Paul Angulo, MD, FACG, AGAF Professor of Medicine, Section Chief of Hepatology Division i i of Digestive i Diseases and Nutrition i University of Kentucky Medical Center Lexington, KY Paul Angulo, MD University of Kentucky August 21, 2009 I have no financial relationships to disclose within the past 12 months relevant to my presentation My presentation does include discussion of off label or investigational use: UDCA, Vitamin E, Betaine, Metformin, Pioglitazone, Rosiglitazone, Probucol, Atorvastatin, Gemfibrozil, Orlistat, Pentoxifylline, Losartan, Bezafibrate, 3n PUFA, melatonin, CB 1 antagonists, caspase 3 inhibitors Prevalence Prevalence Prevalence of NAFLD Hepatic steatosis is highly prevalent in the general population on July 1, 2008 U.S. population (millions) 34% Adults (30 65 yr) 47.7 Browning JD et al: Hepatology 2004 9.6% Children & adolescents (2 19 yr) 7.5 Schwimmer JB et al: Pediatrics, 2006 Prevalence of hepatic steatosis 55.2 1.6% HCV infection (6 70 yr) Armstrong GL et al: Ann Intern Med 2006 Prevalence of HCV 4.0 9% Alcoholic liver disease (18 75 yr) NIAAA National Epidemiologic Survey on Alcohol and related Conditions Prevalence of alcoholic liver disease 20.2 Prevalence of NAFLD Estimated prevalence of diabetes in Adults worldwide SOURCE: Diabetes Atlas 2006 1
Prevalence of NAFLD Obesity prevalence (BMI 30) in adults worldwide Prevalence of NAFLD Obesity prevalence (BMI 30 kg/m 2 ) by age and sex United States, 2005 20062006 50 Men Women tage Percent 40 30 20 33.3 35.5 28.1 30.5 40 41.1 32.2 33.3 10 SOURCE: WHO 2005 0 Total 20-39 40-59 60 & over Age in years SOURCE: CDC/NCHS, National Health and Nutrition Examination Survey. tage Percent Obesity prevalence (BMI 30 kg/m 2 ) by age and sex United States, 2005 20062006 Healthy People Men 2010 target 50 Women 15% 40 30 20 10 0 33.3 35.5 Prevalence of NAFLD 28.1 30.5 40 41.1 32.2 33.3 Total 20-39 40-59 60 & over Age in years Prevalence SOURCE: CDC/NCHS, National Health and Nutrition Examination Survey. Prevalence of NAFLD Different types of weight gain Fat in NAFLD Is all fat equally bad? Courtesy: Dr. Michael Jensen 2
Visceral adipose tissue is characterized by inflammation Prevalence Wellen & Hotamisligil, J Clin Invest 2003: 112:1785 NAFLD Liver Histology Prognosis of NAFLD Olmsted County, MN N = 420 Swedish Study N = 129 General population General population 0.8 NAFLD 0.8 NAFLD Su rvival (%) 0.6 04 0.4 0.6 04 0.4 0.2 0.2 P = 3 P = 06 0 4 8 12 16 Years 0 5 10 15 20 Years Median F-U 7.6 yr Overall mortality 52 (13%) Cirrhosis prevalence 21 (5%) Median F-U 13.7 yr Overall mortality 26 (20%) Cirrhosis prevalence 10 (7.7%) Adams LA et al: Gastroenterology 2005 Ekstedt M et al: Hepatology 2006 Prognosis of NAFLD A community based cohort study n = 420 patients with NAFLD, Olmsted County, MN. 1980 2000 Expected survival in age and gender matched population Bland steatosis = 58 Deaths = 7 Causes of death Steatosis Prognosis of NAFLD Swedish Study N = 129 NASH = 71 Deaths = 19 Causes of death NASH General population p Cardiovascular 8.6% similar to general population Cardiovascular 