Alanineaminotransferase(serum,plasma)

1 Nameanddescriptionofanalyte

1.1 Nameofanalyte
Alanineaminotransferase(ALT)

1.2 Alternativenames
SystematicnameLalanine:2oxoglutarateaminotransferase(EC2.6.1.2);
alsopyruvateaminotransferase,glutamatepyruvateaminotransferase;
formerlyknownasalaninetransaminase.

1.3 NLMCcode

1.4 Descriptionofanalyte
ALTisanintracellularcytoplasmicenzyme.Itiswidelydistributed
throughoutthebodystissues,withthegreatestamountsinliverandthe
kidneys.

1.5 Functionofanalyte
ALTcatalysesthetransferofaminogroupsfromalanine(forming
pyruvate)to2oxoglutarate(formingglutamate).Itisakeyenzymein
gluconeogenesis.
ALTpresentintheplasmaispresumedtobederivedfromthenormal
turnoveroftissuecells;increasedquantities(theenzymeisusually
assayedbymeasuringitsactivity,see4.1)arefoundintissuedamage
(particularlyhepaticdamage).Itisnotknowntohaveanyfunctionin
plasma.

2 Samplerequirementsandprecautions

2.1 ALTismeasuredinplasmaorserum.

2.2 Generalprecautionsonly.

3 Summaryofclinicalusesandlimitationsofmeasurements

3.1 Uses
ALTisusedtoidentifyliverdamagee.g.arisingfromlivercell
inflammationornecrosis.Itsclassificationasaliverfunctiontest(LFT)is
erroneousbuthasbecomeacceptedusageandseemslikelytoprevail.
AlthoughALTiswidelydistributed,significantincreasesinitsplasma
activityarerarelyseenotherthaninliverdisease.Itmaybemeasured
bothinpatientswithclinicalfeaturessuggestiveofliverdiseaseandin
patientsatriskofdevelopingliverdisease.
Thislattercategoryincludesindividualswith:
ahighalcoholintake
ahistoryorknownorpossibleexposuretohepatitisviruses
obesityordiabetes
ahistoryofconsumptionofpotentiallyhepatotoxicdrugs
afamilyhistoryofliverdisease.

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3.2 Limitations
AnincreaseinALTisanindicatorof(hepatic)tissuedamage;thehighest
valuesareseenintoxicdamagee.ginducedbyacetaminophen
(paracetamol)poisoning,butanincreasedoesnotonitsownprovideany
informationaboutthecauseofthatdamage(thoughsee10.1).

4 Analyticalconsiderations

4.1 Analyticalmethods
Incommonwiththemethodsusedformeasuringmostenzymesfor
clinicalpurposes,ALTisassayedbymeasuringitscatalyticactivity,notits
mass.
TheALTreactioninvolvesanaminoacidandanoxoacidbothas
substratesandproducts.Quantitationmakesuseoftheformationofthe
oxoacid(pyruvate),usinglactatedehydrogenase(lactate:NAD+
oxidoreductase,EC1.1.1.27)toreduceitwithNADHtoformlactate.The
reactionisfollowedbymeasuringthedecreaseinabsorbanceat340nm.

Alanine+2oxoglutarate(ALT)pyruvate+glutamate
Pyruvate+NADH+H+(LD)lactate+NAD+

Pyridoxine5phosphateisacoenzymefortheALTreaction;itsaddition
tothereactionmixtureensuresthatalltheapoenzymeiscatalytically
activeandmeasured.Preincubationisrequiredtoremoveany
endogenousoxoacidsfromthereactionmixture,thereactionthenbeing
startedbytheadditionof2oxoglutarate.

4.2 Referencemethod
Thisisbasedonthemethoddescribedin4.1.

4.3 Referencematerials
IRMM(InstituteforReferenceMethodsandMaterials)/IFCC
(InternationalFederationofClinicalChemistry454.

4.4 Interferingsubstances
Interferencebyendogenousoxoacidsiseliminatedasdescribedin(4.1).

4.5 Sourcesoferror
Aswithallassaysinvolvingmeasurementofenzymeactivity,strict
controlofreactionconditions,especiallytemperature,isessential.

