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Francesco NEGRO

Francesco NEGRO. Steatosis and Chronic Hepatitis C: liaisons dangéreuses?. Francesco Negro Unité de Viropathologie Centre Médical Universitaire Genève Paris, January 22, 2007. HCV-induced (i.e. viral ) steatosis. Occurrence and severity of steatosis is associated with genotype 3

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Francesco NEGRO

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  1. Francesco NEGRO

  2. Steatosis and Chronic Hepatitis C:liaisons dangéreuses? Francesco Negro Unité de Viropathologie Centre Médical Universitaire Genève • Paris, January 22, 2007

  3. HCV-induced (i.e. viral ) steatosis • Occurrence and severity of steatosis is associated with genotype 3 MIHM et al, 1997; RUBBIA-BRANDT et al, 2000; ADINOLFI et al, 2001 KUMAR et al, 2002; MONTO et al, 2002; POYNARD et al, 2003 HOFER et al, 2002; WESTIN et al, 2002 • The score of steatosis correlates with the level of HCV RNA in serum and liver, but only in patients with genotype 3 RUBBIA-BRANDT et al, 2000; ADINOLFI et al, 2001 • Virological response to IFN-a is associated with the disappearance of the steatosis, which recurs at the time of virological relapse RUBBIA-BRANDT et al, 2001; KUMAR et al, 2002; POYNARD et al, 2003

  4. Severity of steatosis and HCV genotype The HCV-MAID study (n = 3,068) P = <0.001 LEANDRO et al, Gastroenterology 2006;130:1636-1642

  5. Steatosis score and HCV RNA levels 70 immunocompetent chronic hepatitis C cases RUBBIA-BRANDT et al, J Hepatol 2000;33:106-115

  6. Expression of liver steatosis in HCV infection and pattern of response to a-interferon Liver steatosis in a patient with recurrent hepatitis C after LT, before a-IFN therapy (1a), at the time of virological response (1b) and on occasion of the biochemical and virological relapse after the end of treatment (1c) RUBBIA-BRANDT et al, J Hepatol 2001; 35: 307

  7. Serum lipid profile changes in HCV • In chronic hepatitis C, Apolipoprotein B levels: • are inversely correlated with steatosis score • revert to normal upon response to therapy • HCV type 3a lowers serum cholesterol levels: HCV 1 HCV 3 HCV 4 P 188 ± 36 147 ± 42 172 ± 35 <0.01 • Hypocholesterolemia in genotype 3a: • returns to normal in sustained virological responders • is not shared by other HCV genotypes SERFATY et al, J Hepatol 2001;34:428 HOFER et al, Am J Gastroenterol 2002;97:2880

  8. TG Apo B VLDL assembly impaired VLDL secretion HCV core protein transgenic mouse HCV core protein MTP intracytoplasmic TG storage STEATOSIS PERLEMUTER et al, FASEB J 2002;16:185

  9. P = 0.0017 Intrahepatic MTP mRNA levels steatosis score Intrahepatic MTP mRNA levels are inversely correlated with steatosis scores MIRANDOLA et al, Gastroenterology 2006;130:1661-9

  10. Metabolic steatosis in chronic hepatitis C In most patients with genotype non-3 who do not drink alcohol: • Steatosis occurrence and severity is not (or only partially) modified by antiviral treatment KUMAR et al, 2002; POYNARD et al, 2003 • Steatosis score correlates with body mass index rather than with HCV RNA replication ADINOLFI et al, 2001

  11. Insulin resistance causes liver steatosis BROWNING & HORTON, J Clin Invest 2004;114:147

  12. Risk factors for steatosis in 44 non-3a, alcohol abstinent chronic hepatitis C patients 20% 30% 18% 32% MUZZI et al, J Hepatol 2005;42:41-46

  13. Mechanisms of steatosis in hepatitis C Steatosis in hepatitis C is multifactorial: • viral steatosis: • correlates with viral replication level • responsive to antivirals • likely due to impaired lipoprotein secretion • metabolic steatosis: • mostly unaffected by antivirals • associated with BMI/insulin resistance • other causes (genetic?)

