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NAFLD: The Not So Silent Epidemic

NAFLD: The Not So Silent Epidemic. Shiobhan Weston MB.BCh., FRCPI Director, Center for Liver Disease Winthrop University Hospital. September 16, 2005. Prevalence Data. USA Canada Japan France UK Italy Spain Portugal South America Israel. Adults:

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NAFLD: The Not So Silent Epidemic

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  1. NAFLD: The Not So Silent Epidemic Shiobhan Weston MB.BCh., FRCPI Director, Center for Liver Disease Winthrop University Hospital September 16, 2005

  2. Prevalence Data USA Canada Japan France UK Italy Spain Portugal South America Israel

  3. Adults: Prevalence of Overweight: 54% (USA) Prevalence of Obesity: 22% population > age 20 Steatosis 30.1 million obese adults NASH 8.6 million Angulo, NEJM 2002 Children: Prevalence of Overweight: 22% Non-Hispanic Blacks (girls) Mexican-American (boys) Prevalence of Obesity: 11% NHANES III

  4. Prevalence Data Obesity 60-95% Type II DM 28-55% Hyperlipidemia 20-92%

  5. Who Gets This??? WHO Definitions: Class I Obesity BMI 30-34.9 g/m2 Class II Obesity BMI 35-39.9mg/m2 Class III Obesity BMI > 40mg/m2 Classic TRIAD • Obesity • Type II Diabetes • Dyslipidemia

  6. Metabolic Syndrome “Syndrome of Insulin Resistance” Visceral Obesity Steatosis NASH NIDDM TG HDL Hypertension

  7. HISTOPATHOLOGY

  8. Pathogenesis “2 Hit” Paradigm • “Second hit” – Intrahepatic oxidative stress • Lipid peroxidation • TNF-alpha, cytokine cascade “First hit” – Excess fat accumulation

  9. Worldwide Demographic Data: Adults Author Country Year N Age Female NIDDM Obesity Lipids Expressed as percentages Ludwig USA. 1980 20 54 65 50 90 67 Itoh Japan 1987 16 52 75 5 100 63 Diehl USA 1988 39 52 81 55 71 20 Lee USA 1989 49 53 78 51 69 --- Powell Australia 1990 42 49 83 36 95 81 Pinto Portugal 1996 32 49 75 34 47 28 Bacon USA 1999 132 53 53 33 70 72 Angulo USA 1999 144 51 67 28 60 27

  10. Worldwide Demographic Data : Children and Adolescent NAFLD Author Country year n age range M/F Obesity IDDM Lipids Moran USA 1983 3 13 (10-15) 2/1 3 1 2/3 Baldridge USA 1995 14 13 (10-18) 10/4 14 0 5/10 Rashid Canada 2000 36 12 (4-16) 21/15 30 4 18 Manton Australia 2000 17 11 (9-15) 11/6 16 3 5/2 Schwimmer USA 2003 43 30/14

  11. Histologic Features in Childhood and Adolescent NAFLD Author Country Yr n US NASH Fibrosis Cirrhosis Moran TN 1983 3 n/a 2/3 2 /3 0 Baldridge Boston 1995 14 24/31 14/14 14 /14 1 Rashid Canada 2000 36 24/31 21/24 17/24 1 Manton Australia 2000 17 10/11 8 9 Schwimmer USA 2003 27 27/43 1

  12. Natural History Data for NAFLD Author Study # Pt’s Follow-up % Improve No NASH Fibrosis Cirrhosis (years) Teli 1978-95 n=40 7-16 46% 7.5% 30% 3% 0% Teli et al. Hepatology 1995

  13. Natural History Data for NASH Author Study # Pt’s Follow-up N Improved No Change Fibrosis Cirrhosis (years) Lee 1968-82 n=49 1.2 - 6.9 12/39 0% 58% 25% 16.6% (1989) Powell 1960-89 n=42 1- 9 12/41 8.3% 41.6% 33% 16.6% (1990) Bacon 1990-93 n=33 4 -7 2/33 0% 50% 0% 39% (1994)

  14. Proposed Histologic Spectrum NAFLD Fat Ballooning Degeneration Fibrosis +/-Mallory Bodies Fat Inflammation Ballooning Degeneration Stage IV Fat + Inflammation Stage III Stage II FAT Stage I Matteoni et al, Gastroenterol 1999

  15. Comparison of Outcomes for Individual Histological Types of NAFLD Type I Type II Type III Type IV Outcome (n=49) (n=10) (n=19) (n=54) Cirrhosis 2 (4%) 0 (0%) 4 (21%) 14 (26%) Death 16 (33%) 3 (30%) 5 (26%) 24 (44%) Liver-related 1/49 (2%) 0 (0%) 1/19 (5%)* 7/54 (13%)* Matteoni et al. Gastroenterol 1999

