PROFILES and PITFALLS - Practical Topics in Lab Diagnosis

11/3/2016
PROFILESANDPITFALLS:PracticalTopicsinLabDiagnosis
EdFriedlander,M.D.,Pathologist
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Specialthankstomyfriendandcolleague,CharlesWheelerM.D.,pathologistandformer
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Toparaphrasemyfavoritephilosophyinstructor,SUCCESSFULSTUDENTSOFPATHOLOGYARE
SUCCESSFUL,ULTIMATELY,BECAUSETHEYLEARNTOPARTICIPATEINTHEACTIVITY.
Orderingandinterpretinglabtestswillbe,formostofyou,yourmostcommon"pathology"activityas
youpracticemedicine.
Thisisalsothehardestthingtoteachintheclassroom.Pathologiststhemselvesagreeaboutthis,but
can'tagreehoworwhenit'sbesttaught(Am.J.Clin.Path.100:594,1993).Withoutlivepatients,it's
almostasdeadlytoteachitastostudyit.
WHENIHAVEMORETIMEALLOTTEDANDHAVETOTRYTOTEACHLABMEDICINEINTHE
CLASSROOM,IUSEACASEBYCASE,SORTOFRANDOMORDER,ACTIVELEARNING
APPROACH.Noteveryonelikesthis,butitbeats"passivelearning,followthenoteslectures".Ifyou
canthinkofabetterwaytoteachlabuse,I'mallears.
Asalectureronlabuse,Itrynottoduplicatewhatyouhavelearnedaboutbugtestinginthe
"MicrobiologyImmunology"course.Andtheclinicalfacultywillprobablywanttotellyouaboutdrug
abusescreening,allergytesting,theworkupofgutproblems(diarrhea,malabsorption),andwhatto
dowhenwesuspectapulmonaryembolus.
Asapocketreference,IrecommendBAKERMAN.Labtextbooksfortheclassroomcontradictone
another,especiallywhenitcomestoscreeningalgorithms(i.e.,howmuchofotherpeople'smoneydo
youspendsearchingfortheunlikely).I'MHERETOTEACHYOUTHEWHATS,WHYS,ANDHOWS,
sothatyoucanmakesomesenseoutofthemess.
LEARNINGOBJECTIVES
Mostofthisunitisafantasiacenteredaroundthe"screeningtests"and"profiles"thatyouwillorderin
thehospitalandintheclinic.Youwilllearnhowandwhentoorderthesetests,andthereasons
peoplemayhavevaluesoutsidethe"normalrange"withoutbeingsick.Youwillalsoreviewsome
elementaryconceptsaboutlabtestingthatareoftenpointsofconfusion.
Theclassroomisn'ttheidealplacetolearnhowtoorderandinterpretlabtests.(See,forexample,a
discussionofthisprobleminAm.J.Clin.Path.100:594,1993).ButTHISSTUFFISWORTH
KNOWINGBEFOREYOUGOONROTATIONS.Fornow,hangontothishandoutforuseduringthe
activelearningtimeinlab.Hopefully,thisisn'tallentirelynewmaterial.
ORDERINGYOURLABTESTS
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In2007,about6.8billionclinicallabtestswereperformedintheUS,generatingabout$52billionin
revenue,whichisonly2.3%ofhealthcarespendingbutinfluencesthemajorityofhealthcare
decisions(Am.J.Clin.Path.138:347,2012).Theindustryisquiteefficient(Arch.Path.Lab.Med.
112:235,1988stillgood),andtheDRGguidelinesfromthe1980'swerereallyquitereasonable.A
certainamountofchaosstillreignsintheroutineorderingoflabtests.Butdespitewhatyou'veheard
about"unnecessarytesting",estimatesfromjustbeforemanagedcarejudgedthatonlyaround20%
oftestsweresuperfluous(J.Gen.Int.Med.5:335,1990Arch.Int.Med.149:549,1989).Yes,you
candevelopanemiafromhavingtoomanybloodtests,evenifyou'reagrownup(Crit.Care.Med.17:
1143,1989).Theworst"unnecessarytesting"isprobablycliniciansreorderinglabsfornorealreason
(J.Clin.Path.58:457,2005)ofcourse,thisisfromthepathologist'spointofview,andperhapsthe
clinicianssuspectlaberrors.(Laberrorsstillhappenmostarewithspecimiencollectionanddelivery
"preanalyticerrors"Am.J.Clin.Path.138:477,2012.Whatwasadreaminmyschoolyearsis
nowarealitytotypeapatient'sIDintoacomputer,seetheirfullarrayofcompletedandpendinglab
tests,andperhapsevengetaninterpretationandadvice.
STANDARDIZATIONoflabtestingmeansthataparticularhealthcaresystemusesthesameassay
systeminallitslabs(i.e.,thesamemethodofdetermininghemoglobinA1c).Untilwehavefull
HARMONIZATION(i.e.,allcommerciallyavailableassaysystemsgiveexactlythesamereuslt),
Inthe1980's,itwaspoliticallycorrecttoinveighagainstlaboratorytestsforscreening.Theracketof
chargingmegabucksfor"interpretingthechemicalprofile"hasbeeneliminatedbynewmethodsof
reimbursement.Butperverseincentivesremain(seebelow).Thetruthisthatscreeningisagood,
cheapwaytofinddiseasethatyoucantreatandthushelppeople.Mayo'sgot1%orbettercase
findingfromeachofthefollowing:lipidprofile,chemicalprofile,urinalysis,CBC,thyroidscreen(Am.J.
Med.101:142,1997).Alsoseebelow.
Thehospitallaboratoryisusuallyrunbypathologists.Mostofusenjoyhelpingmedicalstudentsand
cliniciansinterpretthewelterofdatathatthelabprovidesontheirpatients.Infact,thepathologist's
abilitytocommunicatewiththecliniciansisthemostimporantfactorinpreventingclnician
dissatisfaction(Arch.Path.Lab.Med.130:645,2006).Mostlabproceduresareautomated,andvisits
tothelabarefascinating.(There'sadandyseniorpathologyelectiveatUMKC,justdowntheroad.
Call5563785.)Mostphysiciansroutinelydiscusslabtests(andmosteverythingelse)usingjargon
names(acronyms,etc.)Youwilllearntheseonrotations.
Asaclinicalstudent,youwillORDERLABTESTSunderthesupervisionofthehousestaffand
attendingstaffonyourservice.Thisiseasy.YOUwritethenameofthetest(s)youwantonthe
ORDERSHEETinthepatient'schart(thesamesheetwhereordersfordrugs,treatments,etc.,are
listed).YourINTERN,RESIDENT,orATTENDINGmayneedtocountersignyourorder.TheWARD
CLERKtranscribesyourorderontoa"labslip"and,ifthelabneedstodrawblood,sendsittothelab.
Nextmorning(orperhapssooner)thePHLEBOTOMISTfromthelabwillcomeanddrawblood,ifyou
wantabloodtest,ortheNURSESwillgetaurinespecimen.(Justwhocollectswhat,andwhen,
variesfromhospitaltohospital.Youwillhaveplentyofopportunitiestodrawbloodfromyourown
patients.)Headsupunlessthelabistryingextrahardtoenforcestrictpolicies,onetubeofblood
outof400willbefromthewrongpatient(Am.J.Clin.Path.132:164,2009).TheMEDICAL
TECHNOLOGIST(highlyeducatedandregulated)ortheMEDICALTECHNICIAN(notquitesoelite)
performsthetest.Mostroutinetestsarebatchedandruninthemorningassoonasthephlebotomists
aredonecollectingallthespecimens.ThelabreportstheRESULT,usuallyononeplyofthelabslip,
orperhapsonacomputerprintout.Thereportusuallyfindsitswaybacktothepatient'schartby
evening.(Iftheresultissufficientlyabnormaltoindicateanimmediatethreattolife,thelabrecognizes
aCRITICALVALUE("panicvalue")andwillphonethenurse,theresident,orsomebodyotherthan
themedicalstudent(updateonthisimportantarea:Arch.Path.Lab.Med.126:6632002Am.J.Clin.
Path.125:758,2006Am.J.Clin.Path.128:604,2007Arch.Path.Lab.Med.131:1769,2007).
Panicvaluesarenowoncomputer:Arch.Int.Med.163:200,2003costisnearzeroandeverybody
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seemstobenefit.)YOUlookattheresultanddecidewhatitmeans,becauseyouwillbequizzedonit
tomorrow!
Today,POINTOFCAREtestingisbecomingmorecommon.Thesearelabsdoneatthebedside
(outpatientclinic,operatingsuite,homeselfmonitoring).Changingwherethetestisdonedoesn't
seemtoimpactusagemuch,atleastinsurgery:Anesth.Analg.105:1711,2007.EKG'sandcheap
gadgetstodeterminepeaklungoutflow(i.e.,screeningspirometry)haveofcoursebeenavailablefor
decades.Dipstickingurinetosearchforinfection(J.Clin.Path.58:951,2005)andotheracutekidney
problemsisoldhatbutstillveryuseful.Glucometersareubiquitousintoday'shealthcare,anditis
hardtoavoidhavingapulseoximeterattachedinthehospitalbothweredreamswhenIwasin
medicalschool.SalivatestingforHIVhasrevolutionizeddetection.Pointofcaretestingfor
Helicobacterandcholesterolarecomingintouse.Pointofcareelectrolytes(forexample,thenewi
STAT)stillhassomeproblemsbutseemstobeusable(J.ExtraCorporTech.40:57,2008).Pointof
carecreatinineisbeingintroduced(Clin.Chem.Lab.Med.45:1536,2007).
Ofcourse,yourememberthatPLASMAisalltheunformedelementsoftheblood,examinedwhenthe
bloodhasNOTbeenallowedtoclot.SERUMistheliquidthatremainsAFTERbloodhasclotted.
Notably,healthyserumlacksclottingfactorsI,II,V,VII,andXIII.
Youwillorderthefollowingtestsfrequently.(Somemaystillbepartof"routinetestsonadmission"for
"screening"or"baseline".Seebelow.)
COMPLETEBLOODCOUNT(CBC,nowperformedbymachine"Coultercounter",etc.).
Thisincludeshemoglobin,hematocrit,redcellcount,redcellindices(MCV,MCH,MCHC).
(Hemoglobin,redcellcount,andMCVareactuallymeasured,theothersarecalculated.)It
alsoincludesawhitecellcount("WBC",always)andusuallyincludesplatelets.Yourlab's
machinemayalsoestimatepercentagesoflymphocytes,granulocytes,monocytes,
eosinophils,andbasophils,and/ormeasurethe"RDW",RedcellvolumeDistribution
Width,ameasureofanisocytosis.)
*WeprefertheRDWSD(standarddeviation)totheRDWCV(coefficientof
variation)sinceRDWSDwon'tbemaskedbylargercellsorexaggeratedbysmaller
cells.(Whynot?)
*TheAustraliansexperimentwithautomatic(i.e.,computergenerated)orderingof
labtestsbasedondiagnosis:J.Clin.Path.59:533,2006.
COMPLETEBLOODCOUNTWITHDIFFERENTIALWHITECELLCOUNT(CBCwithdiff)
Thisincludeseverythingonyourhospital'sCBC.Italsoincludesadifferentialcountof100
(or200ormore)whitecells,normalandabnormal.(Thisisnowusuallyautomated,also.)
Italsoincludesshortdescriptionsandsemiquantitation(+to+++,etc.)ofredcell,white
cell,andplateletmorphology,areincludedasrequired.
Inagoodlab,there'samanualreviewbyarealtechnicianofanyoutoflinefindingsby
theautomatedmachine.Around15%ofperipheralsmearsgetamanualreview(Arch.
Path.Lab.Med.130:596,2006).Iusedtolookatallofthesemyselfeachmorningand
evening.Veryseldomwouldanexperiencedtechnicianmakeamiscall.
ROUTINECBC:
Dependingonyourhospital,youwillautomaticallygeta"diff"oneverybody,onpeoplewith
abnormalWBC's("reflextesting"),oronnobody.
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CHEMICALURINALYSIS("U/A")
Thisalwaysincludesappearance,specificgravity,pH,protein,glucose,ketones,and
blood,andmayincludebilirubin,nitrite,andurobilinogen.
CHEMICALURINALYSISPLUSSEDIMENTEXAM
Thelabwillusuallyexaminethesedimentifthechemicalurinalysisisabnormal,andwill
alwaysexamineitifyouask.Automatedurinalysis:Clin.Lab.Med.8:449,1988.
"Fishboneconvention":Hereishowyoucanrepresentyourlabvaluesinachart(thanksUCSF).
