joaquin jennifer laura

8/3/2019 Joaquin Jennifer Laura

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Alcoholic LiverAlcoholic Liver

Disease #4Disease #4Laura LaureanoLaura Laureano

Mark SakrMark SakrJennifer FlanneryJennifer Flannery


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Alcohol liver diseaseAlcohol liver disease

Describe the pathogensisDescribe the pathogensisof alcoholic fatty liver,of alcoholic fatty liver,alcoholic hepatitis andalcoholic hepatitis and

alcohol induced cirrhosisalcohol induced cirrhosisof the liver. Includeof the liver. Includesignificance of thesignificance of thepatients liver biopsy.patients liver biopsy.


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Stages of Alcoholic liver DiseaseStages of Alcoholic liver Disease

Occurs in stagesOccurs in stages

Fatty liverFatty liver

Alcohol hepatitisAlcohol hepatitis

Alcohol inducedAlcohol inducedcirrhosiscirrhosis


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Fatty LiverFatty Liver

Fatty Liver (Steatosis)Fatty Liver (Steatosis)

An accumulation of fat in theAn accumulation of fat in the

livers hepatocytes.livers hepatocytes.

ADH level are high in theADH level are high in theattempt to rid the body ofattempt to rid the body of

alcohol toxin.alcohol toxin.

ADH causes an increaseADH causes an increase

NADH

(Plenty of ATP).NADH

(Plenty of ATP).This causes a decrease in theThis causes a decrease in the

oxidation of Fatty Acids andoxidation of Fatty Acids and

its accumulation in the liverits accumulation in the liver


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Aldehyde (end product) willAldehyde (end product) will

also adduct to tubulinalso adduct to tubulinpreventing the secretion ofpreventing the secretion ofVLDL from the liver thus theVLDL from the liver thus thecause of inflammation.cause of inflammation.

This explains why hisThis explains why histriacylglycerol levels (via livertriacylglycerol levels (via liverbiopsy) is well above thebiopsy) is well above thenormal range (35normal range (35--170) of 420170) of 420

mg/D

L as well as hismg/D

L as well as hischolesterol (140cholesterol (140--200) of 223.200) of 223.His abdominal pains are formHis abdominal pains are formthe liver inflammationthe liver inflammation


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Alcoholic HepatitisAlcoholic Hepatitis

The previous condition if continued, will lead toThe previous condition if continued, will lead toAlcoholic hepatitisAlcoholic hepatitis

The patient presented a WBC of 23,000 cells/ ulThe patient presented a WBC of 23,000 cells/ ul (rr 4,300(rr 4,300--10,800)10,800) This condition leads to scarring of the liver in theThis condition leads to scarring of the liver in the

lobule hepatocytes with a pathology of mallory bodieslobule hepatocytes with a pathology of mallory bodieswhich are aggregations of intermediate filaments as wellwhich are aggregations of intermediate filaments as wellas proteins that are released from the scarring.as proteins that are released from the scarring.

Neutraphillic reactions and lymphatic infiltrates whichNeutraphillic reactions and lymphatic infiltrates whichusually collect around the mallory bodies are also inusually collect around the mallory bodies are also incongruence with the increase of WBC. The abovecongruence with the increase of WBC. The abovepathology is indicative of alcoholic hepatitis.pathology is indicative of alcoholic hepatitis.


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Liver CirrhosisLiver Cirrhosis

Necrosis is occurringNecrosis is occurring Damaged liver hepatocytesDamaged liver hepatocytes

are being replaced withare being replaced with

fibrotic tissue and hyperblasticfibrotic tissue and hyperblasticnodules.nodules.

Circulation from the portalCirculation from the portal

vein is blocked leading tovein is blocked leading to

further exacerbation offurther exacerbation of

necrosis as well as other labnecrosis as well as other lab

findings.findings.


