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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