HighYieldConceptsinGeneralPathology

GeneralPrinciplesofLabMedicine
Sensitivityofatcst:"posith;iryilldisease"
A.
TP=pa.t.ienlwiththedisease
n.
FN=palien(withdiseasewhohasanegativeteslresult
C.
fOflllUt:1forsensitivityTPITP+FN
uscofatest"...ithJ00%sensithii)'
bestused10screenfordisease
excludesdiseasewhennegative
includespeople\.vithdiseasewhenpositive'
catchwords:excludesandincludes
interpretationofatestwithJ00%sensirivitywhenitreturnsnor11lalinapaticllt
alwayshasane!..!ativeorediclivevalueof'100%(PY=TN/TN+FN)
itmUStbeaTNlestresult(excludesdisease)sincetherearenoJNs:aTNisatrue
negativeoranomlai[cstresultinapersonwilhoutdisease
e.g..)ci'umANAhas100%sensitivityforSLE:anegativeserumANAexcludesSLE,
interpretationofatestwith100%sensitivitywheuitreturnspositivei11apatient
maybeaTPorFP:
(I)FP=falsepositiveorapositivetestresultinanomlaJperson
(2)
notethatFPsarenotinthefom1ulaforsensitivit)l
peoplewiththediseasearea!wavsincluded
c.g.,apositivesenlmAKAresultincludesall~lewithSLE:itdoesnOTconfirmSLE
sinct!otherdiseasesalsohaveapositiveANA(e.g.,rheumatoida.rthritis.progressive
2.
4.
B.c.
systemicsclerosis)
Disease
;'\rIoD~ease
Positivetest
(TP)100
(FP)10
Negativetest
(FN)
0
(Ti\)90
Calculatesensiriviryorthetest:TPJTP+FN=100I1000==1000,,"i1Calculate
PY:TN1TN+fN=90190+0=100%
"'"
Specificityorarest:
"negativityinhealth"
TN==normaltestresultinapersonwilhomdisease
FP=patientvv'ilholl!diseusewhohasapositivetestresult
C.
formulaforspecificityTN/TN+FP
useofatestwitb100%specificityconfinnsdisease:therearenoFPtestresults,
therefore.apositivetestmustbeaTP

interpretationofatestwith100%specificitywhenitreturnspositiveinapatient
confinnsdiseaseinthatpatient
positivepredictivevalueisalways~:oO%(PV'~TP/TP+FP)
mustbeaTP(confirmsdisease)sincetherearenoFPs
e.g.,antiSmforSLEhas100%specificity(110FPs):glLpatientswithaposiLiveanti
SmhaveSLE
interpretationofatestwith100%specificitywhenitreturnsnegative/normalInapatient
maybeaTNorFN:notethattheFNrateisnotintheformulaforspeci.ficity
itdoesnotexcludeSLE
e.g.,antiSmisnegativeinapatient:(I)doesnotexcludeSLE
(2)
useotherteststoconfirmSLEifyoursuspicionsarehigh
Disease
NoDisease
Positivetest (TP)90
(FP)0
Negativetest(FN)10
(TN)100
Calculatespecificityoftl,etest:TN/TN+FP~100/100+0~100%CalculateP:TP/
TP+FP~90/90+0~100%
CalcuJatethereferenceintervalofthet.estwhengiventhemeanofthetestand1SD
(standarddeviation):
remembertodoubletheSD2SDcovers95%ofthenormalpopulation
example
.
meanofthetest~IOOmzldLandISD~5mgldL(2SD~IOmgldL)
referenceinterval~90110mgldL(l0010~90and100+I0~110)
foreachtest,5%ofnormalpeoplewilthavetestresultsoutsidethereferenceintenal
chanceofaFPincreaseswhenmorethanonetestisorderedonapatient
example.2testsonapatientincreasesthechanceofaFPtestresultononeofthosetests
rolO%
SDisamarkeroftheprecision(reproducibility)ofthetestitisnotamarkerofhow
accuratethetestresultis
Accuracy:good
Accuracy:poor
Precision:good
Precision:good
Effectoftcstsensitivity/specificityofatestonprevalence:
testwithhighestsensitivity(notspecificity)increasesprevalenceofdisease(numberof
peopleinapopulationtbathavedisease)
itpickslipmorepeoplewiththediseasesinceitisagoodscree_ningtest
testswithhighspecificityconfinndiseaseandhelpdifferentiateaTPfromaFPbutthey
arepoorscreeningtests

