Disclosures. The Typical Therapeutic Pyramid $$$ The NAFLD Umbrella. The Big Question: What are the treatment options for NASH?

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1 Disclosures I have the following relationships to disclose: Ethicon Endo Surgery Inc. Galectin Therapeutics Synageva Biopharma Raptor Pharmaceuticals I will be discussing off label use of medications in my presentation The NAFLD Umbrella NASH R Kohli, J Pediatr. 4 Apr;64(4): Percent Survival NASH produces a significant increase in mortality Eksted et al Hepatology 6; 44: Percent Survival NAFL The Typical Therapeutic Pyramid The Big Question: What are the treatment options for NASH? $$$ $$ $

2 NASH Therapeutics NASH Focused Clinic Lifestyle advice Diet: Increase fruits and vegetables Eat healthy portion controlled breakfast Decrease/avoid sugar sweetened beverages Reduce take out/fast food meals Activity: Increase physical activity Reduce screen time Hepatotoxins Alcohol in teens Hepatitis A and B vaccination Steatohepatitis Center: Outcomes 47% patients returned for year follow up What have we learned? Is such a program effective? Z-Score BMI Z-Score Mean Value (U/L) 5 5 ALT Mean Value (U/L) 5 5 AST. Baseline Year Initial Significant reduction in BMI, ALT and AST (p<.5). year Initial year DeVore and Kohli et al. J Pediatr Gastroenterol Nutr. Mar 9. How rapidly can fibrotic NASH worsen? What if all this does not work? Baseline labs JAN 9 Age (years) BMI BMI %ile Waist (cm). 8.7 HDL cholesterol 6 ALT 6 9 AST 59 4 GGT 4 6 Hgb AC (on metformin) Fasting glucose 7 Pyschotropic Meds Abilify, lithium No change Follow up labs APRIL

3 Pediatric NASH with Stage fibrosis Liver MR based Elastography year old boy 5 yo with NASH and mild/moderate diffuse fatty liver infiltration Mean liver stiffness =.9 kpa (range.7.4) ROC Curve for MRE in Children NAFLD patients (n=5) AUROC =.9 (.79,.) MRE able to identify significant fibrosis vs. no fibrosis (p=.).7 kpa 88% sens 85% spec NASH Therapeutics Xanthakos Kohli et al J of Pediatr Feb 4 Agents studied well for treating NASH Insulin sensitizers Metformin Thiazolidenediones Anti oxidants Vitamin E Cysteamine Omega fatty acids no RCTs with histology JAMA Landmark Randomized Placebo Controlled, Double Blinded Pediatric Trial for NAFLD with histologic outcomes

4 However, histological outcomes more promising for Vitamin E Compared to placebo, the % with histological NASH resolution at 96 week follow up biopsy: 8% with placebo 58% with vitamin E (P =.6) 4% with metformin Take Home Message: Vitamin E helps some, but not panacea for NASH Vitamin E reduces ballooning in NASH, and may lead to resolution of NASH in over ½ of pediatric patients with biopsy proven NASH Both vitamin E and metformin no different from placebo in lowering ALT, AST levels after years of therapy. Cysteamine for the Treatment of NASH in Children (CyNCH) Cysteamine bitartrate a cystine depleting agent NASH Therapeutics Increases intracellular glutathione and increases adiponectin multimerization Pilot study of children with NAFLD significant improvement in ALT and AST after 4 weeks of treatment Dohil R et al. Alim Pharma & Therap. ;(9):6 44 Dohil R et al. J of Pediatr. ; 6(4): Background: Bariatric Surgery is a Treatment for Obesity Weight Loss Interventions Lifestyle Drug therapy Bariatric surgery Weight Loss (%) Annals of Surgery (): (995) Diabetes Care 7():55-6 (4) Lifestyle Lifestyle+Orlistat Lifestyle Lifestyle+Orlistat Bariatric Surgery Time (years) Severe NASH now considered indication for surgery in adolescents Selection criteria for adolescent weight loss surgery BMI Comorbidities > 5 Type DM moderate severe OSA (AHI 5 events/hr) pseudotumor cerebri severe NASH > 4 Mild OSA (AHI>5 events/hr) HTN Insulin resistance/igt Dyslipidemia impaired QOL or ADL Pratt, JSA et al. Obesity 9; 7:9 4

5 Common Bariatric Surgery Procedures Effect of Bariatric Surgery on Serum Bile Acid Levels Fasting Total Serum Bile Acids (umol/l) 5 Gastric Banding LAGB Pre Surgery LAGB Post Surgery Gastric Bypass Gastric Banding Sleeve Gastrectomy Fasting Total Serum Bile Acids (umol/l) 4 Gastric Bypass RYGB Pre Surgery RYGB Post Surgery Sleeve Gastrectomy Kohli et al, J Clin Endocrinol Metab. 98(4):E78-. () Steinart et al, Obesity. () E () Bile Acid FXR Pathway C 5 WT-Sham WT-VSG D 4 Body weight (g) Body weight (g) 5 KO-sham 5 KO-VSG Modified from Myronovych, Kohli et al Obesity 4; () 9-4. Modified from Ryan, Kohli, Seeley et al Nature, May 8, 4 Fxr ko mice can eat through a smaller stomach! A B So is that it? HFD intake g/d WT-sham WT-VSG HFD intake g/d KO-sham KO-VSG Is FXR the answer? Modified from Ryan, Kohli, Seeley et al Nature, May 8, 4 5

6 Not so fast NASH Therapeutics What does the futurehold? Drugs in the Pipeline Bile Acid Signaling/FXR : Obeticholic Acid Incretin/ Insulin Sensitizers: Linagliptin, GW556, GFT55 Lipid Absorption/Metabolism : Ezetimibe, Orlistat Antioxidants/Anti-inflammatory: Resveratrol, Losartan Anti-fibrotic agents: Sintuzumab, Galectin (GR-MD-) Mazzella N et al. Clin Liver Dis 8 (4) 7 89 Pearlman M et al. Curr Opin Gastroenterol 4, : 7 6

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