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  • NonNon--Alcoholic Fatty Liver Alcoholic Fatty Liver DiseaseDisease

    -- NAFLD NAFLD --

    Joel S. Levine, M.D., FACPJoel S. Levine, M.D., FACPProfessor of MedicineProfessor of Medicine

    Division of Gastroenterology/HepatologyDivision of Gastroenterology/HepatologyUniversity of Colorado Health Science CenterUniversity of Colorado Health Science Center

  • Objectives Objectives To Understand:To Understand:

    NAFLD the epidemic and its cause NAFLD the clinical spectrum of

    disease NAFLD diagnostic and therapeutic

    decision making

  • NAFLD: Key points

    Most common liver disorder in U.S. The hepatic component of the metabolic syndrome Majority of patients are asymptomatic and do not

    get progressive liver disease (NAFL) At least 20% with associated steatohepatitis

    (NASH) develop cirrhosis The clinical utility of liver biopsy is debated Evidence-based therapies are lacking

  • Causes of fatty liver I will not discussMETABOLIC/

    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

    surgery Amiodarone MushroomsTamoxifen Organic solventsTetracyclineMethotrexateValproic acidCocaineAntivirals

  • Obesity Among U.S. Adults

    Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

  • Body mass indexClassification BMI

    Underweight 40 kg/m2

    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

  • Obesity is proposed to be an inflammatory state with theadipocyte now recognized as an endocrine organ that may be responsible for the production of

    -inflammation-insulin resistance-NAFLD McCullough, 2002, AASLD

  • INCREASED FAT MASS(Adipocyte) TNF

    ResistinLeptin

    Free fatty acidsAdiponectin

    Angiotensinogen

    released byadipocytes

    FAT MASS(Adipocyte)

    FFA

    Increased delivery ofFFA to liver

    insulin

    Peripheral resistanceto insulins normal

    suppression of lipolysis

    - suppression of lipolysis

    Adipocytes as endocrine cells

    insulin

    FIRST HIT:OBESITY

  • Why is fat harmful to the liver?

    Increased lipid peroxidation and production of large amounts of ROS (increased 10-fold in animal models)

    Increased synthesis of TNF Mitochondrial dysfunction

    50% reduction in cytochrome c contentrestricted electron flowultrastructural changes200% increase in endogenous H2O2

  • Normal

    Steatosis(fatty liver)

    Steatohepatitis

    Cirrhosis

    Critical transition (2nd hit)

    Clinical spectrum of fatty liver disease

    25% of adults affectedreversible, few clinical sequelae

    Chronic alcohol and obesity are additiveSeldom reverses to normal histologySusceptible to other forms or liver injuryPrecursor to cirrhosis & HCC

  • Microvesicular steatosis Macrovesicular steatosis

    FATTY LIVER steatosis without inflammation

    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)

    *NO FIBROSIS = GOOD PROGNOSIS*

  • NATURAL HISTORY Patients with simple fatty liver rarely progress, but At the time of presentation, 30-40% of patients with

    NAFLD have advanced fibrosis and 10-15% have established cirrhosis

    Risk of cirrhosis approaches 20% at 20 years of follow up.

    ?

  • 2020 gm

    Grade 3 (severe) Stage 2-3 fibrosis

    NASH

    First described in 1980 by Ludwig

    Associated with fibrosis (15-40%) and cirrhosis (~15%) at the time of diagnosis

    #1 cause of liver disease in US

    Increases the susceptibility to other forms of liver injury.

    Accounts for most cryptogenic cirrhosis.

    Increases the risk of HCC.

    HOW DO YOU IDENTIFY THOSE AT RISK OF FIBROSIS?