USAversionthesevaryfromnationtonation.
AUTOMATEDCHEMICALPROFILE("Chemistry12","SMA18","SMAC",VP,Ektachem400,
Hitachi737,TechniconChem1,etc.,etc.).
Abatteryoftestsdescribedbelow.Unliketheothertestsinthissection,itwillnotbe
availableonanemergencybasis.(Pediatrichospitalsmaynothavesuchabattery.)
*Funread:DoingtheiSTATbloodanalyzerinspaceflight.Clin.Chem.43:1056,1997.
ELECTROLYTES("'lytes","electriclights",etc.)
Thisalwaysincludessodium,potassium,chloride,and"totalCO2"(whichiswithinafew
percentoftherealserumbicarbonateionconcentration).Itoftenincludesglucoseand
BUN,andsometimesevencreatinine.Appropriateordering(intheemergencysetting):
Ann.Emerg.Med.20:16,1991.Aportableanalyzerthatrequiresonlyadropofbloodto
dotheworks:Am.J.Clin.Path.100:599,1993.
BLOODGASES(oftenperformedinadifferentlab)
ThisalwaysincludespH,PaCO2,andPaO2.Youmayalsogethemoglobin(measured),
oxygensaturation,"totalCO2",baseexcess,andothervalues.
YoucanorderahugeselectionofOTHERTESTS."Profiles"mayexistatyourhospitalforvarious
organsorproblems("liverprofile","kidneyfunctiontests","lipidscreen","hypothyroidcheck",etc.)
The"serumporcelain"(for"crackpots")isonlyalegend.Sometestsarerunonlyonceortwicea
week.Mosttestsareruninabatchatthestartoftheday.Pleasedon'tasktohaveaserumprotein
electrophoresisoraroutineautopsydoneinthemiddleofthenight.Ifthehospitallabdoesnot
performaparticulartest,itwillbesendtoaREFERENCELAB,usuallyonafeebasis.(Ora
researcher'slabatthemedschoolmightdoit.)TheLabDirectormaynotapproveeveryexotictest
youorder.
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Ifaresultsuggestsseriousdisease,yourlabmayperformsometestsautomatically(aREFLEX
PROFILE)forexample,ifamonoclonalspikeappearsonproteinelectrophoresisandthepatientis
notknowntothelab,youmaygetaninstantimmunofixationtocharacterizeit.
Ifyouordera"STAT"TEST,thelabpersonnelrunyourtestbeforecontinuingworkonanythingelse.
Youwillgetyourresultinminutes.(Thelabwillprobablyphoneyou.)Ofcourse,thisisinefficientand
overallholdsupeverybodyelse(Arch.Path.Lab.Med.123:607,1999Arch.Path.Lab.Med.121:
1031,1997).Butinemergencysituations,youneedtobeabletoordera"stat"test!Askyourself(1)
Doyoususpectthepatienthasalifethreateningabnormalitythatrequiresimmediateattention?(2)
Doyouneedtheinformationforamanagementdecisionthatyouwillmakewithinthenextfewhours?
Yourstattestmayberunintheregularlab,oritmayberuninasatellitelab("statlab","bloodgas
acutecarelab",etc.)Inmanyhospitals,youcangetatestrunsoonerthanitwouldotherwisebe
withouthavingtoresorttoa"stat".Forexample,youmaybeallowedtotellthelab"PRIORITY",
"TODAY","PATIENTISWAITING,"etc.(Especiallyformonitoringof"peakandtroughlevels"of
therapeuticdrugs,youcanarrangetohaveblooddrawnatparticulartimesduringtheday).
Thefollowingtestscanusuallybeordered"stat"withoutanyhassle:bloodgases(usuallyastat
procedure),electrolytes(serum,urine),osmolality,calcium,glucose,bloodureanitrogen(BUN),
creatinine,ammonia(maybe),amylase,"ketones"(acetoaceticacid,etc.),urinalysis(chemical,
microscopic),CBC,differentialwhitecellcount(maybe,ifyou'reanoncologist),plateletcount(ifnot
regularlypartofCBC),Gramstainandsmearforacidfastbacilli(youmayhavetodotheseyourself),
bloodcultures(ifthelabdrawsthese),serumdigoxinlevel,serumlevelsofvariousantibioticsand
otherdrugs,PT,PTT,fibrinogen,fibrindegradationproducts,LDHtotal(maybe),bloodbank
(crossmatch,plateletsandfreshfrozenplasma),cerebrospinalfluid.Thesetestsshouldalwaysbe
availableona"sameday"basiswithoutyourhavingtoresorttoa"stat"togettimelyresultswhen
thereisnoemergency.
Yourofficelabmaybeequippedwithatleast(1)adesktopbloodcellcounter(2)adesktopchemistry
machine(3)adesktopimmunoassaymachine.Thankfully,CLIA(theFederal"ClinicalLaboratory
ImprovementAct",whichoriginallywasadisasterforcommonsenseofficelabs)wasmodifiedto
waivethestringentguidelinesforthesimple,routinetests.
Ifyoudon'tunderstandtheprincipleofanenzymelinkedimmunosorbentassay(ELISA),takea
minuteandreviewthebiochemistry.YouwanttoknowwhetherathresholdamountofSubstanceXis
presentintheplasma/serum.Weprepareasurface(perhapsanyloncardoraspecialplasticwell)
andbindtoitsomethingthatwillinturnbindSubstanceX.Weaddplasma/serum,letSubstanceX
bindifitispresent,thenrinseeverythingelseoff.Nowweaddsomethingelsethatbindsto
SubstanceXandcanmakeitvisible(favoritechoicesareantibodiesboundtoperoxidaseorbiotin).
It'seasy,convenientandversatile.
Rememberthatmostdefinitivediagnosesofseriousdiseaseslikecanceraremadebyexamining
tissueCYTOLOGIES,BIOPSIES,orlargerSURGICALSPECIMENS.Beforemanagedcare,young
doctorswereindoctrinatedto"doallthenoninvasiveproceduresfirst."Theseincludesbloodand
urinetests,cultures,xraystudies,andsoforth,andthishelpedprolonghospitalstaysandincrease
hospitalprofits.Iwasgladtoseethechange.Andrememberthatthesinglemostusefuldiagnostic
procedureisstillthehistoryandphysicalexam.
WHAT'SINTHOSEVACUUMFILLEDBLOODSAMPLETUBES?
Worthknowing:
Redtop:Nothing(theplasticonecontainssilicagranulesonthewallsasaclotactivator).The
bloodwillclot,andtheserumisseparatedbycentrifugation.Usedformostroutinechemistries.
Nowadaysmost"redtop"tubesareredandblack"tigertop""serumseparator"toptubes
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(SST's),withasiliconeseparatorandaclotactivator.It'sfasterandmoreconvenienttogetthe
serum.
Purpletop:EDTA(calciumchelatinganticoagulant)inliquidform.Bestforbloodcellcounting.
Besuretogetfillthetube,andinverteighttimesforpropermixing.
Today'shightechpinktoptubeshavetheEDTAspraydriedontheinnersurfaceofthe
tubes,soasnottodilutethesample.Stillgottamix.
Lightbluetop:Ameasuredamountofcitrate(calciumchelatinganticoagulant,readily
neutralized).Weaddabitofadenosineandsomeotherstufftokeeptheplateletshappy.Best
forroutinecoagulationstudiesincludingplateletfunctiontests.
Graytop:Fluorideoxalate.Inhibitsglycolyticenzymes.Bestforglucoseandroutinetoxicology.
Greatforlithiumdeterminations.Butbesuretofillthetube,orthenoxiousanticoagulantmay
hemolyzeyourredcells!
Yellowtop:Acidcitratedextrose.Teststhatmustbekeptatroomtemperatureandshippedtoa
referencelab.PCR'sandreferenceimmunologyespecially.Somelabsfavortheseforall
serology/immunologyandhormones.
Lightgreentop(sometimesgreengraytiger):Lithiumheparinanticoagulant.Lesspopularthan
theothers,forplasmalevelsinchemistry.Ifyouneeda"plasmarhubarblevel",thisistheoneto
use.
Gray/yellow"tiger"top:Thrombin.Instantclottingforstatsonserum.
*PaleYellowtop:sodiumpolyanethiolesulfonate(SPS),removescationicantibioticsaswellas
anticoagulatingagain,inverttomix.Notmuchused.
*Tantop:Leadfreeglassforleaddeterminations.Theanticoagulantisheparin.
*Navybluetop:Tracemetalfree.
*Greengraytigertop:Lithiumheparinplusseparatorgel.Bestforplasmadeterminationsin
chemistry.
*Blacktop:Speciallybufferedsodiumcitrate,supposedlythebestfortheWestergrensedrate.
Theplastic"hemogard"stoppersthatseemstobereplacingthebelovedrubberstoppersdifferslightly
incolorcodes...mostnotably,therubberredblacktigertopusesagoldhemogard.
Thelabwillprobablykeepahospitalizedpatient'sbloodfor3days,andanoutpatient'sbloodfor
7days,incasetheclinicianwantsadditionaltests("addon"):Arch.Path.Lab.Med.131:1694,2007.
ROUTINESCREENING
Ahealthypersonissomeonewhohasnotbeencompletelyworkedup.
Internist'sjoke
Theobjectofscreeningistodetectunknown,treatablediseasewithoutexcessivecostoffindingand
workingup,andriskofworkingup,falsepositives.TheDemocrats,theRepublicans,theinsurance
carrier,thepremiumpayer,theprivatepayer,andthetaxpayerareworriedaboutthelatterthepatient
isworriedabouttheformer.
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Dependingonyourhospital,everyoneadmittedmaygetsomeorallofthefollowingtests,whichwill
becalled"theroutineadmittinglabwork".Thefirstsixusuallyfallintothedomainoftheclinical
pathologist.Theseare
(1)CBC(andperhapsa"diff")
(2)chemicalurinalysis(andperhapsasedimentexamination)
(3)automatedchemicalprofile(seebelow)
(4)thyroidscreen(T4,maybemoreSouth.Med.J.83:1259,1990Br.Med.J.314:1175,1997,
"waituntiltheydevelopsymptoms"USPSTFintheAnn.Int.Med.140:128,2004"routine
screeningofpregnantwomenandwomenoverage60":JAMA291:228,2004bloodspottest
toscreenthetrisomy21kids:Arch.Dis.Child.82:27,2000pleasefolksdon'tmissthyroid
disease)
(5)syphilis test(RPRoranothernotabadideaespeciallyinpeoplethatcommonsensewould
tellyouareatrisk:Ann.Emerg.Med.22:781,1993inmanyjurisdictionsitismandatoryfor
pregnantwomen(knowyourstate/nationallaws)overseassyphilistestingisamajorhealth
benefitAm.J.Pub.Health87:1019,1997itmightbeagreatbenefitforUSarrestees,with
around3%testingpositiveforactiveorlatentsyphilis:Am.J.Pub.Health87:1423,1997).You
rememberthatRPRandVDRLaremoreoftenthannotpositiveinprimarysyphilis,butalways
positiveathightitersinsecondarysyphilisinuntreatedlatesyphilisabout70%ofcasesremain
positive.VDRLworksonCSFbutRPRdoesnot.RPRlevelsdropaftereffectivetreatment.You
alsorememberthathFTAAbsandTPHA(treponemapallidumhemagglutination)andELISA
testsforantibodiesstaypositiveforlife.
(6)Prostatebloodwork?
aftermuchtodo,aprostatespecificantigenisnowroutineforoldermen(oldworkJAMA
267:2215&2236,1992update,includingwheretoplacedecisionlevelsJ.Urol.177:
499,2007it'sbeendifficulttoshowthatthisreducesmortalityormorbidityAm.Fam.
Phys.57:1531,April1998morefavorablearticletosupportscreening:Ann.Int.Med.
144:441,2006thecaseagainstextensivescreeningAnn.Int.Med.144:438,2006)
(7)TB skintest(forthosenotknowntobepositive)
(8)electrocardiogram(EKG,ECG)("forbaseline")
(9)chestxray(CXRprobablynotindicated.SeeNEJM312:209,1985there'sanewpushto
returntoroutinechestxraystofindearlycancersinsmokers:Chest112S4:216S,1997)
(10)papsmear/liquidcytology/HPVforwomen
(11)mammogramforwomenoverage40or50(manyarticlesrecommendationsvaryfromnationto
nation)
(12)Watchforroutinescreening(everyfewyears)forlowB12levels.Thisislongoverdueand
peoplearestartingtotalkaboutit.Arch.Phys.Med.86:150,2005Geriatrics58:30,2003.
