Hyperaldosteronism

Author:GeorgePChrousos,MD,FAAP,MACP,MACE,FRCP(London)ChiefEditor:StephenKemp,MD,
PhDmore...
Updated:Dec10,2015

Background
Aldosteroneisasteroidhormoneproducedexclusivelyinthezonaglomerulosaof
theadrenalcortex.Itisthemajorcirculatingmineralocorticoidinhumans.
Numerousaldosteroneprecursors,includingdeoxycorticosteroneand18
hydroxycorticosterone,havemineralocorticoidactivityandmayproduceor
exacerbatefeaturestypicalofmineralocorticoidhypertensionwhenpresentin
excessiveamountsinvariouspathologicstates.
Theprincipalsiteofactionofaldosteroneisthedistalnephron,thoughseveralother
sitesofaldosteronesensitivesodiumregulationarenoted,includingthesweat
glandsandthegastrointestinal(GI)tract.Theprincipalregulatorsofaldosterone
synthesisandsecretionarethereninangiotensinsystemandthepotassiumion
concentration.Minorregulatorsincludeadrenocorticotropichormone(ACTH)from
thepituitary,atrialnatriureticpeptidefromtheheart,andlocaladrenalsecretionof
dopamine.
Hyperaldosteronismischaracterizedbyexcessivesecretionofaldosterone,which
causesincreasesinsodiumreabsorptionandlossofpotassiumandhydrogenions.
Itmaybeeitherprimary(autonomous)orsecondary.Hyperaldosteronismrepresents
partofalargerentityofhypermineralocorticoidismthatmaybecausedby
aldosterone,itsmineralocorticoidprecursors,ordefectsthatmodulatealdosterone
effectsonitstargettissues.

Pathophysiology
Normalaldosteronephysiology
Aldosteroneparticipatesinthehomeostasisofcirculatingbloodvolumeandserum
potassiumconcentrationthese,inturn,feedbacktoregulatealdosteronesecretion
bythezonaglomerulosaoftheadrenalcortex.Aldosteronesecretionisstimulated
byanactualorapparentdepletioninbloodvolumedetectedbystretchreceptors
andbyanincreaseinserumpotassiumionconcentrationsitissuppressedby
hypervolemiaandhypokalemia.
Themechanismsregulatingaldosteronesecretionarecomplex,involvingthezona
glomerulosaoftheadrenalglands,thejuxtaglomerularapparatusinthekidneys,the
cardiovascularsystem,theautonomicnervoussystem,thelungs,andtheliver(see
theimagebelow).Themajorfactorsstimulatingaldosteroneproductionandrelease
bythezonaglomerulosaareangiotensinIIandtheserumpotassiumconcentration.
ThejuxtaglomerularapparatusistheprincipalsiteofregulationofangiotensinII
production.

Physiologicregulationofthereninangiotensinaldosteroneaxis.

ACTHstimulatesaldosteronesecretioninanacuteandtransientfashionbutdoes
notappeartoplayasignificantroleinthelongtermregulationofmineralocorticoid
secretion.Themajorinhibitorsofthezonaglomerulosaincludecirculatingatrial
natriureticpeptide(ANP)and,locally,dopamine.AlthoughANPlevelsareclearly

