N on a lcoholic F atty L iver D isease (NAFLD): Where are we today?

1. Nonalcoholic Fatty Liver Disease (NAFLD):Where are we today? William M. Outlaw Internal Medicine Residency Wake Forest University

2. NAFLD—Presentation Outline • Background • Disease Continuum • Relevance • Risk Factors • Pathogenesis • Natural History • Clinical Features • Treatment • Conclusions

3. Defining NAFLD… Clinico-pathologic syndrome encompassing a wide range of fatty liver disease in the absence of significant alcohol intake (2 drinks or fewer daily) and other common causes of steatosis

4. NAFLD—Background • Zelman et al. reported association of obesity with fatty liver in 1958 • A number of investigators noted liver failure in obese patients undergoing intestinal bypass surgery • Ludwig et al. coined “non-alcoholic steatohepatitis” in 1980

5. NAFLD—Spectrum of Disease Steatosis Steatohepatitis (NASH) NASH with Fibrosis Cirrhosis NAFLD

6. NAFLD—Why Study it? • Prevalence of NAFLD 13-18% and that of NASH specifically 2-3% • NAFLD is a disease of all sexes, ethnicities, and age groups (peak 40-49) • NAFLD is the leading cause of cryptogenic cirrhosis

7. NAFLD—Risk Factors Obesity Diabetes Mellitus Hypertriglyceridemia

8. NAFLD—Demographics Yu et al.. Nonalcoholic Fatty Liver Disease. Reviews in Gastroenterological Disorders. 2002; 2 (1):11-19

9. NAFLD—Pathogenesis Second Hit First Hit Steatosis NASH Lipid peroxidation Insulin resistance  Fatty acids

10. NAFLD—Natural History • Steatosis generally follows a benign course • NASH with fibrosis has increased liver-related morbidity and mortality • Steatosis can progress to NASH ± fibrosis

11. NAFLD—Natural History • Steatosis generally follows a benign course • NASH with fibrosis has increased liver-related morbidity and mortality • Steatosis can progress to NASH ± fibrosis • Harrison et al. The Natural History of NAFLD: A Clinical Histopathological Study. Am J Gastro 2003; 98:9; 2042-7 • Matteoni et al. NAFLD: A Spectrum of Clinical and Pathological Severity. Gastroenterology 1999; 116; 1413-19

12. NAFLD—Symptoms Sanyal et al., 2003

13. NAFLD—Exam Findings Sanyal et al., 2003

14. NAFLD—Laboratory Findings • Mild elevation of ALT most common • Elevated fasting glucose, triglycerides and depressed HDL with insulin resistance • Elevated PT and low albumin with cirrhosis Normal labs do not rule out NAFLD

15. NAFLD—Imaging • Ultrasound • Computed Tomography • Magnetic Resonance Imaging Current non-invasive modalities are unable to detect NASH with or without fibrosis Saadeh et al. The Utility of Radiological Imaging in NAFLD. Gastroenterology 2002; 123: 745-750

16. NAFLD—Histological Spectrum Cirrhosis Time Progression Fibrosis Lobular Inflammation Macrovesicular Steatosis

17. NAFLD—Steatosis Source: Ibdah 2003

18. NAFLD—NASH (without fibrosis) Source: Ibdah 2003

19. NAFLD—NASH (with fibrosis) Source: Ibdah 2003

20. NAFLD—Clinical Predictors Non-invasive predictors of NASH: A. HAIR index (HTN; ALT > 40; Insulin Resistance) ≥ 2 are 80% Sensitive, 89% Specific of NASH B. BAAT index (BMI>28; Age >50; ALT>2x nl; incr. Triglycerides) ≤ 1 has 100% Negative Predictive Value for NASH • Dixon et al. NAFLD—Predictors of NASH and Fibrosis in the Severely Obese. Gastroenterology. 2001; 121: 91-100. • Ratziu et al. Liver Fibrosis in Overweight Patients. Gastroenterology. 2000; 118: 1117-1123.

21. NAFLD—Clinical Predictors Patients at risk to develop NASH with fibrosis: A. Age > 45 B. Obesity (BMI > 31-32) C. Diabetes • Angulo et al. Independent predictors of liver fibrosis in patients with NASH. Hepatology. 2000; 30: 1356-1362.

