NAFLD/NASH. Definitions. Pathology NASH. Vicki Shah PA-C, MMS Rush University Hepatology

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1 NAFLD/NASH Vicki Shah PA-C, MMS Rush University Hepatology Definitions NAFLD Evidence of hepatic steatosis by histology (5%) or imaging No causes for secondary fat accumulation EtOH, Drugs, hereditary disorders NASH NAFLD with inflammation with hepatocyte injury (ballooning) with or without fibrosis Global prevalence of NAFLD is 25.24% ( ) with highest prevalence in Middle East and South America and lowest in Africa Pathology NASH Ballooning Chicken wire fibrosis NASH cirrhosis Yeh, M et al., Pathology of Nonalcoholic Steatohepatitis. Medscape Nov 12.,

2 Lysosomal Acid Lipase Deficiency (LALD) A rare systemic disease characterized by decreased LAL enzyme activity Results in accumulation of lipids Damage to liver, GI tract and blood vessels. Reported in children most often but up to age 68 Non-obese patients with unexplained persistently elevated LFTs or unexplained hepatomegaly Any patient with cryptogenic cirrhosis or microvesicular steatosis on liver bx LDL> 160 and HDL < 40 mg/dl (or <50 in females) Diagnosis: enzymatic blood test Treatment: sebelipase alfa Co-morbid Conditions NASH and fibrosis Results in inflammation and necrosis Associated with moderate to severe fibrosis elevated AST and ALT DM male gender Caucasian ethnicity were

3 NASH and OLT OPTN ( ) Liver transplant list NASH increased by 170% ALD increased by 45% HCV increased by 14% NASH has become the 2nd indication for LT listing (2013) 90 day on the list mortality ALD lower than NASH NASH similar to HCV Compared to HCV, NASH patients had the lowest chance of getting transplanted in 90 days and 1 year NAFLD/NASH and HCC NAFLD is the third most common cause of HCC Incidence of HCC in NASH cirrhosis is 2.6% as compared to 4% in HCV Characteristics: More males (73%) Average age 67 Single lesion (76%) well to moderately differentiated Larger tumors than viral hepatitis and ALD Current Treatments Weight loss Exercise Dietary Interventions Coffee Bariatric surgery Medications

4 Weight loss Loss of > 5% body weight: improved steatosis Loss of > 9%: significant improvement in steatosis, lobular inflammation, ballooning Only 15% achieve a weight loss of > 10% and most regain their weight Exercise Moderate physical activity (min./wk) Minimum: > 150 Best: > 300 Vigorous physical activity (min/wk) Minimum > 75 Best > 150 Diet Low calorie (1200kCal) diet resulted in similar weight loss regardless of composition Reduction of calories by 30% reduced liver lipid content and total/visceral fat Eating Breakfast (protein rich (25-30g before noon) Characteristic of long time losers Multiple small meals maintain euglycemia Starvation Effect on glycemic response to food Hormonal effect on food choices Active throughout day (better than a longer workout)

5 Coffee Protective effect in biopsy proven NASH through a reduction in inflammation and fibrosis Reduces insulin levels and risk of Type II DM Risk Reduction of HCC: 1 to 2 cups = 20% reduction > 5 cups = 75% reduction Bariatic Surgery Lassally G, Gastroenterology 2015 n=191 biopsy proven NASH underwent bariatric surgery in France 1 year follow up 85% resolution of NASH Ballooning (84%) Inflammation (67%) Fibrosis (33%) BMI 49 vs 37 Bypass better than banding 14 vs. 6.4 pt BMI drop Fewer had persistent NASH (7 vs. 30%) Bariatic Surgery 15 studies: 766 paired liver biopsies % BMI reduction: 19 42% Steatosis improved 92% Steatohepatitis improved 81% Fibrosis improved 66% Complete resolution of NASH in 70%

6 Bariatic Surgery Prospective Swedish Obese Subjects (SOS) 5yrs post-bariatric surgery Levels of fibrosis increased significantly Level of insulin resistance independently predictive of ballooning at the 5 year mark Medications Lipid Lowering agents (statins, fibrates etc.) Anti-obesity medications Antioxidants Vitamin E/Vitamin C Betaine N-Acetyl-cysteine Lecithin Silymarin Beta-carotene EPA Treatment of IR PPRA agonists Anti-TNF agents (Pentoxifylline) ACE inhibitors/arbs Caspase inhibitors Bile Acid- Ursodeoxycholic acid (UDCA) Probiotics Vitamin E Vitamin E (a-tocopherol) 800 IU/day improves liver histology in non-diabetic adults with biopsy-proven NASH first-line pharmacotherapy for this patient population. (Strength -1, Quality - B) Vitamin E is not recommended treat NASH in diabetic patients NAFLD without liver biopsy NASH cirrhosis cryptogenic cirrhosis (Strength - 1, Quality - C) Increase in CV risk Increase in all cause mortality

7 Probiotics Role in NASH remains unclear Pioglitazone Treat steatohepatitis in patients with biopsy-proven NASH Patients who participated in clinical trials that investigated pioglitazone for NASH were non-diabetic Long term safety and efficacy of pioglitazone in patients with NASH is not established CHF risk, weight gain Future Treatments

8 References Younossi Z et al. Hepatology 2015 Younossi Z et al. Medicine 2012 Blais P, et al. Am J Gastroenterol. 2015;110:10-14 Hossain N, et al Gastro and Hepatology 2009 Mittal S Clin Gastro Hepatol 2015 Ascha M Hepatology 2010 Soderber C Hepatology 2010 Arasse Y Hep Res 2012 Pocha C Sem LD 2015 Duan X HBPD 2012 Paradis V Hepatology 2008 White D, Kanwal F, El-Serag H. Clin Gastro Hepatol 2012 Wong R, Aguilar M, Cheung R, Perumpail R, Harrison S, Younossi ZM, Ahmed A. Gastroenterology 2015 Bellantani Hepatology 2007 Hepatology 2007 J Natl Cancer Inst 2005 Clin Gastroenterol 2013 PloS ONE 2013 Bajaj J, Hylemon B, Younossi Z. Am J Gastroenterol Suppl (2012) 1:9 14