Non-alcoholic Fatty Liver Disease (NAFLD): Does Anything Help?

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1 Non-alcoholic Fatty Liver Disease (NAFLD): Does Anything Stephen Caldwell, MD Director of Hepatology University of Virginia Case: 36 yo F, T2 DM, abn liver enzymes, mother died of cryptogenic cirrhosis 53 yo Year Age BMI AST ALT plt Too Little Too Late? NAFLD NNFL Non-NASH Fatty Liver NASH 1

2 Treatment No agent is yet approved Cytoprotection and Anti-oxidants Thiazolidinediones Exercise and diet Statins Others 1 st Urso Trial: Placebo Effect Observed Lindor et al Hepatology 2004;39:770 + Urso Placebo Percent Change - AST ALT steatosis inflammation balloon Mallory % Reduction in Key Histological parameters (all improved) Urso and Vitamin E: Double Placebo (Dufour Clin Gastro Hepatol 2006;4:1537) Urso (12-15 mg/kg) + Vitamin E (800 IU/d) Two Years N=15 N=15 N=18 2

3 6 Months Vitamin E (1000 IU/d) + Vitamin C (1000 mg/d) vs Placebo (Harrison Am J Gastro 2003;98:2485) Placebo, N = 22 Vitamin, N = Pre-Post Comparisons Placebo Vitamin Placebo Vitamin BMI ALT * Placebo Inflammation Vitamin Placebo Fibrosis Vitamin Inflammation Pre-Post Comparisons Fibrosis * PPAR Ligands (TZDs): rosiglitazone, pioglitazone Pre-adipocytes + Insulin sensitive small adipocytes Mature adipocytes Fibroblasts TZD: PPAR Ligand Pioglitazone: a thiazolidinedione (TZD): 6 mos (Belfort et al NEJM 2006;355:2297) 3

4 Rosiglitazone: Improves Steatosis but No Change in Fibrosis Ratziu et al Gastroenterol 2008:135:100 One year 8 mg/day Placebo controlled N = 32 vs N = 31 Most Consistent Findings with TZDs Liver Fat Cell Injury Fibrosis Insulin Resistance Adiponectin Total Body Fat Limitations of the TZDs: Weight gain as body fat Limited effect on fibrosis Relapse (Lutchman 2007) if not exercising/dieting (Argo 2009) What about dietary changes and exercise? 4

5 Steatogenic effect of dietary fructose Parks EJ, J Nutri 2008;138:1039 Equal calorie liquid mixtures of glucose and fructose effects on VLDL synthesis Dietary weight loss Harrison SA et al Hepatology 2009 * * NAS = Biopsy NASH Activity Score Weight loss associated with improved histology: especially in the degree of steatosis Liver Fat Exercise without weight loss Johnson NA Hepatology 2009;50 Visceral fat RCT, N = 19 (12 vs 7) All obese Exercise group: Staged 4 weeks 50%, 60% 70% peak VO2 Three times per week No change BMI 21% reduction in liver fat 5

6 Controlled Trials of Exercise and Diet Ueno T et al, J Hepatol 1997;27:103 N=25 adults Nobili et al, DDW-AASLD 2008 N=53 pediatric Improved weight AST and ALT Insulin activity Blood lipids Steatosis Inflammation Ballooning Coronary risks in fatty liver Gastaldelli A Hepatol 2009:49:1537 High risk of CAD in NAFLD/NASH Warrants using statins in those who meet statin criteria FLI = fatty liver index Statins Ekstedt, J Hepatol 2007;47:135 Argo, Hepatology 2008 Cohort comparison in 68 NASH patients 17 treated with statin and 51 untreated f/u biopsy after year Statin treated were more obese f/u mean 14 yr Statin (n=17) No Statin (n=51) % decrease Steatosis % Patients with worse fibrosis % Stage 3-4 at baseline % Stage 3-4 at f/u biopsy 9%* No change 4 (24%) 23 (45%) 1 (6%) 2 (4%) 5 (29%) 2 (12%) 6