5 Referenceintervalsandvariance

5.1.1 Referenceinterval:(adultsandchildren)34U/L(female),45U/L(ale)
5.1.2 Referenceintervals(others):valuesaboveapplicabletoallages
5.1.3 Extentofvariation
5.1.3.1 InterindividualCV:24%
5.1.3.2 IntraindividualCV:16%
5.1.3.3 Indexofindividuality:0.66
5.1.3.4 CVofmethod:12.5%
5.1.3.5 Criticaldifference:65%

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5.1.4 Sourcesofvariation:thehighlevelsofintraandinterindividualvariation
reflectthefactthatnormalplasmalevelsaredeterminedbycellturnover
andnotsubjecttoanyformoffeedbackcontrol.

6 Clinicalusesofmeasurementandinterpretationofresults

6.1 Usesandinterpretation
1.See3.1.ALTismeasuredasanindexofliverdamageforwhichitis
more specificthanaspartateaminotransferase(AST).Values>20xthe
upperlimitofnormalmayoccurwithsevereliverdamage.Smaller
increments(usually<5xULN)mayoccurincholestasis,duetosecondary
damagetohepatocytes.
2.Inestablishedliverdisease,afallingALTvalueusuallyreflects
decreasingcelldamage,butmayoccasionallybeaconsequenceofsuch
massivedestructionthat,withclearanceoftheenzyme,evencontinuing
damagedoesnotmaintainhighlevels.
3.Inthecontextofliverdisease,measuringbothALTandASTprovides
littleadditionalinformationoverthatprovidedbymeasuringeitherone.
Therearetwoexceptions:infattyliverdisease,anactivityratioAST/ALT
of>2suggestsalcoholasacause;aratioof1issuggestiveofanon
alcoholiccause.

6.2 Confoundingfactors
None

7 Causesandinvestigationofabnormalresults

7.1 Highvalues
7.1.1 Causes
1.Hepatobiliarydisease
Livercellnecrosis(e.g.inviralhepatitis,toxicliverdamage);values
maybe>20xupperlimitofnormal(ULN).
Cholestaticandotherformsofhepatiobiliarydisease;valuesrarely
exceed5xULNunlessthereisaccompanyinglivercellnecrosis.
2.Extrahepaticdisease
Relativetoplasma,theactivityofALTinvarioustissuesis:liver,
2850x,kidneys,1200x,heart450x,skeletalmuscle300x.Small
increasesinplasmaALTactivitymaythereforeoccurinacutekidney
injury,myocardialinfarctionorskeletalmuscledamage,butthe
increaseinaspartateaminotransferase(AST)activityinthese
conditionsisusuallyhigher.

7.1.2 Investigation
AlthoughALTshouldonlybemeasuredwhenhepatobiliarydiseaseis
suspectedonclinicalgrounds,inpracticeitisfrequentlymeasuredaspart
ofapaneloftestsliverfunctiontests(butsee3.1).However,chronicliver
diseasecanpresentnonspecificallysothatALTmeasurementis
frequentlyrequestedintheabsenceofclassicfeaturesofliverdisease
(e.g.jaundice).Theimportantpracticalquestionmaythenariseastothe
actiontobetakenifanunexpectedlyhighALTvalueisfound.
Foranyvalue,ahighalcoholintake,diabetesorhypertriglyceridaemia
(allofwhichcancausefattyliver)shouldbeexcluded;ifpresent,these
shouldbemanagedappropriatelybeforerepeatingthetest.
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 Forincreases2xULN,andotherLFTsnormal,repeatin12months.
Ifrepeatvalue3xULN,furtherinvestigationisrequired.
Values>3xULNfurtherinvestigationisrequiredwithoutrepeat
testingirrespectiveofresultsofotherLFTs.
Firstlinefurtherinvestigationmaycomprise:hepatitisvirusserology,full
bloodcount(foralcoholrelatedmacrocytosisorthrombocytopaenia
secondarytohypersplenismcausedbyportalhypertension),autoimmune
serology(antimitochondrialandantismoothmuscleantibodies),ferritin
(forhaemochromatosis)andhepaticultrasound.Ifthesedonotprovidea
diagnosis,testsforWilsonsdisease,alpha1antityrpsindeficiencyand
coeliacdiseaseshouldbeconsidered.

