Fatty Liver Disease Definition A clinicopathologic syndrome encompassing

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) 1

Adipocyte is an Endocrine Organ Inflammation Insulin Resistance NAFLD 2

The Two HIT Concept Lipid Accumulation 1 st HIT Oxidative Stress 2 nd HIT Cytokine Activation 3

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

These are a Continuum Normal NASH 1 st HIT FAT >5% Inflammation NAFLD IR and MS 2 nd HIT Scarring IR and MS DCLD Cirrhosis CV Risk 5

Natural History of Fatty Liver Simple Steatosis or Fat Deposition of > 5% Benign course 3% develop cirrhosis NASH – Ballooning, Inflammation, Fibrosis Worse prognosis 30% develop cirrhosis Severe NASH with fibrosis – 75% go in for cirrhosis 5 yr survival 67% 10 yr survival 45% 6

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

Each Perpetuating the Other NAFLD is the Hepatic component of MS NAFLD IR DM MS 8

What is the implication These are ONE If we find one – look for the other IR 98% NAFLD NASH DM 70% DM, MS, CVD MS 85% 9

IR Obesity, PPAR- Adiponectin Leptin, IL-6 FFA, PC 1 Rad, TNF- Free radicals Antioxidants PC, KC, SC, LEC in oxidation in DAG & TAG CC P 450 A, E 1 NO TNF ATP Kuffer Cells Glutathione PPAR- , in oxidative stress NEFAs NF- B SREBP 1 a, 1 c, 2 NASH, CV Risk O 2 stress, Inflmma. 10

The Risk Factors 11

What Causes Fatty Liver ? • Alcohol • Wilsons’s Disease • Obesity, WC • -1 Anti-trypsin • T 2 DM • AI Hepatitis • Triglycerides • Hepatitis C • Medicines*, TPN • Inherited syndromes * MTX, VA, Acetaminophen, TC, Tamoxifen, Nefidepine, Amiodarone, CCl 4 12

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 13

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 14

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

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) 16

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 & T 2 DM 17

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 18