NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)

1 NONALCOHOLIC NONALCOHOLIC FATTY LIVER FATTY LIVER DISEASE (NAFLD) DISEASE (NAFLD)Joel M. Andres, M. Andres, of FloridaUniversity of FloridaOBJECTIVESOBJECTIVES To understand the To understand the pathophysiologypathophysiologyof of NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)--The link between NAFLD and insulin RThe link between NAFLD and insulin R--The relationship of insulin R to The relationship of insulin R to steatosissteatosis--The The second hitsecond hit theory of theory of steatosissteatosisto NASHto NASH To learn about To learn about adipocytokinesadipocytokinesand and HSCsHSCs,,implicated in the devimplicated in the dev--mentmentof hepatic of hepatic inflaminflamand and fibrosis in patients with NAFLD fibrosis in patients with NAFLD To understand the key items for diagnosis andTo understand the key items for diagnosis andmanagement of NAFLD in childrenmanagement of NAFLD in childrenOBESITYOBESITYBASIC FACTSBASIC FACTSDEFINITIONDEFINITIONE pidemic of obesity, probably Epidemic of obesity.

2 Probably the most common health issue the most common health issue of childrenof childrenBecause BMI norms for children Because BMI norms for children vary with age and gender, BMI vary with age and gender, BMI %tiles rather than absolute %tiles rather than absolute BMIBMI s are determineds are determined% of children 6% of children 6--11 yrs of age 11 yrs of age with BMI >95with BMI >95ththmore than more than doubled from to % doubled from to % betwbetwlate 70late 70 s and 2000s and 2000 Cut off values to define the Cut off values to define the heaviest children are the 85heaviest children are the 85ththand and 9595thth%tiles (BMI%tiles (BMI s of 25 and 30, s of 25 and 30, respectively, as maturity is respectively, as maturity is approached in adolescence)approached in adolescence)Above #Above # s double if one includes s double if one includes children with BMI > 85children with BMI > 85thth%tile%tileNational Center for Health Stats, 2003 Strauss RS.

3 JAMA 2001;286:2845 Medical Conditions Medical Conditions AssocAssoc ededWithWithCHILDHOOD OBESITYCHILDHOOD OBESITY HypertensionHypertension HyperlipidemiaHyperlipidemia Impaired Glucose Tolerance/ DiabetesImpaired Glucose Tolerance/ Diabetes Gallbladder DISEASE / GallstonesGallbladder DISEASE / Gallstones NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)--Elevated LIVER Elevated LIVER TransaminasesTransaminasesCommonCommon-- Severe Fibrosis and Cirrhosis Also OccurSevere Fibrosis and Cirrhosis Also OccurRashid M, et al. JPGHAN2000;30:48 TomuinagaK, et DisSci1995;40: 02 ObesityObesityInsulin Resistance and NAFLDI nsulin Resistance and NAFLDCENTRAL OBESITYI ntra-abdominal fat isthe main adipose depot associated with insulinresistanceVisceral adipocytesare moremetabolically active than subcuadipocytesFFAsfrom visceral adipose sidrain directly to LIVER via theportal veinIoannouGN, et Hepatol2005.

4 3 , potentially exerting > influence on hepatic glucosemetabolism and FATTY acid oxidation, ultimately con-tributingto the development of hepatic steatosisand steatohepatitisin the setting of insulin FactsHistorical Facts KlatskinKlatskin: In 1979, he presented findings of a : In 1979, he presented findings of a landmark landmark histologichistologicstudy about NONALCOHOLIC study about NONALCOHOLIC LIVER DISEASE which mimicked alcohol induced LIVER DISEASE which mimicked alcohol induced hepatitis and cirrhosishepatitis and cirrhosis Ludwig: In 1980, he coined the term Ludwig: In 1980, he coined the term nonnon--alcoholic alcoholic steatohepatitissteatohepatitis in patients whose LIVER in patients whose LIVER histology mimicked alcoholic hepatitishistology mimicked alcoholic hepatitisLudwig J, et al. Mayo ClinProc 1980; 55: 434 Spectrum of NAFLDS pectrum of NAFLDBASIC FACTSBASIC FACTS NAFLD is a broad term NAFLD is a broad term ----Encompasses Encompasses steatosissteatosis, , steatosissteatosisw w inflammation, NASH, and cirrhosis.