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Percentages of liver DeteriorationPercentages of liver Deterioration

Alcohol consumptionAlcohol consumption

100%100% Fatty Liver Fatty Liver

35%35% AlcoholHepatitis Alcohol Hepatitis

50%50% go on to develop cirrhosis go on to develop cirrhosis

1010--15% of all alcoholics will develop15% of all alcoholics will developcirrhosis.cirrhosis.


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Role of CytokinesRole of Cytokines

Cytokines are chemical messengers that areCytokines are chemical messengers that are

importantto the bodys initial response toimportantto the bodys initial response to

infection.infection.

Attract and activate components ofthe immune systemAttract and activate components ofthe immune system

Promote blood clottingPromote blood clotting

Facilitate the release of additional chemical messengersFacilitate the release of additional chemical messengers

Induce liver to shift its physiological function:Induce liver to shift its physiological function:

Emphasizing inflammatory and immune responsesEmphasizing inflammatory and immune responses

Downplaying normal metabolismDownplaying normal metabolism

(McClain 1997)(McClain 1997)


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Cytokines in ALDCytokines in ALD

Persistent alcohol use causes excessive cytokine productionPersistent alcohol use causes excessive cytokine productionin the liver, leading to chronic inflammation.in the liver, leading to chronic inflammation.

AlcoholAlcohol--induced chronic inflammation ofthe liverinduced chronic inflammation ofthe liver(alcoholic hepatitis) is characterized by:(alcoholic hepatitis) is characterized by:

FeverFever JaundiceJaundice

Loss of appetiteLoss of appetite

Condition may progress to alcoholic cirrhosis, which isCondition may progress to alcoholic cirrhosis, which ismarked by progressive development of scar tissue thatmarked by progressive development of scar tissue thatchokes off blood vessels and distorts the normalchokes off blood vessels and distorts the normalarchitecture ofthe liver.architecture ofthe liver.

Because ofthe livers crucial role in many aspects of bodilyBecause ofthe livers crucial role in many aspects of bodilyfunction, either condition can be fatal.function, either condition can be fatal.



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Kupffer Cell Cytokine ProductionKupffer Cell Cytokine Production

The liver plays a role in the inflammatory response, both asThe liver plays a role in the inflammatory response, both asa potential site of chronic inflammatory disease (ALD) anda potential site of chronic inflammatory disease (ALD) andas a source of phagocytes and cytokines.as a source of phagocytes and cytokines.

Most ofthe bodys fixed macrophages reside in the liver asMost ofthe bodys fixed macrophages reside in the liver as

Kupffer cells that screen the blood for infectious or toxicKupffer cells that screen the blood for infectious or toxicsubstances picked up from the digestive tract.substances picked up from the digestive tract.

Alcohol consumption increases the permeability oftheAlcohol consumption increases the permeability oftheintestine, permitting certain toxic bacterial productsintestine, permitting certain toxic bacterial products(endotoxin) to pass through the intestinal wall into the(endotoxin) to pass through the intestinal wall into thebloodstream.bloodstream.

Upon reaching the liver, endotoxin stimulates the KupfferUpon reaching the liver, endotoxin stimulates the Kupffercells to produce cytokines, mainly TNF ,which contributescells to produce cytokines, mainly TNF ,which contributesto subsequent liver inflammation.to subsequent liver inflammation.



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Immunological ActivityImmunological Activity

Patients with ALD will exhibit high levels of:Patients with ALD will exhibit high levels of: TNFTNF

Interleukins 1, 6, and 8Interleukins 1, 6, and 8

MCPMCP--1.1.

Elevated levels of TNF (inflammatory response) in bloodElevated levels of TNF (inflammatory response) in bloodare correlated with poor prognosis in patients withare correlated with poor prognosis in patients withalcoholic hepatitis.alcoholic hepatitis.

Levels of ILLevels of IL--6 markedly increase during the initial6 markedly increase during the initialhospitalization of ALD patients, subsiding as liver functionhospitalization of ALD patients, subsiding as liver functionimproved.improved.