increasedinhyperaldosteronism,neitherANPnordopaminehasbeenimplicatedas
aprimarycauseofclinicallydisorderedaldosteronesecretion.
Metoclopramidehasbeenshowntoincreasealdosteronesecretion,suggestingthat
dopaminemaytonicallyinhibitaldosteronerelease.Thephysiologicrolesof
adrenomedullinandvasoactiveintestinalpeptide(VIP)onaldosteronesecretion
remaintobeclarified,althoughbothoftheseneuropeptidesareproducedinrat
zonaglomerulosa.
Thesynthesisofprorenin,itsconversiontorenin,anditssystemicsecretionare
stimulatedbybloodvolumecontractiondetectedbystretchreceptors,beta
adrenergicstimulationofthesympatheticnervoussystem,andprostaglandinsI 2
andE 2.TheseprocessesareinhibitedbyvolumeexpansionandANP.
Reninconvertsangiotensinogen,aproenzymesynthesizedintheliver,intothe
decapeptideangiotensinI,whichisthenconvertedinthelungsintotheoctapeptide
angiotensinIIbyangiotensinconvertingenzyme(ACE).AngiotensinIIisbotha
stimulatorofaldosteronesecretionandapotentvasopressor.AngiotensinIIis
metabolizedtoangiotensinIII,aheptapeptidethatisalsoastimulatorof
aldosteronesecretion.
ThesynthesisandsecretionofprostaglandinsI 2andE 2andthenormalfunctionof
thestretchreceptorsaredependentontheintracellularionizedcalcium
concentration.Renalprostaglandinsecretionisstimulatedbycatecholaminesand
angiotensinII.Thecomplexregulationofaldosteronesynthesisandsecretion
providesseveralpointsatwhichdisturbanceintheregulationofaldosterone
secretionmayoccur.
Aldosteroneissynthesizedfromcholesterolinaseriesof6biosyntheticsteps(see
theimagebelow).Onlythelast2stepsarespecifictoaldosteronesynthesisthe
first4alsoapplytocortisolsynthesisbythezonafasciculata.Consequently,a
defectinoneofthespecificaldosteronesyntheticenzymesdoesnotleadto
hypercortisolismandsecondaryACTHmediatedadrenalhyperplasia.

Steroidbiosyntheticpathway.

TheenzymealdosteronesynthaseisencodedbythegeneCYP11B2andhas11
hydroxylase,18hydroxylase,and18hydroxydehydrogenaseactivity.Thisgeneis
locatedonhumanchromosomearm8q24.3tel,closetothegeneCYP11B1,which
encodes11hydroxylase,theenzymethatcatalyzesthefinalstepofcortisol
synthesis.Mutationsinthesegenescanresultinanumberofdisordersof
aldosteronesynthesis(seeDifferentials).
Aldosteroneactionontargettissues(eg,thedistalrenaltubule,sweatglands,
salivaryglands,andepitheliumofthelargeintestine)ismediatedviaaspecific
mineralocorticoidreceptor.Mineralocorticoidreceptorsexhibitequalaffinityfor
mineralocorticoidsandcortisol,yetthealdosteronereceptorsinthedistaltubuleand
elsewhereareprotectedfromcortisolmediatedactivationby11hydroxysteroid
dehydrogenasetype2,whichlocallyconvertscortisoltoinactivecortisone.

Primaryaldosteronism
Thetermprimaryhyperaldosteronism(orprimaryaldosteronism[PA])referstoa
reninindependentincreaseinthesecretionofaldosterone.Thisconditionis
principallyadiseaseofadulthood,withitspeakincidenceinthefourthtosixth
decadesoflife.
Approximately99%ofcasesofPAaredueeithertoanaldosteroneproducing
adenoma(APA),whichaccountsforaround40%ofcases,orduetoidiopathic
hyperaldosteronism(IHA),whichaccountsforaround60%ofcases(almostallof
whicharebilateral).About1%ofpatientspresentwithadrenocorticalcarcinomas
thatarepurelyaldosteronesecretingandareusuallylargeatthetimeofdiagnosis
1%presentwithfamilialhyperaldosteronismand,1%presentwithanectopic
aldosteroneproducingadenomaorcarcinoma. [1]
Unilateraladrenalhyperplasiaaccountsfor1417%ofallcasesofunilateralPA.
Theprevalenceofcorticaladenomawithincorticalhyperplasiaisestimatedtobe6
24%.Theclinicalpresentationandoutcomeofpatientswithunilateralprimary
hyperaldosteronismaresimilarregardlessofthehistopathologicdiagnosis.
Unilateraladrenocorticalhyperplasiaisrare. [2]

