Terapia della NAFLD/NASH

1. Terapia della NAFLD/NASH F. Angelico Dottorato in Epatologia Sperimentale e Clinica

2. Attuali conoscenze • La NAFLD è una condizione molto comune con una prevalenza in continuo aumento. • La NAFLD è una causa indipendente di aumento di mortalità. • Non esiste alcuna terapia efficace per la NAFLD

4. La malattia comprende un ampio spettro di danno epatico che va dalla semplice steatosi alla steato-epatite, alla fibrosi di vario grado, alla cirrosi e all’epatocarcinoma. Il quadro istologico simile al danno alcolico in assenza di abuso alcolico (<20gr/die)

5. Proposed Histologic Spectrum NAFLD Fat Ballooning Degeneration Fibrosis +/-Mallory Bodies Fat Inflammation Ballooning Degeneration Stage IV Fat + Inflammation Stage III Stage II FAT Stage I Matteoni et al, Gastroenterol 1999

6. obesity What are the settings for NAFLD 50% steatosis metabolic disorders 33% T2DM steatohepatitis 50% CVD, malignancy fibrosis 15%~30% cirrhosis 30%~40% liver-related morbidity and mortality Patrick L. Altern Med Rev, 2002, 7:276-291

13. NAFLD: Prevalence Data Obesity 60-95% Type II DM 28-55% Hyperlipidemia 20-92%

15. Metabolic Syndrome “Syndrome of Insulin Resistance” Visceral Obesity Steatosis NASH NIDDM TG HDL Hypertension

16. Insulin Sensitizing Agents Troglitazone/Rosiglitazone Metformin Lipid-Lowering Agents Clofibrate, Gemfibrozil Statins, Ezetimibe Future Potential Treatments Antifibrotics Probiotics Silymarin, SAMe Vitamin E Lecithin Vitamin C B-Carotene Selenium Vitamin B Complex Potential Pharmacologic Treatment Options for NALFD Membrane-Stabilizing • Ursodeoxycholic Acid • Betaine ( SAMe) Anti-Oxidants

17. Principali risultati. Solo 3 trials clinici randomizzati sono stati inclusi nell’analisi. Nessuno era in cieco. In due trials la metformina si associava ad una significativa riduzione delle transaminasi e del quadro ecografico rispetto alla dieta e al trattamento con vitamina E. Nell’unico studio effettuato con il pioglitazione si osservava un miglioramento significativo dell’istologia del fegato. Conclusioni. Al momento non ci sono sufficienti informazioni a favore o contro l’impiego dei farmaci insulino-sensibilizzanti nei pazienti con NAFLD/NASH.

18. Metformina verso controllooutcome: normalizzazione delle transaminasi

19. MAIN RESULTSWe identified six trials: two of high and four of low methodological quality. Treatment with antioxidant supplements showed a significant, though not clinically relevant, amelioration of transaminases, as compared to placebo or other interventions. Gamma-GT was decreased, albeit not significantly, in the treatment arm. Radiological and histological data were too limited to draw any definite conclusions on the effectiveness of these agents. CONCLUSIONSThere is insufficient data to either support or refute the use of antioxidant supplements for patients with NAFLD.

25. Probiotics for non-alcoholic fatty liver disease and/or steatohepatitis Lirussi F, Mastropasqua E, Orando S, Orlando R. Bile acids for non-alcoholic fatty liver disease and/or steatohepatitis Orlando R, Azzalini L, Orando S, Lirussi F. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005160

27. STATINE e NAFLD/NASH

28. EZETIMIBE

29. Forty-nine RCTs (30 in NASH) were included: 23 RCTs had post-treatment histology. Most RCTs were small and did not exceed 1-year duration. Weight loss was safe and dose-dependently improved histology in NASH, but more than 50% of patients failed to achieve target weight loss. Thiazolidinediones improved steatosis and inflammation but yielded significant weight gain. Antioxidants yielded conflicting results and were heterogeneous with respect to type and dose of drug. Polyunsaturated fatty acid (PUFA) ameliorated biochemical and radiological markers of NAFLD.

30. Conclusion: Well-designed RCTs of adequate size and duration, with histological endpoints, are needed to assess long-term safety and efficacy of proposed treatments on patient-oriented clinical outcomes.

31. CARDIOVASCOLARE Sindrome metabolica Diabete tipo 2 Dislipidemia aterogena Ipertensione Arteriosclerosi Mortalità cardiovascolare EPATICO Steato-epatite Fibrosi Cirrosi Mortalità epatica NAFLDFATTORE DI RISCHIO

37. Patogenesi della NAFLD/NASH Teoria dei “2 Hit” • “Second hit” – Stress ossidativo intraepatico • Perossidazione lipidica • TNF-alpha, citochine infiammatorie “First hit” – Eccesso di accumulo di grasso

38. Two-hit hypothesis Day & James 1985 • First hit: macrovesicular steatosis * Insulin resistance * Peroxisome proliferators- activated receptor (PPAR) • Sencond hit: oxidative stress * tumor necrosis factor (TNF – α) Day CP, James OF. Gastroenterolgy 1998; 114: 842-5.

39. I hit: Dal fegato normale al fegato grasso

40. II hit: dalla steatosi alla steato-epatite

43. CARDIOVASCOLARE Sindrome metabolica Diabete tipo 2 Dislipidemia aterogena Ipertensione Arteriosclerosi Mortalità cardiovascolare EPATICO Steato-epatite Fibrosi Cirrosi Mortalità epatica NAFLDFATTORE DI RISCHIO

44. The cardiovascular morbidity and mortality is perhaps one of the most important aspects of NAFLD and NASH, and our knowledge of their association is evolving rapidly. The patients with NAFLD have very high prevalence of cardiovascular risk factors and atherosclerosis and high incidence of cardiovascular morbidity and mortality.

45. Recently it has been suggested that NAFLD poses cardiovascular risk above and beyond that is conferred by the presence of the metabolic syndrome. Several longitudinal studies have shown that cardiovascular disease is much more common than liver disease as a cause of death in patients with NAFLD.

46. Many patients with more severe forms of non-alcoholic fatty liver disease will have major cardiovascular events and will ultimately die from cardiovascular disease before advanced liver disease develops.

47. The current body of evidence argues for careful monitoring and evaluation of the risk of cardiovascular disease in all patients with non-alcoholic fatty liver disease. Such patients, especially those with nonalcoholic steatohepatitis, are candidates not only for early treatment of their liver disease but also for early and aggressive treatment aimed at their associated cardiovascular risk factors.