15.5% 7.5% 4 Malignancy 1.7% Liver related related 2.8% 0.2% 4 Renal disease 1.7% Median F U 13.7 yr Liver related related 0 0.9 General population General population General population Survival (% %) 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 p = 3 NAFLD Cause of death Malignancy Heart disease Liver relatedrelated 1 st 2 nd 3 rd 1 st 2 nd 13 th rd 13 p = NS Steatosis p = 1 NASH 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time (years) No. at risk 420 399 389 382 361306306 254 217 176 143 109 71 54 40 31 23 14 Adams LA et al. Gastroenterology 2005 Ekstedt et al. Hepatology 2005 3
Prevalence Role of liver biopsy in NAFLD Gold standard for diagnosis Only accurate tool for staging Degree of liver damage: simple steatosis vs. NASH Severity of inflammation and fibrosis Imaging evaluation of steatosis Imaging evaluation of steatosis Imaging Ultrasound Computer tomography Magnetic resonance MR spectroscopy Characteristics Low cost Noninvasiveness Widespread availability Sensitivity 80% 95% Specificity 84% 100% Steatosis objectively measured via Housfield units (HU) 73% 100% 95% 100% Most definitive imaging for the qualitative and quantitative measurement of steatosis Accurately quantifies fat content in the liver Steatosis >5% >85% Steatosis >5% ~ 100% ~ 100% ~ 100% Imaging Ultrasound Computer tomography Magnetic resonance MR spectroscopy Characteristics Low cost Noninvasiveness Widespread availability Sensitivity 80% 95% Specificity 84% 100% Steatosis objectively measured via Housfield units (HU) 73% 100% 95% 100% Most definitive imaging for the qualitative and quantitative measurement of steatosis Accurately quantifies fat content in the liver Steatosis >5% >85% Steatosis >5% ~ 100% ~ 100% ~ 100% None allows staging of fibrosis or distinguishes between steatosis and NASH Ryan et al. Transpl 2002; 8:1114 112 112 Mottin et al. Obes Surg 2004; 14:635 637 637 Ultrasound in NAFLD Sensitivity (%) 80 60 40 20 0 5 9% 10 19% 19% 20 29% 29% >29% Degree of Steatosis Sensitivity lower than 40% in morbid obese Routine clinical and laboratory indicators of severe fibrosis in NAFLD Author n Patient population Angulo et al. 1999 144 NASH Ratziu et al. 2000 93 Overweight, raised liver tests Dixon et al. 2001 105 Bariatric surgery patients Angulo et al. 2007 733 NAFLD Harrison et al. 2008 827 NAFLD Risk factors Age 45 years Obesity (BMI >30 kg/m2) Diabetes AST/ALT >1 Age 50 years BMI 28 kg/m2 Triglyceride 1.7 mmol/l ALT 2 ULN Hypertension ALT >40 IU/L Insulin resistance >5.0 Age (years) BMI (kg/m 2 ) IFG/diabetes AST/ALT ratio Platelet count ( 10 9 /l) Albumin (g/dl) BMI 28 AST/ALT ratio 0.8 Diabetes 4
