drug classes, preferably including a (14). (14). includingadiuretic classes, preferably drug different medicationsfrom on atleast3antihypertensive diastolic BPof≥90mmHg, oranelevationofboth, (BP) of ≥ 140 mmHg, clinic, systolic pressure or to 21% (12,13). Resistant HTN isdefined as office, of14 HTN,withaprevalence in patientswithresistant patients(10,11).PA common of referred isparticularly 10% andaround care patientsinprimary of hypertensive of 4% HTN with an estimated prevalence of secondary (9). insufficiency (8), and renal infarction (6,7), myocardial failure outcome in HTN (5), heart of adverse predictors levels are elevated balance(4).Severalstudiesdemonstratedthat of HTN in humans can be associated to defects in renal the pathogenesisofHTN(3).Mostmonogenicforms in and clinicalevidenceimplicatesmineralocorticoids deathintheworld(1,2).Robustexperimental premature ;resistanthypertension;diagnosis;aldosterone; Primary Keywords 2017;61(3):305-12. Arch Metab. Endocrinol 2017;61/3 H regarding PA screening,caseconfirmation,subtypeclassification,andtreatment. adrenalectomy or antagonist. In this review, we address the most relevant issues Cardiovascular morbiditycausedbyaldosteroneexcesscanbedecreasedeitherunilateral shouldbetreatedwithmineralocorticoid antagonist(spironolactoneoreplerenone). laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral subtype, butitisnotindicatedinallcases. An experienced radiologistmustperform AVS. Unilateral carcinoma. Bilateraladrenalveinsampling(AVS) isthegoldstandardmethodtodefine PA PA shouldundergoadrenalCTastheinitialstudyinsubtypetestingtoexcludeadrenocortical starting caseconfirmation withthefurosemidetest. After caseconfirmation,allpatientswith does notidentifya “gold standard”confirmatory testfor PA. Inour institution,werecommend screeningtestforPA.most sensitive There areseveralconfirmatorytestsandthecurrent literature idiopathic foraround60%ofPA cases. The aldosterone-to-reninratioisthe degrees ofhypokalemia. Aldosterone-producing (APAs) accountforaround40%and supression, HTN,cardiovascular damage,andincreasedpotassiumexcretion,leadingtovariable characterized byanautonomousaldosteroneproductioncausingsodiumretention,plasmarenin matched patientswithessentialHTNandthesame degreeofbloodpressureelevation.PA is patients. Patients withPA havehighercardiovascular morbidityandmortality thanage-andsex- estimated prevalenceof4%hypertensive patientsinprimarycareandaround10% ofreferred Primary aldosteronism(PA) isthemostcommonformofsecondaryhypertension (HTN),withan ABSTRACT A.Leticia P. Vilela aldosteronismof primary Diagnosis andmanagement Primary aldosteronism (PA) aldosteronism is the most common form Primary general population and is the leading risk fator for general populationandistheleadingriskfatorfor between10to40%ofthe (HTN)affects ypertension 1 , MadsonQ. Almeida 1,2

# aldosteronism (PA) comparedtoessentialhypertension(EH) Table 1. Cardiovascularandmetaboliccomplicationsinprimary ofBPelevation(15,16)(Tablethe samedegree 1). age- andsex-matchedpatientswithessentialHTN than morbidityandmortality have highercardiovascular independentofhighBPlevels,patients withPAthat are ofexcessaldosterone effects of theadversecardiovascular PA ofHTN. Because isthemost commoncurableform Meta analysis. Cardiovascular events Metabolic alterations Atrial fibrilation(17) Coronary artery (17) artery Coronary (17) Nonfatal myocardialinfarction(17) (18) Metabolic syndrome(19) Abnormal glucosemetabolism(20) Arch EndocrinolMetab. # São Paulo, SP, Brasil de SãoPaulo (Icesp),FMUSP, (HCFMUSP), SãoPaulo, SP, Brasil da