Alcoholic liver 2005 UST

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

Update of the VA Twin Panel StudyUpdate of the VA Twin Panel Study

15,924 twins followed until 199415,924 twins followed until 1994

Concordance (%)Concordance (%)

MZMZ DZDZ

AlcoholismAlcoholismPsychosisPsychosisCirrhosisCirrhosis

28.728.717.317.316.916.9

12.212.24.84.85.35.3

However, most of the genetic liability However, most of the genetic liability to develop cirrhosis was the result of to develop cirrhosis was the result of shared genetic liability for alcoholism.shared genetic liability for alcoholism.

Traditional model of pathogenesis of fatty liverTraditional model of pathogenesis of fatty liver

Ethanol increases NADH level inhibiting Ethanol increases NADH level inhibiting enzymes of fatty acid oxidation.enzymes of fatty acid oxidation.

Ethanol increases synthesis of fatty Ethanol increases synthesis of fatty acids associated with induction of acids associated with induction of lipogenic enzymes.lipogenic enzymes.

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

Peroxisome proliferator activated receptorPeroxisome proliferator activated receptor

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

Sterol response element binding proteinSterol response element binding protein

++ ++

++--

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

FFAFFAHOOC(CHHOOC(CH22))NNCHCH33

L-FABPL-FABPFFAFFA






LIPID PEROXIDATIONLIPID PEROXIDATION

CYTOTOXICITYCYTOTOXICITY

Hepatic Fatty Acid MetabolismHepatic Fatty Acid Metabolism

Hepatic Fatty Acid MetabolismHepatic Fatty Acid MetabolismFFAFFA


L-FABPL-FABPFFAFFA






PPAR aPPAR a

TRANSACTIVATIONTRANSACTIVATION

Effects of ethanol on protein metabolismEffects of ethanol on protein metabolism

ETHANOLETHANOL Acetaldehyde, HER +Acetaldehyde, HER + Protein adductsProtein adducts

Enzyme, cytoskeleton, Enzyme, cytoskeleton, membrane protean membrane protean malfunction, neoantigen malfunction, neoantigen formationformation

Inhibition of proteoasomal proteases, Inhibition of proteoasomal proteases, protein accumulation, cell swelling protein accumulation, cell swelling abnormal signalingabnormal signaling

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

Sources of reactive oxygen species Sources of reactive oxygen species in ethanol treated liver cellsin ethanol treated liver cells

Endoplasmic reticulumEndoplasmic reticulum

CYP2E1CYP2E1

ROSROS

NADPH + O2NADPH + O2EthanolEthanol

AcetaldehydeAcetaldehyde NADHNADH

O2O2

ROSROSE TCE TC

H2OH2O

ADHADH

MitochondriaMitochondria

Reductive stressReductive stress

Consequence of oxidant stressConsequence of oxidant stress

SuperoxideSuperoxide Hydrogen peroxideHydrogen peroxide Hydroxyl radicalHydroxyl radical

Attack of polyunsaturated fatty acidsAttack of polyunsaturated fatty acids

Lipid hydroperoxideLipid hydroperoxide

Lipid radicalsLipid radicals

Lipid decompositionLipid decomposition

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

MAA adductsMAA adducts

AutoantibodiesAutoantibodies

AutoimmunAutoimmune responsee response

CollagenCollagen

Fibrotic Fibrotic responseresponse

Stellate cellStellate cell

CHRONIC ETHANOL INGESTIONCHRONIC ETHANOL INGESTION



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

0

20

40

60

80

100

120

ABSTINENCE IMPROVES SURVIVAL ABSTINENCE IMPROVES SURVIVAL OF ALCOHOLIC CIRRHOSISOF ALCOHOLIC CIRRHOSIS

ABSTINENCEABSTINENCE

SURVIVALSURVIVAL

TIME OF OBSERVATIONTIME OF OBSERVATION

Management of ALDManagement of ALD

Abstinence and aggressive nutritional supportAbstinence and aggressive nutritional support

Traditional nutritional supplement Traditional nutritional supplement clearly improves nutritional status, clearly improves nutritional status, hepatic function, and outcome in hepatic function, and outcome in AH/ cirrhosisAH/ cirrhosis

Hepatology, 2000Hepatology, 2000

Cigarette smoking is an Cigarette smoking is an independent risk factor for cirrhosis independent risk factor for cirrhosis in ALDin ALD

Am J Epidemiology, 1994Am J Epidemiology, 1994Eur J of EWpidemiology, 1994Eur J of EWpidemiology, 1994


PropylthiouracilPropylthiouracil

No significant effects of PTU vs No significant effects of PTU vs placebo on mortality, complications placebo on mortality, complications of liver disease or liver histologyof liver disease or liver histology

Cochrane review of 6RCTCochrane review of 6RCT

Attenuates the hypermetabolic state to Attenuates the hypermetabolic state to have antioxidant properties and have antioxidant properties and improve portal blood flow.improve portal blood flow.


