Yves DEUGNIER. HCV and iron The middle age ? Yves Deugnier Dominique Guyader Liver Unit & CIC Inserm...
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Transcript of Yves DEUGNIER. HCV and iron The middle age ? Yves Deugnier Dominique Guyader Liver Unit & CIC Inserm...
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Yves DEUGNIER
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HCV and ironThe middle age ?
Yves DeugnierDominique Guyader
Liver Unit & CIC Inserm 0203Rennes - France
PHC - Paris22 & 23/01/07
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Blumberg BS et al, PNAS 1979;76:2438-41
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IRON
HCV1991-2007 = 527 studies
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IRON
HCV
Iron status in HCV infected patients
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Serum iron-related indices in CHC
Iron 25 - 59 %
Ferritin 25 - 60 %
Transferrin saturation 10 - 25 %
Di Bisceglie AM, Gastroenterology 1992;102:2108-13Alla V, Sem Liver Dis 2005;25:461-72
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Hepatic iron-related indices in CHC
Di Bisceglie AM, Gastroenterology 1992;102:2108-13Alla V, Sem Liver Dis 2005;25:461-72
Hepatic iron concentration 10 - 36 %
Slight increase (x 1.5 - 3 N)
Mesenchymal depositionExcept in cirrhosis
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Distribution of hepatic iron deposits in CHC
Hepatocytic 34%
Mesenchymal 12%
Mixed 54%
Guyader D, J Hepatol 2007 [Epub ahead of print]
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Distribution of hepatic iron deposits in CHC
Hepatocytic 34%
Deugnier Y, Am J Surg Pathol 1997Ludwig J, Gastroenterology 1997
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Guyader D, J Hepatol 2007 [Epub ahead of print]
46%46%
Relationship between iron-related indices in CHC
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IRON
HCV
Iron status in HCV infected patients
MechanismsDirect
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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;25:759-768Alla V, Sem Liver Dis 2005;25:461-472
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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;75:10557-62Saito H, Hepatology Res 2005;31:203-10
Spahn CM, Science 2001;291:1959-62
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IRON
HCV
Iron status in HCV infected patients
MechanismsDirect
Indirect
Hyperferritinemia <> hepatic iron
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Serum ferritin
Serum ferritin in chronic hepatitis C
• Liver damage
• Hepatic iron
Di Bisceglie AM, Gastroenterology 1992;102:2108-13
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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;25:759-768Alla V, Sem Liver Dis 2005;25:461-472
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Hepatic iron
Hepatic iron in chronic hepatitis C
• Liver damage
Guyader D, J Hepatol 2007 [Epub ahead of print]
METAVIR A METAVIR F
Inconstantcorrelation
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NTBI
Transferrin
Stuart KA, Gastroenterology 2004;39:492-7
Detivaud L, Blood 2005;106:746-8
Bridle KR, Alc Clin Exp Res 2006;30:106-112
Hepcidin
TS
Increased hepatic iron content in cirrhosis
Hepatic insufficiency
Alcohol
Tf
Fe
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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;25:759-768Alla V, Sem Liver Dis 2005;25:461-472
Hepatic iron in chronic hepatitis C
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Prevalence of HFE mutations in CHC
Piperno A, Hepatology 1998 - Smith BC, Hepatology 1998 - Hézode C, J Hepatol 1999 - Fontana RJ, Hepatology 2000 - Kazemi-Shirazi, Gastroenterology 1999 - Martinelli AL, Acta Haematol 2000 - Negro F, J Med Virol 2000 - Pirisi M, Am J Clin Pathol, 2000 - Bonkovsky HL, J Hepatol 2002. Diwakaran HH, J Hepatol 2002 - Thung BY, Gastroenterology 2003 - Bonkowsky H, Gastroenterology 2006
C282Y ++ & compound heterozygotes
Excluded Included
NC282Y & H63D
prevalenceVs controls
Aggravative effect on CHC ?
?
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HFE genotypes and iron status in CHC
Piperno A, Hepatology 1998 - Smith BC, Hepatology 1998 - Kazemi-Shirazi, Gastro enterology 1999 - Martinelli AL, Acta Haematol 2000 - Negro F, J Med Virol 2000 - Pirisi M, Am J Clin Pathol, 2000 - Bonkovsky HL, J Hepatol 2002 - Thorburn D, Gut 2002 - Tung BY, Gastroenterology 2003 - Bonkowsky H Gastroenterology 2006.