5 NAFLD is now inflammation, NASH, and cirrhosis. NAFLD is now recognrecogn as as the most common cause of LIVER DISEASE in pediatricsthe most common cause of LIVER DISEASE in pediatrics The terms NAFLD and NASH are not interchangeableThe terms NAFLD and NASH are not interchangeable NASH may be the most common cause of cryptogenic cirrhosis; NASH may be the most common cause of cryptogenic cirrhosis; it may lead to end stage LIVER DISEASE and is a serious it may lead to end stage LIVER DISEASE and is a serious complication of childhood obesitycomplication of childhood obesity The link between NAFLD, insulin resistance and metabolic The link between NAFLD, insulin resistance and metabolic syndrome is not completely understoodsyndrome is not completely understoodPATHOPHYSIOLOGY of NAFLDPATHOPHYSIOLOGY of NAFLDINSULIN RESISTANCESTEATOSIS BENIGN STEATOSISNASHD iabetesDiabetesObesityObesityMcCullough AJ.

6 JourClinGastro 2002;34:255 INSULIN RESISTANCEINSULIN RESISTANCEE ffect on Fat MetabolismEffect on Fat Metabolism Insulin (I) resistance Insulin (I) resistance enhances TG enhances TG lipolysislipolysis& & inhibits inhibits esterificationesterificationof of FFA within adipose FFA within adipose tissuetissue LIVER TG LIVER TG synsynis driven is driven by by FFAsFFAsand by I and by I upregupreg PPAR gammaPPAR gamma& SREBP& SREBP TG export via VLDL TG export via VLDL may be inhibited by may be inhibited by decdecsynsynof of apolipoproteinapolipoproteinBBNAFLDNAFLD A dipocytokinesAdipocytokines/ Hepatic / Hepatic StellateStellateCellsCellsCytokines/Cyto kines/StellateStellateCCEffectsEffectsOu tcomeOutcomeOBESITY Inc LEPTIN OBESITY Inc LEPTIN 1) Inc Exp of 1) Inc Exp of TNFaTNFaand TGFand TGF--B1B12) Deposition of Type I Collagen2) Deposition of Type I CollagenInc LIVER FibrosisInc LIVER FibrosisOBESITY Dec ADIPONECTINOBESITY Dec ADIPONECTIN1) Dec Exp of 1) Dec Exp of TNFaTNFamRNAmRNA2) Down Regulation of TGF2) Down Regulation of TGF--B1B1 Dec LIVER FibrosisDec LIVER FibrosisTNFaTNFaDec ADIPONECTINDec ADIPONECTINInc INSULIN RESISTInc INSULIN RESISTDec Gene Expression and Dec Gene Expression and Secretion of Secretion of AdiponectinAdiponectinDec LIVER FibrosisDec LIVER FibrosisADIPONECTINADIPONECTINS uppresses HSC Proliferation and Suppresses HSC Proliferation and Migration Migration Dec LIVER FibrosisDec LIVER FibrosisHSC MYOFIBROBLASTHSC MYOFIBROBLASTP roduces TGFP roduces TGF--B1 and B1 and ExtracellularExtracellularMatrix ProteinMatrix ProteinInc LIVER FibrosisInc LIVER FibrosisKamadaY, et al.

7 Gastroent2003; 125: NAFLD INSULIN RESISTANCE+METABOLICSYNDROMEA ltered AdipocytokinesInc LeptinDec AdiponectinInc TNFaHepatic StellateCellsImpaired INSULINM ediated SuppressionOf LipolysisFAsSTEATOSISI ncrease in LiverTriglyceridesIncrease FA UptakeBy LIVER Inc sHepGlucose OutpIncreased INSULINO utputOBESITYSTEATOSIS to NASH: STEATOSIS to NASH: 22ndndHitHit Mitochondrial and Mitochondrial and peroxisomalperoxisomaloxidation of oxidation of FFAsFFAsin liverin LIVER Free radicals (Reactive O2 species) Free radicals (Reactive O2 species) Lipid Lipid peroxidationperoxidationof membranesof membranes HepatocyteHepatocytemembrane damagemembrane damage InflammationInflammation FibrosisFibrosisDay CP, et al. NASH. Gastroenterology 1998;114: of NAFLDP rogression of NAFLDSTEATOSISNASHFIBROSIS (35%)CIRRHOSIS (15%) LIVER FAILUREHEPATOCELLULCARCINOMA10%Caldwell SH. Hepatol2003;37: 1202 CHRONIC LIVER DISEASECHRONIC LIVER DISEASEP revalence in the in the NONALCOHOLIC FATTY LIVER DISEASE ~20% NONALCOHOLIC FATTY LIVER DISEASE ~20% NONALCOHOLIC NONALCOHOLIC SteatohepatitisSteatohepatitis~ 3%~ 3% Chronic Hepatitis C ~ 2%Chronic Hepatitis C ~ 2% Alcoholic LIVER DISEASE LIVER DISEASE Chronic Hepatitis B Hepatitis B : EpidemiologyNAFLD.