22. NAFLD—How to Treat? Antioxidants Insulin Sensitizers Cytoprotectants Antihyperlipidemics Second Hit First Hit Steatosis NASH Insulin resistance  Fatty acids Lipid peroxidation Weight Loss Diet/Exercise

23. NAFLD—Weight Loss/Exercise Palmer et al. Gastroenterology 1990 --39 obese patients, no primary liver disease --Retrospective analysis after weight loss --Lower ALT seen in patients with >10% weight loss Anderson et al. Journal Hepatology 1991 --41 obese patients with biopsy-proven NAFLD --Low calorie diet (~400 kcal/d) x 8 months then re-biopsied --Most improved, but 24% with worse fibrosis/inflammation --Histological worsening associated with rapid weight loss

24. NAFLD—Insulin Sensitizers Metformin Marchesini et al. Lancet 2001 --20 patients, biopsy-proven NASH --14 metformin (500 tid) x 4 months; 6 controls --ALT & OGTT improved in metformin Nair et al. Gastroenterology (in press) --22 patients, biopsy-proven NASH --Received metformin 20 mg/kg/d x 12 months --Improvement in ALT & insulin sensitivity --No improvement in liver histology

25. NAFLD—Insulin Sensitizers Thiazolidinediones Neuschwander et al. Journal of Hepatology 2003 --30 patients biopsy-proven NASH and elevated ALT --Received rosiglitazone 4 mg bid x 6 months --Significant improvement of ALT and insulin sensitivity Azuma et al. Hepatology (in press) --12 patients biopsy-proven NASH --Received 15 mg qd pioglitazone x 3 months --Significant improvement in ALT

26. NAFLD—Antihyperlipidemics Laurin et al. Hepatology 1996 --16 patients biopsy-proven NASH --Received clofibrate 2 g/d x 12 months --No significant improvement in ALT or histology Basaranoglu et al. Journal Hepatology 1999 --46 patients biopsy-proven NASH followed 4 months --23 received gemfibrozil, 23 no treatment --74% patients in gemfibrozil group had lower ALT --30% patients no treatment group had lower ALT

27. NAFLD—Cytoprotectants Ursodeoxycholic Acid Laurin et al. Hepatology 1996 --24 patients with biopsy-proven NASH --Treated with UDCA 13-15 mg/kg/d x 12 months --63% had improved ALT and steatosis --No significant improvement in inflammation/fibrosis Lindor et al. Gastroenterology (in press) --Randomized controlled double-blind study --168 patients with biopsy-proven NASH --82 received UDCA and 86 no treatment x 12 months --No significant improvement in ALT or histology

28. NAFLD—Antioxidants Vitamin E Hasegawa et al. Aliment Pharmacol Ther 2001 --22 patients, 10 steatosis and 12 biopsy-proven NASH --6 months standard diet followed by Vitamin E 100 IU tid x 12 mo --Steatosis group showed improvement in ALT after diet --NASH group showed improvement in ALT after Vitamin E --40% NASH patients had histological improvement after Vitamin E Kugelmas et al. Hepatology 2003 --16 patients with biopsy-proven NASH followed for 3 mo --9 received diet/exercise and Vitamin E 800 IU qd --7 diet/exercise only --Vitamin E conferred no significant improvement in ALT

29. NAFLD—Management Summary • Gradual, sustained weight loss hallmark therapy • Rapid weight loss potentially detrimental • Gemfibrozil, Vitamin E and insulin sensitizers require further study • Clofibrate and UDCA do not appear useful in NASH patients

30. NAFLD—Limitations of Studies Few randomized trials Small study populations Short follow-up periods Minimal biopsy data

31. NAFLD—Conclusions • NAFLD affects up to 15% of the US population • Steatosis is relatively benign, but NASH has significant morbidity/mortality risk • Insulin resistance and cellular damage are the key pathogenetic mechanisms • Sustained gradual weight loss and exercise are hallmark therapies • Insulin sensitizers, cytoprotectants, antioxidants may play role in future for those who fail conservative therapy

32. Acknowledgements Dr. Jamal Ibdah Bill and Nedra Outlaw Elizabeth Garwood Department of Internal Medicine Division of Gastroenterology