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European Journal of 10.1530/EJE productionrelativetosuppressedplasma of hypertensioncharacterizedbyhypokalemiaandexcess Conn in1955,wasoncethoughttobeararecondition aldosteronism(PA),Primary firstdescribedbyJerome W. Introduction and currentapproachestothemedicalmanagementofPA. of theguidelineinsomeareasandconfirmcurrentpracticeothers.Herein,wepresentrecentdevelopments Endocrine Societyguideline2016,anumberofkeystudieshavebeenpublished.Theychallengetherecommendations with amineralocorticoidreceptorantagonist(forpatientsbilateralPA). Sincethepublicationofrevised treatment approachofunilaterallaparoscopicadrenalectomy(forpatientswithPA) ormedicaltreatment tests andthedifferentiation ofunilateralfrombilateralforms.Thelatterstepisnecessarytodeterminetheoptimal . ThediagnosticworkupofPA isasequenceofthreephasescomprisingscreeningtests,confirmatory production andisusuallycausedbyeitheraunilateralaldosterone-producingadenomaorbilateraladrenal The syndromeofprimaryaldosteronism(PA) ischaracterizedbyhypertensionwithexcessive,autonomousaldosterone Abstract Turin, Italy Germany and 1 Tracy Ann Williams guideline 2016revisited aldosteronism: theEndocrineSociety Diagnosis andmanagementofprimary MANAGEMENT OFENDOCRINEDISEASE Medizinische KlinikundPoliklinikIV, KlinikumderUniversität,Ludwig-Maximilians-UniversitätMünchen,Munich, https://doi.org/ www.ej Review Review molecular levels excessin resistanthypertensionontheepidemiological,clinical, geneticand Prof. Reincke is heading a research team specifically exploring the prevalence and relevance of ,mineralocorticoidandglucocorticoidaction andstressresearch., pituitary Diabetology. Hisresearch focusincludesadrenalphysiologyandpathophysiology, endocrine Ludwig-Maximilians UniversityinMunichandChair of theDepartmentEndocrinologyand Prof. Drmed. Invited Author’s profile e-online.org 2 10.1530/EJE Division ofInternalMedicineandHypertension,DepartmentMedicalSciences,UniversityTurin, -17-0990 Martin Reincke Martin . -17-0990 1 , 2 and 1 Martin Reincke © 2018EuropeanSociety ofEndocrinology T AWilliamsandMReincke

is theDirectorofMedizinischeKlinikandPoliklinik IV, Printed inGreatBritain 1 patients withhypokalemia)accountingforupto50% of (ARR) toawidertargetpopulation(insteadofrestricted to method ofanelevatedplasmaaldosterone-to-reninratio ( aldosteronism Management ofprimary Published byBioscientifica Ltd. 1 ). Theapplicationofthecurrentscreening Downloaded fromBioscientifica.com at09/27/202105:58:35AM (2018) Endocrinology European Journal of uni-muenchen.de Martin.Reincke@med. Email to MReincke should beaddressed Correspondence 179

