Case#1

14yowhitemale
Referredafterhypercholesterolemiadetectedonroutinescreening
becauseoffathershypercholesterolemia
Totalcholesterol290mg/dl,repeat286mg/dl
Triglycerides108mg/dl,HDLcholesterol55mg/dl,LDL
cholesterol209mg/dl
Otherwisewell/Nocurrentmedications
Physicalexam,BPWNL,50thpercentileforHt/Wt
Noxanthelasma,cutaneousxanthomata,orAchillestendon
thickening

Case#1
Activity
Soccer,swimming,biking

Diet
Familyalreadyattemptingtoreducedietaryfatandcholesterol
afterlearningofelevatedcholesterolinpatientandfather

Social
Notobacco/alcohol/substanceabuse
Bothparentscomewithpatienttoclinic,seemverysupportive

Case#1
Dietaryassessment
3daydietaryrecalltodetermineaveragedailyintake
Totalcalories:2000kcal/day
Compositionas%oftotalcalories
Protein:22%
Fat:28%
Saturated:6%
Monounsaturated:14%
Polyunsaturated:8%
Carbohydrate:49%

Cholesterolcontent:221g/day
Fiber:31g/day

Case#1
53yo
MI

44yo
CH280

69yo
breastCA

42yo
CH310

35yo
healthy
CH152

36yo
healthy
CH299

6yo
healthy
CH?

68yo
diabetes
hypertension

9yo
healthy
CH?

14yo
healthy
CH286

66yo
healthy

XanthelasmaPalpebrarum

XanthomataTuberosa

Case#2
11yowhitemale
Referredafterhypercholesterolemiadetectedafterfatherwasfound
tohavehypercholestrolemiaandrecentmyocardialinfarction
Totalcholesterol254mg/dl,repeat250mg/dl
Triglycerides102mg/dl,HDLcholesterol53mg/dl,LDL
cholesterol181mg/dl
Otherwisewell/Nocurrentmedications
Physicalexam,BPWNL,50thpercentileforHt/Wt
Noxanthelasma,cutaneousxanthomata,orAchillestendon
thickening

Case#2

Activity
Computergames,TV
Biking

Diet
Somemealsathome,butoftenfastfood,snacks
Noeffortyettoalterdiet

Social
Notobacco/alcohol/substanceabuse
Parentsareseparated,liveswithmother,whoworkstwojobs

Case#2
Dietaryassessment
3daydietaryrecalltodetermineaveragedailyintake
Totalcalories:2000kcal/day
Compositionas%oftotalcalories
Protein:16%
Fat:37%
Saturated:17%
Monounsaturated:15%
Polyunsaturated:5%
Carbohydrate:47%

Cholesterolcontent:373g/day
Fiber:13g/day

Case#2
49yo
MI

59yo
hypertension

34yo
MI

34yo
CH159
healthy

36yo
CH299
MI6mosago

6yo
healthy
CH249

66yo
healthy

9yo
healthy
CH255

11yo
healthy
CH250

62yo
healthy

RiskFactorsforAtherosclerotic
HeartDisease

Hypercholesterolemia
Smoking
Hypertension
Diabetes
Sedentarylifestyle
MaleSex
FamilyhistoryofCHD
Age(male>45yoa,female>55yoa)

EvidenceRelatingDiet,SerumCholesterol
Level,andCoronaryHeartDisease
Animalstudies
Geneticdisorders,suchasfamilial
hypercholesterolemiawithelevatedserumLDL
cholesterol,areassociatedwithpremature
atherosclerosis
Epidemiologicstudies
Clinicaltrials
Autopsystudies

DietarySaturatedFatandCholesterol
IntakeandSerumTotalCholesterolin
BoysAged79YearsinSixCountries
Country
Philippines

SaturatedFat
(%ofenergy)
9.3

Cholesterol
(mg/1000kcal)
97

Italy

10.4

159

159

China

10.5

48

128

U.S.

13.5

151

167

Netherlands

15.1

142

174

Finland

17.7

157

190

SerumChol
(mg/dl)
147

SerumCholesterolinBoysandMiddleAged
MenandCHDMortalityRatesinMiddleAged
MeninIndustrializedCountries
SerumTotal
Cholesterol
(mg/dl)
BoysMen

CHDMortality
Per100,000
Menaged
4554years

Portugal

149203

71

Israel

155204

119

Italy

159200

91

Hungary

159203

276*

U.S.

