PCT

Reviewarticle

Pathobiochemistryandclinicaluseofprocalcitonin

MichaelMeisner*

DepartmentofAnesthesiologyandIntensiveCareMedicine,UniversityofJena,Bachstr18,D-07743Jena,Germany

Received14November2001;receivedinrevisedform22March2002;accepted25March2002

Abstract

Inductionoftheproteinprocalcitoninduringinfectionandinflammationwasfirstdescribedapproximately10yearsago.A

largenumberofpublications,primarilyclinicalstudies,demonstratetheincreasinguseofprocalcitonininmodernclinical

practice.However,dataonthebiologicalfunctionandoriginofprocalcitoninisscarce.Findingsregardingthepossibleroleand

sourceofprocalcitonininsepsisandinfectionwererecentlypublished,andthepathophysiologyoftheproteinhasmeanwhile

beeninvestigatedinvariousexperimentalmodels.Procalcitoninobviouslyhascertainbiologicalfunctions,anditisalsoknown

tobespecificallyinduced.Giventhehormonaloriginofthematureproteinandtheinflammation-relatedfunctionsofits

propeptides,someinvestigatorssuggestthatprocalcitoninshouldbereferredtoasa‘‘hormokine,’’althoughitsbiological

functionsshouldbestudiedinmoredetail.Thisreviewwillsurveythedatanowavailableinrecentpublicationsonthe

induction,productionsources,possiblebiologicalfunctionsandclinicalusesofprocalcitonin.

D2002ElsevierScienceB.V.Allrightsreserved.

Keywords:Sepsis;Inflammation;Infection;Genetics;Biochemical;Metabolism;Calcitonin

1.Introduction

Procalcitonin(PCT)wasfirstdescribedasasepsis-inducedproteindetectableintheplasmaofpatients

withsepsisandinfectionintheearly1990s[1].

PreliminaryreportsindicatedthatPCTismainly

inducedduringseveresystemicinflammationcaused

bybacterialinfections,butthatPCTconcentrations

remainlowduringothertypesofinflammation(e.g.,

viralinfections,autoimmunediseases,organtransplant

rejection).Thiswassoonconfirmedbylaterstudies.

Themostcommonlydeterminedcalcitoninprecur-

sormoleculefragments,procalcitonin(PCT)anditscalcitonin–katacalcinfragmentsaremeasuredusing

commerciallyavailableassays(BRAHMS,Hennigs-

dorf,Germany).Theseassaysuseantibodiesthatbind

tothecalcitonin–katacalcinaminoacidchainofthe

molecule.Inadditiontoitsinductionduringsepsis

andinfection,experimentalandclinicaldataalso

indicatethatPCTcanbeinducedbyavarietyof

stimuliincludingbacterialendotoxins,proinflamma-

torycytokinesandtriggeringeventssuchastraumaor

cardiogenicshock.However,thePCTconcentration

remainslowwhenaninfectiondoesnotleadtoa

systemicinflammatoryresponse.Numerousstudies

clearlydemonstratethatPCTispreferentiallyinduced

inpatientswithsepsis,especiallyinseveresepsisor

septicshock,andthatpatientswithsystemicinflam-

mationofnonbacterialorigingenerallyhavelowPCT

levels.

0009-8981/02/$-seefrontmatterD2002ElsevierScienceB.V.Allrightsreserved.

PII:S0009-8981(02)00101-8*Tel.:+49-3641-933-041;fax:+49-3641-933-256.

E-mailaddress:michael.meisner@t-online.de(M.Meisner).www.elsevier.com/locate/clinchimClinicaChimicaActa323(2002)17–29Inadditiontoitspreferentialinductionduring

bacterialinfection,procalcitoninisalsocloselyrelated

totheseverityofsystemicinflammationandhasa

reliablekineticsofinductionandelimination.PCT

can,therefore,beusedtomonitorthecourseof

systemicinflammationandguidethephysicianin

therapeuticanddiagnosticdecision-making.Given

theseproperties,PCTmeasurementfoundapplication

inthecareofcriticallyillpatientsandinnumerous

intensivecareunits,sincethediagnosticqualitiesof

thisparameteraresuperiortothoseofconventional

markersofinflammation(e.g.,temperature,leukocyte

count,C-reactiveproteinandinterleukin-6)ina

varietyofindications.