Universidade deSãoPaulo Clínicas, Faculdade deMedicina das Hospital e Metabologia, LIM42, DivisãodeEndocrinologia Hormônios eGenéticaMolecular– Desenvolvimento, Laboratóriode Endocrinologia do Accepted onMay/4/2017 Received onSept/11/2016 [email protected] –SãoPaulo,05403-900 SP, Brasil 2º andar, Bloco6 Av. Dr. EnéasdeCarvalho Aguiar, 155, Universidade deSãoPaulo Faculdade deMedicina, dasClínicas, Hospital Genética MolecularLIM-42, Laboratório deHormôniose Unidade deSuprarrenal, Q. Almeida Madson Correspondence to: 2 1 DOI: 10.1590/2359-3997000000274 Instituto doCâncerEstado Unidade deSuprarrenal, PA (%) 22.4 41.1 3.9 5.7 4.1 4.4 7.4 EH (%) 16.8 29.6 1.1 2.8 1.2 1.7 3.5 review 0.001 0.003 0.006 0.04 0.03 0.01 0.05 p 305

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. case detectionofPA intheconditions isrecommended The 68% ofthosewithidiopathichyperaldosteronism. andin identified in79%ofpatientswithaldosteronomas was diagnosedinasinglepatient. ofPA) form PA remediable type I ( at ourinstitution.Familial underdiagnosed probably is cases, suggestingthatidiopathichyperaldosteronism in20%ofour 79% andidiopathichyperaldosteronism diagnosed in were Medical School,aldosteronomas the Clinics Hospital of Sao PauloUniversity from inthisreview.elsewhere of104PA Inourcohort cases hyperplasiaandfamilialPA,adrenal whichisdiscussed causes ofPA, unilateral accountingforlessthan1%,are Other rare carcinoma. adrenal aldosterone-producing possibilityofan 4 cm,weshouldconsidertherare If apatientwithPA tumorlarger than hasanadrenal the AVS production. showsalateralizedaldosterone cases canbesmallerthan1cmanddiagnosedonlyif zone, but in few the glomerulosa originating from of PA cases. APAs smallbenigntumors(1-3cm) are 60% foraround and idiopathichyperaldosteronism adenomas(APAs)producing 40% accountforaround in thespecializedcenter. Ingeneral,aldosterone- veinsampling(AVS)patients andifadrenal isavailable whether PA amonghypertensive screened isroutinely dependson cohorts and hypokalemiaindifferent ofPA hyperplasia)(22).Thefrequency adrenal subtypes (bilateral and in17%ofidiopathichyperaldosteronism adenomas(aldosteronomas) aldosterone-producing PA hypokalemiawasidentifiedin48%of prevalence, of hypokalemia (21). In the largestdegree study of leadingtovariable potassiumexcretion, and increased damage, HTN,cardiovascular supression, plasma renin causessodiumretention, production aldosterone plasma potassiumconcentrations.Thisautonomous byangiotensinaIIor state andisnotregulated high for sodium which is inappropriately production 306 BP: bloodpressure. Table 2. aldosteronism(PA) Recommendationsforprimary screeninginclinical setting aldosteronismPrimary diagnosis All hypertensivefirst-degreerelativesof patients with PA ofearlyonsethypertension orcerebrovascularaccidentatayoungage(<40years) Hypertension andafamilyhistory andsleepapnea Controlled BP(<140/90)onfourormore antihypertensivedrugs Hypertension (BP≥140/90)resistanttothree conventionalantihypertensivedrugs(preferablyincludingadiuretic) BP above150/100onthreeseparatemeasurementsobtaineddifferentdays Hypertension andadrenalincidentaloma Hypertension andspontaneousordiuretic-inducedhypokalemia PA ischaracterizedbyanautonomousaldosterone Society ClinicalPracticeGuidelineofPA (23). listed inTable inthe2016Endocrine 2,asaddressed studies to validate the aldosterone-to-renin ratio using ratiousing studies tovalidatethealdosterone-to-renin was 96%forPA diagnosis(24).Althoughweneedmore the A/DRCof3.3,sensitivitywas84%andspecificity valueof99%toPApredictive diagnosis.Whenusing a sensitivityof92%,specificityandnegative