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Advanced Liver Fibrosis Is Associated with Necroinflammatory Grade but Not Hepatic Steatosis in Chronic Hepatitis B Patients

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Abstract

Background and Aims

Patients with chronic hepatitis B (CHB) are at an increased risk of disease progression. The influence of hepatic steatosis (HS) to liver fibrosis was controversial. We aim to investigate the association between HS and liver fibrosis and explore the predicting factors for advanced fibrosis.

Methods

CHB patients undergoing liver biopsy with complete assessments of HS, necroinflammation grade [histological activity index (HAI) score], and fibrosis stage were retrospectively recruited. Logistic regression analysis was performed to determine the factors associated with advanced liver fibrosis.

Results

In this cohort of 672 patients, 342 (50.9%) had HS and 267 (39.4%) were of advanced liver fibrosis. Age [odds ratio (OR) 1.026, 95% confidence interval (CI) 1.007–1.046, p = 0.008], body mass index (BMI, OR 1.091, 95% CI 1.026–1.159, p = 0.005), genotype (C vs. B) (OR 2.790, 95% CI 1.847–4.214, p < 0.001), platelet (OR 0.986, 95% CI 0.982–0.991, p < 0.001), and HAI score (OR 1.197, 95% CI 1.114–1.285, p < 0.001) were independent factors for advanced liver fibrosis in multivariate logistic regression analysis. HAI score was also a significantly associated factor for significant liver fibrosis in non-cirrhotic subpopulation (OR 1.578, 95% CI 1.375–1.810, p < 0.001). HS was not related to advanced/significant liver fibrosis in overall/non-cirrhotic population (p > 0.05).

Conclusions

Significant or advanced liver fibrosis is associated with grade of necroinflammation but not with HS in CHB patients.

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Abbreviations

CHB:

Chronic hepatitis B

HCC:

Hepatocellular carcinoma

ALT:

Alanine aminotransferase

NAFLD:

Nonalcoholic fatty liver disease

MetS:

Metabolic syndrome

LSM:

Liver stiffness measurement

CAP:

Controlled attenuation parameter

BMI:

Body mass index

HCV:

Hepatitis C virus

HDV:

Hepatitis D virus

HIV:

Human immunodeficiency virus

AST:

Aspartate aminotransferase

IQR:

Interquartile ranges

OR:

Odds ratio

CI:

Confidence interval

HS:

Hepatic steatosis

DM:

Diabetes mellitus

NTCP:

Na/taurocholate cotransporter

References

  1. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386:1546–1555

    Article  PubMed  Google Scholar 

  2. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet (London, England). 2009;373:582–592

    Article  CAS  Google Scholar 

  3. Sarin SK, Kumar M, Lau GK 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 

  4. 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;58:546–554

    Article  CAS  PubMed  Google Scholar 

  5. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67:328–357

    Article  PubMed  Google Scholar 

  6. Fan JG, Chitturi S. Hepatitis B and fatty liver: causal or coincidental? J Gastroenterol Hepatol 2008;23:679–681

    Article  PubMed  Google Scholar 

  7. Machado MV, Oliveira AG, Cortez-Pinto H. Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients. J Gastroenterol Hepatol 2011;26:1361–1367

    PubMed  Google Scholar 

  8. Wong GL, Wong VW, Choi PC et al. Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B. Gut 2009;58:111–117

    Article  PubMed  Google Scholar 

  9. Wong GL, Chan HL, Yu Z et al. Coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B–a prospective cohort study with paired transient elastography examinations. Aliment Pharmacol Ther 2014;39:883–893

    Article  CAS  PubMed  Google Scholar 

  10. Hui RWH, Seto WK, Cheung KS 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 

  11. Seto WK, Hui RWH, Mak LY et al. Association between hepatic steatosis, measured by controlled attenuation parameter, and fibrosis burden in chronic hepatitis B. Clin Gastroenterol Hepatol 2018;16:e572

    Google Scholar 

  12. Wong SW, Chan WK, Mohamed R. Fatty liver is associated with advanced fibrosis but does not predict adverse outcomes in patients with chronic hepatitis B. J Viral Hepat. 2020;12:1297–1305

  13. Tsochatzis E, Papatheodoridis GV, Manesis EK, Kafiri G, Tiniakos DG, Archimandritis AJ. Metabolic syndrome is associated with severe fibrosis in chronic viral hepatitis and non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2008;27:80–89

    Article  CAS  PubMed  Google Scholar 

  14. Yun JW, Cho YK, Park JH et al. Hepatic steatosis and fibrosis in young men with treatment-naive chronic hepatitis B. Liver Int 2009;29:878–883