,Effectofincreasingtheupperlimitofnormalofatestreferenceinterval(e.g.,raisinga
referencelnten'a!of04ng/mLto010ng/mL)onsensitivity,specificity,PY+,andPV":
increasesspecificityandpositivepredictivevalue
h.ighervaluesaremorelikelytorepresent\.TPsthanFPs
specificityalwaysincreases,whichautomaticallyincreasesPY+decreasessensitivity
andnegativepredictivevalue(PV)
increasingspecificityofatestalwaysdecreasesitssensitivityandPV
FNrateincreases,sincemorepeople.withdiseaseareencounteredasthereference
intervalincreases
anomlaitestresultismorelikelytobeaFNrarherthanaTN
Effectofdecreasingtheupperlimitofnormalofatestreferenceinterval(e.g.,lowering
thefastingglucoselevel(ordiagnosingdiabetesmellitus(DM]from>140mg/dLto
>126mgldL)onsensitivity,specificity,PV,andPV:
increasessensitivityandnegativepredictivevalue(PV)
droppingtheupperlimittoalowervaluemeansthatmorepeoplewithanegativetest
resultarelikelytobeTNs(nothaveDM)ratherthanFNs
sensitivityandPValwaysi_T'lcreasewhentheupperlimitofatestislowereddecreases
specificityandpositivepredictivevaJue(PV)
fewerpeoplearelikelytohaveOM,atestresult>126mgldLismorelikelytobeaFP
thanaTPtestresult
summaryschematic
2.
Pre\'alence:
Prevalence(numberofpeoplewithdiseaseintbepopu.lationstudied)==(numberofnew
casesoveraperiodoftime)xDurationoftbedisease
P~IxD
asduration(.D)decreases,prevalence(P)decreases
Incidence

asDincreases,Pincreases
incidence(1)isaconstantinthisrelationship
prevalencec.lcuJationTP+FN(allpeoplewithdisease)1TP+FN+TN+FP(all
peoplewithandwithoutdisease)
3,
exampleiftreatmentforleukemialengthensthesurvivalperiodbutdoesnotlead
toits'cure,prevalence(P)ofleukemiaIncreasesowin~totheincreaseindumtion(D):no
effectonincidence(numberofnewcasesofleukemiaY
Exampleofacalculationforsensitivity,specificity,PV+1PV,prevaJence:
Disease
NoDisease
Positivetest (TP)60
(FP)40
Negativetest(FN)20

(TN)80
Sensitivityofthetest:TP/TP+FN~60/80~75%Specificityofthetest:TN/TN+
FP~80I120~66%
PV:TNITN+FN~801100~80%(80%chanceitisaTNanda20%chanceitisa
FN)p\,,:TPITP+FP=60/100~60%(60%chanceitisaTPand40%chanceitisa
FP)Prevalence:TP+FNITP+FN+TN+FP~801200=40%
<ir
Normalcbangesinpregnancy:
greaterincreaseinplasmavolumethanRBCmass
Adecreaseshemoglobin(Hb)andhematocrit(Het):dilutionaleffect
increasesglomerularfiltrationrate(GFR)andcreatinineclearanceincreasedplasma
volume
(CCr):dueto

C.
decreasesserumBUN/creatinine/uricacid:dilutionaleffect+increased
clearance
increasedalkalinephosphataseplacentalorigin
respiratoryaJkalosisestrogen/progesteroneeffectoneNSrespiratorycentercausing
increasedclearanceofCO2perb.reath
increasedT4andcortisol
increasedsynthesisoftheirbindingproteins
freehormonelevelsarenormal
nosignsofhyperthyroidism/bypercortisolism
e.g.,normalserumTSHandACTII,respectively
MainlaboratorydifferenceinadultmaleandfemaJe:
ironstudiesarealllowerinwomene.g"serumironandferritin
lowerHbconcentrationinwomen
Children:
J,
increasedserumalkalinepbosphatase(ALP)
A,
35timeshigherthanadults
osteoblastsreleaseenzymewhenstimulatedbyvitaminD
ALPincreasesbonemineralization
increasedserumphosphaterequiredtodrivecalciumintobone,
slightdecreaseinhemoglobinconcentrationwhencomparedtoadultlevelsNewborn:
highhemoglobin(Hb)duetoincreaseinHbF
leftshiftsoxygendissociationcurve(ODe):causestissuehypoxia+
stinluiusforerythropoietin(EPO)reiease
increasesRBCproductionwithsubsequentincreaseinHbconcentration
I