Using DRC(mU/L),theA/DRCratioof2.1had chemiluminescent assayforDRCandaldosterone. studyvalidatedthis automated ratio (21).Arecent factor of12(DRC/12=PRA)tocalculatetheA/PRA wecanuse theconversion LIAISON XLinstrument), commonly usedautomatedDRCassay(DiaSorin, andalready introduced 1).Inarecently (Figure withPAlevel of12.5ng/dLtoproceed investigation Because ofthat,weusetheminimumaldosterone levelsbetween12.5and 15ng/dL. aldosterone criteria. Inourinstitution,6%ofPA patientshad of thescreening as part of 15 ng/dL has beenproposed concentration not high.Then,aminimumaldosterone is ratio maybeelevatedeven when aldosterone renin levels,thealdosterone-to- oflowrenin In thepresence for PA is30(21). adopted A/PRAcut-off screening ng/dL andPRAinng/mL/h,themostcommonly (A)in 2 mU/L).Whenmeasuringplasmaaldosterone to detectPRAlevelsof0.2-0.3ng/mL/h(orDRC assays should be sensitive enough dependent on renin, ratioismore PRA. Becausethealdosterone-to-renin ratios usedinPA using determined were screening concentration;however,renin thealdosterone-to-renin (DRC). Currently, direct kitsmeasure mostcomercial concentration renin activity(PRA)orfordirect renin eitherbytestingforplasma renin employed tomeasure forPA.test thatscreens Immunometricassayscanbe ratioisthemostsensitive The aldosterone-to-renin SCREENING ANDCASE CONFIRMATION Arch Metab. Endocrinol 2017;61/3 is measured as DRC (25). Then, if premenopausal asDRC(25).Then,if premenopausal is measured forPA,with afalsepositivescreening butonlyifrenin Similarly, theuseoforalcontraceptivesisassociated asDRC. ismeasured luteal phase,butonlyifrenin ovulating women,falsepositives canoccurduringthe confounding factors(Table 3)(21).Inpremenopausal inlightofthepotential ratioshouldbeinterpreted renin HTN. Then, the aldosterone-to- in patients with severe medicationsisnotfeasible antihypertensive interfering testing. often,awashoutofall to confirmatory Very directly delay andallowingthepatienttoproceed ofcontinuedmedications,thusavoiding the effect despite ratiocanbeconfidentlyinterpreted to-renin the aldosterone- treatment), antagonist or diuretic suggestaPA levelsstrongly aldosterone diagnosis. levelsassociatedwithhigh renin suppressed , antagonistsor possible towithdrawmineralocorticoid testing.Whenitis notclinically least 4weeksbefore shouldbewithdrawn forat other typesofdiuretics and oreplerenone) antagonists ( (21). Itshouldbeemphasizedthatmineralocorticoid testingandshouldbepotassium-replete intake before Ideally, salt dietary patientsshouldhaveunrestricted usually aftertheyhavebeenseatedfor5-15minutes. patients havebeenoutofbedforatleast2hours,and after samplesshouldbecollectedinthe morning renin Arch Metab. Endocrinol 2017;61/3 activity; CT: computedtomography. A: aldosterone;DRC: directreninconcentration;PRA: plasmarenin aldosteronism. Figure 1. Algorithm for the detection and confirmationof primary equivalent toA/PRAratioof30. DRC, itseemsthatA/DRCbetween2and3shouldbe Aldosterone ≥12ng/dLand A/DRC ratio≥2.5or A/PRA ratio ≥ 30(correctlowK In many cases (excluding mineralocorticoid In manycases(excludingmineralocorticoid sensitivity, toincrease In order and aldosterone test: DRC<24mUI/mL(PRA2ng/mL/h) Saline infusiontest: Aldosterone >10ng/dL Positive screening for primary aldosteronism: Positive screeningforprimary To performfurosemidetestor saline infusiontest Adrenal CTscan Positive test: A ≥20ng/dL, supressedDRCand (A/PRA ratio≥100) No needtoperform conrmatory tests conrmatory A/DRC ratio≥8.8 + ) confirmatory testing. confirmatory with or duringthefollicularphase,evenproceed the