    Article  CAS  PubMed  Google Scholar 

  15. Charatcharoenwitthaya P, Pongpaibul A, Kaosombatwattana U et al. The prevalence of steatohepatitis in chronic hepatitis B patients and its impact on disease severity and treatment response. Liver Int 2017;37:542–551

    Article  CAS  PubMed  Google Scholar 

  16. Lin CF, Chang YH, Chien SC, Lin YH, Yeh HY. Epidemiology of dyslipidemia in the Asia Pacific Region. Int J Gerontol 2018;12:2–6

    Article  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. Hamidi AA, Oncul A, Ozguven BY et al. Diagnostic accuracy of different noninvasive scores for detecting advanced fibrosis in chronic hepatitis B. Eur J Gastroenterol Hepatol 2019;31:1439–1443

    Article  CAS  PubMed  Google Scholar 

  19. Udompap P, Sukonrut K, Suvannarerg V, Pongpaibul A, Charatcharoenwitthaya P. Prospective comparison of transient elastography, point shear wave elastography, APRI and FIB-4 for staging liver fibrosis in chronic viral hepatitis. J Viral Hepat 2020;27:437–448

    Article  PubMed  Google Scholar 

  20. Ishak K, Baptista A, Bianchi L et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696–699

    Article  CAS  Google Scholar 

  21. Dong XQ, Wu Z, Zhao H, Wang GQ. China Hep BRFARG Evaluation and comparison of thirty noninvasive models for diagnosing liver fibrosis in Chinese hepatitis B patients. J Viral Hepat 2019;26:297–307

    Article  CAS  PubMed  Google Scholar 

  22. Kleiner DE, Brunt EM. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis 2012;32:3–13

    Article  CAS  PubMed  Google Scholar 

  23. Kleiner DE, Brunt EM, Van Natta M et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313–1321

    Article  PubMed  Google Scholar 

  24. Bedossa P, Poitou C, Veyrie N et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012;56:1751–1759

    Article  PubMed  Google Scholar 

  25. Wu YL, Peng XE, Zhu YB, Yan XL, Chen WN, Lin X. Hepatitis B virus X protein induces hepatic steatosis by enhancing the expression of liver fatty acid binding protein. J Virol 2016;90:1729–1740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim KH, Shin HJ, Kim K et al. Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARgamma. Gastroenterology 2007;132:1955–1967

    Article  CAS  PubMed  Google Scholar 

  27. Oehler N, Volz T, Bhadra OD et al. Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism. Hepatology 2014;60:1483–1493

    Article  CAS  PubMed  Google Scholar 

  28. Geier A. Hepatitis B virus: the “metabolovirus” highjacks cholesterol and bile acid metabolism. Hepatology 2014;60:1458–1460

    Article  CAS  PubMed  Google Scholar 

  29. Minakari M, Molaei M, Shalmani HM et al. Liver steatosis in patients with chronic hepatitis B infection: host and viral risk factors. Eur J Gastroenterol Hepatol. 2009;21:512–516

    Article  PubMed  Google Scholar 

  30. Altlparmak E, Koklu S, Yalinkilic M et al. Viral and host causes of fatty liver in chronic hepatitis B. World J Gastroenterol 2005;11:3056–3059

    Article  PubMed  PubMed Central  Google Scholar 

  31. Tsochatzis E, Papatheodoridis GV, Manesis EK, Chrysanthos N, Kafiri G, Archimandritis AJ. Hepatic steatosis in chronic hepatitis B develops due to host metabolic factors: a comparative approach with genotype 1 chronic hepatitis C. Dig Liver Dis 2007;39:936–942

    Article  CAS  PubMed  Google Scholar 

  32. Thomopoulos KC, Arvaniti V, Tsamantas AC et al. Prevalence of liver steatosis in patients with chronic hepatitis B: a study of associated factors and of relationship with fibrosis. Eur J Gastroenterol Hepatol 2006;18:233–237

    Article  PubMed  Google Scholar 

  33. Lanthier N, Horsmans Y, Leclercq IA. The metabolic syndrome: how it may influence hepatic stellate cell activation and hepatic fibrosis. Curr Opin Clin Nutr Metab Care. 2009;12:404–411

    Article  CAS  PubMed  Google Scholar 

  34. Katsiki N, Perez-Martinez P, Anagnostis P, Mikhailidis DP, Karagiannis A. Is nonalcoholic fatty liver disease indeed the hepatic manifestation of metabolic syndrome? Curr Vasc Pharmacol 2018;16:219–227