APAs(sometimesreferredtoasaldosteronomas)areusuallybenignencapsulated
adenomasthatarelessthan2cmindiameter.Mostcasesaresolitary,althoughin
asmanyasonethirdofcases,evidenceexistsofnodularityinthesameadrenal
gland,suggestingthattheconditionhasariseninapreviouslyhyperplasticgland.
PatientswithIHAhavebilateralthickeningandvariablenodularityoftheiradrenal
cortex.Awidespectrumofseverityexistsforthisdisorder,whichmaygo
undetectedforlongperiodswithnohypokalemiaandonlymildhypertension.Ithas
beensuggestedthatIHAarisesasaresultofanundetectedadrenalcortex
stimulatingfactor.Alternatively,thedisordermayariseasaresultofanactivating
mutationinanadrenalcortexspecificgene.Neitherhypothesishasbeenproven.
Inheritedformsofprimaryhyperaldosteronismaccountforonly1%ofcasesbutare
morelikelytooccurduringchildhoodyears.Theseformsincludefamilial
hyperaldosteronism(FH)typesI,II,andIII.
FamilialhyperaldosteronismtypeI
FHtypeI(FHI),alsoreferredtoasglucocorticoidremediablealdosteronism(GRA),
maybedetectedinasymptomaticindividualsduringscreeningoftheoffspringof
affectedindividuals,orpatientsmaypresentininfancywithhypertension,
weakness,andfailuretothriveduetohypokalemia.FHIisinheritedinan
autosomaldominantmannerandhasalowfrequencyofnewmutations.
ThefirstclinicaldescriptionofGRAappearedin1966,andthegeneticmechanism
wasdiscoveredin1992.FHIarisesasaresultofunequalcrossingoverofhighly
relatedCYP11B1(the11hydroxylasegene)andCYP11B2(thealdosterone
synthasegene)duringmeiosis,producinganantiLeporetypefusionproduct. [3,4]
ThisgeneticrearrangementcausestheexpressionofCYP11B2tobeplacedunder
thecontroloftheCYP11B1promoterandthealdosteronesynthesistobe
abnormallyregulatedbyACTHratherthanbythereninangiotensinsystem.
TheresultisACTHdependentaldosteroneproductionandproductionof17
hydroxylatedanaloguesof18hydroxycortisolunderACTHregulationfromectopic
enzymeexpressioninthezonafasciculata.Bilateralhyperplasiaofthezona
fasciculataoccurs,andhighlevelsofnovel18hydroxysteroidsappearintheurine.
Adenomaformationisrare,butpatientsdohaveasignificantincreaseinincidence
ofcerebrovascularaneurysms,forwhichtheyrequirescreening.
FamilialhyperaldosteronismtypeII
FHtypeII(FHII)isanonglucocorticoidsuppressibleinheritedformof
hyperaldosteronismthatwasfirstrecognizedasadistinctentitybyGordonetal,
thoughcaseshadpreviouslybeendescribedinthe1980s.LikeFHI,itisinherited
inanautosomaldominantmanner.IncontrasttoFHI,someFHIIkindredsexhibit
ahighrateofadenomaformation.
Themechanismandgenelocushavenotyetbeenidentified,thoughCYP11Band
thereninandangiotensinIIreceptorgeneshavebeenexcluded.However,linkage
hasbeenestablishedforanumberoffamiliestoband7p22. [5,6]Ithasalsobeen
speculatedthatFHIIisnotasingledisorder.
FamilialhyperaldosteronismtypeIII
FHIIIisarareautosomaldominantformofPAcharacterizedbyearlyonset
hypertension,nonglucocorticoidremediablehyperaldosteronism,andhypokalemia.
GermlineheterozygousmissensemutationsoftheKCNJ5gene,encodingKir3.4,a
memberoftheinwardlyrectifyingK +channelfamily,havebeenidentifiedasa
causeofFHIII.Thusfar,4mutations(G151R,G151E,T158A,andI157S)have
beenreportedin6families. [7,8,9]
Theclinicalphenotypeofpatientsharboringtheabovemutationsrangesfrom
severePAandhypertensionrefractorytomedicaltreatmentthatrequiresbilateral
adrenalectomy,tomildormoderatehypertensionresponsivetomedicaltherapy.In
somepatients,adrenalhyperplasiahasbeendescribed.
VariousstudiesfromdifferentcentersreportaprevalenceofsomaticKCNJ5
mutationsinsporadicAPAsrangingfrom3065%. [7,10,11,12]Thereare2recurrent
mutations,G151RandL168R,reportedbyallstudies,whereasthereisonereport
ofa3nucleotidedeletion,thedelI157. [13]
Theaffectedresiduesofboththegermlineandthesomaticmutationsareinornear
theselectivityfilteroftheKir3.4potassiumchannelandarehighlyconserved
amongdifferentspecies.Electrophysiologicstudiesdemonstratethatthese
mutationsresultinlossofchannelselectivity,withincreasedNa+conductance
leadingtomembranedepolarization.Inzonaglomerulosacells,membrane
depolarizationleadstoopeningofvoltageactivatedCa2+channels,withactivation
ofthecalciumsignallingpathway,themajormediatorofaldosteroneproduction.
APAswithKCNJ5mutationsaremoreprevalentinfemalesthanmalesandin
youngerpatients.Theyarealsoassociatedwithhigherpreoperativealdosterone
levels.Theyarenotrelatedwiththetumorsize,buttheyarerelatedwithhigher
aldosteronelevelsandlowerK +concentrations.
Transcriptomeandrealtimepolymerasechainreaction(PCR)analyses
demonstratethatAPAswithKCNJ5mutationsexhibitincreasedexpressionofthe
CYP11B2geneanditstranscriptionalregulatorNR4A2,thusincreasingaldosterone
production.IthasalsobeenfoundthatAPAswithandwithoutKCNJ5mutations

