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Elevated adiponectin and sTNFRII serum levels can predict progression to hepatocellular carcinoma in patients with compensated HCV1 cirrhosis

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European Cytokine Network Aims and scope

Abstract

Background and aims

An obesity-related altered adipose tissue secretion is suggested as a risk factor for hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) cirrhosis. However, no prospective study has yet examined the predictive value of circulating adipokines and immuno-inflammatory biomarkers regarding this risk.

Methods

This was a case-control study nested in a prospective French national cohort of HCV-infected patients with biopsy-proven compensated cirrhosis.We selected 56 HCV1-infected patients who subsequently developed HCC (cases), and 96 controls matched for age, gender and diabetes, not developing HCC after a similar period. Adipokines and immuno-inflammatory biomarkers were determined on baseline frozen serum samples. Their influence on the occurrence of HCC was assessed using a mixed logistic regression model under univariate analysis and a backward stepwise procedure under multivariate analysis.

Results

The patients were mostly male (62.5%) with active HCV replication (83%) and had been followed for a median duration of 6.3 years during which 44.4% achieved a sustained viral response. Higher adiponectinemia levels were found in cases than in controls (P = 0.01). Levels of the immuno-inflammatory markers were similar in both groups except sTNFRII >5,000 pg/mL (52% cases versus 24% controls; P = 0.001). No marker was associated with histological steatosis. Under multivariate analysis, baseline adiponectin and sTNFRII levels were independently associated with the occurrence of HCC,alongside previous excessive alcohol intake and HCV viral load.

Conclusions

High baseline circulating adiponectin and sTNFRII levels were associated with an increased risk of HCC in patients with HCV1 cirrhosis, independently of their HCV replication status.

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References

  1. Thrift AP, El-Serag HB, Kanwal F. Global epidemiology and burden of HCV infection and HCV-related disease. Nat Rev Gastroenterol Hepatol 2017; 14: 122–32.

    Article  PubMed  Google Scholar 

  2. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020–2.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Nahon P, Bourcier V, Layese R, et al. Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications. Gastroenterology 2017; 152: 142–156 e2.

    Article  PubMed  Google Scholar 

  4. Younossi ZM, Kanwal F, Saab S, et al. The impact of hepatitis C burden: an evidence-based approach. Aliment Pharmacol Ther 2014; 39: 518–31.

    Article  CAS  PubMed  Google Scholar 

  5. 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: 533–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. N’Kontchou G, Paries J, Htar MT, et al. Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis. Clin Gastroenterol Hepatol 2006; 4: 1062–8.

    Article  PubMed  Google Scholar 

  7. Chen CL, Yang HI, Yang WS, et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 2008; 135: 111–21.

    Article  CAS  PubMed  Google Scholar 

  8. Bastard JP, Maachi M, Lagathu C, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 2006; 17: 4–12.

    CAS  PubMed  Google Scholar 

  9. Font-Burgada J, Sun B, Karin M. Obesity and cancer: the oil that feeds the flame. Cell Metab 2016; 23: 48–62.

    Article  CAS  PubMed  Google Scholar 

  10. Castello G, Scala S, Palmieri G, Crley SA, Izzo F. HCV-related hepatocellualr carcinoma: from chronic inflammation to cancer. Clin Immunol 2010; 134: 237–50.

    Article  CAS  PubMed  Google Scholar 

  11. Maki A, KOno H, Gupta M, et al. Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis C virus-associated hepatocellular carcinoma. Ann Surg Oncol 2007; 14: 1182–90.

    Article  PubMed  Google Scholar 

  12. Liu D, Li S, Li Z. Adiponectin: a biomarker for chronic hepatitis C? Cytokine 2017; 89: 27–33.

    Article  CAS  PubMed  Google Scholar 

  13. Nkontchou G, Bastard JP, Ziol M, et al. Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitisCcirrhosis. J Hepatol 2010; 53: 827–33.

    Article  CAS  PubMed  Google Scholar 

  14. Sandler NG, Koh C, Roque A, et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology 2011; 141: 1220–30.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Trinchet JC, Bourcier V, Chaffaut C, et al. Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort). Hepatology 2015; 62: 737–50.

    Article  PubMed  Google Scholar 

  16. Nahon P, Lescat M, Layese R, et al. Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort). Gut 2017; 66: 330–41.

    Article  PubMed  Google Scholar 

  17. Ganne-Carrie N, Layese R, Bourcier V, et al. Nomogram for individualized prediction of hepatocellular carcinoma occurrence in hepatitis C virus cirrhosis (ANRS CO12 CirVir). Hepatology 2016; 64: 1136–47.

