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<ul><li><p>NonNon--Alcoholic Fatty Liver Alcoholic Fatty Liver DiseaseDisease</p><p>-- NAFLD NAFLD --</p><p>Joel S. Levine, M.D., FACPJoel S. Levine, M.D., FACPProfessor of MedicineProfessor of Medicine</p><p>Division of Gastroenterology/HepatologyDivision of Gastroenterology/HepatologyUniversity of Colorado Health Science CenterUniversity of Colorado Health Science Center</p></li><li><p>Objectives Objectives To Understand:To Understand:</p><p> NAFLD the epidemic and its cause NAFLD the clinical spectrum of </p><p>disease NAFLD diagnostic and therapeutic </p><p>decision making </p></li><li><p>NAFLD: Key points</p><p> Most common liver disorder in U.S. The hepatic component of the metabolic syndrome Majority of patients are asymptomatic and do not </p><p>get progressive liver disease (NAFL) At least 20% with associated steatohepatitis</p><p>(NASH) develop cirrhosis The clinical utility of liver biopsy is debated Evidence-based therapies are lacking</p></li><li><p>Causes of fatty liver I will not discussMETABOLIC/</p><p>NUTRITIONAL DRUGS GENETIC OTHERProtein-calorie malnut. Glucocorticoids Lipodystrophy IBDStarvation Estrogens Weber-Christian Bacterial overgrowthTPN Aspirin Wolmans disease HIV infectionRapid weight loss Calcium channel Fatty liver of PhosphorusWeight reduction blockers pregnancy Petrochemicals</p><p>surgery Amiodarone MushroomsTamoxifen Organic solventsTetracyclineMethotrexateValproic acidCocaineAntivirals</p></li><li><p>Obesity Among U.S. Adults</p><p>Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.</p></li><li><p>Body mass indexClassification BMI</p><p>Underweight 40 kg/m2</p><p>Sylvester Stallone 59 228 lbs ObeseHarrison Ford 61 218 lbs OverweightGov. Arnold 62 257 lbs ObeseJoel Levine 62 192 lbs Normal (just)Bruce Willis 60 211 lbs OverweightBrad Pitt 60 203 lbs Overweight</p></li><li><p>Obesity is proposed to be an inflammatory state with theadipocyte now recognized as an endocrine organ that may be responsible for the production of </p><p>-inflammation-insulin resistance-NAFLD McCullough, 2002, AASLD</p></li><li><p>INCREASED FAT MASS(Adipocyte) TNF</p><p>ResistinLeptin </p><p>Free fatty acidsAdiponectin</p><p>Angiotensinogen</p><p>released byadipocytes</p><p>FAT MASS(Adipocyte)</p><p>FFA</p><p>Increased delivery ofFFA to liver</p><p>insulin</p><p>Peripheral resistanceto insulins normal </p><p>suppression of lipolysis</p><p>- suppression of lipolysis</p><p>Adipocytes as endocrine cells</p><p>insulin</p><p>FIRST HIT:OBESITY</p></li><li><p>Why is fat harmful to the liver?</p><p> Increased lipid peroxidation and production of large amounts of ROS (increased 10-fold in animal models)</p><p> Increased synthesis of TNF Mitochondrial dysfunction</p><p>50% reduction in cytochrome c contentrestricted electron flowultrastructural changes200% increase in endogenous H2O2</p></li><li><p>Normal</p><p>Steatosis(fatty liver)</p><p>Steatohepatitis</p><p>Cirrhosis</p><p>Critical transition (2nd hit)</p><p>Clinical spectrum of fatty liver disease</p><p>25% of adults affectedreversible, few clinical sequelae</p><p>Chronic alcohol and obesity are additiveSeldom reverses to normal histologySusceptible to other forms or liver injuryPrecursor to cirrhosis &amp; HCC</p></li><li><p>Microvesicular steatosis Macrovesicular steatosis</p><p>FATTY LIVER steatosis without inflammation</p><p>Dam-Larsen et al GUT 2004;53:750. Danish patients with steatosis but noinflammation. After average follow up of 20 years, only 3% developed significant fibrosis or cirrhosis (as compared to 23% with steatosis related to alcohol) </p><p>*NO FIBROSIS = GOOD PROGNOSIS*</p></li><li><p>NATURAL HISTORY Patients with simple fatty liver rarely progress, but At the time of presentation, 30-40% of patients with </p><p>NAFLD have advanced fibrosis and 10-15% have established cirrhosis</p><p> Risk of cirrhosis approaches 20% at 20 years of follow up.</p><p>?</p></li><li><p>2020 gm</p><p>Grade 3 (severe) Stage 2-3 fibrosis</p><p>NASH</p><p> First described in 1980 by Ludwig</p><p>Associated with fibrosis (15-40%) and cirrhosis (~15%) at the time of diagnosis</p><p> #1 cause of liver disease in US</p><p> Increases the susceptibility to other forms of liver injury.</p><p> Accounts for most cryptogenic cirrhosis.</p><p> Increases the risk of HCC.</p><p>HOW DO YOU IDENTIFY THOSE AT RISK OF FIBROSIS?