179 :1 , R19–R29

R19 –R29 via freeaccess European Journal of Endocrinology www.eje-online.org that medicationsinterfering withtherenin- systems islacking. would justifytheincreased costsandburdenonhealth disease of patients with hypertension to an extent that a reductionofmorbidity, mortalityandcardiovascular approach (comparedwithselectivescreening)results in care ( 1672 unselected patients with hypertension in primary study ( ( PA all patients with hypertension should be screened for likelihood ofPA ( recommends screeningpatientswithanincreased The EndocrineSociety(ES)ClinicalPracticeGuideline reliable currentlyavailablemethodofscreeningforPA. renin concentration(DRC)toassesstheARRismost (PACs) andplasmareninactivity(PRA)orthedirect Measurement ofplasmaaldosteroneconcentrations Diagnosis: screening ( therapeutic decisionmakingandappropriatetreatment differentiation of unilateral frombilateral forms ofPA for three phases: screening tests,caseconfirmation and increased risksassociatedwithPA ( tominimizethe (surgical ormedical)ismandatory an earlydiagnosisandappropriateclinicalmanagement co-secretion ( of thesecomorbiditiesmaybeassociatedwithcortisol of depression with a reduced quality of life ( ( increased prevalenceofmetabolicsyndromeanddiabetes with hypertension( profile ( essential hypertensionandamatchedcardiovascularrisk organ damage(heartandkidney)relativetopatientswith cardiovascular and cerebrovascular events and target of aldosteronetotheMR( (MR) antagonistthatcompetitivelyinhibitsthebinding pharmacologically withamineralocorticoidreceptor or adrenalectomy (preferably by laparoscopic surgery) hypertension. PA isspecificallytreated byunilateral this syndromeis the mostcommon form of endocrine the diagnosis of PA ( the populationwithhypertensionhasgreatlyincreased 4 Fig. 1 , Review 9 The diagnosticmanagementofPA comprises Patients withPA haveanincreasedriskof To screenfor PA bytheARR, itisrecommended 19 , 8 ). 10 ), basedonthefindingsofprospective PATO ). However, evidencethatasystematicscreening 8 4 ), whichreporteda5.9%prevalenceofPA in , , 5 11 , 6 ), osteoporotic fractures ( , 15 7 ) orcomparedwiththegeneralpopulation ). Allavailableevidence indicates that Table 1 8 ). PatientswithPA alsodisplayan 2 ). It is now widely accepted that ) ( 3 ). 3 ). Ithasbeensuggestedthat T AWilliamsandMReincke 5 , 16 12 , ) and symptoms 17 , 13 18 , ). 14 ). Some receptor; PA, primaryaldosteronism. computer-assisted tomography;MR,mineralocorticoid hypertension tobescreenedforPA ADX,adrenalectomy;CT, aldosteronism. *PleaserefertoTable 1 forpatientswith Flow chartforthediagnosticworkupofprimary Figure 1 (verapamil ordiltiazem), the vasodilatorhydralazine dihydropyridine long-acting calciumchannelblockers possible without changing interfering medications. Non- many instances,interpretation oftheARRisconfidently dihydropyridine calciumblockers ( drugs, ACE inhibitors, angiotensin receptor blockers and clonidine, methyldopa,non-steroidalanti-inflammatory a lesserperiodof2 weeks priortotesting,are Other drugs thatshould be withdrawn, but for4 weeks. (including ) and should be withdrawn for medication thatinterfereswiththeARRincludesdiuretics conditions ofsuppressedrenin).Antihypertensive procedures alsorelyonmeasurementsofsteroidsunder the diagnosticworkupforPA becauseothertestsand secretion, shouldbewithdrawn(thisappliesthroughout system, andspecificallythosethatmaystimulaterenin aldosteronism Management ofprimary Downloaded fromBioscientifica.com at09/27/202105:58:35AM 3 179 , 20 :1 ). However, in β -blockers, R20 via freeaccess European Journal of Endocrinology assays forPAC andDRC( be reliablealternatives( assays usingchemiluminescence havebeenshownto for themeasurementofplasma PAC, PRAor DRCbut assay ( 150 indicate thattheriskofPA increaseswithPAC (ARR ES Guidelinesrecommendaspecificcut-offfortheARR upper referencelimitsusedacrosscenters.TheJapan value forARRscreeningandthewidevariability in has contributedtothelackofastandardizedcut-off dependence ofaldosteroneandreninmeasurements DRC canhighlyinfluencetheARR( commercial assaysforthemeasurementofPAC, PRAor assay characteristicsandtheuseofdifferentavailable when patientshavebeenoutofbedfor system, bloodsamplesarewithdrawninthemorning corrected. To allowactivationoftherenin-angiotensin of 5 should avoidalowsaltdietandhaveminimumintake high-risk patients. reduced toaminimumafterappropriateexclusionof during screening,andseriousadverseeventshavebeen adjusted medicationaccordingtotheESguideline ( PA accordance withtheESguidelineduringscreeningfor reported byadjustmentofantihypertensivetherapyin 20 elevated pressure requiring medical treatment ( suggested tocontrolhypertensioninthosepatientswith no effects on the ARR compared to the above and are and Includes datafromFunder aldosteronism accordingtoESguideline Risk groupsrecommendedtobescreenedforprimary Table 1 Review All first-degreerelativesofpatientswith PA Patients withhypertensionandafamilyhistoryof Patients withhypertensionandsleepapnea Patients withhypertensionandanadrenalincidentaloma Patients withhypertensionandspontaneousordiuretic Patients withresistanthypertension(bloodpressurenot Patients withsustainedbloodpressureabove ). Asacaveat,severedeleterioussideeffectshavebeen young age( early-onset hypertensionorcerebrovascularaccidentata induced more antihypertensivedrugs diuretic) orcontrolledBP( controlled bythreeconventionaldrugsincludinga 150/100 21 Before performingtheARRscreeningtest,patients pg/mL) withaspecificcommercially available g NaCl/day. Hypokalemia,ifpresent,shouldbe α > 1-adrenergic receptor blockers have limited or ). Inourcenter, morethan90%ofpatientsreceive