displayslightlydifferentgeneexpressionpatterns. [12]AnotherstudyreportsKCNJ5
mRNAlevelshigherintheAPAswithKCNJ5mutationsandsignificantlyhigherin
APAthancortisolproducingadenomasandpheochromocytomas. [11]
SomaticmutationsinATP1A1(genethatencodesthealpha1[catalytic]subunitof
theNa+/K+ATPase,amemberofthePtypeATPasefamily),ATP2B3(genethat
encodestheplasmamembranecalciumtransportingATPase3[PMAC3],another
memberofthePtypeATPasefamily),orCACNA1D(genethatencodesCav1.3,
thealphasubunitofanLtypevoltagegatedcalciumchannel)arepresentin
approximately6%,1%and8%ofallcasesofanaldosteroneproducingadenoma,
respectively.Morerecently,denovogermlinemutationsinCACNA1Dwerereported
in2childrenwithapreviouslyundescribedsyndromethatfeaturedPAand
neuromuscularabnormalities. [14]

Secondaryhyperaldosteronism
Secondaryhyperaldosteronismisacollectivetermforadiversegroupofdisorders
characterizedbyphysiologicactivationofthereninangiotensinaldosterone(RAA)
axisasahomeostaticmechanismdesignedtomaintainserumelectrolyte
concentrationsorfluidvolume.Inthepresenceofnormalrenalfunction,itmaylead
tohypokalemia.
Secondaryhyperaldosteronismcanbedividedinto2categories,1withassociated
hypertensionand1without.Theformercategoryincludesrenovascular
hypertension,whichresultsfromrenalischemiaandhypoperfusionleadingto
activationoftheRAAaxis.Themostcommoncausesofrenalarterystenosisin
childrenarefibromuscularhyperplasiaandneurofibromatosis.Hypokalemiamay
occurinasmanyas20%ofpatients.
Plasmareninactivity(PRA)levelsareofteninthereferencerange,butelevated
levelsofPRAmaybedetectedafterprovocationwithasingledoseofcaptopril1
mg/kg.Renalischemiaisalsothoughttounderliethesecondaryhyperaldosteronism
observedinmalignanthypertension.
Hyperreninemiaandsecondaryaldosteronismhavealsobeenreportedinpatients
withpheochromocytoma,apparentlyasaresultoffunctionalrenalarterystenosis.
Reninproducingtumorsareveryrare,andveryhighlevelsofPRA(upto50
ng/mL/h)arenoted,frequentlywithanincreasedprorenintoreninratio.Thetumors
aregenerallyofrenaloriginandincludeWilmstumorsandrenalcellcarcinomas.
Hyperkalemiaduetochronicrenalfailurealsocausessecondary
hyperaldosteronism.Lowsodiumtopotassiumratioscanbemeasuredinsalivaand
stool.Cyclosporineinducedhypertensioninsolidorgantransplantpatientsmayalso
involveacomponentofhyperaldosteronism.
Secondaryhyperaldosteronismintheabsenceofhypertensionoccursasaresultof
homeostaticattemptstomaintainthesodiumconcentrationorcirculatoryvolumeor
toreducethepotassiumconcentration.Clinicalconditionsinwhichitmayarise