</p></li><li><p>Natural history: Risk factors for fibrotic diseaseAdapted from Angulo et al. Hepatology 1999;30:1356</p><p>DIABETES/OBESITYNo Yes</p><p>45</p><p>AST/ALT</p><p>1</p><p>1</p><p>0</p><p>0</p><p>12</p><p>13</p><p>4</p><p>50</p><p>47</p><p>66</p><p>Number represents % of patients with NAFLD on imagingstudy who had significant fibrosis on biopsy</p><p>AGE</p></li><li><p>DIAGNOSIS &amp;TREATMENT</p></li><li><p>A CaseA Case54 yo healthy WF whose weight increased from 115 to 185 lbs, BMI = 35. Has 2 drinks/week.At local health fair gets biochemical profile</p><p>AST 49ALT 80Alkaline Phosphatase NormalTotal bilirubin Normal</p></li><li><p>CaseCase</p><p>What are the appropriate </p><p>diagnostic tests to perform?</p></li><li><p>What are the appropriate What are the appropriate diagnostic tests to perform?diagnostic tests to perform?</p><p>* Tests for Metabolic Syndrome (BP, Glucose, Lipids) *</p><p>Screening for common liver diseasesHCV antibodyHBV surface antigenANATSHFerritin, iron, transferrinHepatic ultrasound</p></li><li><p>What are the appropriate What are the appropriate diagnostic tests to perform?diagnostic tests to perform?</p><p>Screening for uncommon liver diseases</p><p>Alpha-1 antitrypsin (phenotype and level)</p><p>Ceruloplasmin (Wilson disease) NO !!</p><p>Anti-mitochondrial antibody (AMA) (primary biliary cirrhosis with normal alkaline phosphatase?)</p></li><li><p>The CaseThe Case</p><p>All lab tests normal</p><p>Abdominal ultrasound Fatty Liver</p></li><li><p>CLINICAL FEATURES</p><p>SYMPTOMS - nonspecificasymptomaticfatigueintermittent RUQ fullness </p><p>or discomfort</p><p>PHYSICAL EXAMINATION - nonspecificobesity in 30-100%hepatomegaly in 50%typical features of cirrhosis</p><p>in later stages</p><p>LABORATORY ABNORMALITIES - nonspecificincreased aminotransferase activity in 50-90% (</p></li><li><p>CaseCase</p><p>What now?</p><p>Liver Biopsy?</p><p>Treatment?</p></li><li><p>Pate de Fois Gras Battiste</p><p>WHEN DO YOU BIOPSY?</p></li><li><p>Role of a liver biopsy?</p><p> PRO: Only accurate method of staging and diagnosis, convince patient of need for life-style change</p><p> CON: Generally good prognosis, key risk factors can be addressed without a biopsy, lack of effective therapy, cost, risk.</p><p> JSL: Discuss above with patients. Almost none go on to biopsy</p></li><li><p>Rubens, 1638-1640</p><p>Non-alcoholic fatty liver disease(NAFLD) with steatohepatitis</p></li><li><p>EVALUATION AND MANAGEMENT: THERAPY</p><p>There is no established therapy. Steatosis and steatohepatitis may resolve with weight loss, but the </p><p>benefits of a 10% decrease in BMI have been inconsistent Hepatic fat content decreases, with little effect on fibrosis and </p><p>inflammation Diet and exercise improve insulin sensitivity, increase oxidative </p><p>capacity and utilization of fatty acids</p><p> No guidelines have been established, but weight loss has clear benefits for cardiovascular risk factors and prevention of Type 2 diabetes and overall health and longevity</p><p>Angulo and Lindor, Sem Liver Disease 2001</p></li><li><p>DRUGS EVALUATED IN THE TREATMENT OF NAFLDAUTHOR DRUG PATIENTS ALT HISTOLOGYLaurin et al 1996 UDCA 24 improved improved</p><p>Laurin et al 1996 Clofibrate 16 no no</p><p>Guma et al 1997 UDCA 24 improved ND</p><p>Ceriani et al 1998 UDCA 31 improved ND</p><p>Gulbahar et al 2000 NAC 11 improved ND</p><p>Lavine et al 2000 Vit E 11 improved ND</p><p>Caldwell et al 2001 Troglitazone10 improved improved</p><p>Hasewaga et al 2001 Vit E 22 improved improved</p><p>Marchesini et al 2001 metformin 14 improved ND</p><p>Neuschwander-Tetri 2002 rosiglitzone 30 improved ND</p><p>Nair et aal 2002 metformin 25 improved ND </p></li><li><p>1. Control risk factors- 10% decrease in BMI- Aerobic exercise 30 min 4x/week- statins where indicated- treatment of diabetes</p><p>2. If no response after six months and at higher risk of fibrosis- liver biopsy to distinguish steatosisversus steatohepatitis (prognosis)- add non-evidence based therapy</p><p>Therapeutic Approach</p></li><li><p>Natural history: Risk factors for fibrotic diseaseAdapted from Angulo et al. Hepatology 1999;30:1356</p><p>DIABETES/OBESITYNo Yes</p><p>45</p><p>AST/ALT</p><p>1</p><p>1</p><p>0</p><p>0</p><p>12</p><p>13</p><p>4</p><p>50</p><p>47</p><p>66</p><p>Number represents % of patients with NAFLD on imagingstudy who had significant fibrosis on biopsy</p><p>AGE</p></li></ul>