulter S, Kacevska M, Schrijnders D, et al. Hepatic fat loss in advanced nonalcoholic steatohepatitis: are alterations in serum adiponectin the cause? Hepatology. 2013;57:2180–2188

    Article  PubMed  Google Scholar 

  40. Kanwal F, Kramer JR, Mapakshi S, Natarajan Y, Chayanupatkul M, Richardson PA, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology. 2018;155:1828-1837.e1822

    Article  PubMed  Google Scholar 

  41. Yu MW, Shih WL, Lin CL, Liu CJ, Jian JW, Tsai KS, et al. Body-mass index and progression of hepatitis B: a population-based cohort study in men. J Clin Oncol. 2008;26:5576–5582

    Article  PubMed  Google Scholar 

  42. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut. 2005;54:533–539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology. 2008;135:111–121

    Article  CAS  PubMed  Google Scholar 

  44. Hsueh RC, Wu WJ, Lin CL, Liu CJ, Huang YW, Hu JT, et al. Impact of PNPLA3 p.I148M and hepatic steatosis on long-term outcomes for hepatocellular carcinoma and HBsAg seroclearance in chronic hepatitis B. J Hepatocell Carcinoma. 2022;9:301–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li J, Yang HI, Yeh ML, Le MH, Le AK, Yeo YH, et al. Association between fatty liver and cirrhosis, hepatocellular carcinoma, and hepatitis B surface antigen seroclearance in chronic hepatitis B. J Infect Dis. 2021;224:294–302

    Article  CAS  PubMed  Google Scholar 

  46. Minuk GY, Iliant V, Zhou N, Kaita KD, Wong SG, Peretz D, et al. Concomitant nonalcoholic fatty liver disease does not alter the activity, severity or course of primary biliary cholangitis. Liver Int. 2018;38:1110–1116

    Article  CAS  PubMed  Google Scholar 

  47. De Luca-Johnson J, Wangensteen KJ, Hanson J, Krawitt E, Wilcox R. Natural history of patients presenting with autoimmune hepatitis and coincident nonalcoholic fatty liver disease. Dig Dis Sci. 2016;61:2710–2720

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Miss Shih-Wan Chou for her administrative assistance and the Department of Medical Research, National Taiwan University Hospital staff for the Integrated Medical Database. In addition, we thank the 7th Core Laboratory of the Department of Medical Research, National Taiwan University Hospital, for technical assistance.

Funding

This work was supported by grants from the Ministry of Science and Technology, Taiwan (grant numbers MOST 109-2326-B-002-012-MY3, MOST 110-2326-B-400-004, MOST 110-2628-B-002-041), National Taiwan University Hospital (Grant numbers VN-110-02, 110-S4952, 110-N01, NTUH110-T20).

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Authors and Affiliations

  1. Department of Internal Medicine, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan

    Shang-Chin Huang

  2. Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Shang-Chin Huang, Tung-Hung Su, Shih-Jer Hsu, Chen-Hua Liu, Hung-Chih Yang, Chun-Jen Liu, Pei-Jer Chen & Jia-Horng Kao

  3. Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan

    Shang-Chin Huang, Tung-Hung Su, Tai-Chung Tseng, Chi-Ling Chen, Shih-Jer Hsu, Chen-Hua Liu, Hung-Chih Yang, Chun-Jen Liu, Pei-Jer Chen & Jia-Horng Kao

  4. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    Shang-Chin Huang, Chi-Ling Chen, Chun-Jen Liu, Pei-Jer Chen & Jia-Horng Kao

  5. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

    Tai-Chung Tseng & Pei-Jer Chen

  6. National Taiwan University Cancer Center, Taipei, Taiwan

    Sih-Han Liao

  7. Division of Hospital Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Chun-Ming Hong

  8. Division of Rheumatology, Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan

    Ting-Yuan Lan

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  1. Shang-Chin Huang
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Contributions

SCH: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; statistical analysis. THS: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; obtained funding; study supervision. TCT: analysis and interpretation of data; critical revision of the manuscript for important intellectual content. CLC: analysis and interpretation of data; critical revision of the manuscript for important intellectual content. SJH: analysis and interpretation of data; critical revision of the manuscript for important intellectual content. SHL: analysis and interpretation of data; critical revision of the manuscript for important intellectual content. CMH: analysis and interpretation of data; critical revision of the manuscript for important intellectual content. CHL: analysis and interpretation of data; critical revision of the manuscript for important intellectual content. TYL: critical revision of the manuscript for important intellectual content; technical support. HCY: analysis and interpretation of data; critical revision of the manuscript for important intellectual content; study supervision. CJL: analysis and interpretation of data; critical revision of the manuscript for important intellectual content; study supervision. PJC: analysis and interpretation of data; critical revision of the manuscript for important intellectual content; study supervision. JHK: study concept and design; analysis and interpretation of data; drafting of the manuscript; obtained funding; study supervision. All authors: final approval of the version to be published.

Corresponding authors

Correspondence to Tung-Hung Su or Jia-Horng Kao.

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Conflict of interest

T-HS received a research Grant from Gilead Sciences, and was on speaker’s bureaus for Abbvie, Bayer, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, and Takeda. J-HK has served as a consultant for Abbvie, Abbott, Gilead Sciences, Roche, and Sysmex and on speaker’s bureaus for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp, and Dohme, and Sysmex. S-CH, T-CT, C-LC, S-JH, S-HL, C-MH, C-HL, T-YL, H-CY, C-JL, P-JC declare no conflict of interest.

Ethical approval

This study was approved by the Institutional Review Board of National Taiwan University Hospital (202104086RIND) and conformed to the ethical principles for medical research involving human subjects of the Declaration of Helsinki updated in 2013. The informed consent was waived because this is a retrospective study conducted by a review of medical records only.

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Huang, SC., Su, TH., Tseng, TC. et al. Distinct effects of hepatic steatosis and metabolic dysfunction on the risk of hepatocellular carcinoma in chronic hepatitis B. Hepatol Int 17, 1139–1149 (2023). https://doi.org/10.1007/s12072-023-10545-6

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