Imaging evaluation of fibrosis in NAFLD Transient elastography (FibroScan) Transient Elastography (FibroScan) Failure of fibroscan BMI > 28 k/m Steatosis Foucher et al. Eur J Gastro Hepatol 2006;18:411 Castera et al. Gastroenterology 2005;128:343 Intra class correlation coefficient by two operators was lower in less severe fibrosis, increased BMI and steatosis Fraquelli et al. Gut 2007;56:968 973 973 Talwalkar JA. Gastroenterology 2008; 18:411 Transient Elastography (FibroScan) vs. MR elastography MR vs US based elastography Talwalkar JA. Gastroenterology 2008; 18:411 Sandrin et al. Ultrasound in Med. & Biol 2003; 29:1705 Huwart L et al. Gastroenterology 2008;135:32 40 MR vs US based elastography MR vs US based elastography F 1 F 2 F 3 F = 4 MR elastography 0.962 (0.929 0.995) 0.995) US elastography 0.803 (0.701 0.904) 0.904) APRI 0.676 (0.565 0.787) 0.787) 0.994 (0.985 ) 0.837 (0.756 0.918) 0.918) 0.709 (0.603 0.814) 0.814) 0.985 (0.968 ) 0.906 (0.838 0.975) 0.975) 0.816 (0.717 0.915) 0.915) 0.998 (0.993 ) 0.930 (0.877 0.982) 0.982) 0.820 (0.688 0.952) 0.952) Cutoff (kpa kpa) 2.42 2.49 3.13 4.13 Sensitivity (95% CI) Specificity (95% CI) 0.85 (0.75 0.92) 0.92) 0.91 (0.71 0.99) 0.99) (0.93 ) 0.91 (0.78 0.97) 0.97) 0.91 (0.76 0.98) 0.98) 0.97 (0.89 ) (0.81 ) ) 0.96 (0.89 0.99) 0.99) Positive predictive value (95% CI) 0.97 (0.89 ) 0.93 (0.83 0.98) 0.98) 0.94 (0.79 0.99) 0.99) 0.86 (0.64 0.97) 0.97) Negative predictive value (95% CI) 0.64 (0.45 0.81) 0.81) (0.91 ) ) 0.95 (0.87 0.99) 0.99) (0.95 ) Huwart L et al. Gastroenterology 2008;135:32 40 Huwart L et al. Gastroenterology 2008;135:32 40 5
Prevalence Treatment of NAFLD Treatment of Associated Conditions Obesity Diabetes Hyperlipidemia Pharmacological Therapy Insulin sensitizing medications Antioxidants Lipid lowering medications Antifibrotic Hepatoprotective activities Weight loss in NAFLD 23 patients with NAFLD, and BMI > 25 kg/m 2 Low calorie diet (40% / 40% / 20%) plus exercise for 12 months Parameter Improved NASH score 2 points (n = 9) Stable NASH score (n = 6) Age 47.1 ±11 50.4 ±12 NS Number of males 5 (56%) 3 (50%) NS Mean Δ in weight (kg) 6.63 +1.8 02 Mean Δ in BMI (kg/m 2 ) 2.25 +0.58 01 Mean Δ in waist circumference (cm) 6.94 0.52 1 Mean Δ in visceral fat (cc) 36.18 12.23 0.28 Mean Δ in body fat by BIA (%) +0.63 +1.1 0.82 Mean Δ in HOMA score 4.60 0.42 0.15 Mean Δ in AST (IU/L) 15.44 +12.50 5 Mean Δ in ALT (IU/L) 33.11 +15.67 2 Mean Δ in HDL level +5.11 +3 0.56 Mean Δ in TG level 75.89 37.17 0.48 Huang MA et al. Am J Gastroenterol 2005 p Weight loss in NAFLD 90 children with NAFLD Diet (25 30 cal/kg) plus exercise for 12 mo Randomized to vit E + vit C or placebo Vitamin E and C* Placebo* Age (yr) 12.3 ± 3 12.1 ± 3.3 Sex (M/F) 13/30 15/30 BMI (kg/m 2 ) 25.5±3.6 23.6±2.82.8 001 26.5±3.6 24.1±2.62.6 001 Weight (kg) 59.8±17.8 55.4±15.5 001 64.5±16.5 58.9±14.3 001 ALT (U/L) 57±24 33±8 001 69±33 32±11 001 AST (U/L) 41±12 12 31±8 001 45±17 31±9 001 GGT (U/L) 21±8 20±7 3 27±10 22±15 NS Fasting glucose (mg/dl) 77±9 69±3 001 86±12 72±8 001 Fasting insulin (uu/ml) 11±5 10±5 001 13±7 11±5 001 HOMA-IR 2.11±99 1.53±0.66 001 2.82±1.48 1.84±0.95 001 Cholesterol (mg/dl) 154±37 130±1717 001 153±3434 127±1919 001 Triglycerides (mg/dl) 88±52 68±32 001 80±3 64±27 001 * No difference between placebo and vitamin groups Nobili V. et al. Aliment Pharmacol Ther 2006 Steatosis Lifestyle intervention plus Vit E/C or placebo for 24 months Hepatic histology changes 7 Lobular inflammation 0.7 Weight loss in NAFLD Grade 3.5 3.0 2.5 2.0 1.5 0.5 00 Ballooning Grade 2.5 2.0 1.5 0.5 <01 <01 Placebo 01 Placebo 0.1 Antioxidants <01 Antioxidants Nobili V. et al. Hepatology 2008;48:119 128 128 Grade 2.0 1.6 1.2 0.8 0.4 <01 <01 Placebo NAFLD Activity Score 7 6 5 4 3 2 1 0 Placebo 6 Antioxidants <01 <01 Antioxidants Clinical guidelines for weight loss recommended by the NHLBI and NIDDK expert panel: Arch Intern Med 1998 6
