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Faculty Disclosure

Faculty Disclosure. Fernando Zapata, MD Dr. Zapata has listed no financial interest/arrangement that would be considered a conflict of interest. NAFLD Epidemic. Fernando Zapata Assistant Professor Pediatric Gastroenterology Division Children’s Hospital and Medical Center- Omaha.

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Faculty Disclosure

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  1. Faculty Disclosure Fernando Zapata, MD Dr. Zapata has listed no financial interest/arrangement that would be considered a conflict of interest.

  2. NAFLD Epidemic Fernando Zapata Assistant Professor Pediatric Gastroenterology Division Children’s Hospital and Medical Center- Omaha

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

  4. 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

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

  6. 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

  7. 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

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

  9. HISTOPATHOLOGY

  10. Non-Alcoholic Fatty Liver Disease (NAFLD) A new consequence of the obesity epidemic.

  11. Non-Alcoholic Fatty Liver Disease (NAFLD) Fatty liver (Steatosis) Normal liver Steatohepatitis - inflammation - fibrosis Cirrhosis

  12. NAFLD 1.Most common of all liver disorders. 2. Most frequent cause of chronic liver disease. 3. Affects 3-20% of general population. 4. Present in up to 75% of individuals with obesity, type 2 diabetes. 5. Present in 3% of children and >50% of obese children. Fatty Liver Disease: NASH and Related Disorders Blackwell Publishing, 2005

  13. The Brief History of NAFLD • 1979~8 papers published • 1998First NIH conference • 1999 First Clinical Trials • 2002~60 papers published • Release of first book on NAFLD/NASH • 2005~354 papers published Fatty Liver Disease: NASH and Related Disorders Blackwell Publishing, 2005

  14. Non-Alcoholic Fatty Liver Disease (NAFLD) Fatty liver (Steatosis) ? ? Steatohepatitis - inflammation - fibrosis Cirrhosis

  15. Two-hit Hypothesis Fatty Liver Diet FFA Burned VLDL-TG 1st Hit Susceptibility Oxidative Stress Toxins 2nd Hit Inflammatory Molecules Damaged Liver Donnelly et al. J. Clin. Invest. 113: 1343, 2005 Day and James. Gastroenterol. 114: 842, 1998

  16. Addition to the Two-hit Hypothesis Type Saturated vs. Unsaturated Fatty Liver 1st Hit Susceptible Oxidative Stress Toxins 2nd Hit Inflammatory Molecules Damaged Liver

  17. Subject Characteristics Collaboration with UT Southwestern

  18. Hypothesis TypeSaturated vs. Unsaturated Fatty Liver 1st Hit Susceptible Oxidative Stress Toxins 2nd Hit Inflammatory Molecules Damaged Liver

  19. Relationship between saturated fatty acids and liver injury in morbidly obese subjects Liver Injury Normal Amount of saturated lipids in liver

  20. Dietary models of hepatic steatosis Endocrinology 147:943, 2006

  21. Increased susceptibility to lipopolysaccharide in steatosis characterized by increased saturated fatty acids Sat FA - + - + - + - + Steatosis - + + + - + + + Liver Injury Endocrinology 147: 943, 2006

  22. Two-hit Hypothesis + 1 Fatty Liver 1st Hit Susceptible Saturated Fats Oxidative Stress Toxins 2nd Hit Inflammatory Molecules Damaged Liver Damage

  23. Non-Alcoholic Fatty Liver Disease (NAFLD) Fatty Liver NASH Fibrosis Cirrhosis Hepatocyte apoptosis increased in patients with non-alcoholic steatohepatitis (NASH). Canbay et al. Hepatol. 39: 273, 2004

  24. Saturated fatty acids induce apoptosis in liver cells 6 Hours 16 Hours Am. J. Physiol. (In Press)

  25. Ratio of saturated to unsaturated fatty acids determines degree of apoptosis in liver cells 16 Hours Am. J. Physiol. (In Press)

  26. Two-hit Hypothesis + 1 Fatty Liver 1st Hit Susceptible Saturated Fats Unsaturated Fats Oxidative Stress Toxins 2nd Hit Inflammatory Molecules Damaged Liver Apoptosis

  27. Fatty Liver 2nd Hit 2nd Hit Sat FA Liver Damage Liver Damage Apoptosis Hepatocyte Mass

  28. Fatty Liver + Saturated Lipids ? Metabolism of and signals generated by saturated fatty acids Liver Damage ? ? Apoptosis Fibrosis ?

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

  30. 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

  31. 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

  32. 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

  33. 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)

  34. 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

  35. 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

  36. 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

  37. 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%

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

  39. 100% 60% 15% Post-OLT Steatosis Post-OLT Steatohepatitis NASH Cryptogenic NASH Cryptogenic Charlton et al. 2002 Ong et. al. 2001

  40. 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

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

  42. Post-transplant Allograft Fibrosis HistologyPrimary Liver Disease

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

  44. Post-transplant Recurrence of NASH

  45. 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

  46. Role of Familial Factors and Ethnicity (Cont’d) • 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. “ Ninety Patients with Nonalcoholic Steatohepatitis: Insulin Resistance, Familial Tendency, and Severity Willner et al, Am J Gastroenterol, 2001

  47. 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

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

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

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