MCPMCP--1 promotes monocyte infiltration of liver.1 promotes monocyte infiltration of liver.



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ILIL--8 promotes neutrophilia, increased neutrophil levels in8 promotes neutrophilia, increased neutrophil levels inthe blood, as well as neutrophil infiltration of liver tissue inthe blood, as well as neutrophil infiltration of liver tissue in

ALD.ALD.

Conversely, production of ILConversely, production of IL--10 by monocytes is decreased10 by monocytes is decreased

in patients with ALD.in patients with ALD. This cytokine normally helps curb the inflammatory response.This cytokine normally helps curb the inflammatory response.

Inadequate levels of ILInadequate levels of IL--10 contribute to the uncontrolled production10 contribute to the uncontrolled productionof inflammatory cytokines such as TNF.of inflammatory cytokines such as TNF.

This abnormal cytokine activity not only causesThis abnormal cytokine activity not only causes

inflammation, but T cell, macrophage, monocyte andinflammation, but T cell, macrophage, monocyte andneutrophil mediated apoptosis will occur, further damagingneutrophil mediated apoptosis will occur, further damagingthe liver.the liver.



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ProteinProtein--Aldehyde AdductProductionAldehyde AdductProduction

Ethanol consumption activatesEthanol consumption activatesseveral systems that generateseveral systems that generateoxygen free radicals.oxygen free radicals.

These reactive oxygen species,These reactive oxygen species,namely reactive aldehydesnamely reactive aldehydes(CH(CH33CHO), products of lipidCHO), products of lipidperoxidation, can bind toperoxidation, can bind toproteins forming stable adducts.proteins forming stable adducts.

This leads to several adverseThis leads to several adverseconsequences:consequences:

Interference with proteinInterference with proteinfunctionfunction

Improper stimulation ofImproper stimulation offibrogenesisfibrogenesis

Induction of immune responsesInduction of immune responses

(Niemel 1999)(Niemel 1999)


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ProteinProtein--Aldehyde AdductsAldehyde Adducts

Malondialdehyde (MDA) is a highly reactive dialdehydeMalondialdehyde (MDA) is a highly reactive dialdehydeoriginating from nonenzymatic lipid peroxidation of a variety oforiginating from nonenzymatic lipid peroxidation of a variety ofunsaturated fatty acids.unsaturated fatty acids.

The free radical mediated oxidation of longThe free radical mediated oxidation of long--chainchain

polyunsaturated fatty acids leads to the production of 4polyunsaturated fatty acids leads to the production of 4--hydroxynonenal (HNE), which can react with the sulfhydrylhydroxynonenal (HNE), which can react with the sulfhydrylgroups of proteins.groups of proteins.

Oxidative modification of proteins with MDA and HNEOxidative modification of proteins with MDA and HNEthrough covalent binding to proteins is known to interfere withthrough covalent binding to proteins is known to interfere withprotein function particularly when there is a lysine residue in aprotein function particularly when there is a lysine residue in afunctionally critical location, such as in tubulin.functionally critical location, such as in tubulin.

This can lead to altered microtubule function may subsequently lead to anThis can lead to altered microtubule function may subsequently lead to animpairment in protein secretion and plasma membrane fidelity.impairment in protein secretion and plasma membrane fidelity.

(Niemel 1999)(Niemel 1999)


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AldehydeAldehyde--protein adducts and hydroxyl radicals stimulateprotein adducts and hydroxyl radicals stimulateimmunological responses directed against specificimmunological responses directed against specificmodified proteins.modified proteins.

Studies have shown that chronic administration of ethanolStudies have shown that chronic administration of ethanol

to rats leads to the generation of circulatingto rats leads to the generation of circulatingimmunoglobulins with antiimmunoglobulins with anti--acetaldehyde adduct or antiacetaldehyde adduct or anti--MDAMDA--adduct specificity.adduct specificity. High levels of both IgA and IgG autoantibody isotypes have beenHigh levels of both IgA and IgG autoantibody isotypes have been

observed in patients with severe alcoholic liver disease.observed in patients with severe alcoholic liver disease.

