1. La steatosi epatica quale fattore di rischio epatico e cardiovascolare: fattori genetici ed ambientali nel suo sviluppo Gianluca Svegliati Baroni Clinica di Gastroenterologia Responsabile SOS Epatopatie Croniche e Trapianto di Fegato Universit Politecnica delle Marche Ancona, 15 settembre 2011

2.

NonAlcoholic Fatty Liver Disease (NAFLD)

Ampio spettro di lesioni anatomopatologiche simili a quelle osservate in corso di epatopatia alcolica ma che compaiono in pazienti che non abusano di etanolo(Ludwig J. et al., Mayo Clin Proc 1980; 55:434-438)

Lesione anatomopatologica comune:accumulo di trigliceridi a livello intraepatocitario

3. HISTOPATHOLOGICAL SPECTRUM OF NAFLD 4. CONDIZIONI ASSOCIATE

OBESITA

58%-74% degli obesi hanno la NAFLD

(Ann Intern Med 2000;132:112-117)

DIABETE

21%-78% dei diabetici hanno la NAFLD

(Prog Liver Dis 1970;3:371-407)

5. Prevalenza et-specifica di alterazione degli indici di danno epatico nella popolazione generale di Cittanova (Italia Meridionale) per eziologia, 2002-2003 Pendino et al. Hepatology 2005 % 6. Prevalence FL = 43-56% P= (52.4*43/100) =22.5% P= (41*43/100) =17% P= (79.1*43/100) =34.0% P= (21*43/100) =9% NAFLD and AFLD in the Nutrition and Liver Dionysos Study (2005) 7. NAFLD: classificazione

Primary NAFLD/NASH is associated with insulin resistance (IR) and its phenotypic manifestations.

Secondary NAFLD/NASH is rare in adults, is unrelated to insulin resistance or the metabolic syndrome, and is due to a number of medical or surgical conditions or drug intake.

EASL position statement 2010 8. G. Svegliati-Baroni et al., AISF Expert Committee, Dig Liv Dis 2010 9. Svegliati-Baroni G, Dig Liv Dis 2010;Svegliati-Baroni G. Trends Mol Med 2008 60% 15% 25% 10. Farrell GC, Hepatology 2010 11. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.Valenti et al., Hepatology 2010 The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease.Rotman et al., Hepatology 2010 PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease.Speliotes et al., Hepatology 2010 12. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease Dongiovanni et al, GUT 2010 13. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease Dongiovanni et al, GUT 2010 14.

Steatosis is part ofearly adaptive responseto IR rather than a first hit in disease progression;

Individuals thatfail to adaptdevelop progressive disease;

Excess fatper sedoes notcause liver disease and it is not a treatment target.

Day C. EASL Special Conference 2009 NAFLD 15. The lipotoxicity model of NASH Neuschwander-Tetri BA, Hepatology 2010 16. Azioni tossiche dei NEFA Svegliati-Baroni G et al., Dig Liv Dis 2010 17. The Multiple Parallel Hits Hypothesis Tilg & Moschen, Hepatology 2010; Svegliati-Baroni G et al., Dig Liv Dis 2010 18. G. Svegliati-Baroni et al., Am J Pathol 2007 19.

..ma la NAFLD progredisce SEMPRE verso malattie ( epatiche ) gravi?

20. Storia naturale della Steatosi Epaticanon alcolica (NAFLD/NASH)12-40% 5-10% 25-50% Steatosi NAFLD NASH Cirrosi (criptogenetica) HCC/Morte x causa epatica OLT 21. La epidemia NAFLD/NASHin Italia (stima)

Prevalenzaobesit:18-20% (9-11 milioni)

Prevalenza delFL :43-51% (24-29 milioni)

Prevalenza dellaNAFLD :20-25% (11-14 milioni)

• Obesit nella NAFLD: 65-75%

• Diabete nella NAFLD: 25-30%

IncidenzaNAFLD :400.000 nuovi casi/anno

PrevalenzaNASH :10-20% della NAFLD (1.1-1.4 milioni)

IncidenzaNASH :40.000-80.000 nuovi casi/anno

Progressione dellaNASH a cirrosi :10% (110.000-140.000; 4.000-8.000 allanno)

22. Storia Naturale della NAFLD: conclusioni Dionysos

La NAFLD nell80-90% dei casi ha evoluzione benigna ed reversibile

La mortalit fegato-correlata per NAFLD rispetto alle altre cause di malattie epatiche (virus, alcol) bassa .

