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Published on August 13, 2007

Author: Malbern

Source: authorstream.com

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:  Prevalence Data USA Canada Japan France UK Italy Spain Portugal South America Israel Slide3:  Adults: Prevalence of Overweight: 54% (USA) Prevalence of Obesity: 22% population andgt; 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 Prevalence Data:  Prevalence Data Type II DM 28-55% Hyperlipidemia 20-92% Obesity 60-95% Slide5:  Who Gets This??? Obesity Type II Diabetes Dyslipidemia Classic TRIAD Class I Obesity BMI 30-34.9 g/m2 Class II Obesity BMI 35-39.9mg/m2 Class III Obesity BMI andgt; 40mg/m2 WHO Definitions: Slide6:  Metabolic Syndrome 'Syndrome of Insulin Resistance' Steatosis NASH HISTOPATHOLOGY:  HISTOPATHOLOGY Slide8:  Pathogenesis '2 Hit' Paradigm 'Second hit' – Intrahepatic oxidative stress Lipid peroxidation TNF-alpha, cytokine cascade 'First hit' – Excess fat accumulation Worldwide Demographic Data: Adults:  Worldwide Demographic Data: Adults 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 Author Country Year N Age Female NIDDM Obesity Lipids Expressed as percentages Worldwide Demographic Data : Children and Adolescent NAFLD:  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 Histologic Features in Childhood and Adolescent NAFLD:  Histologic Features in Childhood and Adolescent NAFLD 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 Author Country Yr n US NASH Fibrosis Cirrhosis Natural History Data for NAFLD:  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 Natural History Data for NASH:  Natural History Data for NASH 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) Author Study # Pt’s Follow-up N Improved No Change Fibrosis Cirrhosis (years) Proposed Histologic Spectrum NAFLD:  Proposed Histologic Spectrum NAFLD FAT Stage I Stage II Stage III Stage IV Matteoni et al, Gastroenterol 1999 Comparison of Outcomes for Individual Histological Types of NAFLD:  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 Clinical Outcomes Based on the Presence or Absence of Necroinflammation :  Clinical Outcomes Based on the Presence or Absence of Necroinflammation Type I + II Type III + IV p-value Cirrhosis 3.4% 24.7% (pandlt;0.0001) 5-yr Survival 75.6% 70.9% (p=0.12) Liver-Related 5.6% 30.8% (p=0.06) Deaths Matteoni et al. Gastroenterol 1999 11% liver – related mortality for those with hepatocellular necrosis (Type III+IV) Cryptogenic Cirrhosis:  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% Prevalence of Risk Factors for NAFLD among Patients with Cryptogenic Cirrhosis:  Prevalence of Risk Factors for NAFLD among Patients with Cryptogenic Cirrhosis Study Population Female Obesity NIDDM Lipids Ethnicity Author Female Obese DM Lipids Slide19:  NASH Cryptogenic 100% 60% 15% NASH Cryptogenic Post-OLT Steatosis Post-OLT Steatohepatitis Charlton et al. 2002 Ong et. al. 2001 NASH as a Cause of End-StageLiver Disease :  NASH as a Cause of End-Stage Liver 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 Post-transplant Allograft Steatosis :  Post-transplant Allograft Steatosis Histology Primary Liver Disease Charlton et al. Liver Transpl, 2001 Post-transplant Allograft Fibrosis:  Post-transplant Allograft Fibrosis Histology Primary Liver Disease Post-transplant NASH :  Post-transplant NASH Steatosis NASH Cirrhosis Re-transplantation 33% 12.5% 60% Post-transplant Recurrence of NASH:  Post-transplant Recurrence of NASH Steatosis Increases The Rate of Fibrosis in HCV:  Steatosis Increases The Rate of Fibrosis in HCV None 1-30% andgt;30% Hepatocytes with fat 8 yrs Per stage 7 yrs Per stage 4 yrs per stage Change in HAI Score/yrs of infection Pandlt;0.01 Pandlt;0.05 0.12 .3 .2 .1 0 0.14 .23 Genotype 1b, 10-14 yrs HCV infection Adinolfi et al, Hepatol 2001 Role of Familial Factors and Ethnicity (Cont’d):  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 Distribution of NAFLD by Racial/Ethnic Group:  Distribution of NAFLD by Racial/Ethnic Group NAFLD Study Population Estimated Alameda County Population (represented by KP Membership) Distribution of Serum Aminotransferase Levels in Persons With NAFLD:  Distribution of Serum Aminotransferase Levels in Persons With NAFLD Mean Value U/L Disease Associations in Different Racial /Ethnic Groups With NAFLD:  Disease Associations in Different Racial /Ethnic Groups With NAFLD * Asian versus other groups combined Distribution of Gender in Persons with NAFLD:  Distribution of Gender in Persons with NAFLD Number of Patients Steatosis or NASH?:  Steatosis or NASH? Liver Histopathology in Morbidly Obese Patients Undergoing Roux-en-Y Bypass:  Liver Histopathology in Morbidly Obese Patients Undergoing Roux-en-Y Bypass Normal Liver Histology 40% 40% 22% Steatosis 19% 19% 56% NASH 31% 28% 22% Bridging fibrosis/cirrhosis 2.9% 3.5% 0% Total Normal LFT’s Elevated LFT’s n=68 n-57 n=11 UCSF Bariatric Database NAFLD 36/68 (53%) Slide33:  Potential Pharmacologic Treatment Options for NALFD:  Potential Pharmacologic Treatment Options for NALFD 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 Anti-Oxidants Membrane-Stabilizing Ursodeoxycholic Acid Betaine ( SAMe) Drugs Evaluated for NAFLD:  Drugs Evaluated for NAFLD 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 Author Treatment # Pt’s Design Duration LFT’s Histology Slide36:  Patient Sources:  Patient Sources

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