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Chapter70

LiverasanOrgan

PhysiologicAnatomyoftheLiver

-Liveristhelargestorganinthebodyatabout2%bodyweightintheadult-Basicfunctionalunitistheliverlobule

Constructedaroundacentralveinemptiesintothehepaticveinsthenthevenacava

Lobulecomposedoflivercellularplatesradiateoutlikespokesusuallytwocellsthickinb/wadjacentcellsliebilecannuliculitheseemptyinto

bileducts

Portalvenulesintheseptagettheirbloodfromportalveinfromherebloodflowsintohepaticsinusoidslieb/whepaticplatesandcentral

veinsohepaticcellsareexposedtoportalvenousblood Hepaticarteriolesarealsointhesepta

-VenoussinusoidsarelinebyendothelialcellsandKupffercells

Kupffercellsareresidentmacrophages EndothelialliningisporousspaceofDisselieunderneathconnectwithlymphaticvesselsexcessfluidisremovedbythelymphaticsplasma

substance(plasmaproteinsforex.)canmovefreelyintothespaces

-Littlepressureinthehepaticveintothevenacavasoresistancetobloodflow

throughthehepaticsinusoidsisnormallyverylow

Cirrhosis

-Liverparenchymalcellsaredestroyedreplacedwithfibroustissue

-Thisfibroustissuecontractsaroundbloodvesselsimpedesportalbloodflow

-Commonlyaresultofchronicalcoholism

-Fataccumulationinthelivercanalsobeacausesubsequentliverinflammation

namednonalcoholicsteatohepatitis(NASH)

-Lesssevereformofthisisnonalcoholicfattyliverdisease(NAFLD)

Mostcommoncauseofliverdiseaseinmanyindustrializedcountries(includingUS)

UsuallyassociatedwithtypeIIdiabetes

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-Cirrhosiscanalsobearesultof:

1)Poisons(ex.CCl4)

2)Viraldiseases(ex.infectioushepatitis)

3)Bileductobstruction

4)Infectionofthebileducts

PortalHypertension

-Suddenblockageofportalsystem

-Impedimentofreturningbloodflowfromtheintestinesandspleenbackintothe

systemiccirculation

-Increasescapillarypressureintheintestinalwallto15-20mmHgabovenormal

-Deathcanoccurinhoursfromtheexcessivelossoffluidfromthecapillariesinto

thelumensandwallsoftheintestines

Liver

-anexpandableorgan

-storeslargeamountsofblood

-normal450mLstored10%ofbodystotalblood

-Increasedpressureintherightatrium(usuallylow)venousbackup(since

venousbloodflowsintorightatrium)causesbackpressureintheliverandit

expandstohold.5-1LofbloodthissituationisfrequentlyseenwithCHF

-VerypermeableporesinthehepaticsinusoidsallowreadypassageoffluidandproteinsintothespaceofDisse

Sothelymphdrainingtheliverhasaslightlylowerproteinconc.thanthatofplasma

Largequantitiesofthelymphformsbecauseofthispermeabilitylivergivesrisetoaboutthelymphinthebody

TransudateandAscites

-excessfluidtransudestothelymphwithhepaticveinpressure3-7mmHgabove

normal Fluidisalmostpureplasma Only80-90%asmuchoftheproteinfoundinnormalplasma

-Withpressureof10-15mmHgabovenormalinthevenacava

Hepaticlymphflowisupto20xabovenormal Releaseoffluidfromthesurfaceoftheliver

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LeadstolargeamountsoffreefluidintheperitonealcavityAscites-Anothercauseofascites:

PortalflowblockagehighcapillarypressureintheGIportalsystemresultsinedemaofthegutwallfluidtransudesthroughthe

serosaofthegutintotheabdominalcavity

LiverRegeneration

-Regenerationafterpartialhepatectomyoracuteliverinjuryaslongastheres

noviralinfection,inflammation,orfibrosis

-Hepatocytesreplicateonceortwicetoregaintheoriginalsizeandvolumeofthe

liver

-Hepatocytegrowthfactor(HGF)andothergrowthfactorsplayanimportantrole

inthecelldivisionandgrowth

-TGF-issuggestedtoterminateregeneration

-Preliverportalbloodlotsofbacteria

-Thisisbecauseofthespecializedmacrophages(Kupffercells)thatlinethe

hepaticvenoussinuses

-Preventscolonbacillifromenteringsystemiccirculation(

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Summarizedfatmetabolismfunctionsintheliver