1111,' "/#
+~cIJ~.
_
HbF:
Pv~l(tt.('
[flO''''!f.,,I;0I
leftshiftsoxygendissociationcun'e(ODe)

~;L::.'.:~

protectsnewbornswithsicklecelldisease
mostoftheRBCsatbirthcontainHbF:inhibitssickling
lessHbS:
(1)concentrationnothighenoughforsickling
(2)HbSmustbe>60%inRBCforspontaneoussickling(3)dactylitis(boneinfarctions
ofdigits)beginsin69md1S
protectsnewbornfromsevere~thalassemia
HbFcontain20:and2ychains
adultHbAwillbemarkedlydecreasedafterafewmonthssi.nce/3chainsynthesisIS
decreased:HbA=2exand2~
HbFsynthesisisincreasedwithhydroxyureausedtoreducesicklecellcris.es.
HbFisresistanttoalkali/aciddenaturationbasisforKleihauerBetketestindetermining
amountoffetalbloodinmaternalc"irculationafterdelivery
Analytesincreasedwithhemolyzedbloodsamplesecondarytovenipuncture:
LDH
LDH\isoenzymefractionisprimarilyincreasedandisgreaterthanLDH2isoenzyme
fraction(LDH,ILDH,flip)
falsepositiveacutemyocardialinfarction
LDHIisoenzymeisalsoincardiacmuscle
potassium
pseudohyperkalemia
K+isthemajorintracellularcation
ECGwillnotshowapeakedTwave
Lipidmostaffectedbyfasting:
triglyceride(TG)componentcomingfromcbylomicronschylomicronsconta.indiet~
derivedTG
fastingorlackoffastingdoesnotaffectcholesterol(CH)andhighdensitylipoprotein
(lIDL)concentration
A.
nonnally,CHis<3%ofthechylomicronfraction
B,
fastingisunnecessaryforanaccurateCHorHDL
fastingisnecessaryforanaccuratecalculatedlowdensitylipoprotein(LDL)
LDL~CHHDLTG!5
ifTGisfalselyincreasedbychylomicronsfromthediet,itwillfalselylowerthe
calculatedLDL
2.
Drugsenhancingthecytochromesystemintheliversmoothendoplasmicreticulum
(SER):
drugs
alcohol
barbirurates
effectonSER
A.
SERhyperplasia

B,
increasedsynthesisofyglutamyltransferase(GGT):enzymeisnormally
locatedinSER
C.
decreasesdruglevelsowingtoincreasedmetabolismofthedrug
Drugsinhibitingcytochromesystemintheliver:
drugs ..)
H,blockersIci",eftJ,.<
protonblockers
2.
dangerofdrugtoxicity
Significanceoferythrocytesedimentationrate(ESR)inoldage:probablyindicatesa
diseaseprocess
notanage~relatedfinding
notrecommendedasageneralstreenfordiseaseintheelderly
Laboratorytestalterationsinalcoholics:
enhancementofthelivercytocbromeP~450system
increasedsynthesisofyglutamyltransferase(GGT)
excellentenzymemarkerforalcoholicliverdisease
increasedproductionofNADDinitsmetabolicbreakdowncausesbiochemicalreactions
involvingNADDtomoveinitsdirectionresultinginthefollowing
A
lacticacidosis:pyruvate~lactate
fastingbypoglycemia:pyruvateisunavailableforgluconeogenesis
hypenriglyceridemia: 1,3bisphosphog!ycerate>dihydroxyacetonephosphate~
glycerol3phosphate....TGincreaseinketoacidsyntbesis
acetyleoA,theendproductofalcoholmetabolismisusedinthefollowingreaction
acetylCoA+acetylCoA....
ace[Q3cetylCoAt
HMGCOAtacetoaceticacid:increaseinNADHconvertsitinto~hydroxybutyricacid
(POHB)
increaseinfattyacidsyntbesisduetotheincreaseinacetyleoAhyperuricemialactic
acidlketoacidscompetewithuricacidforexcretioninthekidneysincreasedaniongap
metabolicacidosislactate+i3~OHB
o