These antibodies have specificitytowards the aldehydeThese antibodies have specificitytowards the aldehyde--lysinelysine

residues.residues. Autoantibodies recognizing cytochrome P450IIE1 hydroxyethylAutoantibodies recognizing cytochrome P450IIE1 hydroxyethyl

radical adducts have also been found from the blood of humanradical adducts have also been found from the blood of humanalcoholics.alcoholics.

Antibody induced, T cell mediated apoptosis will occur.Antibody induced, T cell mediated apoptosis will occur.(Niemel 1999)(Niemel 1999)


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Stellate cell activationStellate cell activationand collagen synthesis inand collagen synthesis in

alcoholic liver diseasealcoholic liver disease


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Stellate cell (HSC) activationStellate cell (HSC) activation

Stellate cells: major fibrogenic cells in the liver thatStellate cells: major fibrogenic cells in the liver thatcontribute to collagen accumulation duringcontribute to collagen accumulation duringchronic liver diseasechronic liver disease

Gene induction of stellate cells is a central event inGene induction of stellate cells is a central event inliver fibrosisliver fibrosis

Oxidative stress activates the transcription factorsOxidative stress activates the transcription factorsNrf2 and AP1 through shared kinase signalingNrf2 and AP1 through shared kinase signalingpathwayspathways

Nrf2Nrf2 induction of redox protective phase IIinduction of redox protective phase IImetabolizing enzymesmetabolizing enzymes

AP1AP1 stellate cell activation, proliferation, andstellate cell activation, proliferation, andextracellular matrix accumulationextracellular matrix accumulation

(Reichard & Petersen, 2004; Friedman 2000; Armendariz(Reichard & Petersen, 2004; Friedman 2000; Armendariz--Borunda, Simkevich, et al., 1994)Borunda, Simkevich, et al., 1994)


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Stellate cell activationStellate cell activation

HSCs undergo myofibroblastic transformationHSCs undergo myofibroblastic transformation

once activated by oxidative stressonce activated by oxidative stress

Transformation is characterized by assembly ofTransformation is characterized by assembly of

smooth muscle actin stress fibers, loss ofsmooth muscle actin stress fibers, loss ofcytosolic retinol, and increased proliferationcytosolic retinol, and increased proliferation

Results in accumulation of extracellular matrix andResults in accumulation of extracellular matrix and

replacement of subendothelial matrix with densereplacement of subendothelial matrix with dense

fibril forming matrixfibril forming matrix

(Reichard & Petersen, 2004; Friedman 2000)(Reichard & Petersen, 2004; Friedman 2000)


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Hepatic Stellate cellsHepatic Stellate cells

A & B: InactiveA & B: Inactivestellate cellsstellate cells autofluorescence ofautofluorescence of

cytoplasmic vitamin Acytoplasmic vitamin A

C & D: ActivatedC & D: Activated

stellate cellsstellate cells immunofluorescentimmunofluorescentdetection of smoothdetection of smoothmuscle muscle --actinactin

(Reichard & Petersen, 2004)(Reichard & Petersen, 2004)


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MMP and TIMP ActivationMMP and TIMP Activation

Matrix metalloproteinasesMatrix metalloproteinases(MMPs)(MMPs) are expressed andare expressed andsecreted by HSCssecreted by HSCs

Extracellular matrixExtracellular matrixremodeling proteinsremodeling proteins

contribute to fibril forming matrixcontribute to fibril forming matrix

Tissue Inhibitors (TIMP)Tissue Inhibitors (TIMP)also expressed by HSCsalso expressed by HSCs

Inhibit collagen degradationInhibit collagen degradation

(Xu, Hui, Albanis, et al., 2005)(Xu, Hui, Albanis, et al., 2005)