  • Natural history: Risk factors for fibrotic diseaseAdapted from Angulo et al. Hepatology 1999;30:1356

    DIABETES/OBESITYNo Yes

    45

    AST/ALT

    1

    1

    0

    0

    12

    13

    4

    50

    47

    66

    Number represents % of patients with NAFLD on imagingstudy who had significant fibrosis on biopsy

    AGE

  • DIAGNOSIS &TREATMENT

  • 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

    AST 49ALT 80Alkaline Phosphatase NormalTotal bilirubin Normal

  • CaseCase

    What are the appropriate

    diagnostic tests to perform?

  • What are the appropriate What are the appropriate diagnostic tests to perform?diagnostic tests to perform?

    * Tests for Metabolic Syndrome (BP, Glucose, Lipids) *

    Screening for common liver diseasesHCV antibodyHBV surface antigenANATSHFerritin, iron, transferrinHepatic ultrasound

  • What are the appropriate What are the appropriate diagnostic tests to perform?diagnostic tests to perform?

    Screening for uncommon liver diseases

    Alpha-1 antitrypsin (phenotype and level)

    Ceruloplasmin (Wilson disease) NO !!

    Anti-mitochondrial antibody (AMA) (primary biliary cirrhosis with normal alkaline phosphatase?)

  • The CaseThe Case

    All lab tests normal

    Abdominal ultrasound Fatty Liver

  • CLINICAL FEATURES

    SYMPTOMS - nonspecificasymptomaticfatigueintermittent RUQ fullness

    or discomfort

    PHYSICAL EXAMINATION - nonspecificobesity in 30-100%hepatomegaly in 50%typical features of cirrhosis

    in later stages

    LABORATORY ABNORMALITIES - nonspecificincreased aminotransferase activity in 50-90% (

  • CaseCase

    What now?

    Liver Biopsy?

    Treatment?

  • Pate de Fois Gras Battiste

    WHEN DO YOU BIOPSY?

  • Role of a liver biopsy?

    PRO: Only accurate method of staging and diagnosis, convince patient of need for life-style change

    CON: Generally good prognosis, key risk factors can be addressed without a biopsy, lack of effective therapy, cost, risk.

    JSL: Discuss above with patients. Almost none go on to biopsy

  • Rubens, 1638-1640

    Non-alcoholic fatty liver disease(NAFLD) with steatohepatitis

  • EVALUATION AND MANAGEMENT: THERAPY

    There is no established therapy. Steatosis and steatohepatitis may resolve with weight loss, but the

    benefits of a 10% decrease in BMI have been inconsistent Hepatic fat content decreases, with little effect on fibrosis and

    inflammation Diet and exercise improve insulin sensitivity, increase oxidative

    capacity and utilization of fatty acids

    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

    Angulo and Lindor, Sem Liver Disease 2001

  • DRUGS EVALUATED IN THE TREATMENT OF NAFLDAUTHOR DRUG PATIENTS ALT HISTOLOGYLaurin et al 1996 UDCA 24 improved improved

    Laurin et al 1996 Clofibrate 16 no no

    Guma et al 1997 UDCA 24 improved ND

    Ceriani et al 1998 UDCA 31 improved ND

    Gulbahar et al 2000 NAC 11 improved ND

    Lavine et al 2000 Vit E 11 improved ND

    Caldwell et al 2001 Troglitazone10 improved improved

    Hasewaga et al 2001 Vit E 22 improved improved

    Marchesini et al 2001 metformin 14 improved ND

    Neuschwander-Tetri 2002 rosiglitzone 30 improved ND

    Nair et aal 2002 metformin 25 improved ND

  • 1. Control risk factors- 10% decrease in BMI- Aerobic exercise 30 min 4x/week- statins where indicated- treatment of diabetes

    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

    Therapeutic Approach

  • Natural history: Risk factors for fibrotic diseaseAdapted from Angulo et al. Hepatology 1999;30:1356

    DIABETES/OBESITYNo Yes

    45

    AST/ALT

    1

    1

    0

    0

    12

    13

    4

    50

    47

    66

    Number represents % of patients with NAFLD on imagingstudy who had significant fibrosis on biopsy

    AGE

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