Download presentation
Presentation is loading. Please wait.
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;76:2438-41
4
IRON = 527 studies HCV
5
Iron status in HCV infected patients
6
Serum iron-related indices in CHC
% 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
Hepatic iron concentration % Slight increase (x N) Mesenchymal deposition Except in cirrhosis Di Bisceglie AM, Gastroenterology 1992;102: Alla V, Sem Liver Dis 2005;25:461-72
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
Relationship between iron-related indices in CHC
46% 46% Guyader D, J Hepatol 2007 [Epub ahead of print]
11
Iron status in HCV infected patients
Direct Mechanisms HCV
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 HCV-induced modification in HFE metabolism ?
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 US 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;31:203-10 Spahn CM, Science 2001;291:
14
IRON HCV Iron status in HCV infected patients Direct Mechanisms
Indirect Hyperferritinemia <> hepatic iron HCV
15
Serum ferritin in chronic hepatitis C
• Liver damage • Hepatic iron Serum ferritin Di Bisceglie AM, Gastroenterology 1992;102:
16
Serum ferritin in chronic hepatitis C
• Liver damage • Hepatic iron Associated factors • Age • Sex • Alcohol consumption • Metabolic syndrome • Steatosis • Thyroïditis, PCT… Serum ferritin Bonkovsky HL, Hepatology 1997;25: Alla V, Sem Liver Dis 2005;25:
17
Hepatic iron in chronic hepatitis C
• Liver damage Inconstant correlation Hepatic iron METAVIR A METAVIR F Guyader D, J Hepatol 2007 [Epub ahead of print]
18
NTBI Tf TS Fe Increased hepatic iron content in cirrhosis Hepatic
insufficiency Transferrin Tf NTBI TS Hepcidin Fe Alcohol Stuart KA, Gastroenterology 2004;39:492-7 Detivaud L, Blood 2005;106:746-8 Bridle KR, Alc Clin Exp Res 2006;30:
19
Hepatic iron in chronic hepatitis C
• Liver damage • Antiviral drugs • Duration of infection Associated factors • Age and sex • Alcohol consumption • Metabolic syndrome • PCT • HFE mutations Hepatic iron Bonkovsky HL, Hepatology 1997;25: Alla V, Sem Liver Dis 2005;25:
20
Aggravative effect on CHC ?
Prevalence of HFE mutations in CHC Aggravative effect on CHC ? ? C282Y ++ & compound heterozygotes Excluded Included N C282Y & H63D prevalence Vs controls 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
21
HFE genotypes and iron status in CHC
Serum iron-related indices Hepatic iron deposition C282Y H63D Inclusion bias Small samples Confounding factors 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 2006.
22
IRON HCV Iron status in HCV infected patients Direct Mechanisms
Indirect Mechanisms HCV
23
Effects of iron on HCV replication
IRES EMCV IRES HCV 3’UTR NPT II NS3 NS4A NS4B NS5A NS5B HCV subgenomic replicon Huh 7 cells Fillebeen C, JBC 2005;280:
24
IRON HCV Iron status in HCV infected patients Direct Mechanisms
Indirect Mechanisms Liver damage Hepatitis course HCV
25
Hepatic iron ROS Fibrosis progression
Iron as an aggravating factor for fibrosis in CHC Biological evidence Hepatic iron ROS Fibrosis progression Fujita N, Free Rad Biol Med 2007;42:353-62
26
Hepatic iron ? Fibrosis progression
Iron as an aggravating factor for fibrosis in CHC Clinical relevance Hepatic iron ? Fibrosis progression Pietrangelo A, Gastroenterology 2003;124: Guyader D, J Hepatol 2007 [Epub ahead of print]
27
Hepatic iron ? Fibrosis progression
Iron as an aggravating factor for fibrosis in CHC Clinical relevance 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]
28
Necroinflammatory activity
Effects of phlebotomies in chronic hepatitis C Serum transaminases Necroinflammatory activity Fibrosis progression Risk of cancer Phlebotomies 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 2002.
29
No effect on viral load Effects of phlebotomies in chronic hepatitis C
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 2002.
30
IRON HCV Iron status in HCV infected patients Direct Mechanisms
Indirect Mechanisms Fibrosis Hepatitis course Cancer HCV
31
NTBI Tf TS Fe Lipid peroxidation DNA damage
Increased hepatic iron and cancer risk Transferrin Tf NTBI TS Hepcidin Fe Lipid peroxidation DNA damage Turlin B, Hepatology 1995 Deugnier Y, Alcohol 2003
32
Furutani T, Gastroenterology 2006;130:2087-98
Diet with either normal (45 mg/kg) or excessive iron (225 mg/kg) content (carbonyl iron - CI) for 12 months CI - 45 CI - 225 Liver tumors 45% Hepatic 8 OHdG 1 x 2 PCNA index x 5 Lipid peroxidation Ab mitochondria No Yes Steatosis x 3 Hepatic Tg ALT Hepatic iron FL-N/35 transgenic* mouse *polyprotein-coding region of HCV 1b Furutani T, Gastroenterology 2006;130:
33
IRON HCV Iron status in HCV infected patients Direct Mechanisms
Indirect Fibrosis Cancer Hepatitis course HCV Response to therapy
34
Hepatic iron and response to antiviral therapy
IFN Increased HIC Mesenchymal iron PEG + RBV Endothelial iron Prediction of poor SVR Olynyk J, Gastroenterology 1995;108:1104-9 Barton AL, Am J Clin Pathol 1995;103:419-24 Rulyak SJ, Am J Gastroenterol 2005;100:332-7 Bonkowsky H, Gastroenterology 2006;131:
35
No effect on sustained virological response
Effects of phlebotomies on response to therapy No effect on sustained virological response Antiviral therapy + Phlebotomies 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 2002.
36
Effect of HFE mutations on virological response rate
HALT C study NR C282Y H63D S65C Bonkowsky H, Gastroenterology 2006;131: Distante S, Liver 2002;22: (SVR - C282Y) Lebray P, J Viral Hepat 2004;11: (VR - H63D)
37
IRON HCV Disease progression Response to therapy HFE mutations
Liver damage Antiviral drugs Diet, alcohol PCT, MS… ROS HFE mutations Iron proteins Immune fcts Disease progression (fibrosis, cancer…) Response to therapy
38
Hyperferritinemia <> Increased hepatic iron
Alcohol, PCT Thyroïditis Inflammation Metabolic syndrome… Direct assessment of hepatic iron
39
Hepatic iron Naive NR Normal ? LIC/age < 2 + LIC/age >2
Indication of phlebotomies Hepatic iron Naive NR Normal ? LIC/age < 2 + LIC/age >2 + Avoid to induce anemia in order not to impair compliance to antiviral Tt
41
HCV and iron The middle age ? Yves Deugnier Dominique Guyader
Liver Unit & CIC Inserm 0203 Rennes - France PHC - Paris 22 & 23/01/07
Similar presentations