4.5.6.
,
Laboratorytestalterationsinsmokers:
respiratoryacidosisairgetsinbutcannotgetout,soCO2isretained
bypoxemia(JowPaOl)seeCellInjurynotes
increasedcarbonmonoxide(CO)le,'elsCOispresentincigarettesmoke
4,
secondarypolycythemjalowF"a02stimulateserythropoietinrelease
absoluteneutrophilicleukocytosismetabolitesinsmokemobilizetheneutrophil
marginatingpoolinthecirculationbydecreasingleukocyteadhesiontoendothelialcells
Plasma/serumturbidity:

duetoanincreaseintriglyceride(TG)turbiditydoesnotoccurwithanincreaseIn
cholesterol(CH)inplasma
TGiscarriedbylipoproteins
chylomicrons:85%
verylowdensitylipoprotein(VLDL):55%
TGisfalselyincreasedaftereatingduetodietMderivedchylomicrons
cbylomicronsformasupranateinplasmacontainverylittleprotei.n:lessdensethan
VLDL
VLDLformsaninfranate(nosupraoate)containsmoreproteinthanchylomicronsand
doesnotfloatonthesurfaceofplasma
increasedturbidityinterfereswithmeasurementofenzymesandserumNa+falselylow
enzymevaluesandsodium(pseudohyponatremia)
Relationofserumalbuminconcentrationwithserumcalciumconcentration:
albuminbinds40%oftotalcalciuminblood
13%ofcalciumisboundtoothersubstrates
47%calciumisfree,ionizedcalcium:metabolicallyactivecalcium
lowserumalbumindecreasescalciumboundtoalbumin
hYPocalcemia
00tetanyispresent,sincetheionizedlevelsarenonnal
SMLEsce.n~ari'Ds"'~
calculationofsensitivity,specificity,py+andPV
twotestsareorderedonapatient,whatischanceforaFPresultansweris10%
increaseJdecreaseupperlimitofatest
effectofsensitivityonprevalence
usingtripletherapyforHIVpositivepeopleaDdeffectonprevalence
ithasextendedthetimeinterval(Duration)beforeanAIDSdefiningconditionoccurs
prevalenceofHIVpositivepeoplehasincreased
effectofpregnancyonserumcortisolansweristhatitisincreasedduetoanincreasein
thebindingproteinandnotthefreehormonelevel
Q_uestionsu!:Iej:linBoardReview:
t;Jr Assumingtheuseof2standarddeviationstoestablishthereferenceintervalofa
test,inatestwitha.referenceintervalof1030mg/dL,1standarddeviationwould
equal...
,
2.5
5.0
7.5
10.0
20.0
Bmeanofthetestis20mgldL,2SD=10mgldl,thereforeISD=5mgldL
Cir Iftheprostatespecificantigen(PSA)testforprostatecancerisloweredfroma
referenceintervalof010nglmLto04nglmL,thiswill...

increasethenumberoffalsenegatives
decreasethenumberoffalsepositives
increasethetest'sspecificity
increasethePV
increasetheFVI"
D
SnldythefoHowingschematicinvolvingacontrolgroupanddiseaseX.
NormaJ
DiseaseX
D

"E
~
Referenceinterval
Whichofthefollowingcorrectlydescribestestresultsinthespaceoccilpiedbyeach
offheletteredgroups?
GroupA:truenegatives+falsenegatives
Group8:truenegatives+falsepositives
GroupC:truepos.itives+falsepositives
GroupD:truepositives+falsenegatives
C:groupA=allTN"groupB=TNs+FNs,groupC=FPs+TPs,groupD=allTPs
r:r
Apregnantwomaninherfirsttrimestercomplainsofheatintoleranceand
palpitations.Physicalexamrevealsanenlarged,nontenderthyrojdgland.HerserumT4
is.elevatedandtheTSHisnon.nat.Whichofthefollowingapplies[0thiscase?
Thyroidbindingglobulinisincreased
FreeT4hormonelevelsareincreased
Estrogenincreasedthesynthesisofthyroidhormone
Progesteroneincreasedthesynthesisofthyroidbindingglobulin
A