7 Simvastatin: RCT Nelson A et al J Clin Gastro 2009 N = 6 (placebo) vs N = months No difference mean BMI (34 vs 37) No difference % hyperlipidemia (50% vs 70%) Other Pharmacological Studies Pioglitazone (PIVENs trial) Omega 3 PUFA supplementation - UVA Anti-apoptosis agents (caspase inhibitors) Pravastatin (UVA Argo) High dose or conjugated Urso Angiotensin II blockers (ARBs) Grehlin-leptin modulators Pentoxifyllin (anti-tnf) Anti-platelet agents: blocks plt signaling PPAR Delta: lowers liver fat increases fat oxidation Riserus U et al Diabetes 2008;57:332-9 % Liver Fat PPAR Fatty acid oxidation PPAR Increased muscle carnitine palmitoyl-transferase c/w increased muscle fat oxidation 7

8 Bariatric Surgery: Prospective Study Klein S, Gastro 2006;130:1564 * * * * * Bariatric Surgery: 1 and 5 years Later Mathurin P et al Gastroenterol 2009;137:532 Systematic f/u in 381 patients undergoing bariatric surgery Raises questions about extended course Treating Gut Flora? Miele L et al Hepatol 2009;49:1877 Gut permeability is increased in NAFLD: Endotoxin exposure? 8

9 Since we lack definitive therapy, why diagnose? 53 yo female with fatty liver 6 years later, age 59: ascites Pharmacology of common agents such as aspirin and Ace Inhibitors, antidepressants and pain medications may be significantly altered. Be aware of silent cirrhosis Fatigue encephalopathy Dyspnea hepatopulmonary Edema portal hypertension GI blood loss GAVE or variceal oozing 9

10 Summary Evidence supports diet / exercise in all Exercise without weight loss Frequency and Intensity of Exercise Target daily 30-60, kcal Reduce calorie / fructose, more omega 3? Consider Pharmacological Rx in NASH studies in progress Summary More intense Rx with family history (20%) Urso/vitamin E? Safe, modest effect Glitazones? Statins? Other? Beware effects of occult cirrhosis as comorbid condition Should we advise Cold Exposure??? NEJM April Brown fat correlates to cold exposure and inversely to BMI and fat (thermogenesis enhances BMR) Cold exposure enhances brown fat expression in adults 10

11 Fatty Liver and Energy Homeostasis Skeletal Muscle Uptake, Activity Energy Utilization β oxidation Fatty acids TCA cycle Mitochondrion ATP Production PPAR/PPAR Coactivator Liver fat oxidation and fat storage Liver Fat Storage Lipid Export Oxidation Peripheral fat stores Insulin resistance/sensitivity Physical deconditioning in NASH: Metabolic Obesity and the Role of Exercise 32 patients with NASH, BMI overweight and 20 obese All scored wellbelow age-sex adjusted average Including 7 males with BMI ml/kg VO2 at LT Trained athlete Mod exercise Sedentary Peak VO2 Types of Obesity: Insulin Sensitive vs Insulin Resistant Stefan N Arch Int Med 2008;168: IS = Insulin Sensitive IR = Insulin Resistant N = 314 Fat measured by MR spectroscopy Muscle fat Liver Fat (%) < >30 (IS) >30 (IR) < >30 (IS) >30(IR) 11

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14 Enhanced Imaging of Lipid Droplet Injury Encrusted Oxidation droplet of the unattached surface of to lipid the cytoskeleton droplets: and resistant? Effects to on external insulin signals signaling (lipase)? Effects on cytoskeleton CAP- PAT The Role of Exercise Diet with TZDs: Bx 5 Years After Stopping TZD Argo C et al, Hepatol 2006;104 (Suppl 1) 5 Change BMI Change Biopsy Stage Change in BMI and Biopsy Fibrosis Stage from Pre-Treatment to 8 years after Therapy and Final Fibrosis Stage What happens after stopping pioglitazone? Lutchman et al Hepatol 2007;46:424 (follow-up on Promrat Study) Baseline 48 week Therapy 48 week After P 1 vs 2 P 2 vs 3 Inflamm < Steatosis Injury Activity Fibrosis

15 Points of Intervention Steatosis Oxidative stress Mitochondrial injury Fatty acid toxicity ER stress Cytoskeletal injury Cell death Inflammation Fibrosis Treating Gut Flora? Miele L et al Hepatol 2009;49:1877 Gut permeability in NAFLD and NASH Therapy of NAFLD depends on: Patient selection for intervention: Natural History of Disease Risks: Familial, Nutritional, Activity Risks of Therapy Endpoints of Therapy Outcomes of Therapy 15