testwithoutoralcontraceptives(ifiscase) forPA,women haveapositivescreening wecanrepeat several confirmatory tests and the current literature literature testsand thecurrent several confirmatory are 1).There testing toexcludefalsepositives (Figure confirmatory etiology (26). In othercases,we perform a computed tomography (CT) scan to investigate PA with testing and wecanproceed confirmatory further isnoneedfor PRAorDRClevels,there suppressed medication isneeded. or prazosin).Clonidinecanbeaddedifafourth verapamil, hydralazine,andα medicationswith oftheantihypertensive replacement the range),werecommend within thelowernormal (but notsuppressed < 20ng/dLandPRAorDRCare levelsare medications.Ifaldosterone antihypertensive thePA withallother screening weperform Otherwise, foratleast4weekswhenclinically feasible. diuretics antagonistsand the withdrawnofmineralocorticoid or A/DRCratioabove2.5whenDRCwasdetermined. allPAcohort, patientshadtheA/PRAratioabove30 ≥ 2.5,thePA positive.Inour isconsidered screening PRA (ng/mL/h) ratio ≥ 30 or A/DRC (mU/L) ratio levels≥12.5 ng/dLandA/ If apatienthasaldosterone ratio. thealdosterone-to-renin to adequatelyinterpret 1.First,potassiumlevelsshould benormal in Figure of algorithm for detection and confirmation PA shown University ofSaoPauloMedicalSchool,wefollowthe type 1receptorblockers;DHP: dihydropyridines. DRC: direct renin concentration; FP: false positive; FN: false negative; ARBs: II aldosteronism Table 3. Ca Diuretics α-methyldopa) (clonidine, Central agonists β-Adrenergic blockers (vs. Male) Premenopausal women Advancing age inhibitors,ACE ARBs 2 blockers(DHPs) If a patient has aldosterone levels≥20ng/dLand If apatienthasaldosterone wealwaysrecommend As mentionedbefore, In theEndocrineDivisionofClinicsHospital Factors that may interfere with screening for primary Factors that may interfere with screening for primary Aldosterone        Primary aldosteronismPrimary diagnosis -1 blockers(doxazosin DRC        Aldosterone/  (FN)  (FN)  (FN)  (FP)  (FP)  (FP)  (FP) DRC 307

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. • • 308 • tests mentionedabove: confirmatory Below isdetaileddescriptionofthethree hypokalemia. andshouldcorrect normal levels are test, we should check to see if confirmatory of itstoolowreproducibility. any performing Before function,because renal impaired patients withvery we onlyusethecaptopriltestasafirstoptionin Currently, failure. HTNorcongestiveheart resistant in patients with severe/ period performed in a short with thesalineinfusiontestisvolumeoverload thesalineinfusiontest.Themainproblem perform doesn’t havecontraindicationforsodiumloading,we testisnotconclusiveandthepatient furosemide accuracy higherthan 90% indiagnosingPA. Ifthe test had an test. Inourexperience, the furosemide withthefurosemide caseconfirmation suggest starting testbasedontheirownexperience. We confirmatory for PA (21).Specializedcenterschoosetheirpreferred test confirmatory does notidentifya“goldstandard” aldosteronismPrimary diagnosis and renin remains suppressed (26). APAs suppressed remains and renin can be patients withPA, elevated levelremains aldosterone bycaptopril(>30%). In suppressed is normally seated duringthisperiod. Plasmaaldosterone 1h and 2h after captopril, with the patient remaining andat attimezero andcortisol plasma aldosterone, ofPRAorDRC, drawnformeasurement samples are orally aftersittingorstandingforatleast1h.Blood 50mgofcaptopril Captopril test:Patientsreceive betweensensitivityandspecificity(27). trade-off of6.8ng/dLhasbeenfoundtohavethebest cutoff althougha indeterminate, considered