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Role of Activated HepaticRole of Activated Hepatic

Stellate CellsStellate Cells

Secrete cytokinesSecrete cytokines

Increase the deposition of ECMIncrease the deposition of ECM

Recruit lymphocytesRecruit lymphocytes

Express major histocompatibility complex class IExpress major histocompatibility complex class I(MHC) molecules(MHC) molecules

Enhanced T cell apoptosisEnhanced T cell apoptosis

Interactions between HSCs and immune cells mayInteractions between HSCs and immune cells maycontribute to hepatic immune tolerancecontribute to hepatic immune tolerance

((Yu, Chen, et al.; 2004)Yu, Chen, et al.; 2004)


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Big Picture:Big Picture:

Hepatic stellate cells play anHepatic stellate cells play animportant role in the fibrogenesis ofimportant role in the fibrogenesis of

perisinusoidal spaces in the liverperisinusoidal spaces in the liver

through collagen synthesisthrough collagen synthesis

(Han, Chung, Ahn, et al.; 2001)


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Gene induction of collagenGene induction of collagen

HSP47 mRNA isHSP47 mRNA is

expressed in human HSCsexpressed in human HSCs

HSP47HSP47 collagen specificcollagen specific

chaperone proteinchaperone protein Required for collagenRequired for collagen

biosynthesisbiosynthesis

Involved in procollagenInvolved in procollagen

processing, maturation,processing, maturation,

and secretionand secretion

(Hendershot & Bulleid, 2000)(Hendershot & Bulleid, 2000)


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Collagen depositionCollagen deposition

Thrombin induces collagen depositionThrombin induces collagen depositionthrough activation of a G protein coupledthrough activation of a G protein coupledreceptor: Proteinase Activated Receptor 1receptor: Proteinase Activated Receptor 1

(PAR1)(PAR1)

PAR1 is expressed by hepatic stellate cellsPAR1 is expressed by hepatic stellate cells

(F

iorucci, Antonelli, Distrutti, et al., 2004; Singh, Gerard, Hudson, Boros, 2004)(F

iorucci, Antonelli, Distrutti, et al., 2004; Singh, Gerard, Hudson, Boros, 2004)


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CollagenCollagen Liver FibrosisLiver Fibrosis

Connective tissue is laid down in the sinusoids andConnective tissue is laid down in the sinusoids and

around hepatocytesaround hepatocytes

Collagen fibers invade the space of Disse, creatingCollagen fibers invade the space of Disse, creating

a continuous membrane under the sinusoidala continuous membrane under the sinusoidalendotheliumendothelium

Amount of deposited hepatic collagen increasesAmount of deposited hepatic collagen increases

with the chronicity ofthe infectionwith the chronicity ofthe infection

Accumulating collagen leads to liver fibrosisAccumulating collagen leads to liver fibrosis

prevalent in alcoholic liver diseaseprevalent in alcoholic liver disease

(Han, Chung, Ahn, et al.; 2001)


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ReferencesReferences

ArmendarizArmendariz--Borunda, C.P. Simkevich, N. Roy, R. Raghow, A.H. Kang and J.M. Seyer. Activation ofBorunda, C.P. Simkevich, N. Roy, R. Raghow, A.H. Kang and J.M. Seyer. Activation ofIto cells involves regulation of APIto cells involves regulation of AP--1 binding proteins and induction oftype I collagen gene1 binding proteins and induction oftype I collagen geneexpression.expression. Biochem. J.Biochem. J. 1994; 304, 8171994; 304, 817824.824.

Fiorucci S, Antonelli E, Distrutti E, Severino B, Fiorentina R, Baldoni M, Caliendo G, Santagada V,Fiorucci S, Antonelli E, Distrutti E, Severino B, Fiorentina R, Baldoni M, Caliendo G, Santagada V,Morelli A, Cirino G.Morelli A, Cirino G. PAR1 antagonism protects against experimental liver fibrosis. Role of proteinasePAR1 antagonism protects against experimental liver fibrosis. Role of proteinasereceptors in stellate cell activation.receptors in stellate cell activation. HepatologyHepatology2004: 39, 3652004: 39, 365--75.75.

