Steatosi epatica ed HCV - PDF Free Download

Steatosi epatica ed HCV Malattie delle vie biliari ed Epatologia Rho, Auditorium Padri Oblati, 11 Novembre 2006 Piero L. Almasio Università di Palermo

HISTOPATHOLOGY

Steatosis and accelerated fibrogenesis: a «two hits» mechanism? Overweight Diabetes HCV Steatosis Lipid peroxidation Oxidative stress Alcohol Drugs Iron Fibrogenesis Hourrigan et al, Hepatology 1999 Adinolfi et al, Hepatology 2001 Serfaty et al, Am J Gastroenterol 2002 Monto et al, Hepatology 2002

Pathogenesis

Prevalence of steatosis in chronic hepatitis C Hourigan 1999 Adinolfi 2001 Serfaty 2001 Monto 2002 Poynard 2003 Asselah 2003 Rubbia-Brandt 2004 n 148 180 100 297 1530 290 755 Steatosis 61.5 47.8 100 57.6 65 47 41.7 Type 3 42.5* 14.4 27 13.1 14 20 23.6 BMI 25.9 24.9 24 28.5 27.4 24.1 24.1 Alcohol 31.1 0 0 31.6 0 68 21.7 Cirrhosis na 15 0 9.4 6 5 24.8 Diabetes 2.7 0 0 7.7 12.9 na 5.7 *only 40 patients were genotyped Rubbia-Brandt et al, J Hepatol 2000

Steatosis and progression of chronic hepatitis C: viral vs. non-viral Is steatosis a predictor of fibrosis in chronic hepatitis C?

Fibrosis in chronic hepatitis C correlates significantly with steatosis Steatosis: Level of Fibrosis 0 1 2 3/4 P 0 35.7% 35.7% 16.1% 12.5% 1 18% 32.8% 18% 31.1% 0.01 2/3 13.8% 17.2% 34.5% 34.5% HOURIGAN et al, Hepatology, 1999;29:1215-1219

Fibrosis in chronic hepatitis C correlates significantly with steatosis 148 consecutive patients (Australia) Predictor of steatosis* * : BMI Predictors of fibrosis: : age, BMI, grade of steatosis, portal inflammation (but not gender, alcohol intake, hepatic iron) *HCV genotype available only in 40/148 (27%) patients HOURIGAN et al, Hepatology, 1999;29:1215-1219

Steatosis Increases The Rate of Fibrosis in HCV Change in HAI Score/yrs of infection.3.2.1 0 Genotype 1b, 10-14 yrs HCV infection 0.12 8 yrs Per stage P<0.01 0.14 7 yrs Per stage P<0.05.23 4 yrs per stage None 1-30% >30% Hepatocytes with fat Adinolfi et al, Hepatol 2001

Steatosis and HCV genotype Is the steatosis of chronic HCV patients always due to HCV? 180 Chronic Hepatitis C patients After HCV genotype stratification, the degree of steatosis correlated with: levels of HCV RNA in type 3a (r =.786, p<.001) BMI in type 1 (r =.689; p<.001) Adinolfi et al, Hepatology 2001

Steatosis accelerates fibrosis progression in chronic hepatitis C patients infected with type 3 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% no progression progressed 1 progressed 2 or more P < 0.0001 P < 0.0001 no steatosis steatosis no steatosis steatosis type non-3 type 3 98 patients (25 genotype 3) Follow-up, 5.8 yrs Genotype-3 3 predicted steatosis at entry (OR, 3.1; 1.7-5.7; P = 0.003) Progression of fibrosis was related with steatosis at entry, only in genotype-3 WESTIN et al, J Hepatol 2002;37:837

Liver fibrosis is associated with steatosis in US patients with chronic hepatitis C 297 chronic hepatitis C patients from UCSF/VA (mean BMI = 28.5; 13% with genotype 3) By multivariable logistic regression: BMI and genotype 3 were predictors of steatosis Steatosis and intrahepatic inflammation were both predictors of liver fibrosis MONTO et al, Hepatology 2002;36:729-736

Liver fibrosis is not associated with steatosis in French patients with chronic hepatitis C 290 chronic hepatitis C patients from France (mean BMI = 24.1; 20% with genotype 3) By multivariable logistic regression: Steatosis was associated with genotype 3 and higher BMI Fibrosis was associated with male gender, higher BMI, high grade of necroinflammation ASSELAH et al, Gut 2003