ng/dL are levelsbetween5and10 the diagnosis.Aldosterone diagnosis ofPA, <5ng/dLexcludes andaldosterone the levels > 10 ng/dLconfirm after 4 h. Aldosterone and drawnattime zero or DRC,andpotassiumare PRA 8-9.30 AM.Bloodsamplesforaldosterone, at infusion of2L0.9%salineivover4h,starting andduringthe position foratleast1h before Saline infusiontest:Patientsstayintherecumbent injection. after furosemide above2ng/mL/h activity(PRA)increases renin levels,plasma lowrenin canpresent hypertension diagnosis (26).Althoughpatientswithessential the ng/mL/h (orDRC<24mU/L)confirms PA drawn at time zero andafter2h. PRA <2 drawn attimezero andpotassiumare PRA orDRC,aldosterone, at8-9.30AM.Bloodsamplesfor 2h, starting 40 mgivandstayinanuprightpositionfor furosemide Furosemide test:Patients receive

and normal contralateral adrenal on adrenal CTscan. onadrenal contralateraladrenal and normal lesion(>1cm) 40years andunilateraladrenal before DRC or PRA) with HTN diagnosedand suppressed PApatients with severe (A ≥ 20 ng/dL, hypokalemia AVS we do not recommend on this observation, in delayedinourcountry.that PA Based isvery screening thefact reflects diagnosed after40years.Thistrend 35or40years,butPAwith HTNbefore wasonly mostofpatientswithAPAwords, hadbeendiagnosed PAof HTNbefore diagnosisis14years.Inother the ageofHTNdiagnosis,becausemediantime consider theageofPA diagnosistoindicateAVS but low.incidentaloma isvery Atourinstitution, wedon’t ofanadrenal (21). Inthissituation,theprobability CTscan adenomaonadrenal consistent withacortical lesionswithradiological features unilateral adrenal excess, andhypokalemia, markedaldosterone in youngerpatients(<35years)withspontaneous AVSGuideline ofPA nottoperform recommends 2). incidentaloma inthecontralateralside(Figure findings, butthepatientcanhaveanAPA andanadrenal as bilateral hyperplasiaon the basis ofCT be interpreted nodulesmight situation,bilateraladrenal In adifferent (28). adrenal hyperplasiaandnormal-appearing adrenal diagnosedinapatientwithbilateral can beincorrectly especially inolderpatients(>age40years),andanAPA notuncommon, adenomasare unilateral adrenal detection limitofCT. Moreover, nonfunctioning smallAPA belowthe but thepatientcanhaveavery adrenals, normal-appearing limited. CT scan can reveal limitations, becauseitsaccuracyfordiagnosingAPAs is sampling (AVS) CThasseveral isused.Adrenal vein CTscanorbilateraladrenal subtypes, adrenal antagonists.Forthediagnosisofthesetwo receptor andthelatterbymineralocorticoid by adrenalectomy istreated becausetheformer hyperplasia iscrucial, distinctionbetweenAPAs(21). Proper andbilateral has noadvantageoverCTinsubtypeevaluationofPA imaging Magnetic resonance carcinoma. adrenocortical as theinitialstudyinsubtypetestingtoexclude All patientswithPA CT shouldundergo adrenal SUBTYPE CLASSIFICATION The 2016EndocrineSocietyClinicalPractice variation toanalyzeonlythecaptoprileffect. aldosterone variationfrom ofcortisol the percentage during the test,weshoulddiminish levels decrease byACTH.Then,ifcortisol regulated abnormally Arch Metab. Endocrinol 2017;61/3 the first randomized study to compare CT-the firstrandomizedstudytocompare vs. AlthoughtheSPARTACUSappearing adrenal. trialis in cases with bilateral lesions or normal- particularly ofAVSout theimportance inPA subtype classification, for all PArecommended patients, but it did not rule trial showed that AVSThis important should not be wasnotstatisticallysignificant(29). but thisdifference AVS-basedpatients whoreceived (11%), treatment CT-basedwho received to (20%)compared treatment antagonist). ThepersistenceofPA