Friedman, S.L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissueFriedman, S.L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissueinjury.injury.J. Biol. Chem.J. Biol. Chem. 2000: 275, 22472000: 275, 22472250.2250.

Han NI, Chung KW, Ahn BM, Choi SW, Lee YS, Lee CD, Sun HS. Ultrastructural changes of hepaticHan NI, Chung KW, Ahn BM, Choi SW, Lee YS, Lee CD, Sun HS. Ultrastructural changes of hepaticstellate cells in the space of Disse in alcoholic fatty liver.stellate cells in the space of Disse in alcoholic fatty liver. Korean Journal of Internal MedicineKorean Journal of Internal Medicine2001: 16:1602001: 16:160--6.6.

Hendershot LM, Bulleid NJ. ProteinHendershot LM, Bulleid NJ. Protein--specific chaperones: the role of hsp47 begins to gel.specific chaperones: the role of hsp47 begins to gel. Curr BiolCurr Biol2000: 10, 9122000: 10, 91215.15.

Reichard, J. and D.R. Petersen, Hepatic stellate cells lack APReichard, J. and D.R. Petersen, Hepatic stellate cells lack AP--1 responsiveness to electrophiles and1 responsiveness to electrophiles andphorbol 12phorbol 12--myristatemyristate--1313--acetate.acetate. Biochemical and Biophysical Research CommunicationsBiochemical and Biophysical Research Communications, 322: 2004, 842, 322: 2004, 842--853.853.

Singh KP, Gerard HC, Hudson AP, Boros DL.Singh KP, Gerard HC, Hudson AP, Boros DL. Dynamics of collagen, MMP and TIMP geneDynamics of collagen, MMP and TIMP gene

expression during the granulomatous, fibrotic process induced bySchistosoma mansoni eggs.expression during the granulomatous, fibrotic process induced bySchistosoma mansoni eggs.A

nnA

nnTrop Med ParasitolTrop Med Parasitol2004: 98, 5812004: 98, 581--93.93.

Xu L, AYHui, E Albanis, MJ Arthur, S M OByrne, WS Blaner, P Mukherjee, S L Friedman, F JXu L, AYHui, E Albanis, MJ Arthur, S M OByrne, WS Blaner, P Mukherjee, S L Friedman, F JEng. Human hepatic stellate cell lines, LXEng. Human hepatic stellate cell lines, LX--1 and LX1 and LX--2: newtools for analysis of hepatic fibrosis.2: newtools for analysis of hepatic fibrosis. GutGut2005: 54, 1422005: 54, 142--151151

Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, Lu L, Qian S. Inhibition of TYu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, Lu L, Qian S. Inhibition of T--cellcellresponses by hepatic stellate cells via B7responses by hepatic stellate cells via B7--H1H1--mediated Tmediated T--cell apoptosis in mice.cell apoptosis in mice. HepatologyHepatology2004: 40,2004: 40,13121312--21.21.


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ReferencesReferences

Huether S. McCance K. 2002. pg 1294. 53. Mosby St louis Ms.Huether S. McCance K. 2002. pg 1294. 53. Mosby St louis Ms.

http://www.ias.ac.in/resonance/Oct2004/pdf/Oct2004p41http://www.ias.ac.in/resonance/Oct2004/pdf/Oct2004p41--47.pdf47.pdf

http://www.niaaa.nih.gov/publications/arh25http://www.niaaa.nih.gov/publications/arh25--3/1753/175--184.htm184.htm

CPMCNET.columbia.eduCPMCNET.columbia.edu

http://www.meddean.luc.edu/lumen/MedEd/orfpath/alcoholi.htmhttp://www.meddean.luc.edu/lumen/MedEd/orfpath/alcoholi.htm

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