PoliticsiscertaintodeterminethestatusofroutineHIVscreeningyou(thephysician)aremorelikely
toberequiredtosubmittoscreeningthanisyoursurgicalpatient.Therearesupposedlyabout
300,000peopleintheUSwhoareHIVpositivebutdon'tknowit(Arch.Int.Med.162:887,2002).
Sincethefirsttenyearsoftheepidemic,therhetorichasshiftedfrom"protectingpeople'srightnotto
betested"to"gettingpeopleinforvoluntarytesting"andbewailingthefactthatmostprimarycare
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physiciansdon'tscreenpeopleatrisk(Am.J.Pub.Health92:1784,2002).Probablyyoustillcan'ttest
withouttheperson'sconsent(eveninprisoners:Pub.HealthRev.116:520,2001).Intheearly2000's,
hospitalsservingunderclasscommunitieshaveteamstogetinpatientstoaccepttesting(Arch.Int.
Med.162:887,2002).Especially,theavailabilityofmedicationstokeepBabyfromcatchingHIVfrom
Momhasmadescreeningimportant,andevenmost(notall)ethicistsconsiderthatsocietymay
requireMomtoaccepttreatment.OraSurehasrevolutionizedHIVtestingamongtheunderclass(Am.
J.Pub.Health94:29,2004),andPCRforthevirustestingis(orshouldbe)routinesoasnottomiss
theacuteinfections(JAMA288:216,2002).Withtoday'seasysalivascreening,"consent"isturning
into"optout"(i.e.,yousay,"YouwantthequickieHIVtest,don'tyou?")
Curiously,the"ethicists"areonlynowstartingtonoticethatwe'vebeentestingfordrugsofabusefor
decadeswithoutinformedconsent(Am.J.Med.115:54,2003)Ipredictthiswillgonowherebecause
people'slivesinanemergencysettingdependonourbeingabletogetthisinformationwithoutany
interferencefrompersonsofdelicateconscience.(Thepersonscreenedisstillprotectedbytherules
ofphysicianpatientconfidentialityandtherequirementthatifatestistohavealegalimpact,itmust
beconfirmedbyaseparatetestusingadifferentchemicalprinciple.)
Oneofthegreatlandmarkswasthe1989UnitedStatesPreventiveServicesTaskforce(USPSTF
availablefromWilliam&Wilkins).Itchangesastheyearsgoby.TheUSPSTFmarchesonward,its
methodsbeingreviewedhere:Ann.Int.Med.147:871,2007.Theirmainwebsiteseemstobedown
(July8,2008).Clickhereforthepocketguideonpreventiveservices."Cookbookisbetterthanno
book",especiallywhenitcomestoscreening,theopportunitiestowastemoneyandtimeare
enormous,andguidelinescoverone'sreputationifyoudidmisssomethingbynotorderinganultra
lowyieldtest.Foranolderoverviewofscreening,seeJAMA254:1480and1499,1985.Duringthe
followingyears,aconsensusseemstohavebeenreachedthathealthyyoungfolkscominginfor
minorsurgeriesdon'tneedanylabsatall.ApplicationofUSPSTFguidelinestotheelderly(with"cost
effectiveness"data):J.Fam.Pract.34:320,1992.
Lawmandatesthescreeningofnewbornsforsuchthingsrequiringearlyrecognitionas
hemoglobinopathies,phenylketonuria,galactosemia,andcongenitalhypothyroidism(Arch.Dis.Child.
67:1073,1992).Manystatesalsomandatescreeningforcongenitaladrenalhyperplasia,biotinidase
deficiency(limbparalysisandblindness,controllablebygivingbiotin),sicklecelldisease,G6PD
deficiency,homocystinuria,tyrosinemia,Duchenne's,and/ormaplesyrupurinedisease(progressive
braindamage,preventablebylimitingintakeofbranchedchainaminoacids).Today'stestsareso
sensitive(whichisgood)thatthereareabout50falsepositivesforeverycasefound(Arch.Ped.Adol.
Med.154:714,2000).Theseprobablygetdoneautomatically.Neonatalscreeningandtheproblems
causedbyfalsepositives:Clin.Chim.Acta.315:99,2002Arch.Ped.Adolesc.Med.154:714,2000.
Youwillalsoscreenyoungkidsforleadpoisoning(Am.J.Pub.Health93:1253,2003)oldleadpaint
inhousesremainsamajorhealththreataboutwhichthepoliticiansaredoingnothing(contrastthe
"asbestosintheschools"hooplaofthelate1980's).
Likewise,protocols(oratleastrecommendations)existforlabtestingaspartofprenatalcare
everythingfrombloodpressuretoglucosetoillegaldrugs(Am.J.ObGyn.166:588,1992)toalpha
fetoproteintotrackdownneuraltubedetects(Am.J.Clin.Path.97:541,1992).
Futureclinicianstakenote:Here'sareasonablycurrentlistofthingsthatareprobablyworthdoing
routinelyforASYMPATOMATICCLEANLIVINGGROWNUPSWITHOUTFAMILYHISTORIESOF
ANYTHINGESPECIALLYBADORPOSSIBLEEXPOSURETOSLOWACTINGPOISONS.Askthe
localUSPSTFguru:
urgingpeopletoturntheirhotwatertemperaturedownto120F
urgingpeoplenottosmokeinbed
urgingpeopletoinstallsmokealarms
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tryingtofindoutwho'saproblemdrinker(goodluck!)
askthewomenaboutdomesticviolence(MayoClin.Proc.73:271,1998)
urgingpeopletogetregulardentalcare
urgingpeopletoexercise
urgingpeopletowearseatbelts
urgingcycliststowearhelmets(Am.J.Pub.Health84:653,1994)
discussinggeneralnutrition
tryingtofindoutjustwhatmedicationsthepersonistaking
recommendingcessationofsmoking
urgingmonthlybreastselfexamforwomen
urgingadvancedirectives,durablepowerofattorney
urginganaspirinaday(topreventstrokesandheartattacksmaybe,wait'llyou'reinpracticefor
abetterassessmentofbenefit/riskratio)
considerurgingpostmenopausalwomenwithhysterectomies(andperhapswithout)totake
supplementalestrogen
offering'flushotsyearlytoeveryone65andover
offeringpneumococcalvaccineoncetoeveryoneage65andover
tetanus toxoideverytenyears(ordiphtheriatetanusvaccine)
officehealthmaintenancevisitmaybeyearly(maybemoreintheoldold)thisincludesabasic
physicalexam(remembertolookaroundinthemouth,especiallyifit'sanoldsmoker:Cancer
72(S3):1061,1993
checkeveryguyforherniasandtesticularmasses
doarectal(andcheckprostate,ifamanBr.Med.J.300:1041,1990)
checkingbloodpressure
annualclinicalbreastexamandmammogramtoage75(oneUSPSTFrec)recommendations
varyfromnationstonation.TheNCIwentthroughaseriesofflipflopsinmaking
recommendationsfortheUSAduringthepasttwodecades.Changeswillcontinue.
papsmears/HPVtestingforwomen(historicallywestartedwithfirstintercoursedoevery13
years,stopatage65ifthelasttwowerenormalthiswillchangebythetimeyouareinpractice)
stooloccultbloodyearly(oldrecommendation:everytwoyearsages4050,thenyearly),maybe
aflexsigeverythreeyears(longerthanthatisprobablytoolong:JAMA290:41,2003)
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Coloncancerscreening:Sowellestablishedthatroutinecolonoscopyshouldbethe
provinceoftheprimarycarephysician(Cancer109(S2):378,2007)
WhentheJointCommissiononAccreditationofHospitalsissuedelaborateregulations
requiringdocumentofqualitycontrolonoccultbloodtesting,physicianssimplystopped
doingrectals(Ann.Emerg.Med.51:197,2008).
takeagoodlookattheskinformelanomasandothercancersandprecancers,especiallyif
there'sahistoryofsunexposureorsomeotherriskfactor(butyoushouldlookateverybody:
Cancer75(S2):674,1995)
listenforacarotidbruit,maybegetaDopplerforthoseoldfolks
doacheaphearingtest
checkvisualacuity(evenonkids,Doc:Pediatrics89:834,1992)
quickglaucomatestifyou'reaneyespecialist
ultrasoundwomenforovariancancer(probablynot,butstillacurrenttopic,seeBr.Med.J.299:
1363,1989negativeappraisalAnn.Int.Med.121:124,1994negativeNIHconsensus
statementJAMA273:481,1995morePostgrad.Med.102:112,1997)
ultrasoundolder(>50yr.)peopleforabdominalaorticaneurysms(well,thiswasanideaawhile
backseeSurg.Clin.N.A.69:713,1989)
serum(orfingerstickPrev.Med.20:364,1991Am.J.Card.65:6,1992)cholesterol,starting
inteenagedyearsorbefore(kidsatriskarethosewithaparentwhohadcoronarydisease
beforeage60,oraknowncholesterolproblem:Pediatrics88:269,1991,Pediatrics94:296,
1994)repeatedoccasionallytoage75considerfractionatingintoLDLc/HDLc(much
ballyhooed,butnotallthatusefulintheabsenceofaseriousproblemsomepeoplecheck
everybody'sratio)despitepredictions,apolipoproteinBassaydidnotreplaceroutine
cholesterolscreeninginthe1990's(Can.J.Card.8:133,1992).NIHconsensusdocumenton
cholesteroltesting(JAMA269:505,1993)therehasbeennorealchangeinthepasttenyears.
chemicalurinalysis(yearly,maybethere'sacasetobemadeforscreeningfolksover60for
bacteria,pregnantwomenforproteinuria,andteens:Postgrad.Med.100:173,July1996)
syphilistest(oldrecommendation:everyfiveyearstoage50routinescreeningseems
unpopulartoday)
serumironandironbindingcapacityinamanonceinawhileasayoungadult(oneofthemost
costeffectivethingsyoucando:Arch.Int.Med.154:769,1994Gastroent.107:453,1994
Postgrad.Med.102:83,Dec.1997Ann.Int.Med.129:925&962&971&980,1998
Postgrad.Med.102:83,1997.notaUSPSTFrecommendation,whichwasdim).
lipoproteinLp(a)screen,once,foranybodywithafamilyhistoryofunexplainedcoronary
disease(Arch.Int.Med.157:1170,1997).
serumhomocysteine?staytuned
hepatitisCscreenforswingersandneedleusers(about1/3ofhepatitisCpositivepeoplehave
normalSGOT)
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screenforceliacsprue(?!antiendomysialorantigliadinantibodies:Am.Fam.Phys.57:1023,
1998).Sinceonewhitepersonin300hasit,andit'llmakeyouhorriblysick,perhapsthisis
worthdoingoccasionallyonhealthypeople,oranybodywho'sgotvaguesymptoms.
serumCA125screenforwomentodetectcanceroftheovary(discreditedthankstopoor
sensitivityandspecificity:J.Clin.Path.58:308,2005)
Helicobacterscreenforanybodywithafamilyhistoryofthisorofstomachcancer(Am.J.Med.
106:222,1999)
serumprostatespecificantigenforoldermen
(maybe,seeabove)
screenoneyearoldsandtwoyearolds,andmaybeolderkids,forleadpoisoning
Screeningisnowinplaceyoushouldscreenkidsifthey'veeverlivedinahousebuilt
before1960,orifyourequiredtodosobythestrangepoliticsrememberthere'splentyof
leadevenoutsidetheurbanslums:Pediatrics94:59,1994,buttheyieldinnonslumkids
willbeverylowrememberparentslieabouttheageoftheirhouse(Arch.Ped.Lab.Med.
157:584,2003).Thereisnoconsensusaboutwhentotreat,butit'sstillgoodthat
screeningistakingplace.
serumsupersensitivehTSH(orsomeotherthyroidtest)tocheckforpreclinicalthyroiddisease
(mayberememberthyroiddiseaseiscommon,insidious,anddevastatingseeClin.Endocrin.
32:185,1990maybedoitevery5yearsJAMA276:285,1996)
bloodglucoseonlyifthere'ssomesymptomtosuggestdiabetes(whatsymptomdoesn't?,see
forexampleJ.Fam.Pract.33:155,1991)
EKG(once,baseline,maybe)
TBskintestunlessknownpositive(occasionally,maybe,ifthere'slotsofTBinthecommunity
olderrecommendationwaseverytenyears)
chlamydia screenforyoungfolks(huh?!whichones?)NewDNAtechnologymakesitpossible
tospotchlamydiaandtreatwithonedoseazithromycin,benefittingthecommunity,andmass
screeningisnowcomingintofashion(J.Inf.Dis.179S2:S380,1999,muchmoresince
USPSTFAnn.Int.Med.147:128,2007)
NOTETHATTHISLISTDOESNOTINCLUDEAWHOLELOTOFBLOODWORK!Thereare
additionalinterventions(includinglabtests)thatshouldberoutineduringpregnancy,andthingstodo
forchildren.
