1

Cholesterol(blood,plasma,serum)
1 Nameanddescriptionofanalyte

1.1 Nameofanalyte
Cholesterol(plasma;alsoblood,serum)

1.2 Alternativenames
2,15dimethyl14(1,5dimethylhexyl)tetracyclo[8.7.0.02,7011,15]heptacos
7en5ol(systematic);3cholesten5en3ol(IUPAC);alsofrequently
includedinthecollectivetermlipids,whichincludestotaltriglycerides
(triacylglycerols)andsometimesotherlipoproteins.

1.3 NLMCcode
Tofollow

1.4. Function(s)ofanalyte
Cholesterolistheprincipalsterolsynthesisedbyanimals,anessential
componentofcellmembranes,andprecursorofsteroidhormones,
vitaminDandbileacids.Itisalsoacomponentoflipoproteins,whichare
requiredfortransportoftriglycerides.Althoughmostcellsinhumansare
abletosynthesizecholesterol,themajorityissynthesizedintheliver;
dietaryintakecontributesless,althoughdietdoesinfluenceplasma
[cholesterol]throughvariationoflipoproteinproductioninresponseto
theoverallenergyintake.Cholesterolistransportedinplasmaprimarily
(butnotexclusively)intheformoflowdensitylipoproteins(LDL);the
principalrouteforitsremovalfromtissuestotheliverisinhighdensity
lipoproteins(HDL),followedbyexcretioninthebile.
Plasma[cholesterol]haslongbeenknowntobeassociatedwith
cardiovascularrisk;thisisbecausethetotalplasma[cholesterol]
correlateswiththepresenceoflipoproteins(LDLandsmall,dense,LDL
inparticular)thatmaybecometrappedintheintimaofcoronary(and
other)arteriestoformatheroscleroticplaque.Manytherapieshave
thereforebeenaimedatreducingthisprocess,theprincipalatpresent
beingstatins,drugswhichinhibittheratelimitingstepofcholesterol
synthesiscatalysedby3hydroxy3methylglutarylcoenzymeA(HMG
CoA)reductase.Theyalsosuppressinflammationthatisthoughtto
induceplaqueinstability.Cholesterolmetabolismis,however,alsolinked
withinflammation:reducingplasma[cholesterol]reduceslowgrade
inflammationwhereasongoinginflammationdecreasesplasma
[cholesterol].

2 Samplerequirementsandprecautions

2.1 Mediuminwhichmeasured
Cholesterolcanbemeasuredinserumorplasma:thisarticlerefersonly
tomeasurementsinthesefluidsmadeinlaboratories.Pointofcare
testing(usingcapillaryblood)is,however,alsowellestablished.

2.2 Precautionsresampling,handlingetc.
Cholesterolisstableinbloodandrequiresnospecifichandling
precautions,howevergiventheinfluenceofinflammationonplasma
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[cholesterol],itisbettertoavoidsamplingwhenthepresenceofanacute
phaseresponseislikelytogivemisleadingresults.Forexample,
cholesterolshouldbemeasuredatthetimeofadmissionwithchestpain
ratherthanthefollowingday,bywhichtimetheconcentrationmayhave
droppedsignificantly.Itisimportanttonotethatthissuppressionmay
lastseveralmonths.
Samplesforlipidsotherthancholesterolarebesttakenafterfastingto
reducetheinfluenceofrecentdietaryintake.
Itisoftenrecommendedthatdiagnosisandtreatmentshouldnotbe
basedonindividualmeasurementsbecauseoftherelativelyhigh
biologicalvariation.

3 Summaryofclinicalusesandlimitationsofmeasurements

3.1 Uses
Cholesterolmeasurementsareusedtodiagnoseandmonitor
hypercholesterolaemia(monogenic,polygenicandsecondary),andto
assesscardiovascularrisk.

3.2 Limitations
Cholesterolmeasurementscannotprovideinformationastothecauseof
hypercholesterolaemia,andwillnotprovideaccurateassessmentof
hypercholesterolaemiaorcardiovascularriskinthepresenceofanacute
phaseresponse.Inriskassessment,cholesterolmeasurementsshouldbe
consideredinrelationtootherriskfactors(e.g.cigarettesmoking,
hypertension,diabetesmellitus,apersonalhistoryofcardiovascular
diseaseetc.)