167217

170

Netherlands

171221

134

Poland

176192

218*

Country

Finland

190240

264

CoronaryPrimaryPrevention
Trial(CPPT)
Hypercholesterolemic,middleagedmen
Treatedwithcholestyramine
19%reductioninfataland/ornonfatalMIover7
years
A25%reductioninserumcholesterollevel
resultedina50%reductioninCHDrisk

ControlledAngiographicTrialsof
CholesterolLowering
Severalstudiestodateinadults
Regressionoflesionsin1647%withlarge
decreasesinserumLDLcholesterollevels(34
48%reduction)for25years
Mainbenefitmaybeslowingofprogressionof
atheroscleroticlesions

WhyInterveneinChildren
Roleofhypercholesterolemiainatherosclerosiswell
establishedinadults
Childrenwithelevatedcholesterolaremorelikelytohave
familymemberswithelevatedlevelsandcomefrom
familieswithprematureatherosclerosis
Tracking
Childrenwithelevatedserumcholesterollevelsarelikelytohave
hypercholesterolemialaterinlife

Autopsystudies

AutopsyStudies
U.S.soldiersinKoreanWar(Enosetal,1955)
Grosscoronarydiseasein77%ofsubjectsstudied
Meanage22years
ConfirmedinstudiesfromVietNamWar
Holman,1961;StrongandMcGill,1962;Stary,1989
Aorticfattystreaksareextensiveinchildhood
Coronaryfattystreaksappearinadolescence
Fibrousplaquesappearintheseconddecadewithprogression
intotheseconddecade
BogalusaStudy
PDAYStudy

BogalusaStudy

N=93,239yoa

NEJM338:1650,1998

PathobiologicalDeterminantsof
AtherosclerosisinYouth(PDAY)
Multicenterpostmortemstudyin1079males,364
females,1534yearsofage
Violentdeath
Arteriesgradedforatheroscleroticlesionsinaorta
andrightcoronaryartery
Serumlipoproteinsmeasured
Serumthiocyanatemeasuredasanindexofsmoking

ArteriosclerThrombVascBiol17:95,1997

PDAYResults

Extentofsurfaceareawithfattystreaksandraisedlesions
increasedwithageinallvessels
SerumVLDLplusLDLcholesterolpositivelycorrelated
withextentoffattystreaksandraisedlesionsinallvessels
SerumHDLcholesterolnegativelycorrelatedwithextent
offattystreaksandraisedlesionsinallvessels
Smokingassociatedwithmoreextensivefattystreaksand
raisedlesionsinaorta

PediatricScreeningStrategies
Screennoone.Treateveryonewithdiet.
Screenonlythosechildrenwithapositivefamily
historyofprematureatheroscleroticdiseaseor
knownhyperlipidemia.
Screenallchildren.

NationalCholesterolEducation
Program(NCEP)Recommendations
forPediatricCholesterolScreening
Screenafter2yearsofage
Allchildrenwithfirstdegreerelativewith
symptomsordiagnosisofatheroscleroticdisease,
hyperlipidemia(serumcholesterol>240mg/dl),
orsuddencardiacdeathbefore55yearsofage

PercentageofChildrenAged019YearsWhoWouldBe
Screened,andPercentageofThosewithLDLCholesterol130
mg/dlWhoWouldBeIdentified,IfthePresenceofCVDisease
orVariousLevelsofElevatedTotalCholesterolinatLeastOne
ParentIsUsedtoSelectChildrenforScreening
ParentalCholesterol
(mg/dl)HigherThan

ChildrenWhoWould
BeScreened(%)

Sensitivityfor
Identificationof
ChildrenwithLDL
Cholesterol130mg/dl

200

63.5

86.5

220

44.3

63.5

240

25.1

40.5

260

18.3

29.7

280

15.3

28.4

300

13.9

28.4

TheLipidResearchClinicsPrevalenceStudy(N=1042)

