Stéatopathies métaboliques et diabète. Vlad Ratziu Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris, France

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1 Stéatopathies métaboliques et diabète Vlad Ratziu Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris, France

2 NAFLD : diagnostic framework NAFLD/NASH : a prevalent disease? Individual predisposition Strategies for screening Hepatic and extrahepatic complications of NASH Therapeutic management

3 NAFLD STEATOSIS Alone or non-specific inflammation STEATOHEPATITIS Hepatic cell injury + Inflammation Different clinical outcome

4 Stéatose isolée Stéatose sans autres signes histologiques (parfois inflammation minime apsécifique)

5 Stéatohépatite Stéatose Signes de souffrance hépatocytaire Ballonisation, inflammation/nécrose lobulaire, Mallory, PNN ballonisation

6 fibrose peri sinusoidale fibrose portale fibrose en pont cirrhose

7 NAFLD Secondary PRIMARY Metabolic Risk Factors Coexistence other CLDs Positive definition Alcohol

8 NAFLD : diagnostic framework NAFLD/NASH : a prevalent disease? Individual predisposition Strategies for screening Hepatic and extrahepatic complications of NASH Therapeutic management

9 Prevalence of NAFLD/NASH/Fibrosis in asymptomatic outpatients US Army personnel N=328 Primary Care Setting UK Asymptomatic, low risk CLD N=1118 NAFLD 48% NASH 13% (30% of NAFLD) Advanced fibrosis 3% (23% of NAFLD) Williams, Gastroenterology 2011 NAFLD 26% 45% No cause 25% ALD Classical CLD Advanced fibrosis 2% (8% of NAFLD) Armstrong, J Hepatol 2012

10 Prevalence of NAFLD In Patients with Abnormal LFTs Prospective evaluation of liver histology, 21 Centers in France N=274 Pts, 248 with liver biopsy > 10 mm NORMAL 19% OTHER 23% Steatosis 26% NASH 32% NAFLD 58 % De Ledinghen, Ratziu, JHepatol 2006

11 NAFLD : diagnostic framework NAFLD/NASH : a prevalent disease? Individual predisposition Strategies for screening Hepatic and extrahepatic complications of NASH Therapeutic management

12 Individual predisposition to NAFLD? Ethnic differences Hispanics>Caucasians>Blacks Mirrored in differences in body fat distribution and lipoprotein metabolism High heritability of fatty liver Even after adjustment for age, sex, race, BMI Genetic variants?

13 ApoC3 variants and risk of NAFLD 60% increase in fasting TG doubles post-prandial TG 46% reduction in TG clearance more insulin resistant NAFLD 0% 38% RISK OF NAFLD ApoC3 alone : 11% PNLPA3 alone : 6.5% Both : 13% Petersen, NEJM 2010

14 PNLPA3 variants (rs , I48M variant) Association with (ORs 1.5 and 3.5) NAFLD NASH Grade of steatosis Inflammation/cell injury Fibrosis ALT Independent of Age, sex, BMI, T2D, No ass with metabolic traits (IR) Valenti, N=574, Hepatology 2010 Speliotes, N=678; Hepatology 2010 Rotman, N=894, Hepatology 2010

15 NAFLD : diagnostic framework NAFLD/NASH : a prevalent disease? Individual predisposition Strategies for screening Hepatic and extrahepatic complications of NASH Therapeutic management

16 Screening strategies I Diagnostic tools Metabolic RF ULN IU/L Lab variablity Steatosis IR surrogates : HOMA Dynamic tests Waist circumference Adipose tissue IR Lipid metabolism IR US, CT, MRI : if >20-30% not quantifiable

17 Usual diagnostic circumstances for NAFLD LFTs + Ultrasound Cirrhosis X NASH Increased ferritin LFTs + Metabolic RF Metabolic RF + Normal ALT Key points : presence of steatosis (ultrasound, markers) presence of metabolic risk factors

18 Chez quels patients rechercher une NASH? Patients à risque Tests hépatiques anormaux Stéatose à l échographie FDR métaboliques Affections associées au syndrome métabolique (Apnée du sommeil, sd des ovaires polycystiques) Systématiquement en association aux autres hépatopathies