ColchicineColchicine

No beneficial effect on with overall No beneficial effect on with overall mortality or liver related mortality.mortality or liver related mortality.

Morgan, Gastroenterology, 2002Morgan, Gastroenterology, 2002

Anti-fibrotic effects, inhibition of Anti-fibrotic effects, inhibition of collagenase activity and anti-collagenase activity and anti-inflammatory functions.inflammatory functions.


CorticosteroidCorticosteroid

They should be reserved for those They should be reserved for those with severe liver disease (DF >31), with severe liver disease (DF >31), and hepatic encephalopathy.and hepatic encephalopathy.

Carithers, Ann Int Med, 1989Carithers, Ann Int Med, 1989Mendenhall, NEJM, 1984Mendenhall, NEJM, 1984

Decrease the immune response and Decrease the immune response and proinflammatory cytokine responseproinflammatory cytokine response


Pentoxifylline (TRENTAL)Pentoxifylline (TRENTAL)

•Nonselective phosphodiesterase which Nonselective phosphodiesterase which increases intracellular concentration of cAMP and increases intracellular concentration of cAMP and cGMP cGMP •Decreases pro-inflammatory cytokines including Decreases pro-inflammatory cytokines including TNFaTNFa•Improved vascular microcirculationImproved vascular microcirculation•Decreased leucocyte adhesion factorDecreased leucocyte adhesion factor•Antifibrotic Antifibrotic

PTX-TxPTX-TxPTX-txPTX-tx

PlaceboPlacebo

PTX 400 mg TID vs PTX 400 mg TID vs vitamin B 12 for 4 vitamin B 12 for 4 weeks –improved weeks –improved short term survivalshort term survival

Akriviadis, Gastroenterology, 2000Akriviadis, Gastroenterology, 2000

Pentoxyfylline Pentoxyfylline vs placebo in vs placebo in AHAH


Vitamin EVitamin E

No benefit and likely due No benefit and likely due to inadequate doseto inadequate dose

J AM Nutrition, 1995 J AM Nutrition, 1995

Membrane stabilization, reduced NFkB activation Membrane stabilization, reduced NFkB activation and TNF production, inhibition of stellate cell and TNF production, inhibition of stellate cell activation and collagen production.activation and collagen production.

JCI, 1995JCI, 1995


SAMeSAMe

1200 mg daily for 2 years- showed 1200 mg daily for 2 years- showed potential benefitpotential benefit

J Hepatology, 1999J Hepatology, 1999

Precursor for the synthesis of polyamines, choline Precursor for the synthesis of polyamines, choline and GSHand GSHObligatory intermediate in conversion of Obligatory intermediate in conversion of methionine and cysteine in the hepatic methionine and cysteine in the hepatic transulfuration pathway.transulfuration pathway.

JCI, 1995JCI, 1995


GSHGSH

Modulate proinflammatory Modulate proinflammatory cytokine production with inhibition cytokine production with inhibition of cytokines TNFa and IL-8. of cytokines TNFa and IL-8.

Clin Biochem 1999Clin Biochem 1999

ALOCHOLIC HEPATITISALOCHOLIC HEPATITIS

Alcoholic abstinenceAlcoholic abstinenceNutritional supportNutritional support

Discriminatory function >32Discriminatory function >32(with absence of comorbidity)(with absence of comorbidity)

TREATMENT OPTIONSTREATMENT OPTIONS

Preferred Preferred

Prednisilone 32 mg Prednisilone 32 mg POPODaily for 4 weeks Daily for 4 weeks then taper for 4 then taper for 4 weeksweeks

AlternativeAlternative

Pentoxifylline 400 mg Pentoxifylline 400 mg PO TID for 4 weeksPO TID for 4 weeks

Proposed PathophysiologyProposed Pathophysiology

Insulin ResistanceInsulin Resistance

HyperinsulinemiaHyperinsulinemia

LiverLiver

ResistantResistant SensitiveSensitive

PeripheryPeriphery

ResistantResistant

Hepatic SteatosisHepatic Steatosis

Glucose Glucose productioproductionn

Lipid exportLipid exportLipid Lipid peroxidationperoxidationB oxidationB oxidation