8 Epidemiology Overlooked or underestimated in the past, and not well Overlooked or underestimated in the past, and not well known at presentknown at present Highest prevalence is in adults aged 40 Highest prevalence is in adults aged 40--60 yrs, but 60 yrs, but NAFLD occurs in children & adolescentsNAFLD occurs in children & adolescents High prevalence in industrialized countriesHigh prevalence in industrialized countries Females > Males, but controversialFemales > Males, but controversial NASH appears to be overtaking chronic hepatitis C as NASH appears to be overtaking chronic hepatitis C as the next the next epidemicepidemic in LIVER diseasein LIVER diseaseNAFLD in CHILDRENNAFLD in CHILDRENT oronto StudyToronto Study 36 Children, Mean Age 12 yrs (436 Children, Mean Age 12 yrs (4--16 yrs)16 yrs)--30 Obese; 2 Diabetic; 18 30 Obese; 2 Diabetic; 18 AbnAbnLipid ProfilesLipid Profiles--24 LIVER 24 LIVER BiopsiedBiopsied: Fat/: Fat/InflamInflam, 88%, 88%Fibrosis, 75%Fibrosis, 75% Evaluated Because of Evaluated Because of TransaminemiaTransaminemia Tests for Other Diseases were NegativeTests for Other Diseases were Negative Conclusion: NAFLD Occurs in Children and Conclusion: NAFLD Occurs in Children and may not be Benignmay not be BenignRashid M, et al.

9 J PediatrGastro Nutr2000;30:48 NAFLD in CHILDRENNAFLD in CHILDRENSan Diego StudySan Diego Study 43 Children: Mean Age yrs ( )43 Children: Mean Age yrs ( )--38 Obese; 6 Diabetic38 Obese; 6 Diabetic--43 LIVER 43 LIVER BiopsiedBiopsied: : SteatosisSteatosis, 30%; Portal , 30%; Portal Inflammation, 58%; Fibrosis, 63%Inflammation, 58%; Fibrosis, 63% SteatosisSteatosis: Insulin : Insulin SensitivitySensitivity , Age, Ethnicity, Age, Ethnicity Portal Portal InflamInflam: ALT, Fasting Insulin: ALT, Fasting Insulin Portal Fibrosis: RUQ Pain, Insulin Resistance Portal Fibrosis: RUQ Pain, Insulin Resistance SchwimmerJB, et al. J Pediatr2003; 143:500 Clinical Features of NASHC linical Features of NASHSYMPTOMSSYMPTOMSA symtomaticAsymtomatic(majority)(majority )FatigueFatigueRUQ PainRUQ PainPHY EXAMPHY EXAMH epatomegalHepatomegal(common)(common)Spl enomegalSplenomegal(25%)(25%)LABSLABS___ ___ ALT, AST 2 ALT, AST 2--3X normal3X normalGGT (mild GGT (mild elevationelevationPT(INR) PT(INR) abnabnw cirrhosisw cirrhosisU/SOUNDU/SOUNDL arge LIVER w Large LIVER w increased increased echogenicityechogenicityNASH: Association with otherNASH.))

10 Association with otherMedical ProblemsMedical Problems NonNon--Obesity Nutritional AbnormalitiesObesity Nutritional Abnormalities--Central Central HyperalimentationHyperalimentation--Rapi d Weight LossRapid Weight Loss Metabolic Diseases (Other Than Obesity)Metabolic Diseases (Other Than Obesity)--HypertriglyceridemiaHypertrigl yceridemia--AbetalipoproteinemiaAbetalip oproteinemia DrugsDrugs--Steroids, Steroids, MethotrexateMethotrexate, Estrogens, Estrogens Toxins (Environmental and Occupational)Toxins (Environmental and Occupational)egeg., Hydrocarbons., Hydrocarbons GastropexyGastropexy(Much Less Common Than (Much Less Common Than JejunoilealJejunoilealBypassBypass) ) DIAGNOSIS of NASHDIAGNOSIS of NASH Incidental discovery of abnormal LIVER functionIncidental discovery of abnormal LIVER function No specific lab studies suggest the diagnosisNo specific lab studies suggest the diagnosis SteatosisSteatosisvsvsNASH cannot be made reliably on NASH cannot be made reliably on clinical grounds, or with imaging studiesclinical grounds, or with imaging studies HistologicHistologicinflammation does NOT always inflammation does NOT always correlate with elevated AST & ALT correlate with elevated AST & ALT ieie.