    Article  CAS  PubMed  Google Scholar 

  18. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42: 1208–36.

    Article  PubMed  Google Scholar 

  19. 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: 1751–9.

    Article  PubMed  Google Scholar 

  20. Arano T, Nakagawa H, Tateishi R, et al. Serum level of adiponectin and the risk of liver cancer development in chronic hepatitis C patients. Int J Cancer 2011; 129: 2226–35.

    Article  CAS  PubMed  Google Scholar 

  21. Khattab MA, Eslam M, Mousa YI, et al. Association between metabolic abnormalities and hepatitis C-related hepatocellular carcinoma. Ann Hepatol 2012; 11: 487–94.

    Article  Google Scholar 

  22. Michikawa T, Inoue M, Sawada N, et al. Plasma levels of adiponectin and primary liver cancer risk in middle-aged Japanese adults with hepatitis virus infection: a nested case-control study. Cancer Epidemiol Biomarkers Prev 2013; 22: 2250–7.

    Article  CAS  PubMed  Google Scholar 

  23. Nakagawa H, Fujiwara N, Tateishi R, et al. Impact of serum levels of interleukin-6 and adiponectin on all-cause, liver-related, and liverunrelated mortality in chronic hepatitis C patients. J Gastroenterol Hepatol 2015; 30: 379–88.

    Article  CAS  PubMed  Google Scholar 

  24. Hung CH, Wang JH, Hu TH, et al. Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection. World J Gastroenterol 2010; 16: 2265–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sumie S, Kawaguchi T, Kuromatsu R, et al. Total and high molecular weight adiponectin and hepatocellular carcinoma with HCV infection. PLoS One 2011; 6: e26840. doi: 10.1371/journal.pone.0026840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Siegel AB, Goyal A, Salomao M, et al. Serum adiponectin is associated with worsened overall survival in a prospective cohort of hepatocellular carcinoma patients. Oncology 2015; 88: 57–68.

    Article  CAS  PubMed  Google Scholar 

  27. Wang SN, Yang SF, Tsai HH, Lee KT, Yeh YT. Increased adiponectin associated with poor survival in hepatocellular carcinoma. J Gastroenterol 2014; 49: 1342–51.

    Article  CAS  PubMed  Google Scholar 

  28. Shen J, Yeh CC, Wang Q, Gurvich I, Siegel AB, Santella RM. Plasma adiponectin and hepatocellular carcinoma survival among patients without liver transplantation. Anticancer Res 2016; 36: 5307–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nakagawa H1, Maeda S, Yoshida H, et al. Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences. Int J Cancer 2009; 125: 2264–9.

    Article  CAS  PubMed  Google Scholar 

  30. Kessel A, Elias G, Pavlotzky E, Zuckerman E, Rosner I, Toubi E. Anti-C-reactive protein antibodies in chronic hepatitis C infection: correlation with severity and autoimmunity. Hum Immunol 2007; 68: 844–8.

    Article  CAS  PubMed  Google Scholar 

  31. Sjöwall C, Cardell K, Boström EA, et al. High prevalence of autoantibodies to C-reactive protein in patients with chronic hepatitis C infection: association with liver fibrosis and portal inflammation. Hum Immunol 2012; 73: 382–8.

    Article  CAS  PubMed  Google Scholar 

  32. Waters JP, Pober JS, Bradley JR. Tumour necrosis factor in infectious disease. J Pathol 2013; 230: 132–47.

    Article  CAS  PubMed  Google Scholar 

  33. Waters JP, Pober JS, Bradley JR. Tumour necrosis factor and cancer. J Pathol 2013; 230: 241–8.

    Article  CAS  PubMed  Google Scholar 

  34. Spinas GA, Keller U, Brockhaus M. Release of soluble receptors for tumor necrosis factor (TNF) in relation to circulating TNF during experimental endotoxinemia. J Clin Invest 1992; 90: 533–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tornero C, Alberola J, Tamarit A, Navarro D. Effect of highly active anti-retroviral therapy and hepatitis C virus co-infection on serum levels of pro-inflammatory and immunoregulatory cytokines in human immunodeficiency virus-1-infected individuals. Clin Microbiol Infect 2006; 12: 555–60.

    Article  CAS  PubMed  Google Scholar 

  36. Itoh Y, Okanoue T, Ohnishi N, et al. Serum levels of soluble tumor necrosis factor receptors and effects of interferon therapy in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1999; 94: 1332–40.