FFAFFA

LEAF PATHWAYSLEAF PATHWAYS

Carnitine Carnitine Carnitine Carnitine

CarnitineCarnitine

CPT1CPT1

CarnitineCarnitine

Fatty AcidFatty Acid CarnitineCarnitine

FA+CoAFA+CoA

B oxidationB oxidation

Energy ProductionEnergy ProductionATPATP

Protection of the Cell MembraneProtection of the Cell Membrane

Fatty acidFatty acid

Acyl groupAcyl group

TRANSPORT AND TRANSPORT AND OXIDATION OF FATTY OXIDATION OF FATTY ACID IN THE ACID IN THE MITOCHONDRIAMITOCHONDRIA

ALCOHOLIC FATTY ALCOHOLIC FATTY LIVER DISEASELIVER DISEASE

Diana Alcantara-Payawal, MDDiana Alcantara-Payawal, MD

Lipid peroxidation

Ethanol

Microsomes(CYP2E)

Acetaldehyde

GSH

A-amino-N-Butyrate

A ketobutyrate

cysteine

cystathionine

serinehomocysteine

S-adenosylmethionine

phosphatidylcholine

Phosphatidylethanolamine

METABOLITESMETABOLITES

ADH

Free radicals

methionineMAT


Ethanol Ethanol

MicrosomesMicrosomes(CYP2E)(CYP2E)


GSHGSH

A-amino-N-ButyrateA-amino-N-Butyrate

alpha ketobutyratealpha ketobutyrate

cysteinecysteine

cystathioninecystathionine

serineserinehomocysteinehomocysteine

S-adenosylmethionineS-adenosylmethionine

phosphatidylcholinephosphatidylcholine

PhosphatidylethanolaminePhosphatidylethanolamine


ADHADH

Free radicalsFree radicals

methionine

cypcyp MITOMITO

ROSROS Lipid peroxidationLipid peroxidation

FAT DEPOSITSFAT DEPOSITS

Increased Increased FFA FFA synthesissynthesis

Increased Increased hepatic FFA hepatic FFA poolpool

Increased B Increased B oxidationoxidation

Increased fat Increased fat depositsdeposits

Increased Increased triglyceride triglyceride poolpool

Increased glucose/insulinIncreased glucose/insulin

Sustained Sustained lipolysislipolysis

Increased FFAIncreased FFA

Increased triglyceride secretionIncreased triglyceride secretion

Fatty liverFatty liverAHAH

SAHSAH 40%40%

10-35%10-35%

RECOVERYRECOVERY

RECOVERYRECOVERY

8-20%8-20%

cirrhosiscirrhosis

deathdeath

Spectrum of alcoholic liver diseaseSpectrum of alcoholic liver disease

SAHDeath >50%Death >50%

Social Social DrinkingDrinking

Alcohol Liver DiseaseAlcohol Liver Disease

FATFATSteatosisSteatosis

Injury and inflammationInjury and inflammationSteatohepatitisSteatohepatitis

fibrosisfibrosis00

+4+4cirrhosiscirrhosis HCCHCC

Histologic SpectrumHistologic Spectrum

Fatty Fatty LiverLiverFATFAT

SteatosisSteatosis

NASHNASH

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

CirrhosisCirrhosis

ScarScar++NodulesNodules+/- +/- FatFat

MildMildHepatocellular Hepatocellular functionfunctionHistologyHistology

Clinical Clinical symptomssymptoms

OutcomeOutcome

NormalNormal

SteatosisSteatosis

AsymptomaticAsymptomatic

Fully reversibleFully reversible

ModerateModerate

Moderately impairedModerately impaired

Marked SH, mallory Marked SH, mallory bodies, advanced bodies, advanced cirrhosiscirrhosisRUQ painRUQ painHepatosplenomegalyHepatosplenomegalyMild jaundice with PHMild jaundice with PH

Potentially reversible Potentially reversible on alcohol abstinenceon alcohol abstinence

Severe diseaseSevere disease

Hepatocellular failureHepatocellular failure

Marked SH, mallory Marked SH, mallory bodies, advanced bodies, advanced cirrhosiscirrhosisRUQ pain,feverRUQ pain,feverHepatosplenomegalyHepatosplenomegalyDeep jaundice with PHDeep jaundice with PH

Potentially Potentially improvement on improvement on alcohol abstinencealcohol abstinence

Innocent bystanderInnocent bystander

Guilty PartyGuilty Party

Steatosis Steatosis

NormalNormal SteatosisSteatosis(vulnerable)(vulnerable)

SteatohepatitisSteatohepatitis

OxidativOxidative Stresse Stress

11stst hit hit

22ndnd hit hit

Two-hit hypothesis of NASHTwo-hit hypothesis of NASH

IkkBIkkB

TNFaTNFa

NAFLDNAFLDInsulin Insulin ResistancResistancee

ETOHETOH

StasisStasis

Intestinal Intestinal Bacterial Bacterial OvergrowthOvergrowth

Mesenteric FatMesenteric Fat

LiverLiver

TNFaTNFa

Hepatic triglycerideHepatic triglyceridesecretionsecretion

Hepatic triglycerideHepatic triglyceridesynthesissynthesis

FATTY FATTY LIVERLIVER

QuiescentQuiescentRich in retinoidRich in retinoidFew smooth muscle proteinsFew smooth muscle proteinsLittle extracellular matrixLittle extracellular matrixReceptorsReceptorsLittle proliferationLittle proliferation