Weight loss in NAFLD Weight loss in NAFLD Clinical guidelines for weight loss recommended by the NHLBI and NIDDK expert panel: Arch Intern Med 1998 Initial target for weight loss 10% of baseline in 6 mo (1 2 lbs/wk) Clinical guidelines for weight loss recommended by the NHLBI and NIDDK expert panel: Arch Intern Med 1998 Initial target for weight loss 10% of baseline in 6 mo (1 2 lbs/wk) Further assessment Multiple intervention strategies Life style modifications Anti obesity medications Psychotherapy Surgery Popular Diets for Weight Loss Diet composition 1200 Energy expenditure of physical activity All out competitive sports ture (kcal/h) Energy Expendit 1000 800 600 400 200 Running 10 mph Running 6 mph Climbing stairs Sexual intercourse Gardening Walking 4 mph Bicycling Walking 2 mph Chewing gum (11 kcal/h) Wadden TA, et al. Gastroenterology 2007 Adapted from: Alpers. Undergraduate Teaching Project. Nutrition: energy and protein. American Gastroenterological Association, 1978. Treatment of NAFLD Pitfalls of weight loss Achieving and maintaining weight control is a difficult task to accomplish by most obese patients ~ 15% of patients with NAFLD are non obese Appropriate control of glucose and lipid levels is not always accompanied db by improvement of NAFLD ~ 5% of patients do not have risk factors (normal BMI, normal glucose tolerance, normal lipid profile) Pharmacological Therapy Drug Pharmacological Therapy in NAFLD In vitro/animal studies Open label pilot Promising Randomized Placebo controlled Efficacy UDCA + + + 166 patients No Vitamin E + + + 45 patients No (?) Betaine + + + 35 patients No (?) Metformin + + + N Acetylcysteine + + + Rosiglitazone + + + 63 patients Yes (?) Pioglitazone + + + 47, 61 patients Yes (?) Gemfibrozil + + + Bezafibrate + + + Pentoxifylline + + + Probiotics + + + Orlistat + + + 41 No (?) Sibutramine + + + Losartan + + + 3n PUFA + + + Telmisartan + FABAC + Melatonin + Acarbose + Rimonabant + 7
Pioglitazone 45 mg/d vs. placebo for 6 months in NASH All on a hypocaloric diet Pioglitazone 45 mg/d vs. placebo for 6 months in NASH All on a hypocaloric diet Belfort R et al. N Engl J Med 2006;355:2297 2307 2307 Belfort R et al. N Engl J Med 2006;355:2297 2307 2307 Pioglitazone 45 mg/d vs. placebo for 6 months in NASH All on a hypocaloric diet Pioglitazone 45 mg/d vs. placebo for 6 months in NASH All on a hypocaloric diet Belfort R et al. N Engl J Med 2006;355:2297 2307 2307 Belfort R et al. N Engl J Med 2006;355:2297 2307 2307 Pioglitazone 45 mg/d vs. placebo for 6 months in NASH Hepatic histology changes Pioglitazone 30 mg/d vs. placebo (1 year) All on diet and exercise Pioglitazone (n=31) Placebo (n=30) p Weight change (kg) 2.7 0.5.04 Statistical significant decrease (baseline vs. one yr) in the pioglitazone arm on values of: glucose, HbA1c, insulin, c peptide, ALT, GGT, ferritin, abd TIMP 1 Histology Pioglitazone (n=31) Placebo (n=30) Pio (end) vs. Pla (end) Start vs. End Start vs. End Steatosis (.001) (.03) (.2) Lob. inflam (.04) (.3) (.25) Cell injury (.09) (.04) (.005) Fibrosis (.006) (.8) (.05) Belfort R et al. N Engl J Med 2006;355:2297 2307 2307 Aithal G, et al. Gastroenterology 2008;135:1176-1184 1184 8