    Article  CAS  PubMed  Google Scholar 

  37. Fouad SA, Elsaaid NH, Mohamed NA, Abutaleb OM. Diagnostic value of serum level of soluble tumor necrosis factor receptor IIα in Egyptian patients with chronic hepatitis C virus infection and hepatocellular carcinoma. Hepat Mon 2014; 14(9): e19346. doi: 10.5812/hepatmon.19346.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zekri AR, Youssef AS, Bakr YM, et al. Serum biomarkers for early detection of hepatocellular carcinoma associated withHCVinfection in Egyptian patients. Asian Pac J Cancer Prev 2015; 16: 1281–7.

    Article  PubMed  Google Scholar 

  39. Zekri AR, Alam El-Din HM, Bahnassy AA, et al. Serum levels of soluble Fas, soluble tumor necrosis factor-receptor II, interleukin-2 receptor and interleukin-8 as early predictors of hepatocellular carcinoma in Egyptian patients with hepatitis C virus genotype-4. Comp Hepatol 2010; 9: 1. doi: 10.1186/1476-5926-9-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kazankov K, Barrera F, Møller HJ, et al. Soluble CD163, a macrophage activation marker, is independently associated with fibrosis in patients with chronic viral hepatitis B and C. Hepatology 2014; 60: 521–30.

    Article  CAS  PubMed  Google Scholar 

  41. Kazankov K, Rode A, Simonsen K, et al. Macrophage activation marker soluble CD163 may predict disease progression in hepatocellular carcinoma. Scand J Clin Lab Invest 2016; 76: 64–73.

    Article  CAS  PubMed  Google Scholar 

  42. Waidmann O, Köberle V, Bettinger D, et al. Diagnostic and prognostic significance of cell death and macrophage activation markers in patients with hepatocellular carcinoma. J Hepatol 2013; 59: 769–79.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Participated equally in this work.

Authors and Affiliations

  1. AP-HP, hôpital Tenon, UF biomarqueurs inflammatoires et métaboliques, service de biochimie, 75020, Paris, France

    Jean-Philippe Bastard & Soraya Fellahi

  2. Sorbonne université, faculté de médecine, 75012, Paris, France

    Jean-Philippe Bastard, Soraya Fellahi & Jacqueline Capeau

  3. Inserm, CRSA, UMR_S 938, 75012, Paris, France

    Jean-Philippe Bastard, Soraya Fellahi & Jacqueline Capeau

  4. AP-HP, hôpital Henri-Mondor, Public Health Department, Clinical Research Unit (URC-Mondor), 94000, Créteil, France

    Étienne Audureau, Richard Layese & Françoise Roudot-Thoraval

  5. université Paris-Est, UPEC, DHU A-TVB, IMRB-EA 7376 CEpiA (Clinical Epidemiology and Ageing Unit), 94000, Créteil, France

    Étienne Audureau, Richard Layese & Françoise Roudot-Thoraval

  6. Unit for Basic and Clinical Research on Viral Hepatitis, ANRS, Paris, France

    Carole Cagnot

  7. AP-HP, hôpital Jean-Verdier, service d’hépatologie, Bondy, France

    Valérie Mahuas-Bourcier & Pierre Nahon

  8. CRB (Liver Disease Biobank), groupe hospitalier Paris, Seine-Saint-Denis BB-0033-00027, France

    Angela Sutton

  9. AP-HP, hôpital Jean-Verdier, service de biochimie, Bondy, France

    Angela Sutton

  10. Inserm U1148, université Paris 13, Bobigny, France

    Angela Sutton

  11. Université Paris 13, Sorbonne Paris-Cité, Bobigny, France

    Marianne Ziol

  12. Inserm UMR_S 1162, « Génomique fonctionnelle des tumeurs solides », 75005, Paris, France

    Marianne Ziol & Pierre Nahon

  13. APHP, hôpital Jean-Verdier, anatomie pathologique, Bondy, France

    Marianne Ziol

  14. Université Paris 13, Sorbonne Paris-Cité, « Équipe labellisée Ligue contre le cancer », 93206, Saint-Denis, France

    Pierre Nahon

  15. Hôpital Tenon, UF biomarqueurs inflammatoires et métaboliques, service de biochimie et hormonologie, 4, rue de la Chine, 75970, Paris cedex 20, France

    Jean-Philippe Bastard

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  1. Jean-Philippe Bastard
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ANRS CO12 CirVir Group

Corresponding author

Correspondence to Jean-Philippe Bastard.

