Fatty Liver Disease - Definition

1. Fatty Liver Disease - Definition A clinico-pathologic syndrome encompassing a wide range of fatty liver disease in the absence of significant alcohol intake and other common causes of Steatosis. The following are the stages. Non Alcoholic Fatty Liver Disease – NAFLD Non Alcoholic Steato Hepatitis – NASH Non Alcoholic Cirrhosis (> 60% of cryptogenic)

2. Adipocyte is an Endocrine Organ

3. The Two HIT Concept 1st HIT 2nd HIT

4. The Two Hit Concept Fatty Liver Fats Burnt VLDL-TG Diet FFA 1st Hit Susceptibility Saturated > Unsaturated Oxidative Stress 2nd Hit Toxins Inflammatory Molecules Damaged Liver Apoptosis Donnelly et al. J. Clin. Invest. 113: 1343, 2005; Day and James. Gastroenterol. 114: 842, 1998

5. These are a Continuum  CV Risk 2nd HIT 1st HIT FAT >5% DCLD Inflammation Scarring IR and MS IR and MS

6. Natural History of Fatty Liver

7. The New Definition of MS Waist Circum  90 (M), 80 (F) Triglycerides >150 mg HDL <40 (M) < 50 (F) Dysglycemia FPG >100 or DM 2 of 5 Hypertension >130 or 85 Rx. for any of the above conditions 7

8. Each Perpetuating the Other NAFLD is the Hepatic component of MS

9. What is the implication These are ONE If we find one – look for the other

10. IR Adiponectin  Obesity, PPAR-  Leptin,  IL-6  FFA, PC1  Rad, TNF-  NEFAs  NO  TNF- PC, KC, SC, LEC  ATP  in  oxidation  in DAG & TAG Kuffer Cells  Free radicals  Antioxidants  CC P450 A,E1  Glutathione  PPAR- ,   NF-B  in oxidative stress  SREBP1a,1c,2 NASH, CV Risk O2 stress, Inflmma.

11. The Risk Factors

12. What Causes Fatty Liver ? • Alcohol • Obesity,  WC • T2DM •  Triglycerides • Medicines*, TPN • Wilsons’s Disease • -1 Anti-trypsin  • AI Hepatitis • Hepatitis C • Inherited syndromes * MTX, VA, Acetaminophen, TC, Tamoxifen, Nefidepine, Amiodarone, CCl4

13. Clinical Presentation • Asymptomatic • Routine blood tests •  Liver enzymes • Enlarged Liver (1/3) • RUQ periumb. Pain • Fatigue. Malaise • Anorexia, Nausea • > 90% are obese • USG e/o fatty liver • Acanthosis Nigricans • DM, HTN, Lipid abn. • OSAS, Snoring

14. Laboratory Abnormalities • 2 - 4 fold  GPT & GOT • SGOT: SGPT Ratio < 1 • AKP slight  in 1/3 • Dyslipidemia -  TG • FBG and PPBG  • BUN & Creatinine - N • Normal Albumin. PT • Low ANA + < 1 in 320 •  Serum Ferritin •  Iron saturation • SGOT: SGPT Ratio > 1 if Cirrhosis sets in

15. Potential Drugs for NAFLD Insulin Sensitizing Agents • Glitazones; Metformin Lipid-Lowering Agents • Clofibrate; Gemfibrozil Future Potential Treatments • Anti-fibrotics; Probiotics • Silymarin; Selenium Membrane-Stabilizing • Urso deoxy cholic Acid • Betaine (SAM) Anti-Oxidants • Vitamin E; Vitamin C • Lecithin;  -Carotene • Vitamin B Complex

16. Urso deoxy cholic Acid - UDCA • Evidence of efficacy in NASH/NAFLD is equivocal • 300 mg bid or 10 mg/kg in two divided doses PO • Given up to 12 to 24 months - depends on response • Cholestasis, PBC, PSC, Acute viral hepatitis, HBV, HCV • Chronic hepatitis, Alcoholic liver disease • Dissolution of cholesterol microliths / gallstones • Class E drug in pregnancy (not to be used in COP)

17. There is No Effective Drug Rx. • NAFLD and NASH may resolve with weight loss • Liver fat content ; No effect on fibrosis & Inflam. • Diet and exercise improve insulin sensitivity, increase oxidative capacity and utilization of FFAs • Weight loss has clear benefits for CV risk & T2DM

18. Take Home Points • It is the main cause of  liver enzymes; Isn’t that benign • Spectrum of disease – NAFLD – NASH – Cirrhosis - HCC • Insulin resistance, MS are the key pathogenic features • DM, TG, Non fatty abdominal obesity, increasing age • Always look for DM, TG, CVD if you see fatty liver • Presently, the management is to improve IR, TG, DM • It is a marker of CV Risk. Rx. improve insulin sensitivity • Modify underlying metabolic risk factors – diet, exercise • Use Mayo scoring to predict NASH (fibrosis). No biopsy