19 En pratique... que faire? FDR Métaboliques BHC Echographie BHC anormal stéatose Avis spé

20 Que va faire l avis spécialisé? Eliminer autres causes maladie du foie FibroTest + Fibroscan Poser l indication de la biopsie du foie Mettre en place une surveillance

21 Quelle gravitécherche-t-on? Stéatose simple ou NASH? Activité inflammatoire? Stade de fibrose Si cirrhose, complications et surveillance

22 Screening strategies II non invasive prediction WHAT Fibrosis Steatohepatitis Steatosis WHY Prognosis Cirrhosis surveillance Pharmacol treatment Prognosis Intensive counselling Pharmacol treatment Diagnosis (if > sensitive US) Early changes therapy Risk of metabolic complications HOW Serum markers (FibroTest, FibroMeter, ELF, Angulo*) Elastometry* Serum markers (CK18*, NASHDiagnostics, NASHTest) Serum markers (SteatoTest*, FLI*, Kotronen index) Elastometry- CAP attenuation

23 Screening strategies III General population - NO Patients with IR (metabolic RF, PCOS, lipodystrophia) : ALT Steatosis + ALT N Steatosis + ALT No Steatosis ALT N No Steatosis LB FT + FS -/- discordance +/+ Nothing monitoring LB

24 Screening strategies IV General population - NO Patients with IR (metabolic RF, PCOS, lipodystrophia) : Chronic liver disease Metabolic risk factors IR Stéatose Liver biopsy Bariatric surgery, cholecystectomy Liver biopsy

25 When to perform liver biopsy on an individual basis? Metabolically stable? Attempt diet and lifestyle change Failure (s) previous attempts? Never tried No change Improvement weight, IR, ALT N Comorbidities Patient motivation Trials Fibrosis risk FT/FS (or clinical) +/+ +/- -/- MONITORING LB

26 NAFLD : diagnostic framework NAFLD/NASH : a prevalent disease? Individual predisposition Strategies for screening Hepatic and extrahepatic complications of NASH Therapeutic management

27 NAFLD STEATOHEPATITIS STEATOSIS F0 F2 F1 F3 F4 Cirrhosis No or minimal fibrosis

28 NAFLD NASH Steatosis Good prognosis Insulin resistance

29 High ALT 20 yr f/u Diabetes Goessling, Gastroenterology 2008 Metabolic Sd CV events Schindhelm, Atherosclerosis 2007 Even within the normal range Even after adjustment for interim weight change and baseline glucose levels

30 NAFLD Center stage of the metabolic syndrome? Hypertension Cardiovascular Prevalence essential HTN Incident diabetes Insulin requirements NAFLD Diabetes Endothelial & coronary dysfunction Carotid plaques Impaired ventricular fct and metabolism CV events

31 NAFLD NASH? Steatosis Good prognosis Insulin resistance

32 Progression of mild NAFLD (Matteoni I, II) Initial biopsy (N=25) 25 Mild NAFLD Follow-up biopsy 9 8 8* Mild NAFLD Ballooning progression (* Bal score 1; Bal score 2) Progression to bridging fibrosis Patients with disease progression were older (58 vs 46 yrs, p=0.04) and had a higher BMI (30.1 vs 26.2 kg/m²) and more often diabetes (43vs 19%) than those without progression. Pais, AASLD 2010

33 NAFLD NASH? Steatosis Good prognosis Insulin resistance Fibrosis progression Cirrhosis Liver failure Liver Cancer

34 NASH : effect on survival Survival vs. the general population STEATOSIS NASH General population Ong, J Hepatol 2008 Dunn AJG 2008, Jepsen, Hepatogastro 20 Community-based Adams, Gastro 2005 Referral center Ekstedt, Hepatology 2006 Same survival as the general population Dam-Larsen, Gut 2004 Ekstedt, Hepatology 2006

35 NASH : a severe hepatic disease? Hepatocellular carcinoma Significant fibrosis and fibrosis progression Survival Potential for Severe clinical outcomes Cirrhosis and cryptogenic cirrhosis Liver failure

36 NASH : effect on survival Survival vs. the general population STEATOSIS NASH Liver-related related mortality All Same survival as the general population Cardiovascular mortality Cirrhosis : an independent risk factor of death Ekstedt, Hepatology 2006 All incl. Matteoni Gastro 1999