Mychoicefor"biggestwasteofeverybody'stimeandmoney"...asputumcytology"toscreenfor
lungcancer"(J.Clin.Path.50:566,1997).Runnerup:Sedrates"toscreenfordisease"in
healthypeople(Postgrad.Med.103:257,1998).Andobviouslyyoucan't"doeverythingthat
theyrecommend"onyourpatientsastheycomethroughyou'dNEVERgetdone.
Whenwefigureouthowtotreatthethrombophilias,wemayscreeneverybodyrightnow,
there'sprobablynoreasonto(Ann.Int.Med.127:895,1997).
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THEAUTOMATEDCHEMICALPROFILINGMACHINE
Today,almostalladultpatientswhopresentdiagnosticproblems(orwhosomebodywants
"screened")receiveanAUTOMATEDCHEMICALPROFILE(apanelofcolorimetricassaysonthe
serumdonebyamachine).Theseareruneverymorning(maybenotonweekends).Thebestknown
ofthemachinesincludetheTechniconSMAC,EastmanKodak'sEktachem400,andtheHitachi7377.
Testsontheprofilewillusuallyinclude:
Totalprotein
Albumin
Calcium
InorganicPhosphate
Cholesterol
UricAcid
Creatinine
Bilirubin
AlkalinePhosphatase(AlkPhos)
LactateDehydrogenase(LD,LDH)
AspartateAminotransferase(AST,SGOT,
GOT)
Andtheprofileatyourhospitalcouldalsoincludeoneormoreofthese:
Triglycerides
Iron
TotalIronBindingCapacity(TIBC)
UnsaturatedIronBindingCapacity(UIBC)
DirectBilirubin
AlbuminGlobulinRatio(A/Gratio)
AlanineAminotransferase(ALT,SGPT,GPT)
GammaGlutamylTransferase(GGT,GGTP,"drunkscreen")
Magnesium
Amylase
CreatineKinase
Glucose
Urea("BloodUreaNitrogen",BUN)
"Electrolytes":sodium,potassium,chloride,and"totalcarbondioxidecontent."(Theseare
usuallyrunonadifferentmachinethatstaysupallnight.)
Theautomatedchemicalprofileprovidesmuchinformationatlesscostthananyindividualtest.The
machineitselfcostsaround$200,000topurchaseandinstall.Doingeachprofile,however,costs
penniesinreagents,andadollarorlessoverall.(Forbigbatches,one1983estimateplacedthe
actualcosttothelabat17centsperprofile.)
Ofcourse,thelabchargesalittlemorebecauseofoverheadandtomakeuptheoriginalcostofthe
machine.Intherecentpast,cliniciansinprivatepracticecouldgougethepatient$150ormorefor
"interpretingtheprofile".)Theautomatedchemistryprofilemachinehasbeenoneofthebigmoney
makersformosthospitals,andithaspaidforotherservicesthatlosemoney.And,ofcourse,reducing
theorderingofavailabletestsdoesnotresultinalineardecreaseinthetruecostofhealthcare.("The
firstonecostsamilliondollars,andalltherestcostpennies....")SeeHum.Pathol.15:499,1984
largelyofhistoricalinterestnow.
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Thelabhasothermachinestodoindividualtestsonanemergencybasis.Thesetypicallyinvolve
readymadepackagesofreagentsthatcostafewdollarseach.
INDICATIONSforanautomatedchemistryprofilearestill"controversial"becauseofthe"expense"
andforotherreasons.WheneverthereisREASONTOSUSPECTSERIOUSDISEASE(eveninsuch
acommonsituationasmildhighbloodpressure),andBEFOREGENERALANESTHESIA,a
chemistryprofileisusuallyordered.("Beforegeneralanesthesia"ahistoryandphysicalisprobably
sufficient:MayoClin.Proc.72:505,1997).Serialprofilesmaybeusedtofollowthecourseofa
diseaseanditsresponsetotreatment.(Aprofileeveryfewdaysisplenty.)Chemistryprofilesmaybe
orderedonASYMPATOMATICPEOPLE,nowadaysparticularlytoscreenforcholesterolproblems.
Thethreemostcommonseriousdiseasesdetectedby"screeningeverybody"are
(1)HYPERPARATHYROIDISM,(2)HYPERCHOLESTEROLEMIA,and(3)ALCOHOLICLIVER
DISEASE.Ifyouscreenalotofolderpeople,you'llalsopickupsomecasesof(4)ADULTONSET
DIABETES,thoughthesepeoplegenerallyhaveatleastsomecomplaintthatwarrantsscreening
(obesity,neuropathy,vasculardisease,etc.,etc.)You'llalsopickupacertainnumberofpatientswith
(5)UNEXPLAINEDELEVATEDLIVERENZYMES("transaminasitis")whichisprobablyworthworking
up(mostarejustdrinkersorfolkstakingibuprofenorfolkswithmildNASH/SyndromeXbutyou
mightfindsomethingtreatablelikehepatitisB,hepatitisC,hemochromatosis,autoimmunehepatitis,
orWilson's).ItisnotoriouslyimpossibletofullyruleoutWilson'susinganyofthecommonlabs
(urinarycopperismuchbetterthanserumceruloplasminbutstillnot100%sensitive):
Gastroenterology113:350,1997.ISAYTHATTHESEALONEJUSTIFYWIDESPREAD
SCREENINGOF"ASYMPATOMATICADULTS"USINGTHECHEMICALPROFILER.Noteverybody
agrees.Pro:J.Gen.Int.Med.7:393,1992Am.J.Med.94:141,1993("$12,000tofindaserious,
treatabledisease").Con:Br.J.Gen.Pract.41:496,1991.
Thetwomostcommontrivialfindingsare(6)minorpermanentelevationsoftotalbilirubin(i.e.,
"Gilbert's",lessoften"thalminor"),and(7)lowserumalbumininthechronicallysick(why?),whichis
usuallyaccompaniedbylowtotalserumcalcium(why?).Ifyouarescreeninghealthyfolk,you'llalso
find(8)plentyofathletesandpeopledoinghardphysicallabor,whowillhaveelevatedcreatine
kinase.Thegreatdrawbacksofmassscreeningarethatdatafromtestsonpeoplewithoutsignsor
symptomsofsystemicdiseaseGENERATESCONFUSIONANDADDITIONALEXPENSEtothe
hospital,andacertainperverseincentive...
THINK.Today'shealthcareplanshaveagoodreasontodelaythedetectionofdisease,evenifthis
meansthepatientwillgothroughaperiodofsickness,suffering,anddisability.Ifyouspendadollar
foraserumcalciumscreenandyoudetectaparathyroidadenoma,takingitoutwillcosttheplanbig
moneytoday.Ifyouletthepatientbecomedepressed,haveafewyearsoffeelingterrible,andpassa
fewkidneystones"beforescreeningisjustified",heorsheislikelytobeunderthecareofadifferent
"provider",andsomebodyelsepays.Getit?
LABTESTSFOR"THEMENTALLYILL"
Mylist,alittlelongerthantheNIH'sdementiaworkup.Apsychiatrist(oranyotherphysician)should
diagnosepsychiatricdiseasewithoutaphysicalexamandsomelabsonlyifthelifehistoryis
absolutelyclassicforsomefamiliarentity.Rememberthatfibromyalgiaisdiagnosedonthehistory
andphysicalexam.
chestXray(paraneoplasticneurologiceffectsofoatcellcarcinomaareinfamous)
CBCandUA
chemicalprofile(notably,how'sthatcalcium?thatGGT?thosetransaminases?)
syphilisscreen
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thyroidscreen
porphyriascreen
serumB12
serumfolate
fANA
antiRo/antiLa(onthe"neuro"serviceseeAm.J.Med90:479,1991)
drugscreen
considerAddison,Cushing,Wilson,pheochromocytoma,Lyme screens
considermonitoredfasttocheckforfastinghypoglycemia
considerassaysforlead,mercury,otherbadmetals
considercytokineassaysorothertestsofimmunefunctiontodetectbonefide"chronicfatigue
syndrome"
checkneedleusersandswingersforHBV,HCV,HIV
PITVALLS:GETTINGTHEBLOOD
Ifyouhaveorderedbloodtests,thequalityoftheresultsdependsonyourpatientandyourspecimen.
It'syourcallastowhetheryourpatientneedstoFASTlongenoughforthechylomicronstobecleared
fromthebloodandforlipidlevelstoreturntobaseline(i.e.,overnight).Otherwise,the"lipemic"blood
willcauseinaccuraciesinmostphotometrictests.(Thislimitstheusefulnessofroutinescreeningson
electiveafternoonadmissions.)Somelabsnotice(andtellyouabout)a"lipemic"serum,otherswill
missit.HIGHSERUMTRIGLYCERIDELEVELS(over1000mg/dL)willincreasethefollowingvalues
enoughtomakeadifferenceclinically:hemoglobin,MCH,MCHCalbumin,totalprotein,fibrinogen,
hemoglobinA1ctransaminaseenzymes(ALT,AST)bilirubin,calcium,creatinine,glucose,iron,urea.
Thesevalueswillbedecreased:amylase,lipase.(Thelatter'sabigdealifyouthinkyoupatienthas
hyperlipidemiatypeI,or"meltedstrawberryicecreamblooddisease".)
IfthepatientcomestothelabwithaFULLSTOMACH,ofcourse,youmayseetrueelevatedglucose
(slightly)andtriglycerides(uptoseveralhundredmg/dL)anddecreasedbilirubin(ifanybodycares).If
thevaluefortheserumironiscriticaltoyourinvestigations,yourspecimenshouldbefasting,andthe
patientshouldhavetakennoironsupplementsforafewdays.Serumalkalinephosphataseis
increasedwhilefoodisinthesmallbowelinpatientswithbloodgroupsOandBwhoaresecretors.If
thepatienthasbeenon"CLEARLIQUIDS"forafewdays,bilirubinmaygoup.Youcanfigureoutfor
yourselfthechangesseenindehydration,ketosis,andproteindepletionyou'llbecomeveryfamiliar
withtheseonrotations.
Forroutinescreening(i.e.,you'relookingforanemia,earlykidneytroubles,calcium,transaminases,
wayoutoflinecholesterolorglucose)fastingisn'tcritical.Patientsmaybeunwillingtoreturninthe
morningjustforbloodwork,soyou'reusuallymorelikelytogetwhatyoureallyneedifyouorderthe
labsonthespot.
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IfyourpatientisANXIOUSabouttheneedlestick,itwillraiseserumglucoseandcatecholaminesand
sometimes(ifhyperventilationoccurs)producesalkalosis.
UsingaTOURNIQUETtodrawbloodisoftennecessary,butcauseserrorsifitisinplaceforalong
time.Ifthereismuchfistclenching,serumlacticacidgoeswayup,pHgoesdown,andserum
potassiumcanincreaseby1.0mEq/L(aBIGincrease).Bycausingtransudationofwaterfromthe
vesselstotheinterstitialfluid,thetourniquetcanalsocausesmallelevationsofcalcium,iron,
magnesium,andproteins.(*Youdon'tmeasure"plasmapotassium"itisnormallylowerbecausea
certainamountofpotassiumisreleasedwhenbloodclots.)
AcommonblunderisdrawingabloodsamplefromasiteDOWNSTREAMFROMANINTRAVENOUS
LINE.If(forexample)it'sinfusing"D5",whichis5%dextrose(glucose)inwater,yourpatientwill
appeartohaveaveryhighbloodglucoseandloweverythingelse(KarenCarpenter).
IfthebloodspecimenundergoesHEMOLYSISasaresultofclumsyphlebotomy,toonarrowaneedle,
oronthewaytothelab(beingplacedontopoftheradiator,inthefreezer,dropped,shaken,sipped,
etc.,etc.),RESULTINGERRORSCANBEVERYSERIOUS.Serummagnesium,phosphate,
potassium,andsomeenzymes(LD,AST,acidphosphatase)aregreatlyincreased.LD1maybe
higherthanLD2("flip").(Serumironwillnotbesignificantlyincreased.)Therewillalsobeminor
changesinotherresults,butthefalsehighpotassiumcanresultinlethalerrors.Serumwillbevisibly
pinkwhenenoughhemolysishasoccurredtoelevateserumpotassium0.1mEq/L.However,thelab
maynotnoticethis.
