Fatty Liver Disease - Definition Fatty Liver - NAFLD - NASH - CV Risk 21-Jun-09 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) Dr. R.V.S.N.Sarma., M.D., M.Sc., (Canada)

Adipocyte is an Endocrine Organ Inflammation Insulin Resistance NAFLD

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

The Two Hit Concept 1st Hit Saturated > Unsaturated 2nd Hit Fatty Liver Fats Burnt VLDL-TG Diet FFA Susceptibility 1st Hit 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

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

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%

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

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

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

IR Adiponectin  Obesity, PPAR- PC, KC, SC, LEC Kuffer Cells  Leptin,  IL-6  FFA, PC1  Rad, TNF-  NEFAs  NO PC, KC, SC, LEC  TNF-  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.

The Risk Factors

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

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

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

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

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)

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

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