Yves DEUGNIER

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
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Blumberg BS et al, PNAS 1979762438-41
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IRON
1991-2007 527 studies
HCV
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Iron status in HCV infected patients
IRON

HCV
6
Serum iron-related indices in CHC
Iron 25 - 59
Ferritin 25 - 60
Transferrin saturation 10 - 25
Di Bisceglie AM, Gastroenterology
19921022108-13 Alla V, Sem Liver Dis
200525461-72
7
Hepatic iron-related indices in CHC
Except in cirrhosis
Di Bisceglie AM, Gastroenterology
19921022108-13 Alla V, Sem Liver Dis
200525461-72
8
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 1997 Ludwig J,
Gastroenterology 1997
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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
IRON
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 199725759-768 Alla V,
Sem Liver Dis 200525461-472
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 20017510557-62 Saito H,
Hepatology Res 200531203-10 Spahn CM, Science
20012911959-62
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Iron status in HCV infected patients
IRON
Mechanisms
Indirect
Hyperferritinemia ltgt hepatic iron
HCV
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Serum ferritin in chronic hepatitis C
 Liver damage Hepatic iron
Serum ferritin
Di Bisceglie AM, Gastroenterology
19921022108-13
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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 199725759-768 Alla V,
Sem Liver Dis 200525461-472
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
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Increased hepatic iron content in cirrhosis
Tf
NTBI
TS
Fe
Stuart KA, Gastroenterology 200439492-7
Detivaud L, Blood 2005106746-8 Bridle KR, Alc
Clin Exp Res 200630106-112
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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 199725759-768 Alla V,
Sem Liver Dis 200525461-472
20
Prevalence of HFE mutations in CHC
C282Y compound heterozygotes Excluded Inclu
ded N
C282Y H63D prevalence Vs controls
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
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HFE genotypes and iron status in CHC
Inclusion bias Small samples Confounding factors
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.
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Iron status in HCV infected patients
IRON
Mechanisms

HCV
23
Effects of iron on HCV replication
HCV IRES
EMCV IRES
HCV 3UTR
NPT II
NS4B
NS4A
NS3
NS5B
NS5A
HCV subgenomic replicon
Huh 7 cells
Fillebeen C, JBC 20052809049-9057
24
Iron status in HCV infected patients
IRON
Mechanisms

Liver damage
Hepatitis course
HCV
25
Iron as an aggravating factor for fibrosis in CHC
Biological evidence
ROS
Hepatic iron
Fibrosis progression
Fujita N, Free Rad Biol Med 200742353-62
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Iron as an aggravating factor for fibrosis in CHC
Clinical relevance
?
Hepatic iron
Fibrosis progression
Pietrangelo A, Gastroenterology
20031241509-23 Guyader D, J Hepatol 2007 Epub
ahead of print
27
Iron as an aggravating factor for fibrosis in CHC
Clinical relevance
?
Hepatic iron
Fibrosis progression
Pietrangelo A, Gastroenterology
20031241509-23 Guyader D, J Hepatol 2007 Epub
ahead of print
28
Effects of phlebotomies in chronic hepatitis C
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.
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Effects of phlebotomies in chronic hepatitis C
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.
30
Iron status in HCV infected patients
IRON
Mechanisms

Fibrosis
Hepatitis course
Cancer
HCV
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Increased hepatic iron and cancer risk
Tf
NTBI
TS
Fe
Lipid peroxidation
DNA damage
Turlin B, Hepatology 1995 Deugnier Y, Alcohol 2003
32
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
Furutani T, Gastroenterology 20061302087-98
33
Iron status in HCV infected patients
IRON
Direct
Mechanisms
Indirect

Hepatitis course
HCV
Response to therapy
34
Hepatic iron and response to antiviral therapy
Olynyk J, Gastroenterology 19951081104-9 Barton
AL, Am J Clin Pathol 1995103419-24 Rulyak SJ,
Am J Gastroenterol 2005100332-7 Bonkowsky H,
Gastroenterology 20061311440-51
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Effects of phlebotomies on response to therapy
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.
36
Effect of HFE mutations on virological response
rate
HALT C study - 1145 NR
C282Y H63D S65C
Bonkowsky H, Gastroenterology 20061311440-51 Dis
tante S, Liver 200222269-75 (SVR -
C282Y) Lebray P, J Viral Hepat 200411175-82 (VR
- H63D)
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Hyperferritinemia ltgt Increased hepatic iron
Direct assessment of hepatic iron
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Indication of phlebotomies
Hepatic iron Naive NR
Normal 0 ?
LIC/age lt 2 0
LIC/age gt2
Avoid to induce anemia in order not to impair
compliance to antiviral Tt
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HCV and iron The middle age ? Yves
Deugnier Dominique Guyader Liver Unit CIC
Inserm 0203 Rennes - France PHC - Paris 22
23/01/07