Gli aspetti terapeutici La steatoepatite: a sfavore

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1 UNIGASTRO COORDINAMENTO NAZIONALE DOCENTI UNIVERSITARI DI GASTROENTEROLOGIA Corso residenziale di formazione per specializzandi in Gastroenterologia IL FEGATO COME CENTRALE METABOLICA E I FATTORI DI DANNO OLTRE I VIRUS EPATITICI San Vincenzo (LI), Riva degli Etruschi 4-6 maggio 2008 Gli aspetti terapeutici La steatoepatite: a sfavore Piero L. Almasio Gastroenterologia & Epatologia, Di.Bi.M.I.S., Università di Palermo

2 Prevalence of NAFLD and NASH NAFLD NASH NHANES III 23% Patients undergoing liver biopsy 15-39% % Patients undergoing CT scan 9.7% Post-mortem analysis (random deaths) General population ultrasound screening % % %

3 La epidemia NAFLD/NASH in Italia (stima) Prevalenza obesità : 18-20% (9-11 milioni) Prevalenza di FL: 43-51% (24-29 milioni) Prevalenza NAFLD: 20-25% (11-14 milioni) Obesità nella NAFLD: 65-75% Diabete nella NAFLD: 25-30% Incidenza NAFLD: nuovi casi/anno Prevalenza NASH: 10-20% della NAFLD ( milioni) Incidenza NASH: nuovi casi/anno Progressione della NASH a cirrosi: 10% ( ; all anno)

4 STORIA NATURALE DELLA NAFLD Steatosi epatica Infiammazione (8-20%) (NASH) Steatosi non infiammatoria Fibrosi progressiva (10-50%) Assenza di fibrosi Tasso di mortalità invariato Cirrosi (10%) Tasso di mortalità invariato

5 Histologic follow up of NASH Author N Follow up duration, yrs Improved fibrosis, n No change in fibrosis, n Increase in fibrosis, n Powell Lee 13 1,2-6, Bacon Ratziu 4 2, Harrison 19 1,4-15, Lindor TOTAL % 58% 26% Modifyied from Falck-Ytter et al, Semin Liver Dis 2001

6 Survival of NAFLD compared to ageand sex-matched general population Liver disease was the cause of death in 7/53 patients (13%) ANGULO et al, Gastroenterology 2005;129:

7 Factors of NAFLD progression Survival of patients with simple steatosis is comparable to the reference population Most deaths in NAFLD (malignancies, CHD, end-stage liver disease including HCC) are explained by diabetes Predictors of progression: NASH, periportal fibrosis (NPV 100%), insulin resistance, diabetes, increasing BMI ALT and AST/ALT ratio do NOT predict

8 McCullough AJ. N Engl J Med 2006; 355:

9 Weight Loss + Physical Exercise Insulin Sensitivity Glycemia Cholesterol and TG HDL Cholesterol Blood pressure Markers of Inflammation

10 Effect of body weight changes on ALT levels P< SUZUKI et al, J Hepatol 2005;43:

11 NAFLD Treatment Treatment Cases Type Alternative Duration Outcome Result Weight Loss or Lifestyle Modifications Eriksson 3 Observational mo ALT, Biopsy ++ Palmer 39 Observational Unspecified ALT Ueno 15 Controlled none 3 mo ALT, Biopsy +++ Franzese 38 Observational mo ALT, US Knobler 49 Observational mo ALT +++ Kugelmans 16 Observational mo ALT ++ Hickman 21 Observational mo ALT,HRQL,Biopsy +++ Insulin-sensitizers - Glitazones Caldwell 10 Observational mo ALT, Biopsy +++ Neuschwander 25 Observational mo ALT, Biopsy +++ Promrat 18 Observational mo ALT, Biopsy +++ -Metformin Marchesini 14 Controlled Counseling 4 mo ALT, US +++ Coyle (abs) 2 Observational mo ALT, Biopsy + Uygun 36 RCT Diet alone 6 mo ALT, Biopsy ++ Nair 15 Observational mo ALT, Biopsy ± Bugianesi 110 RCT Diet/Vitamin E 12 mo ALT, (Biopsy) +++

12 NAFLD Treatment - Diet & Exercise 25 NASH Patients: 15 compliant to lifestyle changes, 10 non compliant Diet: 25 Kcal/kg i.b.w. (20% Protein, 30% Lipid, 50% CHO) Exercise: Walking (3000 to 10,000) steps at 500 step increase every 3rd day, then Jogging, 20 min twice a day Duration: 3 months Biopsy: at entry and at 3-month Outcome: Anthropometry, Biochemistry, Histology Ueno et al, J Hepatol 1997

13 Therapeutic effects of diet and exercise in obese patients with NASH 90 ALT values Control pretreatment Control posttreatment Treatedpretreatment Treated posttreatment Ueno et al., J Hepatol 1997

14 Therapeutic effects of diet and exercise in obese patients with NASH cholesterol levels Control pretreatment Control posttreatment Treatedpretreatment Treated posttreatment Ueno et al., J Hepatol 1997