Multivariate analysis to predict steatosis in 291 Nondiabetic Patients With Genotype 1 Chronic Hepatitis Cammà et al, 2006

Multivariate analysis to predict fibrosis in 291 Nondiabetic Patients With Genotype 1 Chronic Hepatitis Cammà et al, 2006

Baseline features of chronic hepatitis C patients Hourigan Adinolfi Serfaty Monto Poynard Asselah Rubbia-Brandt 1999 2001 2001 2002 2003 2003 2003 n 148 180 100 297 1530 290 755 Steatosis 61.5 47.8 100 57.6 65 47 41.7 Type 3 42.5* 14.4 27 13.1 14 20 23.6 BMI 25.9 24.9 24 28.5 27.4 24.1 24.1 Alcohol 31.1 0 0 31.6 0 68 21.7 Cirrhosis na 15 0 9.4 6 5 24.8 Diabetes 2.7 0 0 7.7 12.9 na 5.7 *only 40 patients were genotyped

Steatosis and progression of chronic hepatitis C: viral vs. non-viral Is there a HCV-related steatosis as opposed to a non-hcv HCV-related?

Is the steatosis of chronic hepatitis C patients always due to HCV? 180 chronic hepatitis C patients After HCV genotype stratification, the degree of steatosis correlated with: BMI in type 1 (r =.689; p<.001) levels of HCV RNA in type 3a (r =.786, p<.001) ADINOLFI et al, Hepatology 2001;33:1358

A moderate to severe steatosis of the liver is diagnostic of HCV type 3 infection (n = 254) % without % with steatosis steatosis 1 2 3 total HCV 1 67 28 3.5 1.5 33 HCV 2 63 30.4 3.3 3.3 37 HCV 3 29.5 28 18 24.5 70.5 HCV 4 62 27 8 3 38 HCV non-3 65.8 28 4.1 2.1 34.2 RUBBIA-BRANDT et al, Histopathology 2001;39:119

Expression of liver steatosis in HCV infection and pattern of response to α-interferon Liver steatosis in a patient with recurrent hepatitis C after LT, before α-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

Reversal of hepatic steatosis after sustained therapeutic response Morphometric assessment of pre- and post- treatment steatosis in 62 chronic hepatitis C patients (28 type 1, 34 type 3) After treatment: Steatosis did not change in patients with type 1, even if responding to therapy Steatosis was reduced significantly (P<.001) in patients with type 3 and SVR, but not in those without virological response at end of FU KUMAR et a, Hepatology 2003;36:1266-1272

Steatosis and IFN Response in HCV In genotype 3, SVR was the only predictor of steatosis reversal (OR 36) Is genotype 3 directly cytopathic to hepatocytes? Does steatosis prevent SVR in genotype 1? 28 Pts with genotype 1 (steatosis in 16) and 34 with genotype 3 (steatosis 21) SVR defined as no HCV-RNA 6 months after completion of treatment Steatosis measured by morphometry and computer assisted image analysis Kumar et al, Hepatology 2002

POYNARD et al, Hepatology 2003; 38:75-85 Evolution of steatosis according to genotype and virological response: genotype 3 (n = 121) Steatosis at 1st Bx: 0% 1-5% 6-32% 33-100% Steatosis at 2nd Bx: 0% 1-5% 6-32% 33-100% SVR (n=113) 5 (9%) 23 (43%) 16 (30%) 9 (18%) 24 (34%) 21 (40%) 4 (8%) 4 (8%) NR (n=8) 2 (25%) 2 (25%) 2 (25%) 2 (25%) 2 (25%) 3 (37%) 0 3 (38%)

Evolution of steatosis according to genotype and virological response: genotypes non-3 3 (n = 679) Steatosis at 1st Bx: 0% 1-5% 6-32% 33-100% Steatosis at 2nd Bx: 0% 1-5% 6-32% 33-100% SVR (n=461) 109 (52%) 74 (35%) 22 (10%) 6 (3%) 127 (60%) 65 (31%) 15 (7%) 4 (7%) NR (n=218) 62 (28%) 90 (41%) 51 (23%) 15 (7%) 76 (35%) 100 (46%) 39 (18%) 3 (1%) POYNARD et al, Hepatology 2003; 38:75-85

Natural history of HCV-related and non-hcv HCV- related steatosis in chronic hepatitis C Conclusions The respective role of viral vs. non-viral factors in fibrosis progression can only be assessed by prospective studies Baseline features of study populations vary depending on geographical area and other enrollment biases Role of diabetes possibly underestimated Steatosis may disappear at late stages of disease