WhattoMeasure

Totalcholesterol
Triglycerides
HDLcholesterol
CalculateLDLcholesterol
LDLcholesterol=totalcholesterolHDLcholesteroltriglycerides/5
Notaccurateiftriglycerides>400mg/dl
SomecommerciallabsnowmeasureLDLcholesteroldirectly

Fastingnotnecessaryforcholesterolmeasurementalone,
butovernightfastisrequiredforprofile

ClassificationofTotalandLDLCholesterol
LevelsinChildrenandAdolescents

Acceptable

TotalCholesterol
(mg/dl)
<170

LDLCholesterol
(mg/dl)
<110

Borderline

170199

110129

High

200

130

WhattodoAfterScreening
Iftotalcholesterol>95th%tile(200mg/dl),
repeatwithfullprofile
Ifconfirmed,ruleoutsecondarycauses
Screenfamilymembers
StartPhaseIdietandriskfactor
reduction/prevention
FollowupandconsiderPhaseIIdiettoreduce
LDLcholesteroltobelow95thpercentile

BorderlineCases
70th90thpercentile(170199mg/dl)
Repeat,ifaverageoftwostillborderline,get
completeanalysis
IfLDLcholesterolisborderline,startphaseIdiet
andriskfactorreduction/prevention
Recheckin1year

Abnormalitiesnotdetectedbya
simplecholesterolmeasurement
Hypertriglyceridemia
Hypoalphalipoproteinemia(lowHDL)
ElevatedapolipoproteinBlevelwithnormal
LDLC(excessnumberofsmallLDLparticles)
Elevatedlipoprotein(a)level
Elevatedhomocysteinelevel

SecondaryCausesofHyperlipidemia
Endocrine
Hypothyroidism
Diabetesmellitus
Glycogenstoragedisease

Pregnancy
RenalDisease
Nephroticsyndrome

Obstructiveliverdisease
Drugs
Corticosteroids,isotretinoin,thiazides,anticonvulsants,blockers,
anabolicsteroids,oralcontraceptives

FamilialAggregationof
Hyperlipidemia
Monogenic
Heterozygousfamilialhypercholesterolemia
MutationsinLDLreceptor
90%willhaveCHDby65yoa
4%ofallcasesofprematureCHD

FamilialCombinedHyperlipidemia
Expressionvariable(cholesteroland/ortriglycerideelevation)andmaybedelayed
11%ofallcasesofprematureCHD

Polygenic
AccountsformajorityofcasesofprematureCHD
Expressionofanumberofgenescontributingtohypercholesterolemiaand
atherosclerosiscombinedwithenvironmentalfactors

DietaryFatinChildrenand
AdolescentsintheUnitedStates
Age119years14%oftotalcaloriesfrom
saturatedfat
Age111years35%oftotalcaloriesfromfat
Age1219years36%oftotalcaloriesfromfat

PhaseIDiet

Nomorethan30%oftotalcaloriesfromfat
Lessthan10%oftotalcaloriesfromsaturatedfat
Lessthan300mgofcholesterol/day
Totalcaloricintakeappropriatefornormal
growthandidealbodyweight

PhaseIIDiet

Nomorethan30%oftotalcaloriesfromfat
Lessthan7%oftotalcaloriesfromsaturatedfat
Lessthan200mgofcholesterol/day
Totalcaloricintakeappropriatefornormal
growthandidealbodyweight

CriteriaforDrugTherapy
InChildrenandAdolescents

10yearsofageorolder
Adequatetrialofdietarytherapy(6mos1yr)
LDLcholesterollevel190mg/dl
LDLcholesterollevel160mg/dland

PositivefamilyhistoryofprematureCVD
or
2ormoreCVDriskfactorspersistingaftervigorous
effortstocontroloreliminatethesefactors

GoalsofDrugTherapy
inChildrenandAdolescents
AcceptableLDLcholesterollevel<130mg/dl
IdealLDLcholesterollevel<110mg/dl
Monitor6weeksafterstartingtherapy,thenevery
3monthsuntilmaximaleffect,thenevery6
months
Monitorcompliance,lipids,growth,and
appearanceofsideeffects