Serum iron-related indices
Hepatic iron deposition
Inclusion biasSmall samples
Confounding factors
C282Y H63D
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IRON
HCV
Iron status in HCV infected patients
MechanismsDirect
Indirect
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Fillebeen C, JBC 2005;280:9049-9057
NPT II NS4BNS4ANS3 NS5BNS5A
HCVIRES
EMCVIRES
HCV3’UTR
Huh 7 cells
HCV subgenomic replicon
Effects of iron on HCV replication
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IRON
HCVHepatitis course
Liver damage
Iron status in HCV infected patients
MechanismsDirect
Indirect
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Iron as an aggravating factor for fibrosis in CHC
ROSHepatic iron
Fibrosisprogression
Fujita N, Free Rad Biol Med 2007;42:353-62
Biological evidence
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?Hepatic iron
Fibrosisprogression
Pietrangelo A, Gastroenterology 2003;124:1509-23Guyader D, J Hepatol 2007 [Epub ahead of print]
Iron as an aggravating factor for fibrosis in CHC
Clinical relevance
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?Hepatic iron
Fibrosisprogression
Male sexAge at contamination > 40 y
Duration of infectionDaily alcohol consumption > 50 g
Necroinflammatory activitySteatosis
Metabolic syndromeHFE mutations
Pietrangelo A, Gastroenterology 2003;124:1509-23Guyader D, J Hepatol 2007 [Epub ahead of print]
Iron as an aggravating factor for fibrosis in CHC
Clinical relevance
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Serum transaminases
Necroinflammatory activity
Fibrosis progression
Risk of cancer
Hayashi H, Am J Gastroenterol 1994 & J Hepatol 1995 - Fong TL, J Hepatol 1998 - Guyader D, Am J Gastroenterol 1999 - Fontana RJ, Hepatology 2000 - Di Bisceglie AM, Hepatology 2000 - Yano M, AJGE 2002.
Effects of phlebotomies in chronic hepatitis C
Phlebotomies
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No effect on viral load
Hayashi H, Am J Gastroenterol 1994 & J Hepatol 1995 - Fong TL, J Hepatol 1998 - Guyader D, Am J Gastroenterol 1999 - Fontana RJ, Hepatology 2000 - Di Bisceglie AM, Hepatology 2000 - Yano M, AJGE 2002.
Effects of phlebotomies in chronic hepatitis C
Phlebotomies
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IRON
HCVHepatitis course
Fibrosis
Cancer
Iron status in HCV infected patients
MechanismsDirect
Indirect
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Increased hepatic iron and cancer risk
DNAdamage
Lipidperoxidation
Turlin B, Hepatology 1995Deugnier Y, Alcohol 2003
NTBI
Transferrin
Hepcidin
TS
Tf
Fe
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Furutani T, Gastroenterology 2006;130:2087-98
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 - 45 CI - 225
Liver tumors 0 45%
Hepatic 8 OHdG 1 x 2
PCNA index 1 x 5
Lipid peroxidation 1 x 2
Ab mitochondria No Yes
Steatosis 1 x 3
Hepatic Tg 1 x 3
ALT 1 x 3
Hepatic iron 1 x 2
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IRON
HCVHepatitis course
Response to therapy
Iron status in HCV infected patients
Mechanisms
Fibrosis
Cancer
Direct
Indirect
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IFN Increased HICMesenchymal iron
PEG + RBV Endothelial ironMesenchymal iron
Prediction of poor SVR
Hepatic iron and response to antiviral therapy
Olynyk J, Gastroenterology 1995;108:1104-9Barton AL, Am J Clin Pathol 1995;103:419-24
Rulyak SJ, Am J Gastroenterol 2005;100:332-7Bonkowsky H, Gastroenterology 2006;131:1440-51
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Hayashi H, Am J Gastroenterol 1994 & J Hepatol 1995 - Fong TL, J Hepatol 1998 - Guyader D, Am J Gastroenterol 1999 - Fontana RJ, Hepatology 2000 - Di Bisceglie AM, Hepatology 2000 - Yano M, AJGE 2002.
Effects of phlebotomies on response to therapy
No effect on sustainedvirological response
Antiviral therapy+
Phlebotomies
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QuickTime™ et undécompresseur TIFF (LZW)
sont requis pour visionner cette image.
Bonkowsky H, Gastroenterology 2006;131:1440-51Distante S, Liver 2002;22:269-75 (SVR - C282Y)
Lebray P, J Viral Hepat 2004;11:175-82 (VR - H63D)
Effect of HFE mutations on virological response rate
C282YH63DS65C
HALT C study - 1145 NR
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IRON
HCV
Liver damageAntiviral drugs
Diet, alcoholPCT, MS…
ROS
Disease progression(fibrosis, cancer…)
Response to therapy
HFE mutations
Iron proteins
Immune fc
ts
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Hyperferritinemia <> Increased hepatic iron
Direct assessment of hepatic iron
Alcohol, PCTThyroïditisInflammation Metabolic syndrome…
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Indication of phlebotomies
Hepatic ironNaive NR
Normal 0 ?
LIC/age < 2 0 +
LIC/age >2 + +
+ Avoid to induce anemia in order not to impair compliance to antiviral Tt
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HCV and ironThe middle age ?
Yves DeugnierDominique Guyader
Liver Unit & CIC Inserm 0203Rennes - France
PHC - Paris22 & 23/01/07