  16. Clinical Outcomes Based on the Presence or Absence of Necroinflammation Type I + II Type III + IV p-value Cirrhosis 3.4% 24.7% (p<0.0001) 5-yr Survival 75.6% 70.9% (p=0.12) Liver-Related 5.6% 30.8% (p=0.06) Deaths 11% liver – related mortality for those with hepatocellular necrosis (Type III+IV) Matteoni et al. Gastroenterol 1999

  17. Cryptogenic Cirrhosis • Derived from Greek “kryptos” “genesis” • 3rd most common indication for transplant • 7-14% of transplant recipients - Actuarial 1 and 5 year survival: 72% and 58%

  18. Study Population Female Obesity NIDDM Lipids Ethnicity Prevalence of Risk Factors for NAFLD among Patients with Cryptogenic Cirrhosis Author Female Obese DM Lipids

  19. 100% 60% 15% Post-OLT Steatosis Post-OLT Steatohepatitis NASH Cryptogenic NASH Cryptogenic Charlton et al. 2002 Ong et. al. 2001

  20. NASH as a Cause of End-StageLiver Disease • Primary indication for OLT in 31/1,207 (2.6%) of patients evaluated at Mayo between 1993-98. • 16/546 (2.9%) underwent transplantation for end-stage NASH Charlton et al. Liver Transpl, 2001

  21. Post-transplant Allograft Steatosis HistologyPrimary Liver Disease Charlton et al. Liver Transpl, 2001

  22. Post-transplant Allograft Fibrosis HistologyPrimary Liver Disease

  23. Post-transplant NASH Re-transplantation Cirrhosis 12.5% NASH 33% Steatosis 60%

  24. Post-transplant Recurrence of NASH

  25. Steatosis Increases The Rate of Fibrosis in HCV Genotype 1b, 10-14 yrs HCV infection .3 .2 .1 0 P<0.01 P<0.05 .23 4 yrs per stage Change in HAI Score/yrs of infection 0.14 0.12 7 yrs Per stage 8 yrs Per stage None 1-30% >30% Hepatocytes with fat Adinolfi et al, Hepatol 2001

  26. Role of Familial Factors and Ethnicity (Cont’d) “ Ninety Patients with Nonalcoholic Steatohepatitis: Insulin Resistance, Familial Tendency, and Severity • Retrospective review of 90 patients age 14-70 with NASH seen at liver clinics at University of Tennessee or Medical University of South Carolina • NASH seen in 9 families, either in siblings or subsequent generations • 28% patients had cirrhosis, almost ½ with complications of portal hypertension • Familial clustering was common 18% • Insulin resistance found in 85% tested. Willner et al, Am J Gastroenterol, 2001

  27. Caucasian African-American Latino – Hispanic Asian Other Distribution of NAFLD by Racial/Ethnic Group Estimated Alameda County Population (represented by KP Membership) NAFLD Study Population

  28. Distribution of Serum Aminotransferase Levels in Persons With NAFLD Mean Value U/L

  29. Disease Associations in Different Racial /Ethnic Groups With NAFLD * Asian versus other groups combined

  30. Distribution of Gender in Persons with NAFLD Number of Patients

  31. Steatosis or NASH?

  32. Liver Histopathology in Morbidly Obese Patients Undergoing Roux-en-Y Bypass Total Normal LFT’s Elevated LFT’s n=68 n-57 n=11 Normal Liver Histology40% 40% 22% Steatosis19% 19% 56% NASH31% 28% 22% Bridging fibrosis/cirrhosis2.9% 3.5% 0% UCSF Bariatric Database NAFLD 36/68 (53%)

  33. Insulin Sensitizing Agents Troglitazone/Rosiglitazone Metformin Lipid-Lowering Agents Clofibrate Gemfibrizole Future Potential Treatments Antifibrotics Probiotics Silymarin, SAMe Vitamin E Lecithin Vitamin C B-Carotene Selenium Vitamin B Complex Potential Pharmacologic Treatment Options for NALFD Membrane-Stabilizing • Ursodeoxycholic Acid • Betaine ( SAMe) Anti-Oxidants

  34. Drugs Evaluated for NAFLD Author Treatment # Pt’s Design Duration LFT’s Histology Laurin,1999 URSO 24 0pen Label 12 mos Yes Yes Guma,1997 URSO 24 RCT 6 mos Yes none Ceriani,1998 URSO+diet 31 Open Label 6 mos Yes none Lauren, 1996 Clofibrate 16 Open Label 12 mos No none Basaranoglu,1999 Gemfibrozil 46 RCT 1 mo Yes none Levine, 2000 Vitamin E 11 Open Label 12 mos Yes none Abdelmalek, 2000 Betaine 24 Open Label 12 mos Yes Yes Gulbahar, 2000 NAC 11 Open Label 12 mos Yes none Marchesini, 2001 Metformin 20 Open Label 4mos Yes none Neuschwander- Tetri, 2001 Rosiglitazone 12 mos Yes Yes Promrat, 2004 Pioglitazone 18 Open Label 12 mos Yes Yes Lindor, 2004 Urso 166 RCT 24mos Yes Yes

  35. Patient Sources

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