  14. Steatosis as a factorof liver disease progression

  15. Liver failure (2 – 5% / yr) ~70% 2 – 30% / 20 yrs 2 - 4% / yr Natural History of HCV Liver Disease

  16. Factors associated with an accelerated fibrosis progression in chronic hepatitis C Age at infection Sex HIV Coinfection HBV Coinfection Immunosuppression Liver disease activity Overweight Alcohol abuse Steatosis Smoking Iron overload Insulin resistance

  17. Impact of steatosis on liver fibrosis progression in chronic hepatitis CA retrospective study on repeated liver biopsies FARTOUX et al, Hepatology 2005;41:82-87

  18. no progression progressed 1 progressed 2 or more 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% no steatosis steatosis no steatosis steatosis type non-3 type 3 Steatosis accelerates fibrosis progressionin genotype 3 chronic hepatitis C WESTIN et al, J Hepatol 2002;37:837

  19. The HCV MAID StudyPredictors of fibrosis in 3,068 patients LEANDRO et al, Gastroenterology 2006

  20. Fibrogenesis in Chronic Hepatitis C: Steatosis or Insulin Resistance? • By MV, the HOMA insulin resistance index (but not steatosis) is a factor independently associated with fibrosis (P<0.001) and its progression rate (P=0.03) HUI et al, Gastroenterology 2003 • Insulin resistance and/or diabetes are associated with severity of fibrosis RATZIU et al, 2003; HUI et al, 2003; FARTOUX et al, 2005 MUZZI et al, 2005; LEANDRO et al, 2006

  21. Association between diabetes and hepatocellular carcinomaA systematic review of epidemiologic evidence • Diabetes significantly associated with HCC: • In 9 of 13 case-control studies (OR 2.5, 95% CI 1.8 - 3.5) • In 7 of 13 cohort studies (risk ratio 2.5, 95% CI 1.9 - 3.2) • Association independent of alcohol or viral hepatitis (in 10 studies that examined these factors) EL-SERAG et al, Clin Gastroenterol Hepatol 2006;4:369-380

  22. hyperglycemia hyperinsulinemia Insulin resistance and activation of hepatic stellate cellsProduction of CTGF PARADIS et al, Hepatology 2001;34:738-744

  23. F F0 F1-F2 F3-F4 BMI and fibrosis in chronic hepatitis CThe HCV MAID Study (n = 3,068) r = 0.125 LEANDRO et al, Gastroenterology 2006;130:1636-1642

  24. P<0.05 Intrahepatic necroinflammation Omental macrophages are associated with liver necroinflammation CANCELLO et al, Diabetes 2006;55:1554-1561

  25. The Metabolic SyndromeEGIR Definition (1999) Hyperinsulinemia (top 25% of fast insulin values among the non-diabetic population) plus two of the following: •  6.1 mmol/L fasting glucose (non-diabetic) •  140/90 arterial pressure (or treatment) •  2.0 mmol/l triglycerides (or treatment) •  1.0 mmol/l HDL cholesterol (or treatment) • Waist circumference  94 (men) or  80 (women)

  26. Factors associated with an accelerated fibrosis progression in chronic hepatitis C Age at infection Sex HIV Coinfection HBV Coinfection Immunosuppression Liver disease activity Overweight Alcohol abuse Steatosis Smoking Iron overload Insulin resistance Metabolic syndrome

  27. Steatosis as a factorof poor response to interferon-a

  28. Steatosis at baseline and SVR P=0.33 P<0.001 P<0.001 (n = 134) (n = 900) (n = 746) POYNARD et al, Hepatology 2003;38:75-85

  29. Steatosis and SVR in HCV genotype 2 and 3 patients % SVR severity of steatosis ZEUZEM et al, J Hepatol 2004;40:993-999

  30. In HCV patients with virally-induced steatosis:high serum HCV RNAhigh steatosis score

  31. Insulin resistance decreases SVR in chronic hepatitis C ROMERO-GOMEZ et al, Gastroenterology 2005;128:636-641

  32. HCV genotype 1, intrahepatic SOCS-3 and response to IFN-a therapy WALSH et al, Gut 2006

  33. 1b 3a GFP Huh-7 SOCS-7 b-Actin Insulin resistance in HCV infection:additional, direct role of HCV 1b 3a GFP Huh-7 IRS-1 IRS-2 b-Actin PAZIENZA et al, Hepatology 2007

  34. IRS-1 Induction of proteasomal degradation of IRS-1 by members of the SOCS family • After SOCS binding to IRS-1, the SOCS box recruits the E3 ligase which is involved in the ubiquitination of the IRS-1 protein • The complex is then targeted for proteasomal degradation • (adapted from Larsen and Röpke, APMIS 110:833-44, 2002)

  35. HCV  SOCS-n binding to IRS-1 causes its proteasomal degradation binding to Janus kinase inhibits Tyr-phosphorylation of STAT1 interference with the insulin signaling interference with the IFN-a signaling

  36. Steatosis and Chronic Hepatitis C:liaisons dangéreuses?

  37. Increasing insulin sensitivity in chronic hepatitis C patients • Increase physical activity • Reduce body weight • Insulin sensitizers ?? • Metformin • Thiazolidindiones (pioglitazone, rosiglitazone…)

  38. But the best solution is ……

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