*Orderofdraw...Purpletoptubesshouldbedrawnaftertubestakenforelectrolyte
determination,becausethepotassiumintheanticoagulantwillraisethenexttube'spotassium
level.
WhenbloodCLOTS(remembertheautomatedchemistryprofileisrunonserum),potassiumis
releasedfromplatelets,elevatingthevaluebyaround0.5mEq/L.Thisistakenintoaccountin
calculatingthereferencerange.If,however,theserumstaysINCONTACTWITHTHECLOTfora
longwhile,itwillresultininaccuratelyhighiron,LD,andpotassium(leaking,mildhemolysis),and
falselyloweredglucose(usedasenergysourcebyredcells).Thisisonlyaproblemifthespecimen
sitsaroundforseveralhours.Thesiliconeseparatorshelpwiththis.Aspecimenleftontopofa
radiatorhasextremelyhighLD,phosphate,andpotassium,andzeroglucose,andthispatternis
familiartoeverylabworker.
TINYCLOTS(inadequatemixing)orCOLDAGGLUTININS(IgM'sthatbindRBC'stooneanother
belowbodytemperature)inspecimenssubmittedtohematologywillresultinanincreasedmeasured
MCV(anddecreasedcalculatedRBC"uhoh,instantperniciousanemia").
IfyourpatienthasrecentlyhadaRADIOACTIVEISOTOPESCAN,theresultsofradioimmunoassays
willprobablybeinaccurate.Thankfully,radioimmunoassaysarenowuncommon(onemoredream
frommymedicalschooldaysthat'snowcometrue.)Checkwiththelab.
Evenifyoumanagetoavoidanycauseofanalyticinaccuracy,youmustconsideryourpatient'slevel
ofactivitywhileinterpretingyourresults.ValuesobtainedinpatientswhohavebeenSUPINEfora
whiletendtobelowerthaninpatientswhowereSTANDINGUP.(Doyouknowwhy?)Howmuchare
thingsdiluted?TENPERCENT:mostproteinsandnonproteinhormones(theonesthatareprotein
bound)FIVEPERCENT:cholesterol,triglyceridesTWOPERCENT:hemoglobinhematocritNO
CHANGE:electrolytes.Alsoremember:standingupisthecauseoforthostaticproteinuria,the
commonestreasonforexcessproteinintheurineinoutpatientpractice.
PITFALLS:GROWINGUP
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CHILDHOOD:Atbirth,HEMOGLOBINisaround19mg/dLandMCVaround105fL.(Bothare
probablyhigherthanyourswhymightthisbe?)Afewnucleatedredsarenormalinanewborn's
blood.Theseparametersdropofftolowsofabout11mg/dLand78fLatoneyear,thengradually
increasetoadultvaluesbypuberty.TheabsolutecountsofWHITECELLSvarydependingonage.At
birth,allnormalwhitecellsareincreased24xthenormaladultvalue.Bandsandsegspeakduring
thefirstday,thendropoff.Segsarelowerthanadultvaluesduringthefirstyearoflife,andthecount
graduallyincreasesoverthefollowingyears.Theothercelltypesdiminishtonearadultvaluesaround
age6.ALKALINEPHOSPHATASEis25xnormal(growingbones),droppingtoadultlevelswhen
bonegrowthstopsafteradolescence.Cholesterollevelsinhealthychildrenareofcourselow.Alpha1
proteaseinhibitorlevelsareusuallylow("uhoh,instantemphysema"),andangiotensinconverting
enzymelevelsaregenerallyhigh("uhoh,instantsarcoidosis").
MENSTRUATION:RememberthatthePLATELETCOUNTmaydropby50%duringanormalperiod.
PREGNANCY:"Anemiaofpregnancy"isusual,butHEMOGLOBINshouldnotgobelow10gm/dL.
Thereisalwayshemodilution,butmoresevereanemiasuggestsirondeficiencyand/orfolate
deficiency.BICARBgoesdownaswomenperhapsbreatheabitdeeperandmorerapidlyinlater
pregnancy.GLUCOSETOLERANCEdecreases.MostserumproteinschangeasintheACUTE
PHASEREACTION("stressofbeingpregnant").However,SERUMTRANSFERRININCREASES
(andserumirondecreases,ofcourse).SERUMALKALINEPHOSPHATASEincreasesasthe
placentagrows(23xnormal).GRANULOCYTOSISdevelopsbeforeandduringlabor.
OLDAGE:ALKALINEPHOSPHATASEincreases(moreinwomenatandaftermenopause),oftento
severaltimesthe"upperlimitofnormal",withoutanydisease.Cholesterollevelsaveragehigherthan
inyoungadults.Theother"routine"chemistryandhematologyvaluesdonotchangesignificantlyin
"healthyoldage".Variousantibodies,includingrheumatoidfactor,antinuclearantibodies,andsome
syphilisantibodies,mayappearwithouttherebeingdisease.
PITFALLS:MODERNLIFESTYLES
RUNNERSANDOTHERTRAINEDATHLETESshowacharacteristicpatternofchanges.(SeeMayo
Clin.Proc.55:113,1980)(1)increasedplasmavolumewithdecreasedHgb,Hct("jogger'sanemia",
stillalittlebitmysterious)(2)increasedreticulocytes(hemolysisduetopavementpounding)
(3)increasedhighdensitylipoprotein("HDLc",the"good"cholesterol),anddecreasedlowdensity
lipoprotein("LDLc",the"bad"cholesterol)(4)increasedcreatinekinase(CK,CPK)withupto15%
MBfraction(the"myocardialdamage"fraction)...afteramarathon,themajorityofathleteshaveCK
MB,troponinT(TnT),BNPorNTproBNP(heartfailuremarkersofcourse,nowconvenientlyavailable
atpointofcarerememberthatadistendedrightatriumfromkidneyfailurewillincreasethemaswell
theyarereleasedinequimolaramountsBNPisclearnedinavarietyoftissueswhileNPproBNPis
clearedonlybythekidney),myoglobin,andmyeloperoxidaseinthe"heartattack"range(Am.J.Clin.
Path.126:888,2006)(5)IncreasedAST(hepaticischemia,aftermarathons.SeeJAMA252:626,
1984).Nolabsareusefulinscreeningforsportsparticipation(J.Fam.Pract.52:127,2003
interestingpaperthatmatchesthewayI'vealwaysdoneandtaughtit).
ESTROGENUSERS(oralcontraceptivepill,etc.)exhibitacharacteristicgroupofchanges:(1)
increasedthyroxine,decreasedT3RU(increasedthyroidbindingglobulin)(2)increasedcortisol
(becauseofincreasedcortisolbindingglobulin)(3)decreasedantithrombinIII(rememberthese
peoplemaygetthrombosis)(4)increasedceruloplasmin,sometimesincreasedGGTP(5)increased
triglycerides(maybe)
Bettertosleepwithasobercannibalthanwithadrunken....
Melville,MobyDick
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ALCOHOLICSANDOTHERHEAVYDRINKERSpresentmanyproblems.Everyclinicianwouldliketo
haveasimpletesttoidentifyproblemdrinkersaccurately.YouknowtheCAGEquestions:
C:HaveyoutriedtoCutdowndrinking?
A:AreyouAnnoyedbyothers'concernaboutyourdrinking?
G:HaveyoufeltGuiltyaboutdrinking?
E:HaveyouusealcoholasanEyeopener?
Thereareothers(Arch.Int.Med.155:1726,1995).Tostartoff,lookfortolerance.Anyonewhoisn't
obviouslydrunkwithabloodethanolof0.15%drinksoftenandheavilyenoughtohaveatolerance.
Thesameistrueforanyonewhoiswalking(driving,etc.)withabloodethanolof0.3%(thesepeople
aresupposedtobemoreorlessdead).IntheNorth,Iwastaughtthatpeoplewhoidentifythemselves
as"moderatedrinkers"areallchronicheavydrinkers.AserumASTgreaterthanserumALT,inan
otherwisehealthyperson,suggestsheavydrinking.HIGHMCV,highserumuricacid,lowserum
phosphate,hightriglyceride(afterparties,in"typeIV"patients),andhighalkalinephosphataseall
havebeenexaminedbyhopefullaboratoriansassignsofhabitualdrunkenness.(Historyoftrauma
helpstoo,seeAnn.Int.Med.101:847,1984.)Themostenthusiasminrecentyearshasbeenover
GAMMAGLUTAMYLTRANSFERASE(transpeptidase,etc.),elevationofwhichiscommoninheavy
drinkers(3080%,oftentheonlyabnormalityonaprofile.)Ofcourse,thesamepicturecanbeseenin
mildpancreatitis,liverproblems(includingCHF),phenytointherapy,estrogentherapy,rheumatoid
arthritis,awidevarietyofcancerrelatedproblems,andprobablyothers.(SeeBr.Med.J.286:531,
1983.)However,mostoftheaboveareeasytoruleout,andGGTisfairlywellestablishedasa
meansoffollowingcompliancewiththerapyinmanyalcoholictreatmentprograms.(GGTupdate:Br.
Med.J.302:388,1991headsup,AfricanAmericansnormallyhavetwicethelevelsofotherfolks).
SomelabscanmeasuretheACETALDEHYDEINDUCEDHEMOGLOBINFRACTION(HgbA1ach),a
markerforhowmuchalcoholonehasdrunkinthelastfewweeks(Arch.Path.Lab.Med.116:924,
1992neverbecamemainstream).CARBOHYDRATEDDEFICIENTTRANSFERRIN(CDTtest)is
nowa(fad?)assaytoscreenforalcoholabuseandtestone'sabstinence(Clin.Chem.39:866,2001).
Itisalsolikelytobeupifisthereisalreadyadvancedliverdisease(Alcoholism25:1729,2001),in
womenlosingweight(AlcoholandAlcoholism36:603,2001),andinmanyothers.
DIURETICABUSERSANDLAXATIVEABUSERSexhibitdecreasedserumsodium,potassium,total
CO2,magnesium,andincreasedchloride(why?).Thelowpotassiumcanbeveryunhealthy.
ANOREXIANERVOSATYPES(including"flippers")showsurprisinglynormallabtests.Endocrine
testingmayrevealdiminished(butnotabsent)pituitaryresponsetostimulationtesting,which
compoundsconfusionwithSimmonds'sdisease.
ANABOLICSTEROIDABUSERS("breakfastofchampions")alsoexhibitacharacteristicgroupof
changes:(1)Increasedserumcreatinine(increasedmusclemass)(2)increasedLDLccholesterol,
anddecreasedHDLccholesterol(seeJAMA252:507,1984)(3)increasedhemoglobinand
hematocrit(4)increaseddirectbilirubin(cholestasis),andsometimesincreasedalkaline
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phosphatase(5)decreasedthyroxine,increasedT3RU(decreasedthyroidbindingglobulin)(6)
decreasedserumphosphateforsomereason.
PITFALLS:IATROGENICCHANGES
PHYSICALEXAMINATION:Someauthoritiesclaimthatvigorousprostatemassagecausesmild(2x
normal)increaseinserumacidphosphataseand/orprostatespecificantigenforadayorso.(Why?)
Thechangesseemreal,butaren'tgoingtomisleadanyclinicaldecisionmaker(JAMA267:2227,
1992).
INTRAMUSCULARINJECTIONS:Rememberthesewillraiseserumskeletalmuscleenzymes.
(Why?)
DRUGS:Rememberthatdrugscanaffectlabtestsintwodifferentways.
1.Thedrugmayactasaninterferingsubstanceintheassay("METHODOLOGIC
INTERFERENCES").Forexample:(a)vitaminCinhighdosescausesfalsenegativeurinetestsfor
glucoseandblood(b)tetracyclines,beingfluorescent,causefalsepositivefluorescencetestsfor
porphyrinsandcatecholamines(c)tolbutamide,erythromycin,andseveralotherscausefalse
increasesintransaminaseswhencolorimetricmethodsareused(d)bromideionismeasuredas
chloridebymostelectrodes.Andsoforth.
2.ThedrugmayTRULYCHANGETHEPHSYIOLOGICPARAMETERbeingmeasured.Forexample,
(a)spironolactonedecreasesserumsodium(bglucocorticoidsshouldsuppressACTHproduction
andraisebloodglucose(c)methyldopaoftencausesantibodiestobindtoRBC's,makingthem
"Coombspositive"(d)procainamideoftencausesa"lupuslike"syndrome,withpositiveantinuclear
antibodies(e)goldinjectedforrheumatoidarthritiscancauseproteinuria(f)awiderangeofdrugs
cancausedecreasedplateletsand/orneutrophils.Thesearenot"artifacts",theyarereal.