washigher inpatients receptor and46mineralocorticoid adrenalectomy AVS-basedantagonist) and92received (46 treatment receptor and46mineralocorticoid (46 adrenalectomy CT-basedcompleted follow-up, 92 received treatment antagonists)(29).Ofthe184patientsthat receptor withmineralocorticoid (subsequent treatment hyperplasia orbilateraladrenal of adrenalectomy) ofAPApresence consisting (withsubsequenttreatment CTorAVSundergo eitheradrenal the todetermine TRIAL), patientswithPA randomlyassignedto were Arch Metab. Endocrinol 2017;61/3 A: aldosterone; C: ; A/C: aldosterone tocortisolratio;PA: aldosteronism; primary AVS: adrenalveinsampling. adrenalectomy andhadbiochemical cure ofPA. this patienthadanadrenalincidentaloma ontherightsideandanaldosterone-producingadenomaleft side. The patientunderwentleftadrenal left adrenalgland. (B)Fluoroscopicimagingfrom AVS. ( C) Analysis of AVS samplingshowedlateralizationofaldosterone productiontotheleftside. Then, 1.6 mU/mL(PRA0.13); A/DRC ratio=15.25; A/PRA ratio=188. (A) Adrenal CTshowinga1.8cmnoduleatright adrenalglandanda1.2cmnoduleat Figure 2. Amalepatient, 69years, withresistenthypertensionfor30years, diagnosedwithPA. Hormonaldata: aldosterone(A)=24.4ng/dL;DRC< B A In a recent randomised controlled trial(SPARTACUS randomisedcontrolled In arecent Right adrenalvein AVS- Left adrenalvein successful catheterization(31). employed toimprove This strategyhasbeenpreviously Currently, ourrateofsuccessfulcatheterizationis80%. vein. the successful catheterization of the right adrenal duringtheAVS cortisol toevaluate serum procedure an acuteangle(30).We tomeasure started recently andenterstheinferiorvenacavaat because itisshort tocatheterize veinmaybeespeciallydifficult adrenal Theright andaldosterone. cortisol cava tomeasure theinferiorvena veinsandfrom right andleftadrenal the catheterization andcollectingbloodsamplesfrom AVS. toperform radiologist isrequired AVS includes AVS. performing before suppressed Anexperienced to checkifDRC or PRA is itisimportant Therefore, and unilateralPA mightbemisclassifiedasbilateral. toanAPA,the stimulationofcontralateraladrenal antagonistscanleadto ormineralocorticoid diuretics levels by renin because increased renin, suppressed larger cohorts. thisissuein weneedtoreanalyze based approaches, AVS underaconditionof shouldbeperformed C • • • • • • • cava (contralateral supression)=0.67 (contralateral cava A/C Rightadrenalvein/Inferiorvena A/C Left/Right(lateralization): 6.1 cava: 11.06 Cortisol leftadrenalvein/Inferiorvena vena cava: 23.1 Cortisol rightadrenalvein/Inferior Inferior venacava Left adrenalvein Right adrenalvein A/C ratio: 1.37 Aldosterone: 41.6ng/dL Cortisol: 30.3µg/dL A/C ratio: 5.6 Aldosterone: 1890ng/dL Cortisol: 335.2µg/dL A/C ratio: 0.923 Aldosterone: 647ng/dL Cortisol: 701µg/dL Primary aldosteronismPrimary diagnosis 309

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. sulfate. anddehydroepiandrosterone salivar cortisol cortisol, free test,ACTH,24hurinary suppression 1mg for subclinicalCushingisrecommended: bilateralhyperplasia,screening macronodular useful in the subtype definition. and very recommended 2, wedemonstrateaclinicalcaseinwhichAVS was a lateralizationtothehigherside(33).InFigure is< 0.67, itsuggests But ifcontralateralsuppression ratio isbetween3:1and4:1,theAVS isundetermined. of 95%andspecificity100%;5)Ifthelateralization hasasensitivity hypersecretion unilateral aldosterone AVS thesecutoffs, With hypersecretion. fordetecting A ratiooflessthan3:1suggestsbilateralaldosterone excess. than4:1indicatesunilateralaldosterone more