ActivatedActivatedDecreased retinoid acitivityDecreased retinoid acitivityMultiple smooth muscle proteinMultiple smooth muscle proteinAbundant extracellular matrixAbundant extracellular matrixIncreased receptor densityIncreased receptor densityMarked proliferationMarked proliferation

Anti-viral agentsAnti-viral agentsAbstinence from Abstinence from alcoholalcoholRemoval of Iron, Removal of Iron, Copper and toxic Copper and toxic saltssaltsAnti-inflammatory Anti-inflammatory agentsagents

INJURYINJURY

Stellate cellStellate cell

Polyunsaturated soybean lecithin containing:Polyunsaturated soybean lecithin containing:55%-60% phosphatidylcholine55%-60% phosphatidylcholine

Highly purified PC fraction with Highly purified PC fraction with an exceptionally high content of an exceptionally high content of essential fatty acids:essential fatty acids:

70% linoleic acid70% linoleic acid10% linolenic acid10% linolenic acid5% monounsaturated oleic 5% monounsaturated oleic

acidacid15% saturated fatty acid15% saturated fatty acid

EPL reduces fibrogenesis:EPL reduces fibrogenesis:

direct effect on stellate cell activationdirect effect on stellate cell activationlipid peroxidationlipid peroxidation

Aleynik, 1997Aleynik, 1997Promotes breakdown of collagenPromotes breakdown of collagen

Gastroenterology, 1994Gastroenterology, 1994

PPC at 1.5 gm /day vs placeboPPC at 1.5 gm /day vs placebo

Decrease 4 plasma markers of oxidative stressDecrease 4 plasma markers of oxidative stressNo change or presence of regression of fibrosisNo change or presence of regression of fibrosis on liver biopsyon liver biopsy

Leiber, 2000Leiber, 2000


Ethanol Ethanol

MicrosomesMicrosomes(CYP2E)(CYP2E)


GSHGSH

A-amino-N-ButyrateA-amino-N-Butyrate

A ketobutyrateA ketobutyrate

cysteinecysteine

cystathioninecystathionine

serineserinehomocysteinehomocysteine

S-adenosylmethionineS-adenosylmethionine

phosphatidylcholinephosphatidylcholine

PhosphatidylethanolaminePhosphatidylethanolamine


ADHADH

Free radicalsFree radicals

methionine

Healthy liverHealthy liver Hepatic fibrosisHepatic fibrosis

CirrhosisCirrhosis Liver cancerLiver cancer

The basic purpose is to heal…and do no harm!!!The basic purpose is to heal…and do no harm!!!

Ischemic collapse of the liver tissueIschemic collapse of the liver tissue

Parenchymal ExtinctionParenchymal Extinction

Progressive vascular occlusionProgressive vascular occlusionthrombosisthrombosis

Persistent fibrosisPersistent fibrosis

CirrhosisCirrhosis

Parenchyma inflammationParenchyma inflammationAnti-viral agentsAnti-viral agentsAbstinence from Abstinence from alcoholalcoholRemoval of Iron, Removal of Iron, Copper and toxic saltsCopper and toxic saltsAnti-inflammatory Anti-inflammatory agentsagents

Anti-thrombotic agentsAnti-thrombotic agentsVasodilatorsVasodilators

Hepatic Cell membrane:Hepatic Cell membrane:

Represents vital morphological structure of Represents vital morphological structure of every organismevery organismEssential components of cellular and Essential components of cellular and subcellular membranes:subcellular membranes:

65% hepatocells or liver parenchyma65% hepatocells or liver parenchyma80% of liver parenchyma is 80% of liver parenchyma is

membranemembrane60-65% of liver cell membrane is 60-65% of liver cell membrane is

phospholipidsphospholipids70-90% is EPL70-90% is EPL

CholineCholinePhosphatePhosphateglycerolglycerol

Phospholipids Phospholipids serves as hinges serves as hinges between cell-between cell-breathing breathing enzymes and enzymes and mitochondrial mitochondrial crestcrest

EPL:EPL:

Make membranes more fluid and Make membranes more fluid and active enhancing permeabilityactive enhancing permeabilityActivates membrane located Activates membrane located phospholipids dependent phospholipids dependent membranesmembranes

Alcoholic liver 2005 UST

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