SERUMENZYMES
Severalofthetestsonthechemicalprofileareenzymeassays.Whencellsaredamaged(not
necessarilyirreversibly),theymaylosesomeoftheircontentsintothebloodstream.Oftenthese
contentsincludetheintracellularenzymesthatmakeupthemachineryofthecytoplasm.(Orvery
activecellsreleaseextraenzyme).Ifserumlevelsofaparticularenzymeactivityareelevatedabove
normal,itcommonlyindicatesinjurytothecells,andthespeciesofenzymeincreasedintheserum
indicatewhatorganisdamaged.
TheENZYMEACTIVITIESareassayedratherthantheenzymeproteinsthemselves.(Somenewer
techniques,suchas"prostaticacidphosphatase",measureaspecificproteinbyimmunologic
techniques.Thisdoesnotnecessarilymakethetestmoreusefulclinically.)Enzymeactivitiesare
measuredinunitsofactivity,defineddifferentlyfordifferentenzymes.(Theenzymesthemselves
wouldprobablybemeasuredinng/dL.)An"InternationalUnit"(U,IU)ofanenzymeistheamountthat
catalyzestheconversionof1micromoleofsubstrateperminuteunderthedefinedconditionsofthe
test(temperature,pH,substrateconcentration,etc.)Speakingofunits,anattemptwasmadetogetall
clinicallabsandjournalstoswitchtotheSI(InternationalSystem)standardandreporteverythingin
termsofkilograms,meters,andseconds,beginningJuly1,1988.(KCUMBstudents:You'llnoticethis
intheMassGeneralcasesfromthisera.)Therewasnogoodreasontoshoveitontocliniciansor
laboratorians,theyresentedit,andtheattemptwasapredictable,totalfailure(NEJM327:49,1992).
Ifyourtubeofbloodmustwaitfortwoormorehoursbeforebeingassayed,putitonice.
Youwillneedtolearntheseenzymes,whicharefoundinseveraldifferenttissues,becausetheyare
commonlymeasuredbytheclinicallab.
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ALANINETRANSAMINASE(ALT,SGPT,GPT):liver,skeletalmuscle
ALKALINEPHOSPHATASE(alkphos):bone(osteoblasticactivity),intestine(secretorswith
bloodtypesOorB,orafterafattymeal),liver(especiallyobstructivemetastaticdisease),
placenta,somecancers("Regan"isoenzyme).
Theserumlevelsofthreeenzymescorrelatewithhepaticalkalinephosphatase:5'
NUCLEOTIDASE(5'NT,5'N),GAMMAGLUTAMYLTRANSPEPTIDASE(GGTP,GGT),and
LEUCINEAMINOPEPTIDASE(LAP).Checkingoneormoreofthesecanclarifytheoriginofan
elevatedalkalinephosphate.
AMYLASE(alphaamylase):pancreas,salivarygland,and(toamuchlesserextent)manyother
organs
ASPARTATEAMINOTRANSFERASE(AST,SGOT,GOT):heart,liver(especiallyhepatocellular
disease),redcells,skeletalmuscle
LACTATEDEHYDROGENASE:mostorgans,especiallyheart,liver,lung,kidney,redcells,
skeletalmuscle,manycancers
ISOENZYMESarevariantformsofenzymesfoundindifferenttissues.Theydothesamethings,but
theymaybecomposedofdifferentsubunitsorbeentirelydifferentproteins.Knowingwhich
isoenzymeiselevatedwilloftentellwhichofseveraltissueshasbeendamaged.
Themostfamousisoenzymechangeisthe"LDH12flip"(LDH1higherthenLD2).Itindicates
necrosis(infarction)oftheheartorkidney,orhemolysis.(HighLDH5:Liver,skeletalmuscle.
LDH3high?Thinkofapulmonaryinfarct.Allhigh?Shockorinfectiousmononucleosis!Why?)
LDH1:KNOW:Heart,kidney,redcellsandtheirprecursors(verysensitivetomildhemolysis
duringoraftersamplecollection),seminoma
LDH2:
LDH3:KNOW:Lung,lymphocytes,platelets
LDH4:(someacutelymphoblasticleukemiasproducealotofthis)
LDH5:KNOW:Liver,skeletalmuscle,neutrophils,prostate
LDHisoenzymesarefastrecedingintomedicalhistory.Buttheywerefun.
PITFALLS:SERUMCALCIUMANDMAGNESIUM
INDICATIONSforserumcalciumincludesuspicionofcancer,symptomsorsignsof
hyperparathyroidism(kidneystones,psychiatricproblems,manyothers),bonediseases,unexplained
seizures(especiallyinbabies)orcoma,afterthyroidorparathyroidsurgery,orinotherpatientsat
specialrisk(seebelow).
ThelabmeasuresTOTALCALCIUM,i.e.,ionizedplusunionized.Onlyabouthalfthecalciuminthe
serumisthephysiologicallyactiveIONIZEDCALCIUM.Therestisboundtoalbuminandother
proteins,andprotonscompeteforbindingsites.Thefractionofserumcalciumthatisionizedvaries
withpH,becauseprotonscompetewithcalciumtobindtoalbumin.Adecreaseof0.1pHunit
increasestheionizedfractionofcalciumbyabout2%,sotheeffectisnotverymarked.However,the
fractionofserumcalciumthatisionizedalsovarieswiththeserumalbuminlevel.Adecreaseof1
gm/dLinalbumindecreasesbothunionizedandtotalcalciumbyabout0.8mg/dL.Thisisimportant.
Thelabdoesnotreportionizedcalcium(eventhoughthatiswhatyouarereallyworriedabout)
becausemeasuringthisrequiresspecialtechniquesforbloodcollection,acalciumspecificelectrode,
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andotherresources.AroundnormalpH,severalformulashavebeendevisedtoestimateionized
calcium.Forexample:
*ionizedCa++=(97(8xalbumin)(2xglobulin))/100
Or,ataglance:
IonizedCac++(mg/dL)~TotalCa(mg/dL)albumin(g/dL)
Manyinterestinglaboratoryprocedureshavebeendevisedtodistinguishhyperparathyroidismfrom
othercausesofhypercalcemia.Youwilllearnaboutelectrolyteequations,serumparathyroidlevels,
urinarycyclicAMP,tubularresorptionofphosphate("TRP"),etc.,etc.,onrotations.Nowadaysalmost
everybodyusesserumparathormonedeterminations.
Increasedserummagnesiumisusuallyduetorenalfailure(ortohemolysisofthespecimen).
Decreasedserummagnesiumisasubjectofoccasionalcurrentinterest,andisthoughttobe
widespreadamongthesick.
IRONSTUDIES(Am.Fam.Phys.87:98,2013)
Thiswillgetyoustarted....
Irondeficiency:Lowserumiron(Fe),highserumironbindingcapacity(TIBC),nearzeroferritin,
increasedsolubletransferrinreceptor,increasederythrocyteprotoporphyrin(thelasttwotests
areexpensiveandarefortoughcallsbutbeforeyoudoabonemarrowaspirate).
"Anemiaofchronicdisease":Lowserumiron,lowserumironbindingcapacity,normalorhigh
serumferritin
Ironoverload:Highserumiron,Fe/TIBC>60%orso,highserumferritin
Althoughirondeficiencyclassicallygivesamicrocyticanemia,amajorityofpatientshaverelatively
milddeficiencyandthushaveanormocyticanemia.UnlessMCVis95fLorabove,consideriron
studiesinthepresenceofanemiaunlessyourlabgaveyouafreeserumironandironbineing
capacity,startwithserumferritin.
Makingsenseoutofthis:
1.Inirondeficiency,thecapacityoftheserumtobindironincreases"inthehopesofsnarfingup
moreiron".
2.Inanemiaofchronicdisease(i.e.,prolongedinterleukin1releasemakingitdifficulttotransfer
ironfromthebonemarrowmacrophagestothenormoblasts),interleukineffectalsocauses
loweredTIBC(likealbumin,aproteinthatgoesdownintheacutephasereaction).
3.Transferrinsaturation(i.e.,Fe/TIBC)of>60%issuspiciousforironoverload,and>80%is
extremelysuspicious.Rememberthattransferrinlevelsdropduringtheacutephasereaction.
4.Ofcourse,ifyourpatientjusttookahandfulof"multiplevitaminswithiron"priortovisiting
you,interpretationisclouded....
5.Ifserumferritinislessthan30,irondeficiencyispresentifmorethan100,irondeficiencyis
notpresent.Serumferritinshouldn'tbemorethan300ng/mLinaman,or200ng/dLina
woman.Levelscloselyparalleltotalbodyironstoresthefactthatserumferritinrisessomewhat
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intheacutephasereactionisunlikelytocausetroublewhenthelabsarematchedwiththe
clinicalpicture.
*Serumtransferrinreceptorbecomeselevatedintrueirondeficiencybutnotinanemiaof
chronicdiseasethistestmaysomedaybeanadjunct(Am.J.Clin.Path.138:642,
2012).
Caveat:Manyalliedhealthprofessionalsuse"iron"asasynonymforbloodhemoglobincontent.
I'vegivenuparguing....Asnoted,ifyou'rereallyconcernedaboutiron,drawafastingspecimen.
*There'sacircadianrhythmtoserumironbutit'sslightandshouldn'tmatter:Am.J.Clin.Path.
117:802,2002.
ISTHISPATIENTHAVINGAHEARTATTACK?
You'lllearntheprotocolfortheworkupofsuspectedmyocardialinfarctonrotations.Criteria
underwentmajorchangesin2001(Am.HeartJ.144:957,2001).Thetroponins(yourchoiceofIorT)
risebysixhours("thegoldstandard"theymaybeupearlier)andstayupformaybe24days.Most
cliniciansseemtopreferthese.Drawyourlevelseverysixhours(NEJM330:670,1994,stillgood,
cardiactroponincTnTandcTnI)arewhatweusetoday.Regrettably,thetroponinsaremeasuredbya
varietyofassays,eachofwhichhasadifferent"cutoff"andthesevarygreatlyfromsystemtosystem
thegoodnewsisthatmostpeople'sbaselinetroponiniszero(everybodyhassomeCKMBinthe
blood).CreatinekinaseMBbandstartstorisealittlesoonerandstaysupfor12daysorso.Both
peakswillgohigherandvanishsoonerifthereisreperfusion.Thesameistrueforthetroponins.
TroponinIortroponinTisyourbestenzymebecauseoftissuespecificity.However,despitetheir
beingballyhooedas"totallyspecificforheart",weknowthey'renot.Infamously,peoplewithchronic
myopathiesbutwhoareotherwisehealthytendtohaveelevatedtroponinTintheheartattakrange
(J.Am.Coll.Card.58:1819,2011).SGOTandLDHdeterminationstodetectmyocardialinfarctionare
nowonlyofhistoricalinterest.
Creatinekinaselevelsrisefollowingheavyexerciseandcanstaywayupfordays.Afew%MBband
iscommonplace,especiallyafteraheavyworkoutorheavydutymuscleinjury(i.e.,surgery).
Intramuscularinjectionscanbringacouchpotato'screatinekinasetotheupperlimitofnormal.AnMB
bandofmaybe15%ofthetotalCKisprettysuggestiveofmyocardialinjury.Thebandshould
disappear18hoursafterheartsurgeryofcoursetherewillalsobeabandaftercardioversion.
*GettingtaseredraisestheCKtohighnormal(AJFMP30:23,2009).
*Ahostofothermarkersforheartattackareunderinvestigation."Ischemiamodifiedalbumin"
increasesaftersixminutesorsoofrealischemiaanywhereinthebodythetestisarcane,andof
courseifyouexerciseenoughtomakeyourselfbreatheharder,orareshockyorhavenecrotictumor
orwhathaveyou,you'llcomeuppositive.Simplyfindingelevatedlevelsofmyeloperoxidaseinthe
plasmasuggeststhere'sanunstableplaquesomewherethesetendtoloadedwithneutrophilsso
thisisnosurprise,butwhetherthisinformationisofanyvalueisforyoutodecide.
Don'texpecttoseeelevatedCKBBinbraininjury(itmaynotcrossthebloodbrainbarrier,orbe
presentinlargeenoughamounts,orwhatever).
Ofcourse,youwillcontinuetolookfortherequisiteQwavesand/orSTsegmentelevationonEGK,
decreasedwallmotiononechocardiography,andhypoperfusiononscan.Rememberthelattertwo
areonlyabout50%specificscaralsodoesn'ttakeuptracerormoveonecho.