BileAcidSequestrants
Cholestyramine(Questran ),Colestipol(Colestid )
Onlyclassofdrugsapprovedforuseinchildrentotreat
hyperlipidemia
Bindbileacidsandenhancefecalelimination,upregulatehepaticbile
acidsynthesisfromcholesterol,andtherebyupregulatehepaticLDL
receptors
Willoftenincreaseserumtriglyceridelevelsinmixedhyperlipidemias
Notabsorbed,sideeffectsmainlyconstipation,bloating
Canlowerfatsolublevitaminandfolatelevels,butusuallynot
importantclinically
Gritty,sandyconsistency;compliancearealproblem

NCEPTreatmentGuidelines
forLDLCLevelsforAdults
Definite
Twoor
atherosclerotic moreother
disease
riskfactors
No
No

Initiation
level
(mg/dl)
>190

Goal
(mg/dl)
<160

No

Yes

>160

<130

Yes

YesorNo

>130

<100

HMGCoAReductaseInhibitors
Statins

Cerivastatin(BaycolR)
Fluvastatin(LescolR)
Atorvastatin(LipitorR)
Lovastatin(MevacorR)
Pravastatin(PravacholR)
Simvastatin(ZocorR)

Decreasehepaticcholesterolsynthesisresultinginincreased
hepaticLDLreceptorswithincreasedclearanceofplasmaLDL
particles

HMGCoAReductaseInhibitors
DecreaseserumLDLcholesterollevels
ModestincreasesinserumHDLClevels
Themorepotentstatins,atorvastatin,cerivastatin,
andfluvastatin,alsosignificantlydecrease
triglyceridelevels,possiblyservingaseffective
monotherapyinmixedhyperlipidemias

HMGCoAReductaseInhibitors
AdverseEffects
Myalgias,myopathy,rhabdomyolysis
Riskofrhabdomyolysisandacuterenalfailure
especiallyhighwithcombinedtherapywithfibric
acidderivatives,niacin,cyclosporine,
erythromycin,andazoleantifungals
Transaminaseelevation
Fetaltoxicity

Niacin
NiaspanR(extendedreleasetablets)
Ifequivalentdoseofcrystallineniacinissubstituted,
toxicitywillresult,andfulminantliverfailurehasbeen
reported

Decreasestotalcholesterol,LDLC,andtriglycerides
IncreasesHDLC
Escalatingdosetitrationtominimizesideeffects,
particularlyflushing

Niacin
AdverseEffects
Flushing
Usuallytransientandimproveswithdurationof
therapy
ASAorNSAIDpriortodosingmayminimize
Avoidingestionofalcoholorhotdrinksaroundtime
ofdosing
Ifdiscontinuedforanextendedperiod,mustescalate
andtitratedosingagain

Niacin
AdverseEffects
Transaminaseelevation
RarecasesofrhabdomyolysiswithconcomitantHMG
CoAreductaseinhibitors
Glucoseintolerance
Uricacidelevation
Monitoranticoagulanttherapy
Usewithcautioninunstableangina/recoveringMI,
especiallywithconcomitantvasoactivedrugs

FibricAcidDerivatives
Clofibrate(AtromidR),gemfibrozil(LopidR),fenofibrate
(TricorR)
Decreasetriglycerides,increaseHDLClevels
Serumtriglycerides>1000mg/dlassociatedwith
significantriskofpancreatitis
NottobeusedtotreatlowHDLCasonlylipidabnormality
Increasedincidenceofnoncoronaryandageadjustedall
causemortalityinstudies(WHO)

FibricAcidDerivatives
AdverseEffects
Myalgias,myopathy,rhabdomyolysis
Riskofrhabdomyolysisandacuterenalfailureespecially
highwithcombinedtherapywithstatins
Cholelithiasis
TransaminaseelevationandHgb/WBCdepression
Needtoreduceanticoagulantdose
Increasedriskofliverandtesticularmalignancy
Fetaltoxicity

FamilyApproachtoTreating
HyperlipidemiaandReducing
CardiovascularRisk
Affectedfamilymembersgenerallyhavesamelipid
disorder
TeamApproachSpecialistsfrompediatrics,adult
medicine,andnutrition
Programsaredesignedtofitintothefamilyroutineand
altereatinghabitsandphysicalactivity
Familiesdevelopaninternalsupportstructurewhich
improvescompliance