Pioglitazone 30 mg/d vs. placebo (1 year) All on diet and exercise Rosiglitazone 8 mg/d vs. placebo (1 year) Rosiglitazone Placebo (n=32) (n=31) p Normalization of ALT 12 (38%) 2 (7%).005 Change in Steatosis (%) 20 (26) 5 (23).02 Ballooning 0.13 (.71) 0.23.8.61 Necroinflammation 9 (.73) 0.13 (.81).86 Fibrosis 3 (0.54) 0.18 (1.14).43 Perisinusoidal fibrosis 3 (0.54) 6 (0.63).83 NAFLD activity score 1 (4) 0 (4).60 Weight change (kg) 1.5 ± 5.2 1 ± 3.5 <.03 Aithal G, et al. Gastroenterology 2008;135:1176-1184 1184 Ratziu V, et al. Gastroenterology 2008;135:100-110110 Pioglitazone in NASH Pioglitazone in NASH Weight HOMA Lutchman G, et al. Hepatology 2007 Lutchman G, et al. Hepatology 2007 Pioglitazone in NASH Estimates of the Incidence of the Cardiovascular End Points According to Randomized Treatment Assignment to Pioglitazone or Control N = 9 Baseline 48 weeks on 48 weeks off pioglitazone pioglitazone P* P** Parenchymal Inflammation 3.0 ± 1.1 1.2 ± 0.7 2.9 ± 1.4 <1 2 Steatosis 2.6 ± 0.9 ± 0.6 2.1 ± 1.3 2 5 Cell injury 1.6 ± 0.7 0.4 ± 0.7 1.2 ± 2 6 NASH Activity Index 7.1 ± 2.4 2.6 ± 0.9 6.2 ± 3.0 4 1 NASH fibrosis 2.1 ± 1.2 1.1 ± 1.2 1.2 ± 1.3 3 0 Diagnostic criteria for NASH 9 (100%) 1 (11%) 7 (78%) <01 c 2 c Interval between biopsies (wks) 50.6 ± 4.4 50.2 ± 6.3 * P value: baseline vs. 48 weeks on pioglitazone ** P value: 48 weeks on vs. 48 off pioglitazone Lutchman G, et al. Hepatology 2007 Lincoff, A. M. et al. JAMA 2007;298:1180 1188. 1188. 9
Meta analysis analysis of Randomized Controlled Trials of Rosiglitazone vs Control for Myocardial Infarction, Heart Failure, and Cardiovascular Mortality Treatment for NAFLD/NASH Need of carefully controlled clinical trials Adequate statistical power Clinically relevant end points liver enzymes vs. liver histology long term survival? Singh, S. et al. JAMA 2007;298:1189 1195. 1195. Treatment for NAFLD/NASH Randomized, placebo controlled controlled trials in progress NIH sponsored NASH network Pioglitazone Metformin Vitamin E Other Institutions High dose UDCA (28 30 mg/kg/d) Orlistat Pentoxifylline Under development Silymarin (phase II) CB 1 antagonists (i.e., Rimonabant, others) Antiapoptotic (caspase 3 inhibitors) Prevention of NAFLD Diabetes Prevention Program research group in the United States N Engl J Med 2002;346:393 403403 Summary... Treatment for NAFLD/NASH No proved treatment for all patients with NAFLD/NASH is currently available Weight loss, when achieved and sustained improves insulin sensitivity and the liver disease Pharmacological l therapy holds promise Glitazones Promising (?) Conflicting results Questionable safety Prevalence 10