ALCOHOLIC FATTY LIVER DISEASEALCOHOLIC FATTY LIVER DISEASE

Diana Alcantara-Payawal, MDDiana Alcantara-Payawal, MD

Histologic SpectrumHistologic Spectrum

Fatty Fatty LiverLiver

FATFAT

Fat +Fat +InflamInflam+/-+/-FibrosisFibrosis

Scar +Scar +NodulesNodules+/- +/- FatFat

Alcoholic HepatitisAlcoholic Hepatitis

? 40%? 40%

CirrhosisCirrhosis

10- 35 %10- 35 % 8-20%8-20%

NORMALNORMAL

90-100 %90-100 %

Risk factors for alcoholic liver disease:Risk factors for alcoholic liver disease:

•QuantityQuantity•GenderGender•Hepatitis C: Accelerated disease Hepatitis C: Accelerated disease progression, more advanced progression, more advanced histology and decreased survival histology and decreased survival ratesrates•Genetics: alcohol dehydrogenase, Genetics: alcohol dehydrogenase, acetaldehyde dehydrogenaseacetaldehyde dehydrogenase•Malnutrition: Malnutrition:

Major forms of alcoholic liver disease:•Fatty liverFatty liver•Alcoholic hepatitisAlcoholic hepatitis•CirrhosisCirrhosis

Time to develop liver disease = to amount of Time to develop liver disease = to amount of alcohol alcohol consumedconsumed

One beer, 4 ounces of wine, one ounce of 80% One beer, 4 ounces of wine, one ounce of 80% spirits = 12 grams of alcoholspirits = 12 grams of alcohol

Men:60-80 gm/day for 10 yearsMen:60-80 gm/day for 10 yearsWomen 20-40 gm/day for 10 yearsWomen 20-40 gm/day for 10 years

Women’s Risk of ALDWomen’s Risk of ALD

Women alcoholics begin drinking Women alcoholics begin drinking later, and drink less alcohol per day later, and drink less alcohol per day than menthan men

Women drink for fewer years than Women drink for fewer years than men and have a lower cumulative men and have a lower cumulative alcohol exposure at the time of alcohol exposure at the time of diagnosis of cirrhosisdiagnosis of cirrhosis

Women die of ALD at a 10 year Women die of ALD at a 10 year earlier age than men.earlier age than men.

Susceptibility of females to Susceptibility of females to hepatotoxicity of ethanolhepatotoxicity of ethanol

More pronounced fatty liverMore pronounced fatty liverLess induction of fatty acid binding Less induction of fatty acid binding protein (higher FFA)protein (higher FFA)Increased plasma endotoxin levelsIncreased plasma endotoxin levelsIncreased CD 13 and LBPIncreased CD 13 and LBPMore severe pericentral hypoxiaMore severe pericentral hypoxiaMore marked activation of NfkBMore marked activation of NfkB

Enzymatic pathways of ethanol metabolismEnzymatic pathways of ethanol metabolism

EthanolEthanol AcetaldehydeAcetaldehyde AcetateAcetate

NAD+NAD+ NADHNADH NAD+NAD+ NADHNADH

AcetaminophenAcetaminophenCCl4CCl4

Toxic metabolites, Toxic metabolites, reactive oxygen reactive oxygen speciesspecies

CYP2E1

ADHADH ALDHALDH

New mechanism for control of lipid metabolismNew mechanism for control of lipid metabolism

FFAFFA Induction of FFA Induction of FFA oxidation, oxidation, transport and transport and export genesexport genesPPAR/RXRPPAR/RXR

SterolSterol SREBPSREBPInduction of Induction of sterol/fat sterol/fat synthesizing synthesizing genesgenes

++ ++

++--

EthanolEthanol--

++

FFAFFAHOOC(CHHOOC(CH22))NNCHCH33

L-FABPL-FABPFFAFFA

TriglyceridesTriglyceridesPL,CEPL,CE

Peroxismal B OxidationPeroxismal B OxidationAOXAOX

Microsomal B OxidationMicrosomal B OxidationCYP4A1CYP4A1

Mitochondrial B OxidationMitochondrial B OxidationCPT-1CPT-1

HOOC(CHHOOC(CH22))NNCHCH33

Hepatic Fatty Acid MetabolismHepatic Fatty Acid Metabolism

HCHC

ROSROSTNFaTNFaTGFbTGFbIL-6IL-6IL-1IL-1

TXA2TXA2

HSCHSC

Inflammation;Inflammation;HypoxiaHypoxia

KCKC

Ethanol and acetaldehydeEthanol and acetaldehyde

ECECInjuryInjuryDeathDeath(necrosis, (necrosis, apoptosis)apoptosis)