Regardingitspathophysiology,informationonthe

biochemicalcharacteristics,induction,biological

functionsandproductionsourcesofcalcitoninpre-

cursorproteinsisscarce.However,newdataonthe

pathophysiologyofcalcitoninprecursorproteins,

includingPCT,wererecentlypublished.

Inthisreview,dataonthepathophysiologyofPCT

andrelatedproteins,includingtheirgeneticorganisa-

tion,transcription,differentialsplicing,proteinsyn-

thesisandposttranslationalmodifications,willbe

presented.Inaddition,thepotentialproductionsour-

cesandstimuli,measurementtechniquesandindica-

tionsforclinicaluseofPCTwillbesummarizedand

discussed.

2.InductionandsynthesisofPCT

2.1.TheCAPAproteinfamily

Procalcitoninbelongstoagroupofrelatedpro-

teins,includingcalcitoningene-relatedpeptides

(CGRP)IandII,amylin,adrenomedullin,calcitonin

anditsprecursors,oneofwhichisprocalcitonin.

CGRP-IandthemRNAofcalcitoninIandIIpre-

cursors,areencodedontheCALC-Igeneonchromo-

some11.Thisgenethusencodecalcitonin,PCT-I,

PCT-IIanditsvariouscleavageproducts.CGRP-II

arisesfromtheCALC-IIgene(chromosome11).

Adrenomedullinisalsoencodedonchromosome11,

whereasamylinarisesfromchromosome12(seeRef.

[2]forreview).Alltheseproteinsareusuallysecreted.

TogainaccesstotheGolgisystem,theyareinitially

producedinapro–proformconsistingofapproxi-mately100aminoacids.Furthermore,theycontain

twocysteineresiduesusedtoformadisulfidebridge

inadditiontotwoproteincleavagesitesbywhichthey

canbeprocessedtoyieldapproximately35amino

acid‘‘coreproteins,’’whichcanbeamidated.The

cleavageproductsarebiologicallyactiveandbindto

G-coupled7TM-spanningreceptors.However,this

hasnotbeenconfirmedforPCT.Giventhesecommon

features,membersofthisgroupofproteinsmaybe

describedasthe‘‘calcitoningene-relatedpeptide-

amylin-(pro-)calcitonin-adrenomedullinfamily,’’or

the‘‘CAPAproteinfamily.’’

2.2.DifferentialsplicingandmRNAsynthesisin

variouscelltypes

PCTmRNAissynthesizedbytheCALC-Igeneon

chromosome11duringsepsisandinflammation.The

CALC-Igeneisalsothesourceofmaturecalcitoninin

healthysubjects,whichisproducedbyCcellsofthe

thyroid(Fig.1).Noothergenesareknowntoproduce

inflammation-inducedPCT.Thegeneispresentin

variousmammalsandotherspecies(e.g.,salmon),but

theDNAsequencesandaminoacidsfoundinthese

animalsarespecies-dependent(Fig.2).Thelarge

degreeofconservationofthegeneinvariousspecies

indicatesthatitmayhavebiologicallyimportant

functions.TheCALC-Igeneisnotonlythesource

ofPCTandcalcitonin,butalsoofotherproteinsand

theirfragments.Itwasoneofthefirstgenesinwhich

differentialsplicingwasobserved[3].Calcitonin,

PCT-I,PCT-II,andcalcitonin-gene-relatedpeptide

(CGRP)-IareencodedbythisDNAsequence.Two

typesofPCTmRNAaresynthesizedwithinPCT-

producingcells,resultingintwodifferentproteins,

PCT-IandPCT-II,whichexhibitdifferencesateight

C-terminalaminoacids.Variablequantitiesofthetwo

Fig.1.Schematicdiagramofpreprocalcitonin,procalcitoninandits

fragments.AA=aminoacids.M.Meisner/ClinicaChimicaActa323(2002)17–2918