Thenew,verysensitivetroponinpicksuppeoplewithcoronaryinsufficiencywhoarelikelytogoonto
getanginaand/orCHF:NEJM361:2538,2009.
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Weawaitwithinteresttheentryofgalectin3(isthissevereacute/chroniccongestiveheartfailure?)
intothediagnosticpanels.
THESEROLOGYLABAND"TITERS"
Intheolddays"Serology"meantasyphilis test.Today,theserologylabdoesmostoftheprocedures
involvingimmunology.Thereisnoneedforyoutoknowaboutthetechnicalaspectsofthesetests.
TheTITERofasubstancemeasuredintheserologylabisthemaximumdilution(ofaseriesof
dilutions)atwhichthesubstancecanbedetected.Thusatiterof1:2or1:10isa"lowtiter"and
indicatesthatnotverymuchofthesubstanceispresent.Andatiterof1:128000isprobablya"high
titer".Dependingonwhatyouaremeasuring,atiterof1:100mightbe"high"or"low".
"Asignificantriseintiter"suggestsarecentinfectiousdisease.(Why?)"Significant"isusually
consideredtobea"fourfoldrise".Ifatiterrisesfrom1:16to1:64duringanepisodeofacuteillness,or
whenatiterrisesfrom1:10000to1:80000,thepatientprobablyhadtheacutediseasetomatch.
Forinfectiousdiseases,thepresenceofIgMagainstthepathogenusuallyindicatesacuteinfection.
IgGtitersfrompastinfectionmaydisappearslowlyorpersistforlife,dependingonthepersonandthe
illness.
Thisisn'ttheplacetotalkaboutsyphilistesting.Worthremembering:
Thescreening"nontreponemal"tests(RPR,VDRL)oftengivefalsepositives,usuallylowtiter.
Maybe10%ofolderfolksarereactive.Mostpatientswithprimarysyphilisarealreadypositive
allpatientswithsecondarysyphilisarepositivemostbutnotallfolkswithtertiarysyphilisremain
positive.
You'llconfirmyourpositivescreenwithatreponemaltest.TheTPPAgelatinbased
microagglutinationtestisreplacingtheclassicimmunofluorescencemicroscopyFTAABS,
whichsupposedlyeliminatesthefewfalsepositives,andisusuallypositiveinprimaryand
almostalwayspositiveintertiarysyphilis.
Thestandardtreatmentforsyphilisdoesn'tcureneurosyphilis.Theclassicteachingisthatyou
needtodoalumbarpunctureifyoususpectneurosyphilisinordertotreatitproperly.Exactly
whattheserologiesonspinalfluidmeanisstillunderdiscussion(it'sstillconfusing),andnoone
hasexplainedtomewhytreatingpresumptivelyforneurosyphilisislessbenignthanalumbar
puncture.Staytuned.
EFFUSIONS
(Am.Fam.Phys.73:1211,2006)
Effusionsareultrafiltratesofplasmainthepleural,pericardial,orperitonealcavities.Theseare
commonlyencounteredinsickpeople.Youmayremovefluidwhichhasaccumulatedinacavityfor
diagnosticpurposes,ortotreatthepatient(pleuraleffusionsmayrestrictlungexpansion,pericardial
effusionsmaycausetamponade,etc.)Hereisonerecommendedwaytosubmitasampleofthe
effusiontothelabforstudy:
oneEDTAtubetohematologyfora"CBCanddiff"
oneheparintubetomicrobiologyforstainsandcultures(aerobes,anaerobes,acidfastbacilli,
fungi)
oneheparintubetocytology(checkforcancercells,etc.rememberthat"negativecytology"
doesn'tmeanthere'snocancerinthebodycavity,onlythatthecellsaren'tbeingshedintothe
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effusion!)
oneplaintubetochemistry.Selectsuchtestsas....
LD(LDHcomparewithserumvaluestodeterminewhethertheeffusionisatransudateor
exudate)
GLUCOSE(lowinrheumatoidandsepticeffusions)
TRIGLYCERIDESandCHOLESTEROL(milkyeffusions)
AMYLASE(acutepancreatitisrememberthiscanalsocausepleuraleffusions)
*ADENOSINEDEAMINASE,anactivatedmacrophage/angryTcellmarker,fairlyspecific
fortuberculosis ,butthere'snotmuchofthisintheUS
*BILE(bileperitonitis,asfromarupturedgallbladder)
*HYALURONICACID(referencelabprocedurethatmayhelpmakethediagnosisof
mesothelioma).
TRANSUDATESgenerallyareduetocongestiveheartfailure,hepaticcirrhosis,orthenephrotic
syndrome.Theseeffusionstypicallycontainlessthan2.5gm/dLprotein,showspecificgravityless
than1.015,effusionLD:serumLDlessthan0.6.Thesecharacteristicsmustallbepresent,orthefluid
isnotatransudate.Transudatesfailtoclot,andcontainfewerthan10cells/cumcL(lymphs,
mesothelialcells).(Thesecanbetrueofexudates,too.)IftheproteinandLDvaluesindicatea
transudate,nofurthertestsonthefluidareindicated.(Youmaydiscardtheothertubes.)
EXUDATESshouldmakeyouthinkofcancerorinfection(TB,pneumonia,etc.)Lessoften,exudates
areduetotrauma,pancreatitis,rheumatoidarthritis,systemiclupus,infarcts(pulmonary,myocardial,
etc.),trauma.ExudatescontainmoreproteinandLDthantransudates,andmayevenclot.Thetype
ofcellsinanexudatecanhelptellitsorigin.ManyPOLYS(i.e.,a"purulentexudate")ofcourse
suggestsbacterialinfection.BLOODYeffusionssuggestcancer,infarction,oriatrogenicorother
trauma.Perhaps50%ofmalignanteffusionscontainCANCERCELLS.LYMPHOCYTESand
MESOTHELIALCELLSarequitenonspecific.
MILKYEFFUSIONSalwaysraisetheconcernthatthethoracicducthasbeendamaged(cancer,
trauma),producingatrue"chylous"effusion.A"chylous"effusionwillofcourseberichin
chylomicrons,whichgivetheeffusionahightriglyceridecontent,maylayeratthetopofthecollection
tube,etc.Muchmorecommonisa"pseudochylous"milkyeffusion,theresultofcelldegenerationin
anychroniceffusion.Color,turbidity,andodorarevariablecholesterolcontentishighandcholesterol
crystalsoftenimparta"goldpaint"appearancetothesechroniceffusions.
MALABSORPTION/MALDIGESTION
Toseewhetherthepersonisn'tgettingthefoodintothebloodstream,werecommendaFECALFAT
STAIN.ThelabwillputsomeoilredOonasmearofstool,andlookforfatblobbies.Iftherearenone
ofthese,andthepatienteatsareasonablynormalAmericandietofgreaseburgersandfreedomfries,
youdon'thavemalabsorption/maldigestion.Ifthesearepresent,yourpatienthasisn'tabsorbing
dinner.Eitherthereisaproblemwiththeintestine(truemalabsorption),apluggedbileduct(butthe
cholestaticjaundicewouldbeobvious,Doc),orthepancreasisn'tworking(maldigestion).
Todistinguishpancreaticinsufficiency("maldigesetion",thoughyou'reallowedtobesloppyandcall
this"malabsorption")fromintestinalinsufficiency("truemalabsorption"),oneoptionistodoaD
XYLOSEtest.Administerthissimplesugarbymouth.Itisabsorbedbytheproximaljejunum.Seeifit
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endsupintheurine.Ifitdoes,theintestineworks,theproblemispancreatic,andyoumustfigurewhy
(cancer,alcoholism,cysticfibrosis,rarelyanythingelsesubtle).Ifitdoesn't,theintestineisoutof
order,andyououghttodoaBIOPSY.Infact,it'ssoeasytobiopsythesmallintestine(checkfor
malabsorption)andthestoolforpancreaticelastase(checkforpancreaticinsufficiency)nowadays
thatthedxylosetestmaysoongooutoffashion.
BIOPSIESANDSURGICALSPECIMENS
ACYTOLOGYSPECIMENmaybeobtainedbypapsmear,touchprep(remember"Tzanck"for
herpes),takingbodyfluid,orputtingaFINENEEDLEintothelesiontoaspiratecells(throughthe
skin,perhapsguidedbyultrasonography,ornowadaysviascopeonultrasonography,thenewfangled
endoscopicultrasoundguidedfineneedleaspirationEUSFNAforthegutandendobronchial
ultrasounetransbronchialneedleaspirationEBUSTBNA).AnINCISIONALBIOPSYtakesapiece
fromalesion.AbenignlookingskinlesionmaybetakenbySHAVEBIOPSYorPUNCHBIOPSY(as
on"punchahole"),bothvariantsofincisionalbiopsy.AnEXCISIONALBIOPSYtakesthewhole
lesion,probablywithsomeofthesurroundingorgan.
Whenitcomestimetogettissue,youmay...
(1)obtain(orhelpobtain)cellsforcytologicstudybythepathologistandassistants(by
"noninvasive"Papsmearofthecervixorotheraccessiblesites,orby"invasive"needle
aspiration).Manypathologistsliketodotheirownfineneedleaspirationsyoucanlearnthe
technique,also.
(2)obtain(orhelpobtain)atinypieceoftissueforthepathologisttostudy(aBIOpsy,the
oppositeofNECROpsy/autopsy).Cliniciansusuallydothebiopsies.
(3)assistatsurgicalremovaloftissue.
(4)obtainanautopsypermit.(*Howtodoanautopsyproperly:Arch.Path.Lab.Med.118:19,
1994).
Everythingthatcomesoutofapatientatsurgerygoestothepathologist.(Futuresurgeons
rememberthatthetissueformalinratioshouldbe1:10orless.)Ifadiagnosisisneededattimeof
surgery,thepathologistwillperformaFROZENSECTION("intraoperativeconsultation")onsome
tissue.Theseareveryaccurate,thoughthepathologistmaydeferfinaldiagnosis,especiallyifthe
lesionisapapillarytumororapossiblemalignantlymphoma.(Thediscrepancyratebetweenfrozen
sectionandpermanentsectionislessthan1%:Arch.Path.Lab.Med.130:337,2006.False
negativesbyfaroutnumberfalsepositives,whichisgood:Arch.Path.Lab.Med.132:29,2008).The
pathologistwillprobablybeabletotellyousomethingwhentheslidescomeout,usuallyonthe
weekdayafternoonAFTERyouobtainthetissue.
Wepathologistsareprettygoodthelateststudyinwhichalldiagnoseswerereviewedbya
secondpathologistfoundanerrorrateof0.26%(Am.J.Surg.Path.17:1190,1993theseare
errorsthatmightmakeadifferenceclinicallythecostofasecondpathologistwouldbe$2700
pererroravoided.)Pathologistsshowabout20%oftheircasestofriendsinhouse,andthis
helps:Am.J.Clin.Path.117:751,2002.
Futureclinicians:Keepyourbiopsyinstrumentssharpsoasnottointroduce"crushartifact"!
Telepathology,theprocessofturningglassslidesintodigitalimagesandsendingthemfor
diagnosistooneormorepathologistsatremotesites,isstillmuchslowerandsignificantlyless
accuratethanconventionalmicroscopy(Arch.Derm.139:637,2003).
DESCRIBINGTESTPERFORMANCE
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Don'tlaughthis'llbeonboardsforsure...
...andit'sworthunderstanding!
ANALYTICALSENSITIVITYistheabilitytodetectthepresenceofagivensubstance,expressedas
theleastconcentrationdetectableormeasurablebythetest.Modernlaboratorytestsincludevery
sensitiveprocedures.SerumvitaminB12levelsareroutinelymeasuredinpicograms.Themost
sensitivepregnancytestsdetectthehCGproducedbytrophoblasticcellswithinafewdaysfollowing
implantation.Thepolymerasechainreaction,whichdetectsthepresenceorabsenceofasinglecopy
ofagene,isnowcomingtothehospitalbench.Someprocedurestodetect"abnormalsubstances"
(forexample,somesuperduperCKMBisoenzymetests)arenotusedbythelabbecausetheyare
toosensitive,anddetecttracesofthe"abnormalsubstance"inmostnormals.
ANALYTICALSPECIFICITYistheabilitytodetectasinglespecificsubstanceandnoothers.Most
testsinthehospitallabarenotabsolutelyspecific,thoughthisisNOTusuallyaproblemforclinicians.
Forexample,bromideion(ifpresent)willbemeasuredaschlorideionbyroutine"electrolytestudies."