200 withPAC inpg/mLandPRAng/mL/h 23 Screening forprimaryaldosteronism. ). Radioimmunoassays are widely employed mmHg, grade2and3hypertension < 40 years) et al . ( 24 3 24 ) andStowasser&Gordon( < , ). 140/90 25 , T AWilliamsandMReincke 26 mmHg) onfouror ) usingsimultaneous 22 ). Themethod ≥ 20

. The 2 h. ). > 120– 3 , assay detectionlimits( a PAC in evidentcasesofPA withspontaneoushypokalemiaand guideline foradefinitivediagnosisof PA. Anexceptionis bytheES testingisconsideredmandatory Confirmatory Diagnosis: confirmatorytesting as recommendedbytheESguideline( the diagnosisofPA isperformedby tests,asdiscussedlater( normal rangeofconfirmatory test. At least, baseline PAC should be higher than the PAC inadditiontoanelevatedARRforapositivescreening workup ofPA ofsuchpatientsandrequireaminimum with PA. Somecentersdonotproceedwiththediagnostic lowevenifthePACvery islow-normalandinconsistent volume overloadespecially inthosepredisposedbyleft theriskofacute collectionoverdays 3–4) carry intake (6 (2 reliable andhavelowcostsbut salineloadingbyinfusion and are widelyinusebecausetheystraightforward ( orally), (FST) or a captopril challenge use salineloading(eitherbyintravenousinfusion or the test. levelsindicateinappropriatestressattheend of aldosterone response interpretedwithcaution if increased testing, andthe should bemonitoredduringconfirmatory a false-positive test result.Consequently, cortisollevels – caninterferewithaldosteronesuppressionandproduce indicated byanincreaseinplasmacortisolconcentration levels.-inducedincreasesofACTH– administer KCltabletseveninpatientswithlow-normal testing mayfurtherdeteriorateplasmapotassiumlevelswe result. Sincesodiumchlorideinfusionduringconfirmatory because failuretodosomayproduceafalse-negative testing slow-release KCltabletspriortoconfirmatory and hypokalemia(ifpresent)shouldbecorrectedwith autonomous oftherenin-angiotensinsystem. test thereby confirms that aldosterone production is positive regulator of aldosterone production). The inhibit circulating angiotensin IIlevels(theendogenous administered agents that normally completely suppress or production of aldosterone in responseto exogenously aldosteronism Management ofprimary al 2 Table L i.v. infusionof0.9% NaClover4 Confirmatory testsdemonstratetheinappropriate Confirmatory The mostcommonlyemployedsuppressiontests Potassium isakeyregulatorofaldosteroneproduction An elevatedARRcanresultifthePRA(orDRC)is >

