Skip to main content

Advertisement

SpringerLink
Log in

Adipocytokines and liver fibrosis stages in patients with chronic hepatitis B virus infection

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background

Adipocytokines play an important role in lipid metabolism and liver disease progression. However, the interactions between hepatitis B virus (HBV) infection and adipocytokines remain largely unknown.

Aims

To investigate the association of HBV infection with adipocytokines in HBV-infected and noninfected subjects. In addition, the impact of adipocytokines on serum HBV DNA, HBsAg levels and liver fibrosis stage was also examined.

Methods

A case-control analysis of patients with and without chronic HBV infection was performed. The HBV group consisted of 187 patients with chronic HBV infection, and the control group consisted of 184 age-, gender- and body mass index-matched subjects without HBV infection. Fasting blood glucose, lipid profiles, adiponectin, leptin and visfatin levels were compared between the two groups. APRI and FIB-4 were calculated to estimate the severity of liver fibrosis.

Results

Most of the enrolled subjects had lower ALT levels [228 (57.7 %) ALT < ULN] and milder hepatic fibrosis [381 (96.5 %) APRI < 0.7; 307 (77.7 %) FIB4 < 1.45]. The HBV group had significantly higher serum adiponectin and visfatin but lower leptin levels than the control group. This difference remained significant after adjustment for age, sex, BMI and ALT levels (p < 0.05). Serum adiponectin, leptin and visfatin levels were significantly associated with serum HBsAg and HBV DNA levels (p < 0.05). In addition, a higher serum adiponectin level was associated with advanced liver fibrosis in elder male HBeAg-negative patients.

Conclusions

Patients with chronic HBV infection have significantly higher serum adiponectin and visfatin but lower leptin levels than healthy controls. Serum adipocytokine levels independently correlate with HBV viremia, HBsAg levels and liver fibrosis stages.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005–2023

    Article  PubMed  Google Scholar 

  2. Hsu CS, Liu CH, Liu CJ, Hsu SJ, Chen CL, Hwang JJ, Lai MY, et al. Association of metabolic profiles with hepatic fibrosis in chronic hepatitis C patients with genotype 1 or 2 infection. J Gastroenterol Hepatol 2010;25:970–977

    Article  CAS  PubMed  Google Scholar 

  3. Wong GL, Chan HL, Yu Z, Chan AW, Choi PC, Chim AM, Chan HY, 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 

  4. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010;51:1820–1832

    Article  PubMed  Google Scholar 

  5. Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, Wang LY, 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 

  6. Wong GL, Wong VW, Choi PC, Chan AW, Chim AM, Yiu KK, Chan HY, et al. Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B. Gut 2009;58:111–117

    Article  PubMed  Google Scholar 

  7. Wei EK, Giovannucci E, Fuchs CS, Willett WC, Mantzoros CS. Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J Natl Cancer Inst 2005;97:1688–1694

    Article  CAS  PubMed  Google Scholar 

  8. Goktas S, Yilmaz MI, Caglar K, Sonmez A, Kilic S, Bedir S. Prostate cancer and adiponectin. Urology 2005;65:1168–1172

    Article  PubMed  Google Scholar 

  9. Miyoshi Y, Funahashi T, Kihara S, Taguchi T, Tamaki Y, Matsuzawa Y, Noguchi S. Association of serum adiponectin levels with breast cancer risk. Clin Cancer Res 2003;9:5699–5704

    CAS  PubMed  Google Scholar 

  10. Petridou E, Mantzoros C, Dessypris N, Koukoulomatis P, Addy C, Voulgaris Z, Chrousos G, et al. Plasma adiponectin concentrations in relation to endometrial cancer: a case–control study in Greece. J Clin Endocrinol Metab 2003;88:993–997

    Article  CAS  PubMed  Google Scholar 

  11. Chen CL, Yang WS, Yang HI, Chen CF, You SL, Wang LY, Lu SN, et al. Plasma adipokines and risk of hepatocellular carcinoma in chronic hepatitis B virus-infected carriers: a prospective study in taiwan. Cancer Epidemiol Biomarkers Prev 2014;23:1659–1671

    Article  CAS  PubMed  Google Scholar 

  12. Arano T, Nakagawa H, Tateishi R, Ikeda H, Uchino K, Enooku K, Goto E, et al. Serum level of adiponectin and the risk of liver cancer development in chronic hepatitis C patients. Int J Cancer 2011;129:2226–2235