high-sidetolow-side. Aratioof the A/Cratiofrom ratio toevaluatelateralization.We shouldcalculate A/C catheterization wassuccessful);4)Determine (iftheratiois>5on each side,the the periphery veinsand ratiobetweenadrenal cortisol Determine inferiorvenacava;3) veinsandfrom and leftadrenal right from measurements andcortisol for aldosterone AVS); 50mL/h(30minbefore start 2)Collectblood (250µg)in250mLofsaline 0.9%and cosyntropin Sao PauloUniversityMedicalSchoolbelow:1)Dilute cava). SeetheAVS inthe ClinicsHospitalof protocol thelow-sidetoinferiorvena as theA/Cratiofrom (defined we calculatethecontralateralsuppression issuppressed, aldosterone) (notoversecreting adrenal Tofor dilutioneffects. evaluateifthenondominant vein;A/C) tocorrect levelinitsrespective cortisol dividedby ratio(aldosterone aldosterone corrected weusethecortisol- and contralateralsuppression, vein (32).To lateralization thealdosterone determine thesuccessfulsampling oftheadrenal cava, confirming veintoinferiorvena adrenal from gradient ofcortisol infusionmaximizesthe In addition,thecosyntropin byACTHinAPAs). canberegulated aldosterone (since secretion induced fluctuations in aldosterone infusionduringAVScosyntropin minimizesstress- with sequentialbilateralAVS. Theuseofcontinuous 310 PA atayoungage(<40years), theEndocrine orstroke of years ofage,andinthosewho haveafamilyhistory In patientswithanonsetofconfirmed PA earlierthan20 FAMILIAL PRIMARY ALDOSTERONISM aldosteronismPrimary diagnosis If apatientwithPA hasanAPA ≥2.5cmor We AVS perform infusion under cosyntropin

mutations) (21)(Table 4). andtypeIII(causedbyKCNJ5 aldosteronism) testing for familial PA remediable type I (glucocorticoid Society ClinicalPracticeGuidelineofPA suggestsgenetic a link with chromosome 7p22(40). a linkwithchromosome FH-II isstillunknown,butgenetic analysesdemonstrated PA (APA orbilateralhyperplasia).Themolecular basisof membersofthesamefamily haveconfirmed first-degree (39). Familial PA type II is diagnosed when at least two tobeas high as6%inalarge populationwithPA reported was Prevalence sporadic forms. indistinguishable from antagonistcanbeadded(37,38). mineralocorticoid levels, renin BPornormalize tocontrol necessary are in adults(0.125-0.25mg/d).Ifadditionaldrugs (36). FamilialPA withdexamethasone typeIistreated 6hduring48or72h) dexamethasone (0.5mgevery levels(<4ng/dL)after plasmaaldosterone suppressed angiotensin II.PatientswithfamilialPA typeIshow ofACTH insteadof zona fasciculataundercontrol intheadrenal synthase activitythatisexpressed gene encodesanenzymechimerawithaldosterone hybrid synthase) (34,35). The resulting aldosterone 11α between thegenesCYP11B1(whichencodessteroid Table 4. aldosteronism Familialformsofprimary BP: bloodpressure. CT: computedtomography. Treatment severity Hypertension onset Hypertension Transmission Adrenal CT dexamethasone Aldosterone after Hypokalemia Genetic diagnosis Cause Familial PA typeIIisclinicallyandbiochemically Familial PA typeIiscausedbyanunequalcrossover -hydroxylase) and -hydroxylase) Severe toresistant (normal BPisrare) mineralocorticoid Dexamethasone hypertension < 20years Autosomal antagonist CYP11B1/ < 4ng/dL Very often Long PCR CYP11B2 dominant Normal Type I Hybrid Rare or CYP11B2 (which encodes adrenalectomy or mineralocorticoid (normal BPisnot Arch Metab. Endocrinol 2017;61/3 bilateral lesions hypertension Unilateral or Autosomal antagonist Stage 1to > 4ng/dL Adulthood Unilateral dominant Unknown Not often resistant Type III often) No KCNJ5 sequencing adrenalectomy or mineralocorticoid macronodular hypertension hyperplasia < 10years Autosomal