20 ). Confirmatory testing based on saline loading ). Confirmatory g/day for 3 days, aldosteronemeasuredina24 g/day for3 days, ng/dL (550 pmol/L) withPRA(orDRC)below 3 Downloaded fromBioscientifica.com at09/27/202105:58:35AM ). Confirmationorexclusionof ≥ 179 1 confirmatory tests 1 confirmatory 3 h) ororalsodium ). www.eje-online.org :1 R21 20 via freeaccess h ). European Journal of Endocrinology www.eje-online.org as CTscanningormagnetic resonanceimaging(MRI). producing carcinoma usinganimagingtechnique such with arareformofPA causedbyan aldosterone- Subtype diagnosisbeginswith theexclusionofpatients Diagnosis: subtypedifferentiation of hospitalization. limitations imposedbytherequirementforseveraldays nonetheless unfeasibleinmostcountriesbecauseofcost is describedinStowasser&Gordon( compared withothermethods(adetailedprotocol of thetestinexperthandswithasuperiorsensitivity hypokalemia. Proponents of the FST highlight the safety monitored throughoutthetestbecauseofrisk plasma potassium concentrations that must be closely hospitalization toensurecontrolofbloodpressureand andpotassiumsupplementationupto5-day FST requirestheconsumptionoffludrocortisonewith at riskduetocompromisedrenalorcardiacfunction.The circumvents potentialfluid overloadinpatientswhoare or standingfor test (25–50 the seated position ( test isreportedlyincreasedbyperformingthein hypokalemia ( in therecentlypublishedguidelineforpatientswith AVS withoutasuppressiontest,strategyalsoproposed basal aldosteroneconcentrationsmaydirectlyundergo suggest thatpatientswithanelevatedARRand ( aldosteronism andcandidatesforsurgery below 5.0 to 29%ofpatientswithPA withsuppressedaldosterone dL ( dL (188 test hasasensitivityof83%usingcut-off ventricular or renaldysfunction.Thesalineinfusion PAC, plasmaaldosteroneconcentration;PRA,reninactivity;uAldo,urinaryaldosterone. and ARR *At theMayoclinic; Protocols describingconfirmatorytestingindetailaredescribedStowasserandGordon( Captopril challengetest(CCT) Fludrocortisone suppressiontest(FST) Oral saltloadingtest(SLT) Saline infusiontest(SIT) Confirmatory test Table 2 Review < mlL ( 139 pmol/L) > pmol/L) (

200 Confirmatory testingforprimaryaldosteronism. ng/dL (139 pg/mL/ng/mL/h bytheJapanESGuidelines( mg orallyadministeredcaptoprilaftersitting 3 † ). Thesensitivityofthesalineinfusion At theClevelandclinic; > 27 1 28 ) and88%usingacut-offof h) islikewiseeasilyperformedand pmol/L) werepatientswithunilateral 29 ). Arecentstudysuggestedthatup , 30 , 31 ). The captopril challenge T AWilliamsandMReincke ‡ To excludeanyconfoundingeffect ofACTH;**DecreaseinPAC Decrease inPAC Upright PAC uAldo PAC Diagnostic cut-off values cortisol lessthanthevalueat07:00 20 29 > )). Thetestis ). Theauthors gd (140–280 pmol/L) 5–10ng/dL > 23 mldy* or (33 nmol/day)* 12µg/24h ). < < > 5.0 ng/ 6.8 ng/