    Article  CAS  PubMed  Google Scholar 

  13. Marra F, Bertolani C. Adipokines in liver diseases. Hepatology 2009;50:957–969

    Article  CAS  PubMed  Google Scholar 

  14. Lemoine M, Ratziu V, Kim M, Maachi M, Wendum D, Paye F, Bastard JP, et al. Serum adipokine levels predictive of liver injury in non-alcoholic fatty liver disease. Liver Int 2009;29:1431–1438

    Article  CAS  PubMed  Google Scholar 

  15. Khattab MA, Eslam M, Aly MM, Shatat M, Hussen A, Moussa YI, Elsaghir G, et al. Association of serum adipocytokines with insulin resistance and liver injury in patients with chronic hepatitis C genotype 4. J Clin Gastroenterol 2012;46:871–879

    Article  CAS  PubMed  Google Scholar 

  16. Hui CK, Zhang HY, Lee NP, Chan W, Yueng YH, Leung KW, Lu L, et al. Serum adiponectin is increased in advancing liver fibrosis and declines with reduction in fibrosis in chronic hepatitis B. J Hepatol 2007;47:191–202

    Article  CAS  PubMed  Google Scholar 

  17. Wong VW, Wong GL, Yu J, Choi PC, Chan AW, Chan HY, Chu ES, 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 

  18. Kukla M, Ciupinska-Kajor M, Kajor M, Wylezol M, Zwirska-Korczala K, Hartleb M, Berdowska A, et al. Liver visfatin expression in morbidly obese patients with nonalcoholic fatty liver disease undergoing bariatric surgery. Pol J Pathol 2012;61:147–153

    Google Scholar 

  19. Chu CM, Liaw YF. Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B. Gastroenterology 2007;133:1458–1465

    Article  CAS  PubMed  Google Scholar 

  20. Hung CH, Lu SN, Wang JH, Lee CM, Chen TM, Tung HD, Chen CH, et al. Correlation between ultrasonographic and pathologic diagnoses of hepatitis B and C virus-related cirrhosis. J Gastroenterol 2003;38:153–157

    Article  PubMed  Google Scholar 

  21. Lin DY, Sheen IS, Chiu CT, Lin SM, Kuo YC, Liaw YF. Ultrasonographic changes of early liver cirrhosis in chronic hepatitis B: a longitudinal study. J Clin Ultrasound 1993;21:303–308

    Article  CAS  PubMed  Google Scholar 

  22. Liu CH, Lin JW, Tsai FC, Yang PM, Lai MY, Chen JH, Kao JH, et al. Noninvasive tests for the prediction of significant hepatic fibrosis in hepatitis C virus carriers with persistently normal alanine aminotransferases. Liver Int 2006;26:1087–1094

    Article  CAS  PubMed  Google Scholar 

  23. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, 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 

  24. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236

    Article  PubMed  Google Scholar 

  25. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640–1645

    Article  CAS  PubMed  Google Scholar 

  26. Cordero A, Andres E, Ordonez B, Leon M, Laclaustra M, Grima A, Luengo E, et al. Usefulness of triglycerides-to-high-density lipoprotein cholesterol ratio for predicting the first coronary event in men. Am J Cardiol 2009;104:1393–1397

    Article  CAS  PubMed  Google Scholar 

  27. Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ 2004;328:983

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet 2005;366:1059–1062

    Article  PubMed  Google Scholar 

  29. Tseng TC, Liu CJ, Su TH, Wang CC, Chen CL, Chen PJ, Chen DS, et al. Serum hepatitis B surface antigen levels predict surface antigen loss in hepatitis B e antigen seroconverters. Gastroenterology 2013;141:517–525, 525 e511–e512

  30. Su TH, Hsu CS, Chen CL, Liu CH, Huang YW, Tseng TC, Liu CJ, et al. Serum hepatitis B surface antigen concentration correlates with HBV DNA level in patients with chronic hepatitis B. Antivir Ther 2013;15:1133–1139

    Article  Google Scholar 

  31. Yeh SH, Tsai CY, Kao JH, Liu CJ, Kuo TJ, Lin MW, Huang WL, et al. Quantification and genotyping of hepatitis B virus in a single reaction by real-time PCR and melting curve analysis. J Hepatol 2004;41:659–666