    Article  CAS  PubMed  Google Scholar 

  35. Dowman JK, Tomlinson JW, Newsome PN. Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2011;33:525–540

    Article  CAS  PubMed  Google Scholar 

  36. Shen F, Mi YQ, Xu L et al. Moderate to severe hepatic steatosis leads to overestimation of liver stiffness measurement in chronic hepatitis B patients without significant fibrosis. Aliment Pharmacol Ther 2019;50:93–102

    Article  PubMed  Google Scholar 

  37. Shi JP, Fan JG, Wu R 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 

  38. Asselah T, Boyer N, Guimont MC et al. Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C. Gut 2003;52:1638–1643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Khalili M, Kleiner D, W. K, et al. Hepatic fat and steatohepatitis in a large multiethnic north American cohort of adults and children with chronic hepatitis B. Hepatology, City;2019:107A.

  40. Baroni GS, Pastorelli A, Manzin A et al. Hepatic stellate cell activation and liver fibrosis are associated with necroinflammatory injury and Th1-like response in chronic hepatitis C. Liver 1999;19:212–219

    Article  CAS  PubMed  Google Scholar 

  41. Seto WK, Fung J, Cheung KS et al. Body-mass index is associated with fibrosis regression during long-term nucleoside analogue therapy in chronic hepatitis B. Aliment Pharmacol Ther 2016;44:1071–1079

    Article  CAS  PubMed  Google Scholar 

  42. Zheng RD, Xu CR, Jiang L, Dou AX, Zhou K, Lu LG. Predictors of hepatic steatosis in HBeAg-negative chronic hepatitis B patients and their diagnostic values in hepatic fibrosis. Int J Med Sci 2010;7:272–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Saxena NK, Anania FA. Adipocytokines and hepatic fibrosis. Trends Endocrinol Metab 2015;26:153–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Choi HSJ, Brouwer WP, Zanjir WMR 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 

  45. Chen YC, Jeng WJ, Hsu CW, Lin CY. Impact of hepatic steatosis on treatment response in nuclesos(t)ide analogue-treated HBeAg-positive chronic hepatitis B: a retrospective study. BMC Gastroenterol 2020;20:146

    Article  PubMed  PubMed Central  Google Scholar 

  46. Hui JM, Sud A, Farrell GC et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 2003;125:1695–1704

    Article  CAS  PubMed  Google Scholar 

  47. Petta S, Macaluso FS, Barcellona MR et al. Serum gamma-glutamyl transferase levels, insulin resistance and liver fibrosis in patients with chronic liver diseases. PLoS One 2012;7:e51165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Petta S, Camma C, Di Marco V et al. Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection. Liver Int 2011;31:507–515

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Ms Li-Hwa Lu and I-Han Lin for assistance of data collection. This work was supported by grants from Chang Gung Memorial Hospital (Grant Numbers: CORPG3G0631, CORPG3G0641, CORPG3G0651, CORPG1G0041).

Funding

This work was supported by grants from Chang Gung Memorial Hospital (Grant Number: CORPG3G0631, CORPG3G0641, CORPG3G0651, CORPG1G0041). The funder had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and University, Linkou, No. 5, Fu Hsing Street, Guishan Dist., Taoyuan City, 33302, Taiwan, ROC

    Yi-Cheng Chen, Chao-Wei Hsu, Wen-Juei Jeng & Chun-Yen Lin

  2. College of Medicine, Guishan Dist, Chang Gung University, No. 259, Wen Hua 1st Rd, Taoyuan City, 33302, Taiwan, Republic of China

    Yi-Cheng Chen, Chao-Wei Hsu, Wen-Juei Jeng & Chun-Yen Lin

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  1. Yi-Cheng Chen
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Contributions

Y-C C was involved in concept and design; Y-C C, C-W H, W-J J, C-Y L helped in data acquisition, interpretation, and analysis; Y-C C was involved in drafting of the manuscript; Y-C C, C-W H, W-J J, C-Y L contributed to critical revision of the manuscript for important intellectual content; Y-C C helped in statistical analysis. All authors read and approved the final manuscript.

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Correspondence to Yi-Cheng Chen.

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10620_2020_6761_MOESM1_ESM.tiff

Supplementary figure 1. The proportion of hepatic steatosis (HS) in each Ishak fibrosis score. The difference is not statistically different (p=0.112). (TIFF 387 kb)

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Chen, YC., Hsu, CW., Jeng, WJ. et al. Advanced Liver Fibrosis Is Associated with Necroinflammatory Grade but Not Hepatic Steatosis in Chronic Hepatitis B Patients. Dig Dis Sci 66, 4492–4500 (2021). https://doi.org/10.1007/s10620-020-06761-x

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