includediarrhea,excessivesweating,lowcardiacoutputstates,and
hypoalbuminemiaduetoliverorrenaldiseaseornephroticsyndrome.Secondary
hyperaldosteronismmayalsooccurdevelopmentallyinnewborninfants(seebelow).
Increasedmineralocorticoiddependencyintheyoung
Themineralocorticoiddependencyofsodiumreabsorptionisincreasedduring
infancyandchildhood,peakingintheneonatalperiodbeforedecreasing
progressivelywithadvancingage.Thisincreaseoccursbecausethereabsorptionof
sodiumandwaterbytheproximaltubuleisleastefficientinearlylife,resultinginan
increasedsodiumandwaterloadatthelevelofthedistalrenaltubule.
BecausesodiumandwaterresorptionfromthedistaltubuleismediatedbytheRA
Aaxis,thePRAisapproximately10foldto20foldhigherinanewborninfantthan
inanadult.Consequently,neonatesshowrelativeincreasesinaldosterone
productionrates(>300g/m2/dayvs50g/m2/dayinanadult)andplasma
aldosteroneconcentrations(80pg/dLvs16pg/dL).Theseincreasesinearlylife
explainwhyyounginfantsexhibitprofoundclinicalsymptomsofhyperaldosteronism
thatgraduallyimprovewithadvancingage.

Etiology
Thefollowingisasummaryofetiologiesofhyperaldosteronismandconditionsthat
mimichyperaldosteronism:
Causesofprimaryhyperaldosteronismincludethefollowing:
APAHighaldosterone,lowPRA
IHARespondstoposture(bilateraladrenalhyperplasia)
PrimaryadrenalhyperplasiaRespondstoposture(unilateraldisease)
FHI(GRA)Sustainedsuppressionofaldosterone(<4ng/dL)with
dexamethasone
FHII/FHIIIFamilial(probablyautosomaldominant)
Causesofsecondaryhyperaldosteronismincludethefollowing:
Edemadisorders(eg,cardiacfailureandnephroticsyndrome)High
aldosterone,nonsuppressedPRA(>2ng/mL)
Renovascularhypertension

Reninproducingtumors
Pregnancy [15]
Causesofconditionsthatmimicaldosteroneexcessincludethefollowing:
Congenitaladrenalhyperplasia(11hydroxylasedeficiencyand17
hydroxlyasedeficiency)Lowaldosterone,lowPRA,elevatedsteroid
intermediates
PrimaryglucocorticoidresistanceHighglucocorticoidsecretion
unsuppressedbydexamethasone
DeoxycorticosteronesecretingtumorsElevateddeoxycorticosteronelevels
Syndromeofapparentmineralocorticoidexcess
Liddlesyndrome
Gainoffunctionmutationofmineralocorticoidreceptor [16]
Licoriceingestion
Carbenoxolone
Hypokalemiamaybeprecipitatedbyadietthatisrichinsodiumortheconcomitant
administrationofdrugsthatproducekaliuresis(includingdiureticsand
carbenoxolone).Takingcarbenoxoloneoreatinglargequantitiesoflicoricemay
resultinhypokalemiabecauseofblockadeofthetargettissueenzymethatprotects
thealdosteronereceptorfromtherelativelyhigherlevelsofcirculatingcortisol
(apparentmineralocorticoidexcess).

