Cause of death 2548 2550 Cause Cerebrovascular disease

Cause of death 2548 - 2550 Cause % Cerebrovascular disease Ischemic heart disease HIV / AIDS Transport accident COPD Liver Cirrhosis 11. 6 8. 1 7. 7 6. 4 4. 8 4. 3

Normal liver Fatty liver Hepatitis or Steatohepatitis Genetic and metabolic Infection Autoimmune Chemical Fibrosis Liver Cirrhosis

Cause of Liver Cirrhosis • Viral hepatitis • Alcoholic • Metabolic • Cardiac cirrhosis • Cryptogenic • NAFLD

Non-alcoholic Fatty Liver Disease

Fatty liver disease (Steatosis) Fatty liver is excessive accumulation of fat insite the liver cell (Hepatocyte)

Fatty liver disease • Fatty liver is reversible if the patient stops drinking, other causes • Fatty liver can lead to steatohepatitis • Steatohepatitis is fatty liver accompanied by inflammation • Steatohepatitis can lead scarring of the liver and developed cirrhosis

Symptoms and Signs • • • Usually asymptomatic Right upper quadrant pain or discomfort Fatigue or maliase Symptoms of associated condition Hepatomegaly with or without tenderness • Signs of chronic liver disease

Diagnosis for NAFLD by noninvasive method 1. Ultrasonography 4 sonographic finding by diffuse fatty change in liver - Diffuse hyperechoice echotexture (Bright liver) - Increased liver echotexture compared with kidney - Vascular blurring - Deep attenuation 2. Computerized tomography 3. Magnetic resonance imaging

Diagnosis for NASH 1. Histologic picture of steatohepatitis 2. Convincing evidence of minimal or no alcohol consumption (< 40 gm/wk) 3. Absence of serologic evidence of viral hepatitis Powell et al. Hepatology 1990; 11: 74 -80.

Prevalence of NAFLD • The most common liver disease in developed countries • 20 – 40% in western industrial countries • 5 – 30% in Asia – Pacific region • Age 40 – 60 yrs, common in men • Alcohol consumption less than 20 gm/week

Prevalence of NASH

Natural History of NAFLD Normal Fatty liver Steatohepatitis with fibrosis ( Cirrhosis Fat , Fibrosis)

Natural history of NASH 30 - 40% 9 - 20% NASH Cirrhosis 2% Subacute failure 8% HCC Liver related death ? Post OLTx Recurrence

Clinical course and prognosis • Clinically stable disorder • Markedly better prognosis than alcoholic steatohepatitis • NAFLD had slightly lower overall survival than expected for general population • High mortality was associated with • advancing age • impaired fasting glucose • cirrhosis • Important cause of cryptogenic cirrhosis especially in • older • diabetic woman

Causes of fatty liver disease 1. Alcoholic fatty liver disease 2. Non-alcoholic fatty liver disease (NAFLD) • Characterized histologically by mainly macrovesicular hepatic steatosis • Do not consume alcohol more than 20 gm/week • NAFLD + Inflammation (NASH) • • • Macrovesicular steatosis Mallory bodies Ballooning degeneration Hepatocyte necrosis Fibrosis ~Alcoholic hepatitis

Conditions Associated With Fatty Liver Disease 1. Alcohol 2. Metabolic Syndrome 3. Disorder of lipid metabolism 4. Total parenteral nutrition 5. Severe weight loss 6. Refeeding syndrome 7. Toxic exposure 8. Iatrogenic • • • Amiodarone Diltiazem Tamoxifen Steroid Highly active antiretroviral therapy

Pathophysiology of NASH Insulin Resistance Obesity Diabetes First step Hepatic Steatosis (Oxidative Stress) Inflammatory cytokines Lipid Peroxidation NASH Second step

Major risk factors for NAFLD • • Central obesity Diabetes mellitus type 2 Dyslipidemia Metabolic syndrome

Who is metabolic syndrome? Three Make The Diagnosis • Abdominal obesity Men > 40” Women > 35” • Fasting glucose > 110 mg% • Triglyceride > 150 mg% • HDL Men < 40 mg% Women < 50 mg% • Blood pressure : > 130 / > 85 mm. Hg

Prevention and Treatment Normal liver Causes Prevention Risk factors Fatty liver Treatment Prevention Steatohepatitis Liver cirrhosis Treatment

Management of Fatty liver disease 1. Prevention • • • Health promotion Prevention of cause Controlled associated condition 2. Treatment • • No proven effective medical therapy for NAFLD Modify potential risk factors • • Obesity DM Hyperlipidemia Weight reduction • • Gradual weight reduction 1. 6 kg per week Total 10% Increase physical activity and diet controlled

Diet for NAFLD

None

Therapy for Co-morbidities Obesity • Diet with or without exercise • Bariatric surgery • Cannabinoid receptor antagonist Hypertriglyceridemia • Gemfibrozil • Clofibrate • Statin Hypertension • Angiotensin II receptor antagonist Diabetes • Rosiglitozone

Potential medical treatment for NASH • • Vitamin E and C Hypoglycemia agent • Metformin • Pioglitazone • Rosiglitazone Probucal Betaine Ursodeoxycholic acid Losartan Pentoxifylline Orlistat

Treatment trials for NASH Trial Treatment n Study type Duration Improved outcome (mos) Anti-oxidant Lavine Vitamin E 11 Open label Varied Hasegawa Vitamin E 10 Open label 6 ALT, AST, Markers of fibrosis Vitamin E & C 45 RCT 6 Fibrosis (? ) Vitamin E 16 Open label 3 Not different from diet & exercise Betaine 10 Open label 12 ALT, AST, Histology Pentoxifylline 18 Open label 6 ALT, AST, TNF, insulin resistance, Harrison Kugelmas ALT, AST, Alkphos Pro. Anti-oxidant Abdelmalek Anti-cytokine Satapathy steatosis Adams Pentoxifylline 20 Open label 12 ALT, AST Liver Disease : Postgraduate Course 2006.

Summary of studies using insulin sensitizers reporting effects upon hepatic steatosis Author, Year Study Subject Design Number Rosiglitazone Open-label 30 48 weeks Improved Promrat, 2004 Pioglitazone Open-lebel 18 48 weeks Improved Sanyal, 2004 Pioglitazone RCT 8 6 months Improved NCT 55 6 months Improved Neuschwander-Tetri, 2003 Drug Duration Hepatic Steatosis + Vitamin E Belfort, ’ 06 Diet +/Pioglitazone Bugianesi, 2005 Metformin RCT 55 6 months Improved Nair, 2004 Metformin Open-label 15 12 months Limited improvement RCT : Randomized Clinical Trial ; NCT : Non-Controlled Trial ; N/A : Not available; No sig difference : No significant difference

Summary • Fatty liver disease is the most common liver disease in developed countries • Fatty liver disease can be lead to liver cirrhosis • The major risk factors are obesity, DM type 2, dyslipidemia and metabolic syndrome • No proven effective therapy • Treatment are modify risk factors and weight reduction