    Article  CAS  PubMed  Google Scholar 

  32. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996;24:289–293

    Article  CAS  PubMed  Google Scholar 

  33. Xiao G, Yang J, Yan L. Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis. Hepatology 2015;61:292–302

    Article  PubMed  Google Scholar 

  34. Wang H, Xue L, Yan R, Zhou Y, Wang MS, Cheng MJ, Huang HJ. Comparison of FIB-4 and APRI in Chinese HBV-infected patients with persistently normal ALT and mildly elevated ALT. J Viral Hepat 2013;20:e3–e10

    Article  CAS  PubMed  Google Scholar 

  35. Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, Sun Y, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology 2011;53:726–736

    Article  PubMed  Google Scholar 

  36. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 2003;37:1202–1219

    Article  PubMed  Google Scholar 

  37. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423:762–769

    Article  CAS  PubMed  Google Scholar 

  38. Polyzos SA, Kountouras J, Zavos C, Tsiaousi E. The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diabetes Obes Metab 2010;12:365–383

    Article  CAS  PubMed  Google Scholar 

  39. Janeckova R. The role of leptin in human physiology and pathophysiology. Physiol Res 2001;50:443–459

    CAS  PubMed  Google Scholar 

  40. Manolakopoulos S, Bethanis S, Liapi C, Stripeli F, Sklavos P, Margeli A, Christidou A, et al. An assessment of serum leptin levels in patients with chronic viral hepatitis: a prospective study. BMC Gastroenterol 2007;7:17

    Article  PubMed Central  PubMed  Google Scholar 

  41. Kukla M, Mazur W, Buldak RJ, Zwirska-Korczala K. Potential role of leptin, adiponectin and three novel adipokines–visfatin, chemerin and vaspin—in chronic hepatitis. Mol Med 2011;17:1397–1410

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Genc H, Dogru T, Kara M, Tapan S, Ercin CN, Acikel C, Karslioglu Y, et al. Association of plasma visfatin with hepatic and systemic inflammation in nonalcoholic fatty liver disease. Ann Hepatol 2013;12:548–555

    PubMed  Google Scholar 

  43. Bertolani C, Marra F. The role of adipokines in liver fibrosis. Pathophysiology 2008;15:91–101

    Article  CAS  PubMed  Google Scholar 

  44. Bar-Yishay I, Shaul Y, Shlomai A. Hepatocyte metabolic signalling pathways and regulation of hepatitis B virus expression. Liver Int 2011;31:282–290

    Article  CAS  PubMed  Google Scholar 

  45. Hajjou M, Norel R, Carver R, Marion P, Cullen J, Rogler LE, Rogler CE. cDNA microarray analysis of HBV transgenic mouse liver identifies genes in lipid biosynthetic and growth control pathways affected by HBV. J Med Virol 2005;77:57–65

    Article  CAS  PubMed  Google Scholar 

  46. Hsu CS, Liu CH, Wang CC, Tseng TC, Liu CJ, Chen CL, Chen PJ, et al. Impact of hepatitis B virus infection on metabolic profiles and modifying factors. J Viral Hepat 2012;19:e48–e57

    Article  PubMed  Google Scholar 

  47. Chao LT, Wu CF, Sung FY, Lin CL, Liu CJ, Huang CJ, Tsai KS, et al. Insulin, glucose and hepatocellular carcinoma risk in male hepatitis B carriers: results from 17-year follow-up of a population-based cohort. Carcinogenesis 2011;32:876–881

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Jin X, Chen YP, Yang YD, Li YM, Zheng L, Xu CQ. Association between hepatic steatosis and entecavir treatment failure in Chinese patients with chronic hepatitis B. PLoS One 2012;7:e34198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Liu CJ, Chen PJ, Lai MY, Liu CH, Chen CL, Kao JH, Chen DS. High serum adiponectin correlates with advanced liver disease in patients with chronic hepatitis B virus infection. Hepatol Int 2009;3:364–370

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Yokoyama H, Hirose H, Ohgo H, Saito I. Inverse association between serum adiponectin level and transaminase activities in Japanese male workers. J Hepatol 2004;41:19–24