37 BMI and Cause-specific mortality 57 prospective studies including 900,000 adults (Europe, NorthAm) PSC, Lancet 2009 Death by liver cancer HR 1.47 ( ) 1.71)

38 Obesity and mortality by cirrhosis Prospective cohort of 1.23 M middle aged UK women +28% in risk per 5 u BMI 56 yr-old; 36% overweight; 18% obese 6.2 person/year f/u Alcohol and smoking increase the absolute risk 1811 first hospital admissions for cirrhosis or death by cirrhosis Cirrhosis morbi/mortality : 42% alcohol 17% overweight (BMI>25) Liu, BMJ 2010

39 Diabetes mellitus and HCC Risk factor only in the presence of other risk factors such as ALD, HBV, HCV El Serag, Am J Gastro, 2001 Risk of CLD and HCC is doubled in diabetic men independently of ALD or viral hepatitis El Serag, Gastro, 2004 N = diabetic pts vs controls No previous CLD Higher incidence of NAFLD (18.13 vs 9.55 per persons/year, p < fold increase of HCC (HRR 2.16, p < 0.001)

40 Diabetes mellitus and HCC Risk factor only in the presence of other risk factors such as ALD, HBV, HCV El Serag, Am J Gastro, 2001 Risk of CLD and HCC is doubled in diabetic men independently of ALD or viral hepatitis El Serag, Gastro, 2004 Diabetes is associated with a 2-3 fold increase in HCC regardless of other risk factors El Serag, Hepatol Research, 2007 HCC risk is correlated with duration and control of diabetes Hassan, Cancer 2010 Synergistic effect of diabetes and obesity in HCC risk Polesel, Annals of Oncology, 2009

41 NAFLD : diagnostic framework NAFLD/NASH : a prevalent disease? Individual predisposition Strategies for screening Hepatic and extrahepatic complications of NASH Therapeutic management

42 Who should be treated? Steatosis :prevention of extrahepatic complications only; hepatic monitoring. Steatohepatitis : prevention of fibrogenesis No or mild fibrosis : no specific treatment ; lifestyle and diet Significant fibrosis : specific pharmacological therapy Bridging fibrosis OR Portal = perisinusoidal fib + inflammation + risk factors

43 Exercise Diet Drugs

44 Physical Exercice in NAFLD -Rationale Visceral obesity Physical inactivity NAFLD Nutritional intake HOMA Adiponectin Resistin 1/2 amount of any PA 1/2 amount of aerobic PA 1/3 amount of resistance PA Zelber-Sagi, Hepatology 2008

45 Reduces visceral fat Physical activity alone Reduces Whole body IR Improves control of Diabetes Reduces risk of incident Diabetes RECOMMENDATIONS : Any increase over baseline 400 kcal 4 times a week 150 min/wk ; walking OK No sedentarity Physical activity + Diet Synergistic effect on : Insulin resistance Muscular IS Liver fat

46 Modest Weight loss Liver fat No change muscle fat Body fat Improvement in hepatic IR Improvement whole body IR Tiikkainen, Diabetes 2003 Petersen, Diabetes 2005

47 Pharmacological treatment of NASH Insulin sensitizers Glitazones Weight loss agents Metformin CB1R blockers Exenatide Hepatoprotectants Ursodeoxycholic acid Sartans Anti-oxidants Cytoprotective agents (betaine, pentoxifylline, probucol) Anti-apoptotics Anti-inflammatory inflammatory agents PUFAs Improvement of insulin resistance?? Improvement of liver injury

48 A requiem for Metformin FIBROSIS INFLAMMATION STEATOSIS Musso, Hepatology 2010

49 Mechanisms of Action of Glitazones TZD FFA Glucose uptake muscle Adipocytes IR Adipocytes IS Redistribution Fat mass Adiponectin TNF-α Glucose output liver ENHANCED IS Gastaldelli, Hepatology 2009

50 Glitazone RCTs in NASH Ratziu, Caldwell, Tetri, Hepatology 2010

51 PIVENS trial NASH, non diabetic, non cirrhotic, biopsy < 6 months, NASH on biopsy with ballooning and a score of 4 or 5 Pioglitazone 30 mg(n=80) vs. Vit E 800 IU (N=83) vs. placebo(n=84) 2 years of treatment Primary endpoint : decrease in NAS by >2 points. Significance set at 0.025

