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Yves DEUGNIER. HCV and iron The middle age ? Yves Deugnier Dominique Guyader Liver Unit & CIC Inserm 0203 Rennes - France PHC - Paris 22 & 23/01/07.

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Presentation on theme: "Yves DEUGNIER. HCV and iron The middle age ? Yves Deugnier Dominique Guyader Liver Unit & CIC Inserm 0203 Rennes - France PHC - Paris 22 & 23/01/07."— Presentation transcript:

1 Yves DEUGNIER

2 HCV and iron The middle age ? Yves Deugnier Dominique Guyader Liver Unit & CIC Inserm 0203 Rennes - France PHC - Paris 22 & 23/01/07

3 Blumberg BS et al, PNAS 1979;76:

4 IRON HCV = 527 studies

5 IRON HCV Iron status in HCV infected patients

6 Serum iron-related indices in CHC Iron % Ferritin % Transferrin saturation % Di Bisceglie AM, Gastroenterology 1992;102: Alla V, Sem Liver Dis 2005;25:461-72

7 Hepatic iron-related indices in CHC Di Bisceglie AM, Gastroenterology 1992;102: Alla V, Sem Liver Dis 2005;25: Hepatic iron concentration % Slight increase (x N) Mesenchymal deposition Except in cirrhosis

8 Distribution of hepatic iron deposits in CHC Hepatocytic 34% Mesenchymal 12% Mixed 54% Guyader D, J Hepatol 2007 [Epub ahead of print]

9 Distribution of hepatic iron deposits in CHC Hepatocytic 34% Deugnier Y, Am J Surg Pathol 1997 Ludwig J, Gastroenterology 1997

10 Guyader D, J Hepatol 2007 [Epub ahead of print] 46% Relationship between iron-related indices in CHC

11 IRON HCV Iron status in HCV infected patients Mechanisms Direct

12 Clinical data No well-designed comparative study of iron status in various chronic liver diseases Prevalence and type of abnormalities of iron- related indices roughly similar in CHC, NASH and ASH Bonkovsky HL, Hepatology 1997;25: Alla V, Sem Liver Dis 2005;25:

13 Biological data Homology between HCV and iron protein biology 5’ Internal Ribosome Entry Site = 5’ Iron Responsive Elements Synergism / competition between HFE and HCV HCV-induced modification in HFE metabolism ? HFE as a non classical MHC molecule hCMV US2 degradation of HFE in human and mouse cells Upregulation of TfR1 by HCV ? Ben-Arieh SV, J Virol 2001;75: Saito H, Hepatology Res 2005;31: Spahn CM, Science 2001;291:

14 IRON HCV Iron status in HCV infected patients Mechanisms Direct Indirect Hyperferritinemia <> hepatic iron

15 Serum ferritin Serum ferritin in chronic hepatitis C Liver damage Hepatic iron Di Bisceglie AM, Gastroenterology 1992;102:

16 Serum ferritin Serum ferritin in chronic hepatitis C Liver damage Hepatic iron Associated factors Age Sex Alcohol consumption Metabolic syndrome Steatosis Thyroïditis, PCT… Bonkovsky HL, Hepatology 1997;25: Alla V, Sem Liver Dis 2005;25:

17 Hepatic iron Hepatic iron in chronic hepatitis C Liver damage Guyader D, J Hepatol 2007 [Epub ahead of print] METAVIR A METAVIR F Inconstant correlation

18 NTBI Transferrin Stuart KA, Gastroenterology 2004;39:492-7 Detivaud L, Blood 2005;106:746-8 Bridle KR, Alc Clin Exp Res 2006;30: Hepcidin TS Increased hepatic iron content in cirrhosis Hepatic insufficiency Alcohol Tf Fe

19 Hepatic iron Liver damage Antiviral drugs Duration of infection Associated factors Age and sex Alcohol consumption Metabolic syndrome PCT HFE mutations Bonkovsky HL, Hepatology 1997;25: Alla V, Sem Liver Dis 2005;25: Hepatic iron in chronic hepatitis C

20 Prevalence of HFE mutations in CHC Piperno A, Hepatology Smith BC, Hepatology Hézode C, J Hepatol Fontana RJ, Hepatology Kazemi-Shirazi, Gastroenterology Martinelli AL, Acta Haematol Negro F, J Med Virol Pirisi M, Am J Clin Pathol, Bonkovsky HL, J Hepatol Diwakaran HH, J Hepatol Thung BY, Gastroenterology Bonkowsky H, Gastroenterology 2006 C282Y ++ & compound heterozygotes ExcludedIncluded N C282Y & H63D prevalence Vs controls Aggravative effect on CHC ? ?