Additional information

ANRS CO12 CirVir group: Pierre Nahon1, Patrick Marcellin2, Dominique Guyader3, Stanislas Pol4, Hélène Fontaine4, Dominique Larrey5, Victor De Lédinghen6, Denis Ouzan7, Fabien Zoulim8, Dominique Roulot9, Albert Tran10, Jean-Pierre Bronowicki11, Jean-Pierre Zarski12, Vincent Leroy12, Ghassan Riachi13, Paul Calès14, Jean-Marie Péron15, Laurent Alric16, Marc Bourlière17, Philippe Mathurin18, Sebastien Dharancy18, Jean-Frédéric Blanc19, Armand Abergel20, Lawrence Serfaty21, Ariane Mallat22, Jean-Didier Grangé23, Pierre Attali24, Yannick Bacq25, Claire Wartelle26, Thông Dao27, Dominique Thabut28, Christophe Pilette29, Christine Silvain30, Christos Christidis31, Dominique Capron32, Gérard Thiefin33, Sophie Hillaire34, Vincent Di Martino35.

1AP-HP, hôpital Jean-Verdier, service d’hépatologie, Bondy, université Paris 13, Bobigny et Inserm U1162, Université Paris 5, Paris; 2APHP, hôpital Beaujon, service d’hépatologie, Clichy; 3CHU Pontchaillou, service d’hépatologie, Rennes; 4AP-HP, hôpital Cochin, département d’hépatologie et Inserm UMS20 et U1223, Institut Pasteur, université Paris Descartes, Paris; 5Hôpital Saint-Éloi, service d’hépatologie, Montpellier; 6Hôpital Haut-Lévêque, service d’hépatologie, Bordeaux; 7Institut Arnaud-Tzanck, service d’hépatologie, Saint-Laurent-du-Var; 8Hôpital Hôtel-Dieu, service d’hépatologie, Lyon; 9AP-HP, hôpital Avicenne, service d’hépatologie, Bobigny; 10CHU de Nice, service d’hépatologie, et Inserm U1065, université Nice-Sophia-Antipolis, Nice; 11hôpital Brabois, service d’hépatologie, Vandoeuvre-lès-Nancy; 12Hôpital Michallon, service d’hépatologie, Grenoble; 13Hôpital Charles-Nicolle, service d’hépatologie, Rouen; 14CHU d’Angers, service d’hépatologie, Angers; 15Hôpital Purpan, service d’hépatologie, Toulouse; 16CHU de Toulouse, service de médecine interne, pôle digestif UMR152, Toulouse; 17Hôpital Saint-Joseph, service d’hépatologie, Marseille; 18Hôpital Claude-Huriez, service d’hépatologie, Lille; 19Hôpital Saint-André, service d’hépatologie, Bordeaux; 20Hôpital Hôtel-Dieu, service d’hépatologie, Clermont-Ferrand; 21AP-HP, hôpital Saint-Antoine, service d’hépatologie, Paris; 22AP-HP, hôpital Henri-Mondor, service d’hépatologie, Créteil; 23AP-HP, hôpital Tenon, service d’hépatologie, Paris; 24AP-HP, hôpital Paul-Brousse, service d’hépatologie, Villejuif; 25CHRU, hôpital Trousseau, unité d’hépatologie, Tours; 26Hôpital d’Aixen-Provence, service d’hépatologie, Aix-en-Provence; 27Hôpital de la Côte de Nacre, service d’hépatologie, Caen; 28UPMC, AP-HP, groupe hospitalier de la Pitié-Salpêtrière, service d’hépatologie, Paris; 29CHU Le Mans, service d’hépatologie, Le Mans; 30CHU de Poitiers, service d’hépatologie, Poitiers; 31Institut mutualiste Montsouris, service d’hépatologie, Paris; 32Hôpital Amiens-Nord, service d’hépatologie, Amiens; 33Hôpital Robert-Debré, service d’hépatologie, Reims; 34Hôpital Foch, service d’hépatologie, Suresnes; 35Hôpital Jean-Minjoz, service d’hépatologie, Besançon, France.

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Bastard, JP., Fellahi, S., Audureau, É. et al. Elevated adiponectin and sTNFRII serum levels can predict progression to hepatocellular carcinoma in patients with compensated HCV1 cirrhosis. Eur Cytokine Netw 29, 112–120 (2018). https://doi.org/10.1684/ecn.2018.0413

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