6 ng/dL (170 ≤

30% (orARR ES guidelineissuedastrongrecommendationtoperform imaging findings andreduced specificity. Therefore, the incidentalomas increaseswithageleadingtofalse-positive 33 are oftenundetectablebycurrentimagingmethods( aldosterone excess,andmicro-APAs ( since theymightnotfaithfullydistinguishthesource of The valueofCTscanningandMRIhavebeenquestioned long-acting calciumchannel blockers(verapamilor α with less(orminimal)effects onreninsecretionsuchas AVS andsubstitutedforantihypertensive medication weeksbefore MR antagonistsshouldbeinterrupted4 withdrawn. Loop and thiazide diuretics, amiloride and specifically bystimulatingreninsecretion,should be that interfereswiththerenin-angiotensinsystem, predict unilateraldisease( as recommendedbytheESguidelinecouldaccurately and specificimagingbiochemicalcharacteristics study inJapanreportedthatfactorsbasedonyoungage reported tolackspecificity( young age,imagingresultsandPA phenotypehasbeen to bypass AVS on the basis of and proceed to surgery hypokalemia atbaseline)( example, PAC can bypassAVS iftheydisplayamarked phenotype (for ( ( ( predictors of unilateraldiseaseand patient preference in allpatientswithconfirmed PA ( or bilateral source ( overproduction of aldosteroneoriginates from aunilateral from the right and left adrenal veins to determine if the reliably differentiateunilateralfrombilateralPA. AVS to patientwhoisacandidateforsurgery inevery aldosteronism Management ofprimary > < 35 1-adrenergic receptorblockers andnon-dihydropyridine pmol/L) onday4at10:00 10 35 years) with imaging findings of a unilateral ). Inaddition,theproportionofpatientswithadrenal , In preparation for AVS, antihypertensivemedication Blood samples are obtained for steroid measurements 36 mm andanormalappearingcontralateraladrenal) > 200pg/mL/ng/mL/h)** ). AccordingtotheESguideline,youngpatients 20 > h ). IncludesdatafromFunder ‡ (39 nmol/24h) 14 µg/24h > mlL ad spontaneous and (831 pmol/L) 30ng/dL Fig. 2 ≤ Downloaded fromBioscientifica.com at09/27/202105:58:35AM

30% asdefinedbytheESGuideline( ). Some experts recommend AVS h withPRA 38 3 ). Althoughselectingpatients 37 ). ), datafromamulticentric et al † < ≤ gm/ ad plasma and 1ng/mL/h 34 . ( 179 10 3 ). ), othersconsider :1 mm indiameter) R22 3 ) 32 via freeaccess ,