Epidemiology
Primaryhyperaldosteronismisarareconditioninchildren.Theyoungestchild
reportedwithanaldosteronesecretingadenomawasaged3years.Earlieruseof
hypokalemiaasadiagnosticrequirement,asadvocatedbysomeauthorities,may
haveledtounderrecognitionofthecontributionofprimaryhyperaldosteronismto
hypertension.
PatientswithPAcomprisemorethan10%ofhypertensivepatientsand1723%of
thetreatmentresistanthypertensivepopulation. [17,18,19,20,21]
Mostofthehyperaldosteronismobservedinthegeneralpopulationissporadic,with
mostcasesduetobilateraladrenalhyperplasia.APAsarelikelytobediagnosed
earlierthanIHAbecausetheyaremorelikelythanIHAtoproduceearly
symptomatichypertensionandhypokalemia.APAsaccountfor40%ofcasesof
primaryhyperaldosteronism.
Itispossiblethatthedistinctionbetweenadenomaandhyperplasiaisnotasclear
aswasonceassumed.Inonethirdofcases,associatedhyperplasiaornodulesof
theadjacentzonaglomerulosaispresent,implyingthattheadenomamayhave
ariseninpreviouslyhyperplastictissue.
Inheritedformsofprimaryhyperaldosteronism(ie,FHI[GRA],FHII,andavery
rareformknownasFHtypeIII[FHIII])accountforapproximately1%ofcasesof
primaryhyperaldosteronism,thoughtheyaremorelikelytooccurduringchildhood
andadolescentyearsthanotherformsofprimaryhyperaldosteronismare.
Studiesofsecondaryhyperaldosteronismhavefoundthatapproximately15%of
adultswhoattendhypertensionclinicshaveelevatedPRA.Reliablefiguresfor
childrenarenotreadilyavailable.

Age,sex,andracerelateddemographics
Becausethe2causesthataccountforabout99%ofcasesofprimary
hyperaldosteronismhaveapeakageofonsetinadulthood,thelesscommon
causesaccountforalargerpercentageofchildrenwithhyperaldosteronism.Forthis
reason,childrenwithapparenthyperaldosteronismshouldbeevaluatedforevidence
ofcongenitaldefectsoftheRAAaxisandinheritedformsof
hypermineralocorticoidism.
Dataonadultssuggestthathyperaldosteronismhasafemalepreponderance.
Equivalentinformationisnotavailableforchildren,inwhomprimary
hyperaldosteronismduetoinheritedsyndromesislikelytorepresentagreater
proportionofcases.
Theliteratureonadultsdemonstratesthatblacksareatsignificantlygreaterriskfor
hypertensionrelatedmorbidityandmortalitythanwhitesare.Theyarealsomore
likelytodeveloplowreninhypertension,thoughnostudiesindicatethatthe
prevalenceofprimaryhyperaldosteronismissignificantlyhigherinblacks.

Prognosis
Theageofthepatientandthedurationofdiseasebeforediagnosisarethe2most
importantprognosticfactors.Adultstudieshaveshownthathypertensionis
significantlyimprovedin3060%andsignificantlyimprovedinapproximately8095%
ofcases,respectively(seeTreatment). [1,22]Thisfigureislikelytobehigherin
childrenbecausediseasedurationisshorterandtheprevalenceofothercausesof
hypertensionislower.
Primaryhyperaldosteronismcanresultinsubstantialmorbidityandmortalityasa
resultofhypertensivevascularcomplications(hypertrophyfollowedbysclerosisof
intimalsmoothmuscle),renalcomplications(sclerosis),andcardiaccomplications