    Article  CAS  PubMed  Google Scholar 

  52. Nishizawa H, Shimomura I, Kishida K, Maeda N, Kuriyama H, Nagaretani H, Matsuda M, et al. Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes 2002;51:2734–2741

    Article  CAS  PubMed  Google Scholar 

  53. Shimizu I, Kohno N, Tamaki K, Shono M, Huang HW, He JH, Yao DF. Female hepatology: favorable role of estrogen in chronic liver disease with hepatitis B virus infection. World J Gastroenterol 2007;13:4295–4305

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Yu MW, Yang YC, Yang SY, Cheng SW, Liaw YF, Lin SM, Chen CJ. Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case–control study among men. J Natl Cancer Inst 2001;93:1644–1651

    Article  CAS  PubMed  Google Scholar 

  55. Wu D, Li H, Xiang G, Zhang L, Li L, Cao Y, Zhang J. Adiponectin and its receptors in chronic hepatitis B patients with steatosis in china. Hepat Mon 2013;13:e6065

    PubMed Central  PubMed  Google Scholar 

  56. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. Liver biopsy. Hepatology 2009;49:1017–1044

    Article  PubMed  Google Scholar 

  57. Tietge UJ, Boker KH, Manns MP, Bahr MJ. Elevated circulating adiponectin levels in liver cirrhosis are associated with reduced liver function and altered hepatic hemodynamics. Am J Physiol Endocrinol Metab 2004;287:E82–E89

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the colleagues at the Health Management Center of Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, who enrolled and followed the patients, and the research assistants who assisted in the laboratory analyses and collected clinical information. This work was supported by grants from the National Taiwan University Hospital, Taipei Tzu Chi Hospital, Liver Disease Prevention and Treatment Research Foundation, the Department of Heath, and the National Science Council, Executive Yuan, Taiwan (NSC103-2314-B-303-004, TCRD-TPE-99-09, TCRD-TPE-100-C1-2, TCRD-TPE-101-17 and TCRD-TPE-103-35).

Compliance with ethical requirements and Conflict of interest

The study was performed in accordance with the principles of the Declaration of Helsinki and was approved by the Ethical Committee of the National Taiwan University Hospital and Taipei Tzu Chi Hospital. Informed consents were obtained from all patients and controls at enrollment. Ding-Shinn Chen: Consultant for Bristol-Myers Squibb, Novartis, GlaxoSmithKline, Roche and Merck Sharp & Dohme. Jia-Horng Kao: Consultant for Bristol-Myers Squibb, Gilead Sciences and Novartis; on the speaker’s bureau for Roche, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme and Novartis. Ching-Sheng Hsu, Wei-Liang Liu, You-Chen Chao, Hans Hsienhong Lin, Tai-Chung Tseng, Chia-Chi Wang, Ding-Shinn Chen and Jia-Horng Kao declare that they have no conflict of interest.

Informed consent in studies with human subjects

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. This study was approved by the Ethics Committee of the National Taiwan University Hospital and Taipei Tzu Chi Hospital. Informed consents were obtained from all patients and controls at enrollment.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan

    Ching-Sheng Hsu, You-Chen Chao, Hans Hsienhong Lin, Tai-Chung Tseng & Chia-Chi Wang

  2. School of Medicine, Tzu Chi University, Hualien, Taiwan

    Ching-Sheng Hsu, You-Chen Chao, Hans Hsienhong Lin, Tai-Chung Tseng & Chia-Chi Wang

  3. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei, 10002, Taiwan

    Wei-Liang Liu, Ding-Shinn Chen & Jia-Horng Kao

  4. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Ding-Shinn Chen & Jia-Horng Kao

  5. Genomics Research Center, Academia Sinica, Nankang, Taiwan

    Ding-Shinn Chen

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

    Jia-Horng Kao

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

    Jia-Horng Kao

Authors
  1. Ching-Sheng Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei-Liang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. You-Chen Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hans Hsienhong Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tai-Chung Tseng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chia-Chi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ding-Shinn Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jia-Horng Kao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jia-Horng Kao.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hsu, CS., Liu, WL., Chao, YC. et al. Adipocytokines and liver fibrosis stages in patients with chronic hepatitis B virus infection. Hepatol Int 9, 231–242 (2015). https://doi.org/10.1007/s12072-015-9616-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-015-9616-2

Keywords

Search

Navigation