Alta la mortalit per malattie cardiovascolari

(3 volte > rispetto cirrosi/HCC)

Bedogni et al.Hepatology, 2007 23. NAFLD as part of theMetabolic Syndrome Dyslipidemia Insulin Resistance CentralObesity Diabetes Hypertension NAFLD 24. Metabolic Syndrome Classification (IDF-2005) http://www.idf.org/webdata/docs/Metac_syndrome_def.pdf

Visceral Obesity ethnicity specific:[waist circumference > 94 cm (M) o 80 (F)]

Plus any two:

Hyperglycemia: (> 100mg/dl)

Low HDL Cholesterol:(< 40 mg/dl (M) o 50 (F)

Hypertriglyceridaemia: (> 150 mg/dl or specific treatment)

Hypertension:(> 130/85 mmHg or specific treatment)

25. Body-Mass Index and Mortality among 1.46 Million White Adults Berrington de Gonzalez et al., NEJM 2010 26. Mortality Associated WithMetabolic Syndrome Lakka H - M et al.JAMA . 2002;288:2709 - 2716. 18 9 6 8 3 2 0 2 4 6 8 10 12 14 16 18 20 All-cause mortality* CVD mortality* CHD mortality* Metabolic syndrome No metabolic syndrome Mortality (% of patients) 2003 PPS *Adjusted for known CHD risk factors. POWERSEARCHPLUG-IN 2.0 Copyright 2001-02 Accent Graphics, Inc. Slide Source:"R:NDEI-22004 GrantT108ARST095 ARS Case 2 FINAL-Baton Rouge 12-09-03.ppt" Last Modified:December 9, 20032:17:25 PM Slide Number:19 27. SINDROME METABOLICA E NAFLD Dislipidemia aterogeneticaTA Stato protrombotico Stato proinfiammattorio Glicemia IR Et LDL Fumo Rischio Framingham 10 anni Rischio (lifetime) cardiovasculare e aterogeneticoMalattia Cardiovasculare Aterogenetica Grundy S. et al. J.Clin.Endocrinol.Metab. 2007 NAFLD/NASH NAFLD is more tightly associated with IR and with markers of oxidative stress and endothelial dysfunction than ATP III criteria innonobese nondiabetic subjectsandmay help identify individuals at increased cardiometabolic riskin this population.Musso G. et al. Diabetes Care, 2007 28. Fatty liver (FL) is associated with increased CHD risk Gastaldelli A, Hepatology 2009 RISC study, 1300 subjects without diabetes or hypertension 29. E la NAFLD ?

La steatosi deve essere considerata come barometro dello stato metabolico generale

Oggi il fegato grasso domani linfarto ???? !!! 30. Targher G et al. NEJM, 2010 All patients with NAFLD need careful monitoringand evaluation of the risk of cardiovascular disease. Patients with NASH are candidates not onlyfor early treatment of their liver disease but alsofor early and aggressive treatment aimed at theirassociated cardiovascular risk factors. Many patients with more severe forms of NAFLD/NASH will have major cardiovascular events and will ultimately die from cardiovascular disease before advanced liver disease develops. 31. Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a Largely Middle-Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective Study Williams et al., Gastroenterology 2011 32. Angulo P, Hepatology 2010 33. Starley et al., Hepatology 2010 NATURAL HISTORY OF NAFLD 34. Decreased Survival of Subjects with Elevated Liver Function Tests During a 28-Year Follow-Up Soderberg et al., Hepatology 2010 35.