21 HFE genotypes and iron status in CHC Piperno A, Hepatology Smith BC, Hepatology Kazemi-Shirazi, Gastro enterology Martinelli AL, Acta Haematol Negro F, J Med Virol Pirisi M, Am J Clin Pathol, Bonkovsky HL, J Hepatol Thorburn D, Gut Tung BY, Gastroenterology Bonkowsky H Gastroenterology Serum iron-related indices Hepatic iron deposition Inclusion bias Small samples Confounding factors C282Y H63D

22 IRON HCV Iron status in HCV infected patients Mechanisms Direct Indirect

23 Fillebeen C, JBC 2005;280: NPT IINS4BNS4ANS3NS5BNS5A HCV IRES EMCV IRES HCV 3’UTR Huh 7 cells HCV subgenomic replicon Effects of iron on HCV replication

24 IRON HCV Hepatitis course Liver damage Iron status in HCV infected patients Mechanisms Direct Indirect

25 Iron as an aggravating factor for fibrosis in CHC ROS Hepatic iron Fibrosis progression Fujita N, Free Rad Biol Med 2007;42: Biological evidence

26 ? Hepatic iron Fibrosis progression Pietrangelo A, Gastroenterology 2003;124: Guyader D, J Hepatol 2007 [Epub ahead of print] Iron as an aggravating factor for fibrosis in CHC Clinical relevance

27 ? Hepatic iron Fibrosis progression Male sex Age at contamination > 40 y Duration of infection Daily alcohol consumption > 50 g Necroinflammatory activity Steatosis Metabolic syndrome HFE mutations Pietrangelo A, Gastroenterology 2003;124: Guyader D, J Hepatol 2007 [Epub ahead of print] Iron as an aggravating factor for fibrosis in CHC Clinical relevance

28 Serum transaminases Necroinflammatory activity Fibrosis progression Risk of cancer Hayashi H, Am J Gastroenterol 1994 & J Hepatol Fong TL, J Hepatol Guyader D, Am J Gastroenterol Fontana RJ, Hepatology Di Bisceglie AM, Hepatology Yano M, AJGE Effects of phlebotomies in chronic hepatitis C Phlebotomies

29 No effect on viral load Hayashi H, Am J Gastroenterol 1994 & J Hepatol Fong TL, J Hepatol Guyader D, Am J Gastroenterol Fontana RJ, Hepatology Di Bisceglie AM, Hepatology Yano M, AJGE Effects of phlebotomies in chronic hepatitis C Phlebotomies

30 IRON HCV Hepatitis course Fibrosis Cancer Iron status in HCV infected patients Mechanisms Direct Indirect

31 Increased hepatic iron and cancer risk DNA damage Lipid peroxidation Turlin B, Hepatology 1995 Deugnier Y, Alcohol 2003 NTBI Transferrin Hepcidin TS Tf Fe

32 Furutani T, Gastroenterology 2006;130: FL-N/35 transgenic* mouse *polyprotein-coding region of HCV 1b Diet with either normal (45 mg/kg) or excessive iron (225 mg/kg) content (carbonyl iron - CI) for 12 months CI - 45CI Liver tumors045% Hepatic 8 OHdG1x 2 PCNA index1x 5 Lipid peroxidation1x 2 Ab mitochondriaNoYes Steatosis1x 3 Hepatic Tg1x 3 ALT1x 3 Hepatic iron1x 2

33 IRON HCV Hepatitis course Response to therapy Iron status in HCV infected patients Mechanisms Fibrosis Cancer Direct Indirect

34 IFN Increased HIC Mesenchymal iron PEG + RBV Endothelial iron Mesenchymal iron Prediction of poor SVR Hepatic iron and response to antiviral therapy Olynyk J, Gastroenterology 1995;108: Barton AL, Am J Clin Pathol 1995;103: Rulyak SJ, Am J Gastroenterol 2005;100:332-7 Bonkowsky H, Gastroenterology 2006;131:

35 Hayashi H, Am J Gastroenterol 1994 & J Hepatol Fong TL, J Hepatol Guyader D, Am J Gastroenterol Fontana RJ, Hepatology Di Bisceglie AM, Hepatology Yano M, AJGE Effects of phlebotomies on response to therapy No effect on sustained virological response Antiviral therapy + Phlebotomies

36 Bonkowsky H, Gastroenterology 2006;131: Distante S, Liver 2002;22: (SVR - C282Y) Lebray P, J Viral Hepat 2004;11: (VR - H63D) Effect of HFE mutations on virological response rate C282Y H63D S65C HALT C study NR

37 IRON HCV Liver damage Antiviral drugs Diet, alcohol PCT, MS… ROS Disease progression (fibrosis, cancer…) Response to therapy HFE mutations Iron proteins Immune fcts

38 Hyperferritinemia <> Increased hepatic iron Direct assessment of hepatic iron Alcohol, PCT Thyroïditis Inflammation Metabolic syndrome…

39 Indication of phlebotomies Hepatic iron NaiveNR Normal0? LIC/age < 20+ LIC/age >2++ + Avoid to induce anemia in order not to impair compliance to antiviral Tt

40

41 HCV and iron The middle age ? Yves Deugnier Dominique Guyader Liver Unit & CIC Inserm 0203 Rennes - France PHC - Paris 22 & 23/01/07


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