FibrogenesisFibrogenesis

AdhesioAdhesionnMoleculMoleculeecytokinecytokiness

ROSROSTNFaTNFa

Activating Activating factorsfactors

Activated HSCActivated HSC

Irreversible activation maybe mediated by HSC Irreversible activation maybe mediated by HSC products, retinoid depletion, and changes in the products, retinoid depletion, and changes in the matrixmatrix

ECM protein ECM protein collagen I, collagen I, fibronectinfibronectin

Activation of HSCActivation of HSC

TGFTGFBB

Interactions of ethanol and endotoxinInteractions of ethanol and endotoxin

EndotoxinEndotoxin

Scavenger receptorScavenger receptor

EthanolEthanolActivation ofActivation ofKupffer cellKupffer cell

LBPLBP

EndotoxinEndotoxinCD14CD14

Ethanol induces LBP and CD14Ethanol induces LBP and CD14

Kupffer cellKupffer cell

FIRST HITFIRST HIT

Second HitSecond Hit

Activation of Hepatic Stellate CellsActivation of Hepatic Stellate Cells

The very earliest event in HSC activation is unknownThe very earliest event in HSC activation is unknown

Receptors presentReceptors presentTNFa, IL-1TNFa, IL-1

Matrix changes ?Matrix changes ?Activation of NF kBActivation of NF kBVia degradation of IkBVia degradation of IkB

Induction of PDGF-Induction of PDGF-R, TGFB-Rs, ICAM-1R, TGFB-Rs, ICAM-1

Consequences of Kupffer cell activation by ethanolConsequences of Kupffer cell activation by ethanol

CytokinesCytokinesTNFaTNFaIL-1, IL-6IL-1, IL-6PDGFPDGFEicosanoidsEicosanoidsROSROSMIP2, IL-8MIP2, IL-8

Activated Kupffer CellActivated Kupffer Cell

CHRONIC ETHANOL INGESTIONCHRONIC ETHANOL INGESTION

AcetaldehydeAcetaldehyde

Lipid peroxidationLipid peroxidation

AldehydesAldehydes

Protein Protein adductsadducts

MAA adductsMAA adducts

AutoantibodiesAutoantibodies

AutoimmunAutoimmune responsee response

CollagenCollagen

Fibrotic Fibrotic responseresponse

IntestineIntestine++

EndotoxinEndotoxin

Kuppfer cellsKuppfer cells

HepatocyteHepatocytePPARg/RXRPPARg/RXR

Stellate cellStellate cell TNF-a TGF-BTNF-a TGF-BIL-1 IL-6IL-1 IL-6

InflammatoryInflammatoryResponseResponse

Laboratory findingsLaboratory findings

Increased GGT :Not specific to alcohol, easily Increased GGT :Not specific to alcohol, easily inducible, elevated in all forms of fatty liverinducible, elevated in all forms of fatty liverMacrocytosis (Increased PMN). If >5500/uL Macrocytosis (Increased PMN). If >5500/uL predictws asevere alcoholic hepatitis when predictws asevere alcoholic hepatitis when discriminatory index is >32discriminatory index is >32AST>ALT by 2 foldAST>ALT by 2 foldHigh CDTHigh CDTHigh gamma globulin (IgA)High gamma globulin (IgA)High uric acidHigh uric acidHigh serum lactateHigh serum lactateLow albuminLow albuminLow protimeLow protimeHigh triglyceridesHigh triglycerides

Maddrey’s discriminatory functionMaddrey’s discriminatory function4.6(protime- control in seconds) + bilirubin (umol/L)/174.6(protime- control in seconds) + bilirubin (umol/L)/17

>32 assess severity of AH>32 assess severity of AHAlcoholic hepatitis has poor prognosisAlcoholic hepatitis has poor prognosis

Presence of ascites, variceal Presence of ascites, variceal hemmorrhage, deep encephalopathy or hemmorrhage, deep encephalopathy or hepatorenal syndrome has dismal hepatorenal syndrome has dismal prognosisprognosis

Lifestyle modificationLifestyle modification

EtOH intakeEtOH intakeObesityObesitySmokingSmoking