52 Primary end-point in patients with well-defined NASH 52 < Central review : many pts without ballooning (18% vite; 17% PLB, 28% Pio) 23 Many missing biopsies (10 pts VitE; 11 pts PLB; 14 pts Pio) vite PLB Pio

53 Conclusion -PIVENS Trial Both Vit E and Pio improved : Steatosis Inflammation Ballooning NAS score steatohepatitis Neither improved fibrosis Pioglitazonedid not meet the primary endpoint (underpowered) but significantly improved all histological features except for fibrosis

54 FLIRT-2 2 Extension trial RCT OPEN-LABEL EXTENSION TRIAL 1yr Liver Biopsy ROSIGLITAZONE Liver Biopsy RSG-RSG (N=25) ROSIGLITAZONE* 3 yrs PLACEBO PLB-RSG (N=28) Liver Biopsy M0 M12 M16 M40 Ratziu, Hepatology 2010 * Rosiglitazone : 8 mg/d

55 % Steatosis Reduction in liver fat score (%) P M0 M12 M40 PLB -RSG RSG M0 M12 M40 RSG -RSG Ratziu, Hepatology 2010

56 Vit E increases risk of hemorrhagic stroke by 22% Schurks, BMJ 2010 Vit E may increase the risk of prostate cancer? SELECT trial males >50/55yrs, PSA N, rectal ex N. Median f/u f 5.5 yrs 4 arms Se (200µg/d); VitE (400IU/d); Se+VitE; placebo HR for prostate cancer in Vit E group: 1.13 [CI ], p=0.06 Lippman, JAMA 2009

57 URSONASH Study Histologically documented NASH and ALT > 50 UI/L Multicentric French RCT Liver biopsy M0 DELURSAN (28-35 mg/kg/j) N =62 Randomization M12 Endpoints : 1 ary : Drop in ALT 2 ary : safety, fibrosis markers PLACEBO N =62 Ratziu, J Hepatol 2011

58 Reduction in ALT levels Ratziu, J Hepatol 2011

59 Proportion of patients with ALT normalization (<35 IU/L) during treatment 24.5 HD-UDCA PLACEBO M0 M6 M12 M0 M6 M12 Ratziu, J Hepatol in press

60 Conclusion -Pharmacologic options Most evidence-based data : glitazones Glitazones improve : certainly steatosis and ALT, probably inflammation and liver cell injury but not fibrosis The relationship between hepatic and metabolic improvement need to be better understood Hepatoprotectants need to be developed Phase II studies with biochemical end-points are needed Individualized therapy and integrative approaches with diet and lifestyle modifications need to be optimized

61 Academic and Industry Interest in NASH Single topic conference AASLD 2002, 2006, EASL 2004 NIH NASH CRN 2002-present 2 RCTs, papers End Point conference AASLD 2009 NASH EU FP7 Grant 2 Medium-scale 6 M FLIP consortium EASL Special Conference Position Paper 2009 APASL CPG 2007 Industry sponsored clinical trials & Diagnostic methods

62 Conclusion Travailler en collaboration avec les hépatogastroentérologues (réseaux) Rechercher une atteinte du foie chez les patients diabétiques et/ou en surpoids Screening BHC + échographie La stéatose pourrait aggraver l IR et précipiter le syndrome métabolique La NASH est une cause de cirrhose et cancer du foie Le pronostic est liéàla stéatohépâtite et au stade de fibrose du foie Au délàdes régles hygiénodiétetiques des agents pharmacologiques sont nécessaires pour les formes avancées

63 Acknowledgments LIDO * Study Group Pitié-Salpêtrière Hospital, Paris Diabetes Dept : A Grimaldi, A Heurtier Endocrinology / Lipid Clinic : Ph Giral, E Bruckert Internal Medicine : S Pelletier Hepatology Dept : J Moussalli, Y Benhamou Obesity Clinic : A Basdevant, K Clément Hôtel Dieu Hospital, Paris Diabetes Dept : G Slama, E Larger Cochin Hospital, Paris Liver Clinic : P Podevin Saint-Antoine Hospital, Paris Liver Clinic : L Serfaty INSERM : J Capeau, Ch Housset (*Liver Injury in Diabetes and Obesity)