European Journal of Endocrinology withdrawal ( AVS canbeperformedirrespective ofthetimedrug diltiazem). IfPRAorconcentration issuppressed, lateralization indexandthecontralateral ratio(Table 3). measurements ofaldosteroneandcortisolareusedtoderivethe cortisol concentrations(aldosterone-to-cortisolratios).The cava (ontherightside)bydividingrespectiveplasma inferior phrenicvein(ontheleftside)orfromvena concentrations arecorrectedforanydilutionbybloodfromthe all bloodsamples.Adrenalvenousplasmaaldosterone Plasma aldosteroneandcortisolconcentrationsaremeasuredin be determinedbyarapid-onsetcortisolassay( vein isindicatedbytheselectivityindex(Tables 3 and4)thatcan adrenal veins.Thesuccessofcatheterizationeach sampled fromtheinferiorvenacavaandrightleft sequentially catheterizedviathefemoralveinsandbloodis interfering medication(seetextfordetails).Adrenalveinsare protocol inpatientswithconfirmed PA afterwithdrawalof sampling isperformedaccordingtoadefinedstandardized aldosteronism byadrenalvenoussampling.Adrenal Differentiation ofunilateralfrombilateralformsprimary Figure 2 Review 39 ) and,inexceptionalcases,MR antagonist T AWilliamsandMReincke 41 , 42 , 43 ). ). AVS widelyacrosscenters( resultsvary to some extentand the interpretation of remain arbitrary to standardizeAVS protocols( indices used inAVS. Although there have been attempts is no standardized cut-off for the SI, or indeed for any of the requirement forcontralateralsuppressionofaldosterone although theLIissometimesconsideredtogetherwitha is usuallycalculatedbythelateralizationindex(LI) vein ( an increasedsuccessfulcannulationoftherightadrenal 85% in the experienceof one referral center largely due to increased the proportion of successful AVS from 55% to was unsuccessful( iftheAVSassay toascertainwhenresamplingisnecessary rates differ greatlybut can be improved by arapid cortisol between therightandleftadrenalveins( on therightsidebecauseofanatomicaldifferences cannulation oftheadrenalveinsisparticularlychallenging cortisol in theadrenalvein and in aperipheral vein. The selectivity index(SI),whichiscalculatedastheratioof cannulation oftheadrenalveins,ismeasuredby suppressed ( therapy can be continued during AVS if renin remains was observed in 28% of patients, which were mostly was observed time, discordance between basal and post-ACTH values in the basal state to 92% post stimulation. At the same 250 stimulation were illustrated by a study in which a bolus of performing equallywell( infusion (initiated30 as a bolus (usually 0.25 well asunstimulatedprotocolswithACTHadministered technical successrateofAVS ( unilateral PA, AVS withACTHinfusioncanimprovethe contralateral adrenalgland(non-dominantgland) in possible stimulation of aldosterone production from the AVS. Although some concerns have been raised on the by stress-induced ACTH release during non-simultaneous variations incortisolandaldosteroneproductioncaused the production of aldosterone from APAs and minimizing that includeincreasing technical success rates, stimulating called cosyntropin)isusedbysomeforvariousreasons administered syntheticderivativeofACTH(ACTH1–24, system. AnAVS procedurewithanexogenously changes onthestimulationofrenin-angiotensin at least1-hrecumbencytoavoidtheeffectsofpostural stimulated aldosteroneproductionismaximalfollowing production todefinelateralization( aldosteronism Management ofprimary µg ofACTHincreasedbilateral selectivityfrom67% AVS isperformedinthemorningwhenACTH- The success of AVS, determined by the correct 43 ). Thelateralization of aldosteroneproduction 40 ). 41 , min beforetheprocedure(50 42 Downloaded fromBioscientifica.com at09/27/202105:58:35AM ). Theuseofsuchanassayhas mg (10 47 39 45 ). TheeffectsofACTH , , 44 46 Tables 3 ), thereferencelimits IU)) or continuous ) andcanperformas 179 Table 4 www.eje-online.org :1 Fig. 2 and ). ). Success 4 ). There µg/h)) R23 via freeaccess European Journal of Endocrinology www.eje-online.org concentration; SI,selectivityindex. ACTH, adrenocorticotropichormone; AVS, adrenalvenous sampling;LI,lateralizationindex;PA, primaryaldosteronism;PAC, plasma aldosterone *In accordancewiththeJapanESGuidelines ( Includes datafromWilliams Yokohama City Sendai Rochester Brisbane Torino Munich, Paris Referral center Table 4 the surgicalgroups,targetbloodpressurewasreached adrenalectomies and46treatedbyMRA, 3.0 vsinthosereceivingAVS-based treatment(46 (in 46adrenalectomyandinMRAtreatment)was median DDDsof92patientsreceivingCT-based treatment specific treatment.Outcomeswereessentiallysimilar:the afterinitiationof defined dailydrugdose(DDD)1 year intensity of antihypertensive medication measured as making ( determination was equivalent to AVS-based decision randomized fashionwhetherCTimagingbasedsubtype prednisolone/day). low-dose syntheticglucocorticoidtreatment(i.e.5 performed in the afternoon and if patients receive chronic at riskofanallergicreactiontotheanesthetic,ifAVS is restricted to specific situations:for example, ifpatients are AVS withoutACTHstimulation.stimulationis In ourcenter, wegenerallyperformbilateralsimultaneous diagnosed withanACTHinfusionprotocol( with anunstimulatedprotocol( outcomes ofpatientswithunilateralPA diagnosedbyAVS no significantdifferencesinthepost-surgicalclinical reduce theproportionoflateralizedPA. We observed bilateral post-ACTH.Therefore,ACTHstimulationmay lateralized casesunderbasalconditionsthatbecame Contralateral ratio(CLR) Lateralization index(LI) Selectivity index(SI) AVS index Table 3 the adrenalonoppositeside. vena cava);theipsilateralAV istheadrenalvein fromtheadrenalwithexcessaldosteroneproductionandcontralateralAV istheadrenalveinfrom ACTH, adrenocorticotropichormone;AV, adrenalvein;AVS, adrenalvenoussampling;PA, primaryaldosteronism;PV, peripheralvein(oftentheinferior