Acidphosphatasemeasurementsalwaysincludeacontributionfromalkalinephosphatase.Some
procedurestomeasureASTandcreatininelevelsalsomeasureacetoaceticacid,soASTand
creatininevalueswillappearfalselyelevatedinstarvationanddiabeticketoacids.Lipemia(cloudyfat
intheserum)mayfalselyincrease(ordecrease)theresultsofmanycommonchemicaltests.Andso
forth.Youwilllearnaboutmostoftheimportantproblemsduringthiscourse.
ACCURACYisclosenesswithwhichanobtainedresultagreeswithaknownacceptedtruevalue.In
additiontoroutinequalitycontrol,mostclinicallabsreporttheirresultsonsamplesprovidedby
outsideagencies(suchastheCollegeofAmericanPathologists)tocheckontheirownaccuracy.See
Arch.Pathol.Lab.Med.109:709&1066,1985.
PRECISIONisthereproducibilityoftestresults.Serumelectrolytestudiestypicallyvarybyonly1%or
evenless.(Thisisgood,as"'lytes"needtobetightlyregulated.)Mostotherchemicaltestsmayvary
byaround5%.Measurementsofenzymeactivitiesmayvary10%orevenmore.Again,thisisNOT
usuallyaproblemforclinicians.
INTERPRETINGYOURRESULTS
Thefollowingconceptscomeupcontinuallyindiscussionsoflabdata,andarefavoritelicensure
examitems.Labdatainterpretationusuallystartswithcomparingyourpatienttowhateverit"normal."
TheREFERENCERANGE("normalrange"):rangeofvaluesinwhichahealthyperson'stestresultis
"expected"tofall.Thisisusuallythemeanplusorminus2S.D.for"healthy"membersofthe
populationtowhichthepatientbelongs.NoticethatFIVEPERCENTOF"HEALTHY"PEOPLE
ARBITRARILYFALLJUSTOUTSIDETHENORMALRANGE.The"population"isgenerallyhealthy
adults,thoughforsometests,thereareseparate"normalranges"fordifferentages,races,sexes,and
soforth.
Manyothermodelsfordefiningthereferencerangeexist,includingsomeextremelycumbersome
techniqueswherethedistributionisnonGaussian.Medicalstudentswhodonothavethegood
fortunetoattendKCUMBworkhardtomemorize"normalranges"forthecommontests,sometimes
discoveringthattheyvarygreatlyfromhospitaltohospitalbecauseofdifferenttechniquesoreven
differentunitsofmeasurement.TheCentinormalsystem,inwhichthe"upperlimitofnormal"foreach
clinicalchemicaltestissetat100,thankfullyneverbecamepopularintheUSA.
Amoresatisfactoryapproachtotheproblemof"normalranges"couldbetoestablishcertain
abnormalvaluesasDECISIONLEVELS("actionlevels",etc.),dependingonwhethertheclinician
shouldactuallydoanythingaboutthe"abnormal"result.Themostfamiliarexampleisthe
recommendationthatanyonewithacholesterolover200mg/dLorLDLcover160mg/dLorHDLc
under35mg/dLshouldtakeactiontoimprovethings.
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Howeveryoudoit,youwilldecidethateachdiagnosticprocedure'sresultsareeitherPOSITIVE
(suggestingadiseaseispresent)orNEGATIVE(suggestingadiseaseisabsent).Unlessthe
diagnosticprocedureyouhaveusedistheabsolutereferencecriterionforaparticulardisease(that's
usuallyanautopsy),yourresultsarealsoeitherTRUEorFALSEasindicatorsofdisease.(Pleaseuse
commonsense.Don'tjusttellyourpatient,"Yourlabresultsareallnegative."Thepatientmightnot
understand.)
DIAGNOSTICSENSITIVITY("Bayesiansensitivity")isthepercentageofpositiveresultsinpatients
withaparticulardisease.
DiagnosticSensitivity=100X(TP)/(TP+FN)
DIAGNOSTICSPECIFICITY("Bayesianspecificity")isthepercentageofnegativeresultsinpatients
withoutaparticulardisease.
DiagnosticSpecificity=100x(TN)/(TN+FP)
Sensitivetestsarebestforthediagnosisoftreatablediseases:bacterialinfections,earlycancer,
phenylketonuria.YouwantaVERYSENSITIVEtestwhenthebenefitsofdetectingthediseaseare
great(curingit,preventingnewcases,etc).
Specifictestsarebestforthediagnosisofnontreatablediseases:chronicneurologicdisease,
disseminatedcancer,etc.YouwantaVERYSPECIFICtestwhentherisksofawrongdiagnosisare
great(gettingveryupset,losingyourinsurance,gettingcancerchemotherapy,etc.)
Theseareappallingovergeneralizations,butthereisalwaysatradeoffbetweensensitivityand
specificity.Ifanewtestisbothmoresensitiveandmorespecificthananoldtest(andnotmuchmore
expensiveorslower),itreplacesit.Otherwise,whetherweareapathologistsettinga"reference
range"or"decisionlevel",oraclinicianorderingalabtest,wemustrememberthatsensitivetestslack
specificityandspecifictestslacksensitivity.Clinicianscommonlyorderthesensitivetestsfirst,
followedbythespecificones.
PREDICTIVEVALUE:thepercentchancethataresultcorrectlyidentifiesthepatientasdiseasedor
nondiseased.
PredictiveValueofaPositiveResult=100x(TP)/(TP+FP)
PredictiveValueofaNegativeResult=100x(TN)/(TN+FN).
Verysensitivetestshaveahighnegativepredictivevalue.
Veryspecifictestshaveahighpositivepredictivevalue.
DiagnositcAccuracy("DiagnosticEfficiency"):100x(TP+TN)/(TP+FP+TN+FN)
PrevalenceHowwouldyoucalculatehowmanypeoplearesick?
Prevalence:(TP+FN)/(TP+FP+TN+FN)
Prevalencemaybeexpressedindifferentunits.ContrastINCIDENCE:thefractionofnewcasesof
thediseaseinapopulationoveragiventime.
Prevalence=IncidencexAverageDuration
*Bayes'Theorem.
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PVofapositiveresult=((sens)x(prev))/((sensxprev)+((1spec)x(1prev)))
Workingproblems:
Ifsomeonegivesyouaprevalence,sensitivity,andspecificity,hereisanapproachtofinding
predictivevalues.
Consideronemillionpeople.
1000000xprevalence=numbersick
Numbersickxsensitivity=TP
NumbersickTP=FN
1000000numbersick=numberhealthy
Numberhealthyxspecificity=TN
NumberhealthyTN=FP
Takeitfromthere.Ifyouneed,youcanworkbackwards,too.
TheLIKELIHOODRATIOistheprobabilitythatapatietwiththediseasehasagiventestresult
dividedbytheprobabilitythatapatientwithoutthediseasehasthesametestresult.The
advantageisthatthisdoesnotvarywithdiseaseprevalence,aspositiveandnegativepredictive
valuedo.Whenseveraltests,eachnotallthatsensitiveorspecificinthemselves(asinthe
workupforsarcoidosis),canbecombinedtogivea"likelihoodratio",itcanbeabighelpfor
clinicians(Am.J.Clin.Path.134:939,2010).
TOTHINKABOUT:
1."Jargonisnotinsight."Whataresomereasonspeopleusejargon?
2.WhatmightbesomereasonsthatUSphysiciansordermorelabteststhanourBritish
counterparts?(SeeJAMA252:1723,1984andLancet1:1278,1984.)
3.Whymightitbeeasiertotalkaboutlabtestresults("thenumbers")thanaboutchangesinthe
physicalexam("theprotoplasm")?
4.Iftwelvetestsarerunonapanel,andahealthypersonhasonly.95chanceofbeingin"normal
range",andyouassume(unjustifiably)thatthevaluesvaryindependentlyofoneanother,whatare
thisperson'schancesofhavingatleastoneabnormaltestresult?
5.Whataresomereasonsfordoingallthenoninvasivetestsfirst?
6.Whyareenzymeactivities,ratherthantheconcentrationsoftheenzymesthemselves,usually
measured?
7.Whataresomereasonsthatcliniciansliketolookattheglassslidesontheirownbiopsyand
surgicalspecimens?
8.Willabiopsyofacoloncancertellyouthegrade?Thestage?
9.Whataresomeproblemswithsettinga"normalrange"forserumcholesterolintheU.S.?(See
Arch.Path.Lab.Med.112:387,1988).
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10.WhatweresomeoftheproblemswhenmassscreeningsofAfroAmericansforsicklecelldisease
wereintroducedinthelate1960's?
11.Supposeankylosingspondylitisisanunpreventable,easilydiagnosed,untreatable,mildly
disablingdisease,thatonlythe4%ofpeoplewhoareHLAB27positiveareatrisk,andthattherisk
evenforthemis1in100.NoonesuggeststhatbeingHLAB27positiveisareasontoforego
parenthood.Itisproposedtoscreenvisitorstotheshoppingmallusinganew,fiftycent,highly
accuratetestforHLAB27.Whatdoyouthinkofthissuggestion?
12.YouwanttoorderaroutineCBCandchemicalprofiletoscreenanasymptomaticadultinyour
office.Canyoudrawthebloodnow,orwillyoumakethepatientgotothelabtomorrowmorning
beforebreakfast?
13.Whataresomereasonsthatthelabdoesnotpublish"sensitivity"and"specificity"dataforeach
test?
14.Adiseasehasaprevalenceof1in100,000people.Ascreeningtestforthisdiseaseinvolves
flippingacoin,with"heads"apositivetest.Whatisthepredictivevalueofanegativeresult?
15.Itisproposedtouseaparticulartesttoscreenforacertaindisease.Theprevalenceofthe
diseaseinthepopulationbeingscreenedis1%.Thesensitivityandspecificityofthetestareboth
95%.Whatisthepredictivevalueofapositiveresultforthisscreeningtest?Doesitchangeifthe
prevalenceis10%?Iftheprevalenceis50%?
Lash'sBitters
PittsburghPathologyCases
IfIcanstoponeheartfrombreaking
Ishallnotliveinvain,
IfIcaneaseonelifetheaching
Orcoolonepain
Orhelponefaintingrobin
Intohisnestagain,
Ishallnotliveinvain.
EmilyDickinson
BIBLIOGRAPHY/FURTHERREADING
Iurgeanyoneinterestedinlearningmoreaboutgenerallaboratorymedicinetoconsultthese
standardtextbooks.
Bakerman'sABC'sofInterpretiveLaboratoryData
Henry'sClinicalDiagnosisandManagementbyLaboratoryMethods
RobbinsandCotranPathologicBasisofDisease
RosaiandAckerman'sSurgicalPathology
Rubin'sPathology:ClinicopathologicFoundationsofMedicine
Demay'sCytopathology
Inmynotes,themosthelpfulcurrentjournalreferencesareembeddedinthetext.Students
usingtheseduringlecturestronglypreferthis.Andbecausethesiteisconstantlybeingupdated,
numberedendnoteswouldbeunmanageable.What'savailableonline,andforwhom,isalways
changing.Mostpubliclibrarieswillbehappytohelpyougetanarticlethatyouneed.Goodluck
onyourownsearches,andagain,ifthereisanywayinwhichIcanhelpyou,pleasecontactme
33/35
11/3/2016
atscalpel_blade@yahoo.com.Notextingorchatmessages,please.Ordinaryemailsare
welcome.Healthandfriendship!
Newvisitorstowww.pathguy.com
resetJan.30,2005:
DropbyandmeetEd
Edsays,"ThisworldwouldbeasorryplaceifpeoplelikemewhocallourselvesChristiansdidn'ttrytoactasgoodasother
goodpeople."PrayerRequest
IfyouhaveaSecond
Lifeaccount,please
visitmyteammates
andmeattheMedical
Examiner'soffice.
TeachingPathology
PathMaxShawnE.CowperMD'spathologyeducationlinks
Ed'sAutopsyPage
NotesforGoodLecturers
SmallGroupTeaching
SocraticTeaching
Preventing"F"'s
ClassroomControl
"IHateHistology!"
Ed'sPhysiologyChallenge
PathologyIdentificationKeys("KansasCityFieldGuidetoPathology")
Ed'sBasicScienceTriviaQuizhaveachuckle!
34/35
11/3/2016
RudolfVirchowonPathologyEducationhumor
CurriculumPositionPaperhumor
ThePathologyBlues
Ed'sPathologyReviewforUSMLEI
PartI
PartII
PathologicalChess
TaserVideo
83.4MB
7:26min
Clickheretoseetheauthor
proveyoucanhavefun
skydivingwithoutbeing
worldclass.
Clickheretoseethe
author'sfriend,Dr.Ken
Savage,doitright.
35/35

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