(hypertrophyfollowedbydilatation).Throughearlyrecognitionandtreatmentof
hypertension,thesecomplicationscanbeavoidedinchildren.
Appropriatemedicalorsurgicalinterventionofprimaryresultsinlongtermreduction
inbloodpressureandleftventricle(LV)massviaLVinwardremodeling(eg,through
areductioninLVdiametersandvolume). [23]Moreover,asignificantdecreasein
urinaryalbuminexcretionat6monthsaftertreatmenthasbeenreportedinpatients
withPAandassociatedmicroalbuminuria.Bothadrenalectomyand
mineralocorticoidreceptorantagonistscanreversetheintrarenalhemodynamic
patternthatleadstothedeclineinglomerularfiltrationrateandincreased
proteinuria. [9,24]Furthermore,surgicalormedicalmanagementofPAresultsin
improvementinthemetaboliccomplicationsofPA,suchasplasmaglucosecontrol,
andqualityoflifeaswell.
TheAldosteronomaResolutionScore(ARS)iscurrentlythemostaccurate
predictionmodelforcompleteresolutionofhypertensionafteradrenalectomy,taking
intoaccount4preoperativeclinicalparameters:bodymassindex(BMI)of25kg/m2
orhigher,femalesex,durationofpreoperativehypertension6yearsorlonger,and
numberofpreoperativeantihypertensivemedications(2).Eachparameterreceives
ascoreof1,withtheexceptionofnumberofpreoperativemedications,whichis
scoredby2pointsduetoitsrelativesignificanceinthepredictionmodel.Ascoreof
01predictsalowlikelihoodofresolution,whereaspatientswithARSscoresof45
haveahighlikelihoodofresolutionofhypertensionafteradrenalectomy.
Moreover,datasuggestthattheTTgenotypeoftheCYP11B2geneencoding
aldosteronesynthasepredictsresolutionofhypertensioninpatientsundergoing
adrenalectomyforaldosteroneproducingadenoma.
PatientswithGRAmustundergoassessmentoftheircerebralcirculationbecause
thisdisorderisassociatedwithasignificantriskofcerebralvascularaneurysms.
Providedthathypertensioniswelltreated,morbidityandmortalityshouldnotbe
increasedsignificantly.
Hypokalemiaismorefrequentlyobservedinpatientswithadenomas,thoughit
shouldnotbeconsideredadiagnosticfeatureofprimaryhyperaldosteronism,as
wasoncethought.Patientswithadenomasaremorelikelytodevelopthis
complication,asarepatientswhohavemilderdiseasebutreceivetreatmentwith
diureticsfortheirhypertensionbeforethehyperaldosteronismisdiagnosed.
Hypokalemicpatientsmayexperienceneuromuscularsymptomssuchasweakness
orparalysis,constipation,andpolyuriaandpolydipsiabecauseofanassociated
renalconcentratingdefect.Hypokalemiaalsoimpairsinsulinsecretionandcan
promotethedevelopmentofdiabetesmellitus.
Althoughcardiacfibrosishasbeenreportedinadultswithprimary
hyperaldosteronism,nosuchreportsexistinchildren,possiblybecauseofthe
shorterdurationofdiseaseatthetimeofdiagnosis.Cardiacfibrosishasalsobeen
reportedinratstreatedwithexcessiveamountsofmineralocorticoids,especiallyif
hyperglycemiaisalsopresent.Thiseffectcanbeamelioratedwithamiloride.The
roleofaldosteroneindiabeticheartdiseasehasbeenquestioned,andtrialsof
mineralocorticoidantagonistsinthisconditionhavebeeninitiated.