1)Oxidationoffattyacidstosupplyenergyforotherbodyfunctions

2)Synthesisoflargequantitiesofcholesterol,phospholipids,andmost

lipoproteins

3)Synthesisoffatfromproteinsandcarbohydrates

-Derivationofenergyfromneutralfats(oneglycerolandthreeFAchains)

1. FatsplitintoglycerolandFAs2. FAsaresplitbybetaoxidationendsupformingacetyl-CoA)thesecanentertheCAcycle-oxidationcanhappeninallcellsofthebody,but

happensespeciallyrapidintheliver

3. Livercannotusealloftheacetyl-CoA2moleculesofitisconvertedintoacetoaceticacid

4. AcetoaceticacidishighlysolubletransportedviatheECFthroughoutthebody

5. Tissuesreconverttheacetoaceticacidbacktoacetyl-CoA-80%ofcholesterolsynthesizedintheliverconvertedtobilesaltssecretedin

thebile

-Restistransportedinthelipoproteinscarriedinthebloodtotissuesinbody

-Phospholipidsaresynthesizedinthelivertransmittedbythelipoproteins

-Almostallthefatsynthesisinthebodyfromcarbsandproteinsalsooccursinthe

liverafterfatissynthesizedinthelivertransportedbythelipoproteinstothe

adiposetissuetobestored

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Summarizedproteinmetabolismfunctionsintheliver

1)Deaminationofaminoacids

2)Formationofureaforremovalofammoniafromthebodyfluids

3)Formationofplasmaproteins

4)Interconversionsofthevariousaminoacidsandsynthesisofothercompounds

fromaminoacids

-Deathoccursinafewdaysw/oproteinmetabolismfromtheliver

-Deaminationofaminoacids

RequiredbeforeAAscanbeusedforenergyorconvertedintocarbsorfats Greatestamountofdeaminationintheliver(alsosizableinthekidney)

-Ureaformation

Removesammoniafromthebodyfluids Thisammoniaislargelyaresultfromdeamination(alsosomefromgutbacteria)

IfureanotformedinliverplasmaNH3risesresultsinhepaticcomaanddeath

Greatlydecreasedbloodflowcanalsoresultinincreasedammoniaintheblood(Hyperammonemia)

-Allplasmaproteins(exceptsomegammaglobulins)aremadeintheliver

Accountsfor90%ofallplasmaproteins Formedbyliveratamaxrateof15-50g/daysocanbereplenishedfairlyquickly

Plasmaproteindepletioncausesmitosisofhepaticcellsandrapidgrowthofliversizerapidproductionofplasmaproteinsuntillevelsreturnto

normal

Ifthereisachronicliverdiseaseverylowplasmaproteinlevels,suchaswithalbumin)leadstoedemaandascites(fluidleaksoutofthe

vasculaturetothetissuebecauseofthepressuregradient)

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-Livercansynthesizecertainaminoacidsalsocertainchemicalcompoundsfrom

aminoacids

Ex.:Nonessentialaminoacidscanallbesynthesizedintheliver(nonessentialmeaningtheycanbesynthesizedinthebodyanddonthave

tocomefromthediet)1)Ketoacidwiththesamechemicalcompositionoftheaminoacid(except

attheketooxygen)tobeformissynthesized

2)Nextanaminoradicalistransferred,throughseveralstagesof

transanimation,fromanavailableaminoacidovertotheketoacidtotake

theplaceoftheketooxygen

-Liverisastoragesiteofvitamins

GreatestquantityisvitaminAstorageforupto10monthsw/odeficiency AlsoseenarevitaminsDandB12Dfor3-4months,B12foratleast1yearuptoseveral

-Greatestproportionofironstorageinthebodyisintheliver(exceptforthe

hemoglobininblood)

Storedintheformofferritin Hepaticcellscontainapoferritincapableofcombiningreversiblywithiron Withexcessironapoferritincombineswiththeirontoformferritin Ferritinstoreduntillowironlevelsinbodyfluidferritinreleasesiron Systemworksasabloodironbufferaswellasanironstoragesystem

-Liverformsthebloodsubstancesusedincoagulationwhichinclude:

1)Fibrinogen

2)Prothrombin

3)Acceleratorglobulin

4)FactorVII

VitaminKisneededintheliverfortheirformationespeciallywithprothrombinandfactorsVII,IX,andX

W/OvitaminK.theircocnc.decreasesalmostpreventingcoagulation

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Bilirubin

-Excretedinthebileandeliminatedinthefeces

-Greenish-yellowpigment

-Majorendproductofdegradation

-Valuabletoolindiagnosinghemolyticblooddiseaseandvariousliverdiseases-Explanation:

RBCsruptureattheendoftheirlifespanwhentheybecometoofragile(onaverage120days)

Hemoglobinisreleasedandthenphagocytizedbytissuemacrophages(oftheRES)

Hemoglobinissplitintofirst1)Globin

and

2)Heme Hemeringisopened(byhemeoxygenase)togive1)Freeirontransportedinbloodbytransferrin

2)Astraightchainoffourpyrrolenucleisubstrateforwhichbilirubinwill

beformed

Forthefirstsubstanceformedfromthisisbiliverdin Biliverdinisrapidlyreducedtoformunconjugated(AKAfree)bilirubin Unconjugatedbilirubinisreleasedfromthemacrophagesintotheplasmawhereitcombineswithalbumin

Plasmaalbuminboundunconjugatedbilirubinistransportedthroughoutthebloodandinterstitialfluids

Thisisthensenttotheliverwherethebilirubinisabsorbedbyhepatocytesandreleasedfromtheplasmaalbumin

o 80%isconjugatedwithglucuronicacidformsbilirubinglucuronide

o 10%isconjugatedwithsulfateformsbilirubinsulfateo 10%withmultipleothersubstances

Initsconjugatedformitsexcretedfromthehepatocytesbyactivetransportandintothebilecanaliculiandthenintotheintestines

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-Onceintheintestines

Aboutisconvertedbybacteriatourobilinogen-Urobiligen

Highlysoluble Someisreabsorbedthroughtheintestinalmucosabackintotheblood-

o Mostofthisisre-excretedbytheliverbackintotheguto About5%thoughisexcretedbythekidneysintotheurinewhenexposedtoairitsoxidizedtoform urobilin

o Inthefecesitbecomesoxidizedtoformstercobilin

Jaundice

-Usualcauseislargequantitiesofbilirubin(eitherunconjugatedornot)intheECF

-Normalplasmaconc.is0.5mg/dlofplasmaalmostentirelyunconjugated

-Withabnormalconditionscanrisetoasmuchas40mg/dlmuchcanbecometheconjugatedtype

-Skinusuallyappearsyellowtintedatabout3xnormal(1.5mg/dl)

-Commoncausesofjaundice:

1)HemolyticJaundice

Excretoryfunctionisnormal RBCsrapidlyhemolyzedleadingtobilirubinformationhepaticcellscantexcretebilirubinfastenough

Unconjugatedbilirubinlevelsrise Alsoincreasedurobilinogenlevels

2)Obstructivejaundice

Bilirubinformationrateisnormal Bilirubincannotpassintotheintestines Thisisbecauseofeitherobstructionofthebileducts(gallstoneorcancerblockingtheCBD)orfromdamagetothehepaticcells(seen

withhepatitis)

Conjugationstilloccursinthenormalway Conjugatebilirubinisthenreturnedtotheblood(soitsnotexcretedinbile,urine,orwaste,butratherstaysinthebodyviablood)

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FunctionTest Pre-Hepatic

Jaundice

(Hemolytic)

HepaticJaundice

(Cirrhosis,

Hepatitisforex.)

Post-HepaticJaundice

(obstructiveofsomevariety)

TotalBilirubin Normal/Increased

Increased Increased

Conjugated

Bilirubin

Normal Increased Increased

Unconjugated

Bilirubin

Normal/

Increased

Increased Normal

Urobilinogen Normal/

Increased

Decreased Decreased/Negative

UrineColor Normal Dark(Urobilinogen+

ConjugatedBilirubin

Dark(ConjugatedBilirubin)

StoolColor Normal Normal/Pale Pale

Alkaline

Phosphotase

Levels

Normal Increased Increased

AST/ALT Normal Increased Increased

Conjugated

Bilirubinin

Urine

Notpresent Present Present

Splenomegaly Present Present Absent

-Inhemolyticjaundice:

almostallofthebilirubinisunconjugated-Inobstructivejaundice:

almostallofthebilirubinisconjugated withtotalobstructionnobilirubincanmakeittotheintestinesmeansnoconversiontourobilinogenbybacteria

sonourobilinogenisreabsorbedintothebloodnoneexcretedbykideneys

testsarecompletelynegativeforurobilinogen stoolsareclaycolored(nostercobilin) conjugatedbilirubinisexcretedintheurinebecauseitcanpassthroughthekidneyswhilealbuminboundunconjugatedbilirubincannot