Et > 50 anni

BMI > 28/Kg/m2

Obesit centrale

Attivit necroinfiammatoria alla bx

ALT> 2x normale

AST/ALT > 1

Trigliceridi > 150 mg/dl

Insulino-resistenza o DM2

Ipertensione

Chi a rischio di progressione 36. 37. 38. 39. Post-load insulin resistance is an independent predictor of hepatic fibrosis in virus C chronic hepatitis and in nonalcoholicfatty liver disease Svegliati-Baroni G et al . GUT 2007 & GUT 2010 40. Patatin-Like Phospholipase Domain-Containing 3 I148M Polymorphism, Steatosis, and Liver Damage in Chronic Hepatitis C Valenti et al., Hepatology 2011; Trep et al., Hepatology 2011 41. Patatin-Like Phospholipase Domain-Containing 3 I148M Polymorphism, Steatosis, and Liver Damage in Chronic Hepatitis C Valenti et al., Hepatology 2011; Trep et al., Hepatology 2011 Valenti et al., Hepatology 2011 42. The long-term outcome of HCV compensated cirrhosis: a 17-yr follow-up of 214 Pts Cumulative probability of events 25 50 100 0 Years HCC GI bleeding Ascites Jaundice EPS Sangiovanni A et al Hepatology 2006 Annual Incidence rate HCC 3.9% Ascites 2.9% Jaundice 2.0% GI bleeding0.7% EPS 0.1% Pts still at risk 214 196 168 186 153 142 129 110 116 96 89 66 74 57 36 48 214 198 171 188 160 151 142 122 129 105 94 73 81 64 42 58 214 196 164 184 152 144 134 114 122 100 89 69 75 60 40 54 214 197 163 182 151 142 133 105 114 92 86 68 74 60 39 55 214 198 173 190 162 152 146 122 129 108 98 77 84 66 43 59 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 43. Etiology of HCC in Italy : observed and expected temporal trends(23 centres: 1733 HCC) Stroffolini et al, 2009 ( submitted) *: 4 Alcoholic Units in 91% Percentage 24% 61% 13% 3% 44. Dietary habits and their relations to insulin resistance and postprandial lipemia in NASH

grassi saturi

colesterolo

grassi poliinsaturi

fibre

vitamina C ed E ( frutta e verdura)

Pagano et al., 2003 Azione diretta sulla steatosi

Modulazione TG post-prandiali

e della sensibilit insulinica

post-prandiale TG e VLDL-TG

secrezione delle VLDL

sensibilit insulinica

45. Increased Fructose Consumption Is Associated with Fibrosis Severity in Patients with Nonalcoholic Fatty Liver Disease Abdelmalek et al., Hepatology 2010; Kohli et al., Hepatology 2010 J Am Diet Ass 2010 46. The Multiple Parallel Hits Hypothesis Tilg & Moschen, Hepatology 2010 47. Steatosis (NAFLD) Decreased insulin clearance, increased IR, lipolysis,glucaneogenesis, and VLDL secretion Wrong diet, physicalinactivity Increasedinsulin , increasedfree fatty acid,decreased adiponectin Insulin resistance Oxidative stress Inflammation Apoptosis Fibrosis Increased chemokines (IL-6, MCP-1, etc.) increasedfibrogenic factors (PDGF,TGF ) increasedinflammatory cells, activation of Kupfer cellsIncreasedbeta-oxidation, lipidperoxidation, reactive oxygen species (ROS), increasedendotelium reticulum stress, Increased cell damage and death, activation of hepatocyte stellate cells (HSC)Increasedmodulators of hepatic fibrogenesisActivationofpattern recognition receptors Activation of renin-angiotensin-aldosterone system

Lifestyle modification

Weight-loss drugs

Oral hypoglaechemic agents

Statins

Incretin analogs

Bariatric surgery

Anti-oxidants (Sylimarine, SAME, UDCA)

Betaine

Metformin

Caspase inhibitors

Anti-cannabinoids

Anti-nuclear receptors

Inhibitorsofrenin-angiotensin-aldosterone system,

Anti-hypertensive drugs

Adiponectin

Steatosis and damage (NASH) 48. Current therapeutic options in NAFLD/NASH Ratziu V. EASL Special Conference 2009, modified. ALT Steatosis NAS Fibrosis IR Glitazones + + +/- - + Metformin + - ?/- - + Orlistat +/? +/? - - + HD-UDCA + - - - +/? Pentoxifillin + +/? +/? - - Vitamins E - - + - - 49. International Guidelines on Treatment of Different Features of Metabolic Syndrome (WHO, NIH, ADA, ISH, NAASO) Non Pharmacologic Treatment: Correct CV Risk Profile by a Behavioral Approach Diabetes Hypertension Obesity Dyslipidemia Pharmacologic Treatment An ounce of prevention is worth a pound of treatment (B. Franklin, 1735) 50. Tuomilehto et al., NEJM 2001 Diabetes Prevention Program Research Group, NEJM 2002 Bellentani et al., Hepatology 2008 51. Take-home messages

La NAFLD associata ad un aumento del rischio di mortalit per malattia cardiovascolare;

I soggetti a rischio di NASH devono essere adeguatamente valutati per il rischio di evoluzione dell epatopatia e per il rischio di sviluppo dell HCC;

La terapia comportamentale , al momento, il cardine del trattamento della sindrome metabolica e delle sue manifestazioni cliniche.

52.