PatientEducation
Patientswithmildhyperaldosteronismmustlearnhowtoavoidfoodsthatarehigh
insodiumsuchfoodswillexacerbatetheirhypertensionandincreasetheirtendency
todevelophypokalemia.
Patientsalsoshouldbeinformedthatmedicationscanleadtohyperkalemiaand
hypotension,particularlyinthepresenceofintercurrentillness,andshouldbe
advisedtoseetheirpediatricianiftheseconditionsdevelop.
ClinicalPresentation

ContributorInformationandDisclosures
Author
GeorgePChrousos,MD,FAAP,MACP,MACE,FRCP(London)ProfessorandChair,FirstDepartmentof
Pediatrics,AthensUniversityMedicalSchool,AghiaSophiaChildren'sHospital,GreeceUNESCOChairon
AdolescentHealthCare,UniversityofAthens,Greece
GeorgePChrousos,MD,FAAP,MACP,MACE,FRCP(London)isamemberofthefollowingmedicalsocieties:
AmericanAcademyofPediatrics,AmericanCollegeofPhysicians,AmericanPediatricSociety,AmericanSociety
forClinicalInvestigation,AssociationofAmericanPhysicians,EndocrineSociety,PediatricEndocrineSociety,
SocietyforPediatricResearch,AmericanCollegeofEndocrinology
Disclosure:Nothingtodisclose.
Coauthor(s)
AmaliaSertedaki,PhDResearchAssociate,MolecularEndocrinologyLaboratory,DivisionofEndocrinology,
DiabetesandMetabolism,FirstDepartmentofPediatrics,AghiaSophiaChildren'sHospital,UniversityofAthens
MedicalSchool,Greece
Disclosure:Nothingtodisclose.
EleniMagdaliniKyritsi,MD,PhDClinicalResidentinEndocrinology,DivisionofEndocrinology,Metabolism
andDiabetes,FirstDepartmentofPediatrics,"AghiaSophia"Children'sHospital,UniversityofAthensMedical
School,Greece

Disclosure:Nothingtodisclose.
ChiefEditor
StephenKemp,MD,PhDProfessor,DepartmentofPediatrics,SectionofPediatricEndocrinology,Universityof
ArkansasforMedicalSciencesCollegeofMedicine,ArkansasChildren'sHospital
StephenKemp,MD,PhDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,
AmericanAssociationofClinicalEndocrinologists,AmericanPediatricSociety,EndocrineSociety,PhiBeta
Kappa,SouthernMedicalAssociation,SouthernSocietyforPediatricResearch
Disclosure:Nothingtodisclose.
Acknowledgements
AntonyLafferty,MBChB,FRACPSeniorLecturerofPediatricEndocrinology,MonashUniversityDepartment
ofPediatrics,NationalInstitutesofHealth,Bethesda,MD,andPrincessMargaretHospitalforChildren,Perth,
WesternAustralia
AntonyLafferty,MBChB,FRACPisamemberofthefollowingmedicalsocieties:EndocrineSociety
Disclosure:Nothingtodisclose.
LynneLiptonLevitsky,MDChief,PediatricEndocrineUnit,MassachusettsGeneralHospitalAssociate
ProfessorofPediatrics,HarvardMedicalSchool
LynneLiptonLevitsky,MDisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,American
AcademyofPediatrics,AmericanDiabetesAssociation,AmericanPediatricSociety,EndocrineSociety,Pediatric
EndocrineSociety,andSocietyforPediatricResearch
Disclosure:PfizerGrant/researchfundsP.I.TercicaGrant/researchfundsOtherEliLilyGrant/researchfunds
PINovoNordiskGrant/researchfundsPINovoNordiskConsultingfeeConsultingOnyxHeartValveConsulting
feeConsulting
ThomasAWilson,MDProfessorofClinicalPediatrics,ChiefandProgramDirector,DivisionofPediatric
Endocrinology,DepartmentofPediatrics,TheSchoolofMedicineatStonyBrookUniversityMedicalCenter
ThomasAWilson,MDisamemberofthefollowingmedicalsocieties:EndocrineSociety,PediatricEndocrine
Society,andPhiBetaKappa
Disclosure:Nothingtodisclose.
MaryLWindle,PharmDAdjunctAssociateProfessor,UniversityofNebraskaMedicalCenterCollegeof
PharmacyEditorinChief,MedscapeDrugReference
Disclosure:Nothingtodisclose.

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