Yves DEUGNIER

HCV and ironThe middle age ?

Yves DeugnierDominique Guyader

Liver Unit & CIC Inserm 0203Rennes - France

PHC - Paris22 & 23/01/07

Blumberg BS et al, PNAS 1979;76:2438-41

IRON

HCV1991-2007 = 527 studies

IRON

HCV

Iron status in HCV infected patients

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

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

Distribution of hepatic iron deposits in CHC

Hepatocytic 34%

Mesenchymal 12%

Mixed 54%

Guyader D, J Hepatol 2007 [Epub ahead of print]

Distribution of hepatic iron deposits in CHC

Hepatocytic 34%

Deugnier Y, Am J Surg Pathol 1997Ludwig J, Gastroenterology 1997

Guyader D, J Hepatol 2007 [Epub ahead of print]

46%46%

Relationship between iron-related indices in CHC

IRON

HCV

Iron status in HCV infected patients

MechanismsDirect

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

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

IRON

HCV

Iron status in HCV infected patients

MechanismsDirect

Indirect

Hyperferritinemia <> hepatic iron

Serum ferritin

Serum ferritin in chronic hepatitis C

• Liver damage

• Hepatic iron

Di Bisceglie AM, Gastroenterology 1992;102:2108-13

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

Hepatic iron

Hepatic iron in chronic hepatitis C

• Liver damage

Guyader D, J Hepatol 2007 [Epub ahead of print]

METAVIR A METAVIR F

Inconstantcorrelation

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

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

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 ?

?

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

IRON

HCV

Iron status in HCV infected patients

MechanismsDirect

Indirect

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

IRON

HCVHepatitis course

Liver damage

Iron status in HCV infected patients

MechanismsDirect

Indirect

Iron as an aggravating factor for fibrosis in CHC

ROSHepatic iron

Fibrosisprogression

Fujita N, Free Rad Biol Med 2007;42:353-62

Biological evidence

?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

?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

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

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

IRON

HCVHepatitis course

Fibrosis

Cancer

Iron status in HCV infected patients

MechanismsDirect

Indirect

Increased hepatic iron and cancer risk

DNAdamage

Lipidperoxidation

Turlin B, Hepatology 1995Deugnier Y, Alcohol 2003

NTBI

Transferrin

Hepcidin

TS

Tf

Fe

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

IRON

HCVHepatitis course

Response to therapy

Iron status in HCV infected patients

Mechanisms

Fibrosis

Cancer

Direct

Indirect

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

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

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

IRON

HCV

Liver damageAntiviral drugs

Diet, alcoholPCT, MS…

ROS

Disease progression(fibrosis, cancer…)

Response to therapy

HFE mutations

Iron proteins

Immune fc

ts

Hyperferritinemia <> Increased hepatic iron

Direct assessment of hepatic iron

Alcohol, PCTThyroïditisInflammation Metabolic syndrome…

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

HCV and ironThe middle age ?

Yves DeugnierDominique Guyader

Liver Unit & CIC Inserm 0203Rennes - France

PHC - Paris22 & 23/01/07