7.2 Lowvalues
Thelowerreferencelimitiszero:lownormalvaluesareofno
significance.
7.2.1 Investigation
Notrequired.

7.3 Notes

8 Performance

8.1 Sensitivity,specificityetc.forindividualconditions
1.GarciaMonzonC,MartinPerezE,IaconoOLetal.Characterizationof
pathogenicandprognosticfactorsofnonalcoholicsteatohepatitis
associatedwithobesity.JHepatol2000;33:716724.Datasuggestthata
cutoffof40U/Lidentifiesasymptomaticpatientswithhepaticsteatosis
withasensitivityof45%andspecificityof100%;forsteatohepatitis,the
respectivevaluesare45%and64%.
2.SorbiD,BoyntonJ,LindonKD.Theratioofaspartateaminotransferase
toalanineaminotransferase:potentialvalueindifferentiating
nonalcoholicsteatohepatitisfromalcoholicliverdisease.AmJ
Gastroenterol1999;94:10181022.AnALT/ASTratio1.3provided
sensitivityandspecificityof75%forthediagnosisofnonalcoholic
steatohepatitis(NASH)inpatientswitheitherNASHoralcoholicliver
disease;thecorrespondingfiguresforaratioof2.0wereapproximately
100%and50%.
3.GianniniE,RissoD,BottaFetal.Validityandclinicalutilityofthe
aspartateaminotransferasealanineaminotransferaseratioinassessing
diseaseseverityandprognosisinpatientswithhepatitisCvirusrelated
chronicliverdisease.ArchInternMed.2003;163:218224.Oneof
numerousstudiessuggestingthatachangeinthevalueoftheALT/AST
ratiofrom>1(normal)to<1hashighsensitivityfordiagnosingcirrhosisin
patientswithchronichepatitisBorCinfection.

9 Systematicreviewsandguidelines

9.1 Systematicreviews
1.FraserA,HarrisR,SattarNetal.DiabetesCare.2009;32:741750.Epub
2009Jan8.Alanineaminotransferase,gammaglutamyltransferase,and
incidentdiabetes:theBritishWomen'sHeartandHealthStudyandmeta
analysis.Thissystematicreviewemphasisestheimportanceof

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 investigationsfordiabetesinindividualsfoundtohaveelevatedserumALT
activities(see7.1).
2.GeboKA,HerlongHF,TorbensonMSetal.Roleofliverbiopsyin
managementofchronichepatitisC:asystematicreview.Hepatology
2002;36(Suppl.1):S161172.DatasuggestthatALTpredictsfibrosisin
chronichepatitisCinfectionwithasensitivityofapproximately65%and
specificityof6694%.

9.2 Guidelines
Noneidentified.

9.3 Recommendations
TherearerecommendationsformeasuringALTinpatientsonvarious
drugs (e.g.statins,glitazones):themanufacturersliteratureshouldbe
consultedforfutherinformation.

10 Links

10.1Relatedanalytes
Aspartateaminotransferase(AST)isalsousedasanindicatoroftissue
damage;itismorewidelydistributedthanALTandthuslessspecificfor
theliver.

10.2 Relatedtests
ALTisusuallymeasuredaspartofapanelofliverfunctiontests(orliver
profile)(butsee3.1)typicallyincludingserumbilirubinandalbumin
concentrationsandalkalinephosphataseactivity.Aspartate
aminotransferase(AST)mayalsobeincluded,butalthoughcomparisonof
ALTandASTactivityinaratio(see8.1)mayprovidehelpfulinformation,
theinclusionofbothenzymesinaroutineliverprofileisofdoubtful
value(asistheroutineinclusionofgammaglutamyltransferase(GGT)in
aliverprofile).


Author:WilliamMarshall

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