4 Analyticalconsiderations

4.1 Analyticalmethods
Totalcholesterolismeasuredusinganenzymaticcolorimetricmethod,
typicallyusingcholesterylesterhydrolase(EC3.1.1.13)tohydrolyze
cholesterylesters,cholesteroloxidase(EC1.1.3.6)toproducehydrogen
peroxideandperoxidase(EC1.11.1.7)plusadyetoformacoloured
product;theabsorbanceofthecomplexismeasuredasanendpoint
reaction:

Cholesterylester+H20 (cholesterylesterhydrolase) Cholesterol+
Fattyacid

Cholesterol+O2 (cholesteroloxidase) Cholest4en3one+H202

H202+Phenol+4Aminoantipyrine(peroxidase)Quinoneiminedye
+2H20

4.2 Referencemethod
(CenterforDiseaseControl(USA):modifiedAbellKendallmethod).The
cholesterolinesterformisreleasedbysaponificationofaserumsample
withalcoholicpotassiumhydroxide.Thisisfollowedbyextractionwith
hexane,evaporationofanaliquotoftheextract,anddevelopmentofa

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chromophoreat620nmwithLiebermannBurchardreagent(acetic
anhydride,glacialacetic,andconcentratedsulfuricacid).

4.3 Referencematerials
Cholesterol(TheNationalInstituteofStandardsandTechnology,
StandardReferenceMaterial(NISTSRM)911c(WashingtonDC,USA)).

4.4 Interferingsubstances
Thestandardlaboratorymethodsarenotspecificforcholesterol:other
hydroxysteroidsandplantsterolssuchassitosterolalsoreact.
Thereisnosignificantinterferencefromhaemolysis,icterusorlipaemia,
butnotethat,wherelipaemicsamplesrequirepretreatmentwitha
clearingagent,cholesterolshouldbeassayedpriortothetreatment.

4.5 Sourcesoferror
Noneofsignificance

5 Referenceintervalsandvariance

5.1.1 Referenceinterval(adults)
Becausetheassociationbetweenincreasedcardiovascularriskand
plasma[cholesterol]extendstovaluestypicallyseeninhealthy
individuals,measurementsareusuallycomparedtorecommendedaction
limitsratherthanreferenceintervals(seesection9).Concentrations
typicallyrisethroughoutchildhoodandafterinfancyareslightlyhigherin
femalesthanmales,e.g.lateteenagefemale3.085.18mmol/l,male
2.935.10mmol/l;olderadultfemale4.437.85mmol/l,male4.097.10
mmol/l.
5.1.2 Referenceintervals(others)
Concentrationstypicallyrisethroughoutchildhoodandarehigherin
femalesthaninmalese.g.infantfemale2.905.18mmol/l,male2.955.25
mmol/l;earlyteenagefemale3.215.20mmol/l,male3.085.23mmol/l.
5.1.3 Extentofvariation
5.1.3.1 InterindividualCV:22.3%(tendstobehigherinolderfemales)
5.1.3.2 IntraindividualCV:8.2%
5.1.3.3 Indexofindividuality0.37
5.1.3.4 CVofmethodapprox.4.5%
5.1.3.5 Criticaldifferenceapprox.22%
5.1.4 Sourcesofvariation
[Cholesterol]isreducedinacuteandchronicdisease,especiallyinthe
presenceofinflammation.Itisalsodecreasedduringperiodsofreduced
calorieintake.