antagonist Stage 3to > 4ng/dL Very often Very often dominant Germline resistant Bilateral Bilateral Type III KCNJ5 germline germline be needed to control BP(36). be neededtocontrol Because oftheHTNseverity, may bilateraladrenalectomy bilateralhyperplasia(42). hypokalemia, andmacronodular HTNinearlychildhoodassociatedwithPA,by severe depolarization (41).FamilialPA typeIII is characterized sodiumconductanceandcell inincreased resulting KCNJ5 geneencodingthepotassiumchannelKir3.4, Arch Metab. Endocrinol 2017;61/3 dose-dependent andlossoflibidoin it promotes production, and inhibits androgen receptor levels. potassiumandrenin normalize andto bloodpressure weaimtocontrol treatment, by50mgeach3-4weeks.During should beincreased is50mginasingledose.Thedose spironolactone dosefor (47).Thestarting drugs antihypertensive of PA, BPlevelsaswelltheneedfor reducing been theagentofchoiceinmedicaltreatment (50-400mg/d)has Spironolactone for treatment. isavailable InBrazil,onlyspironolactone ). or antagonist(spironolactone mineralocorticoid (45,46). adrenalectomy afterunilateral associated withlowratesofHTNcure diagnosing PAa longerdurationofHTNbefore are relatives and HTNinfirst-degree APA (21). Primary inabout50%(rangeof35-80%) of patientswith cured Afterunilateraladrenalectomy,response. HTNis to monitor treatment levels in the first weekafter surgery andrenin sodium,potassium,aldosterone, measure in thepostoperativeperiod.Inaddition,weshould levels,avoidinghyporeninemic renin potassiumlevelsand tonormalize antagonist inorder withmineralocorticoid the patientshouldbetreated unilateraladrenalectomy, Before is recommended. antagonist includingamineralocorticoid treatment is unableorunwillingtoundergo surgery, medical for patientswithAPAs. IfthepatientwithanAPA tobeconducted. remains mortality cardiovascular However, of interms astudycomparingbothtreatments attheendofa6.4yearfollow-up (44). treatment antagonist ormineralocorticoid unilateral adrenalectomy left ventricularmasshasbeendemonstratedtobesimilarin of antagonist(43).Overallreduction mineralocorticoid or byeitherunilateraladrenalectomy can bedecreased excess morbiditycausedbyaldosterone Cardiovascular TREATMENT Familial PA typeIIIiscausedbymutationsinthe Since spironolactone antagonizes androgen antagonizesandrogen Since spironolactone with Bilateral hyperplasiashouldbetreated isindicated adrenalectomy Unilateral laparoscopic will be available to treat PAwill beavailabletotreat (21). synthaseinhibitors antagonists andselectivealdosterone the nextyears,itislikelythatnewmineralocorticoid of PAto lower BP in the medical treatment (50). In than spironolactone higher cost and can be less effective daily (49).Despiteitsbettertolerability, hasa eplerenone andgiventwice associated withendocrinesideeffects isless and,therefore, effects without function. worsening renal with cautionbecauseoftheriskhyperkalemiaand antagonistshouldbeadministered mineralocorticoid disease orinolderpatients, stage IIIchronic Inpatientswith a higherdoseofspironolactone. canbeusedtoavoid a smalldoseofthiazidediuretic (48). To amiloride or side effects, avoid or decrease andenlargement tenderness andbreast irregularities men. 1 REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. . Eplerenone is a selective mineralocorticoid antagonist antagonist isaselectivemineralocorticoid Eplerenone Nephrol Dial Transplant. 2004;19(4):774-7. surgically correctable aldosterone-dependent hypertension. primary aldosteronism,aldosterone-producing adenomas,and Plouin PF, Amar L, ChatellierG. 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