BMI impacts on response to therapy Retrospective analysis on 253 chronic hepatitis C patients treated between 1989 and 2000 at a single center SVR was significantly reduced by obesity (p=0.01), infection with genotypes non-2/non 2/non-33 (p<0.01) and cirrhosis (p<0.01) Obese patients had an OR of achieving SVR of 0.23 as compared to normal and overweight BRESSLER et al, Hepatology 2003;38:639-644 644

OVERWEIGHT Subtherapeutic doses of IFN-α (?) Reduced bioavailability of IFN-α Leptin resistance (IL-1Ra?) Non-response to antiviral therapy MCCULLOUGH, Hepatology 2003;38:557-559

Change in steatosis grade before and after weight reduction in chronic hepatitis C HICKMAN et al, Gut 2004;53:413-419

Risk factors for HCC: synergism of alcohol with viral hepatitis and diabetes mellitus Case-control study on 115 HCC patients and 230 non-liver cancer patients Multivariate OR: Chronic OH abuse = 15.3 Anti-HCV = 12.6 HBsAg = 4.5 Diabetes mellitus = 4.3 OH + chronic viral = 53.9 OH + D.M. = 9.9 Common pathway for hepatocarcinogenesis? HASSAN et al, Hepatology 2003

HCV core protein induces IR, then liver steatosis and then hepatocellular carcinoma in transgenic mice at birth 16 mo 17 mo "nodule-in-nodule" MORIYA et al, Nature Med 1998;4:1065-7

Does insulin resistance influence the treatment outcome of chronic hepatitis C? In a retrospective study (n = 123), patients with SVR were younger (p=0.012), had lower serum leptin (p=0.028), and lower HOMA (p=0.023) ROMERO-GOMEZ et al, Hepatology 2003;38:747A Preliminary data seem to suggest that HOMA- IR may be associated with a poor response to therapy HUI et al, Gastroenterology 2003:125:1695-1704 1704

Steatosis may affect chronic hepatitis C progression in a genotype-specific way A study on 574 patients from a single center Among patients with genotype 1, BMI and Metavir fibrosis stage were the only characteristics associated with severity of steatosis (p<0.01) In patients with genotype 3, BMI and serum HCV RNA level were associated with steatosis (p<0.03) PATTON et al, J Hepatol 2004;40:570-577 577

Hepatic steatosis as a risk factor for hepatocellular carcinoma in chronic hepatitis C 290 chronic hepatitis C patients from Nagasaki analysed retrospectively Cumulative incidence of HCC: 24%, 51% and 63% at 5, 10 and 15 years of FU By multivariate te analysis, HCC was associated with steatosis (P=0.0135), age (P=0.039), cirrhosis (P=0.0068) and no IFN therapy (P=0.0142) OHATA et al, Cancer 2003

HCV-3 steatosis overweight fibrosis insulin resistance HCV-non-3??

Steatosis in chronic hepatitis C Clinical features Steatosis in chronic hepatitis C is multifactorial: viral steatosis is mostly associated with genotype 3, is responsive to antivirals,, may be due to impairment of VLDL secretion, and its diagnostic hallmark is a low serum level of ApoB metabolic steatosis is mostly found in genotype non-3 3 infected patients, is not affected by antivirals,, and appears to be associated with BMI many cases possibly recognize multiple coexisting mechanisms

Impact of hepatic steatosis on treatment response in HCV infection

Steatosis and response to therapy in chronic hepatitis C By multivariable logistic regression, (metabolic) steatosis is an independent factor associated with lack of early and sustained virological response in patients with genotype 1 In those infected with genotype 3, presence of steatosis does not affect response POYNARD et al, 2003, PATTON et al, 2004

Therapeutic Options Antiviral Treatments Genotype Lifestyle Changes Obesity HCV Response to Antivirals Steatosis Fibrosis Cirrhosis Diabetes HCC - Liver Failure

Risk factors for steatosis in chronic hepatitis C Overweight Diabetes Steatosis HCV genotype 3 Alcohol Drugs Adinolfi et al, Hepatology 2001 Serfaty et al, Am J Gastoenterol 2002 Rubbia-Brandt et al, J Hepatol 2000 Monto et al, Hepatology 2002

Clinical studies say: A V O I D - Alcohol - Overweight - Hyperlipemia - Hyperglicemia - Excess iron - HBV - STEATOSIS Recent experiments in the replicon system say: Alcohol and morphine increase HCV replication what is left to stay happy??