15 Therapeutic effects of diet and exercise in obese patients with NASH 3 degree of steatosis Control pretreatment Control posttreatment Treatedpretreatment Treated posttreatment Ueno et al., J Hepatol 1997

16 Insulin sensitizer: Metformin A biquanide, reduces hyperinsulinaemia and improves hepatic insulin resistance Site of action in the mitochondria to stimulate pyruvate-kinase, fatty acid betaoxidation, anaerobic respiration (i.e. lactate production) suppress the expression of lipogenic enzymes

17 EFFECT OF METFORMIN ON PATIENTS WITH NASH ALT values Diet Diet + Metformin 20 0 Entry months Marchesini et al., Lancet 2001

18 METFORMIN THERAPY IN PATIENTS WITH NASH 15 patients with NASH 1 year of treatment of metformin (20 mg/kg) Initial 3 months improvement in ALT/AST and insulin sensitivity After 3 months no further improvement in insulin sensitivity A gradual rise in AST/ALT back to pretreatment levels Nair S, Aliment Pharmacol Ther 2004; 20: 23 8.

19 EFFECT OF METFORMIN IN PATIENTS WITH NASH Controlled trial, randomized 36 patients with NASH A dietary treatment group and a dietary treatment plus metformin, for 6-month A significant decrease in ALT/AST, insulin and C-peptide Uygun, Aliment Pharmacol Ther 2004; 19: PIVENS and TONIC trials by the NIH to clarify long-term benefits

20 Regression of MS in 1171 patients: Metformin vs life-style changes (average FU 3.2 yrs) P=0.002 ORCHARD et al, Ann Intern Med 2005;142:

21 Insulin sensitizer: Thiazolidinediones (TZDs) Peroxisome proliferator activated receptor (PPAR) stimulator Increase insulin sensitivity in peripheral adipocytes Lower plasma fatty acid concentrations and redistribute intracellular lipids Reduces extracellular matrix deposition and hepatic stellate cells activation in both toxic and cholestatic models of liver fibrosis

22 Piogitlazone (ACTOS) 18 non-dm with biopsy-proven NASH treated with pioglitazone (30 mg daily) for 48 weeks ALT/AST were in the normal range in 13 patients (72%) ALT levels decreased an average of 50 U/L from baseline Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies and fibrosis were also significantly improved from baseline PROMRAT et al, Hepatology 2004;39:

23 Effect of pioglitazone of histological parameters in NAFLD Pre Week 48 P NASH (%) <0.01 Steatosis 2.5 ± ± 0.9 <0.001 Lobular inflammation 3.3 ± ± 1.2 <0.001 Mallory bodies 2.2 ± ± Fibrosis 2.0 ± ± PROMRAT et al, Hepatology 2004;39:

24 Pioglitazone and NASH n=18 Promrat et al, Hepatology 2004

25 Pioglitazone and NASH Promrat et al, Hepatology 2004

26 Pioglitazone Belfort et al performed first placebocontrolled trial investigating Pioglitazone in patients with biopsy-proven NASH and glucose intolerance or type 2 DM Improvement in hepatic histologic features, except fibrosis Decrease in peripheral and hepatic insulin resistance Decrease in serum aminotransfereases Increase in serum adiponectin Belfort R, et al. N Engl J Med 2006; 355:

27 Pioglitazone: Results P=0.04 P<0.001 Belfort R, et al. N Engl J Med 2006; 355:

28 Pioglitazone: Results Belfort R, et al. N Engl J Med 2006; 355:

29 Study Limitations Small sample size only 47 patients Short study period 6 months Shows promise, but need more info

30 Antioxidant Oxidative stress is believed to be a key catalyst in the development of NASH Presume vitamins E and C would help protect against the damaging effects of free radicals in the liver

31 Effetto del calo ponderale e della somministrazione di vitamina E sulla elevazione delle ALT ALT Kugelmas et al., Hepatology 2003

32 Effetto della somministrazione di vitamina C e vitamina E in pazienti con NASH fibrosis Harrison 2003

33 Ursodeoxycholic Acid RCT 166 NASH pts (122 completed the 2-yr treatment) Stratification for diabetes, obesity, high triglycerides Liver biopsy at entry and at study end (107 pts) Counseling for overweight pts UDCA (13-15 mg/kg/d or identical placebo) Changes in liver enzymes from baseline in both groups Improvement in steatosis, no difference in fibrosis and necroinflammation No difference between groups

34 Conclusions (1) NAFLD affects a large proportion of the world's population. I.R. and oxidative stress have critical roles in the pathogenesis of NAFLD. Liver biopsy remains the most sensitive and specific means of providing important prognostic information. Simple steatosis may have the best prognosis within the spectrum of NAFLD, but it has the potential to progress to steatohepatitis, fibrosis, and even cirrhosis. No effective medical therapy is currently available for all NAFLD. Weight reduction, when achieved and sustained, may improve the liver disease.

35 Conclusions (2) Pharmacologic therapy aimed at the underlying liver disease holds promise. However, questions remain regarding the use of drug therapy and the effect of recommended dietary measures. Liver transplantation is a therapeutic alternative for some p'ts with decompensated, end-stage NAFLD, but NAFLD may recur after liver transplantation.