6 Clinicalusesofmeasurementandinterpretationofresults

6.1 Indicationsandinterpretation
1.Screeningforhypercholesterolaemia/dyslipidaemia.Concentrations
shouldbeinterpretedaspartofaglobalcardiovascularriskassessment
(e.g.accordingtoalgorithmsdevelopedbytheFraminghamStudy,
ProspectiveCardiovascularMunsterStudy(PROCAM),QRISK2,ASSIGN
(ASSessingcardiovascularriskusingScottishIntercollegiateGuidelines
Networkguidelines),unlessparticularlyhigh,inwhichcaseotherreasons
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ofhypercholesterolaemiashouldbeconsidered.TheSimonBroome
criteriaareusedwhenfamilialhypercholesterolaemia(FH)isbeing
considered.Riskcanbefurtherrefinedbymeasurementofplasma
triglycerides,HDLcholesterolandLDLcholesterol.
2.Monitoringoftreatmentmostrecommendationssuggesttreatingtoa
target[cholesterol],particularlyforpatientswithFHorexisting
cardiovasculardisease;measurementsarealsousedforassessing
adherencetotreatment.

6.2 Confoundingfactors
None,buttherelativelyhighbiologicalvariationshouldbeborninmind
whenconsideringserialmeasurements.

7 Causesofabnormalresults

7.1 Highvalues
7.1.1 Causes
familial(monogenic)hypercholesterolaemiaandvariants
polygenichypercholesterolaemia
mixedhyperlipidaemias
secondaryhyperlipidaemia
o chronicliverdisease(particularlywithcholestasis)
o hypothyroidism
o chronickidneydisease
o myeloma
o alcoholexcess(particularlyinconnectionwithsevere
hypertriglyceridaemia)
o drugs(steroids,retinoids,antiretroviralsandtamoxifencan
inducesignificant(usuallymixed)hyperlipidaemia.
7.1.2 Investigation
Raisedconcentrationsshouldbeconfirmedwitharepeat,togetherwith
measurementsofotherlipidsincludingtriglycerideandHDLcholesterol,
andLDLcholesterol(usuallybycalculation);measurementsof
apolipoproteinmaybeappropriate.Betaquantificationoflipidsusing
ultracentrifugationcanhelpdeterminewhichlipoproteinfractionsare
raised.
Secondarycausesofhypercholesterolaemiamustbeexcludedbefore
initiatingspecifictreatment.
InindividualswithpossibleFH,geneticstudiesandcascadetestingof
relativesmaybeappropriate.

7.2 Lowvalues
7.2.1 Causes
Usuallycausedbyongoinginflammatoryresponsetoinjuryordisease,
includingvarioustypesofcancer.
7.2.2 Investigation
Investigationofunderlyingdiseaseifappropriate

7.3 Notes

8 Performance

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8.1 Sensitivity,specificityetc.forindividualconditions
Theseconceptsareinappropriateforcholesterol:hypercholesterolaemia
isdefinedbycutoffpointsrelatingtooverallcardiovascularrisk.

9 Systematicreviewsandguidelines

9.1 Systematicreviews
Reviewshavefocusedonspecificconditionsratherthanoncholesterol
specifically;thesereviewsareincorporatedintoguidelines,below.

9.2 Guidelines
1.NCEPATP(NationalCholesterolEducationProgram,AdultTreatment
Panel)http://circ.ahajournals.org/content/106/25/3143.citation
2.NICE:Preventionofcardiovasculardisease(PH25)2010
http://publications.nice.org.uk/preventionofcardiovasculardisease
ph25
3.NICE:Lipidmodification(CG67)2008(currentlybeingupdated:
http://guidance.nice.org.uk/CG/WaveR/123)
4.NICE:Familialhypercholesterolaemia(CG71)2008
http://www.nice.org.uk/nicemedia/live/12048/41700/41700.
5.SIGN97:Riskestimationandthepreventionofcardiovasculardisease.
2007http://www.sign.ac.uk/pdf/sign97.pdf
6.JointBritishSocietiesGuidelineonPreventionofCardiovascular
DiseaseinClinicalPractice(JBS2)2005
http://heart.bmj.com/content/91/suppl_5/v1.full.pdf+html

9.3 Recommendations
Incorporatedintoguidelines,above

10 Links

10.1Relatedanalytes
HDLcholesterol,LDLcholesterol

10.2Relatedtests
Otherroutinelyanalysedlipids:triglycerides,apolipoproteins;othertests
relatedtotheassessmentofcardiovascularriskorsecondary
dyslipidaemia,e.g.bloodglucose,thyroidfunction,renalfunctionetc.

Author:WilliamSimpson

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