Review The recentlypublishedSPARTACUS trialstudiedina Different protocolsandinterpretationofadrenalvenoussampling. Definition andinterpretationofadrenalvenoussamplingcriteria. 49 ). The primary outcomeofthestudywas ). Theprimary otnos CH infusion ACTH Bolus +continuous Bolus ACTHinfusion Continuous ACTHinfusion Unstimulated infusion ACTH Unstimulated +continuous Unstimulated Unstimulated orACTHinfusion et al

. ( 48 ((Aldosterone)/(Cortisol)) Measures lateralizationofaldosteroneproduction ((Aldosterone)/(Cortisol)) Indicates successfulAVS withcorrectcannulationofadrenalveins (Cortisol) Definition andinterpretation Inhibition ofaldosteroneproductionfromthenon-dominantadrenalgland(contralateral ). suppression, CLR n

= T AWilliamsandMReincke 331) relativetopatients 23 AV ). /(Cortisol) n ≤ P 7) ( =374) 1) .3. In =0.53). PV IpsilateralAV ContralateralAV 48 mg ). /((Aldosterone)/(Cortisol)) /((Aldosterone)/(Cortisol)) ( an unprecedented and ongoingflood ofcommentaries in itsdesignandmethodologyhavebeendiscussed different. Detailsofthestudyandperceived weaknesses biochemical remission(80%vs89%, endpoints, suchashealth-relatedqualityoflifeor patients, respectively( in 39(42%)patientsand41(45%)oftheoperated treatment, surgicalormedicalmanagement.Forpatients The underlyingcauseofPA determinestheappropriate Treatment a failurerateofupto20%( CT imaging,acknowledgingthatthisstrategymighthave base theirdecisionmakingwithincreasedconfidenceon positive .CenterswithoutaccesstoAVS will do sobutwilllikelyexemptyoungpatients with imaging- used AVS fortherapeuticdecisionmakingwillcontinueto thought. Asaconsequenceofthisdebate,centersthat CT-based managementmightbebetterthanpreviously having afailurerateofapproximately5%( sophisticated proceduresuchasAVS isnot100%accurate, study areinpartduetothetrialhighlightingthata were fororagainstAVS. Theemotionsarisingfromthe aldosteronism Management ofprimary 50 (Cortisol) , 51 Successful AVS , 52 AV SI SI SI SI SI ,

≥ ≥ ≥ ≥ ≥ 53 > 5 5 3 3 2 200 µg/dL* ) splittingthecommunityintothosewho ContralateralAV PV Downloaded fromBioscientifica.com at09/27/202105:58:35AM P 0.82). Additional secondary secondary Additional =0.82). 49 (PAC) ). Diagnosis ofunilateralPA LI LI LI LI LI ≥ ≥ ≥ ≥ ≥ ipsilateralAV 2.6 4 4 2.5 andCLR 4 orLI 179 P .5, ee not were =0.25), ≥ :1

3 andCLR > 1400 ng/dL* 48 ≤ 1 ), andthat ≤ R24 1 via freeaccess European Journal of Endocrinology suggests thattitratingtheincrease inPRAasaresponse suppressed ( to patientswithPA whosereninactivity remained risk forcardiovascularevents andmortalitywaslimited mortality, diabetes andatrialfibrillation.Theexcess with PA alsohadhigheradjustedrisksforincident controlinthe PA group ( higher ratesofcardiovasculareventsindependent of treated conventionallydemonstratedasignificantly 41 853 age-matchedpatientswithessentialhypertension with PA (treatedwithaMRantagonist)compared failure afteramyocardialinfarction. and in Europe, for the treatment of congestive heart for thetreatmentofhypertension,inUnitedStates spironolactone ( but displayslowerefficacyandhighcostcomparedwith is aselectiveMRantagonistthathasnoadverseeffects of incidence ofgynecomastiaincreasesfrom erectile dysfunction and menstrual irregularities. The the associatedadverseeffectsincludinggynecomastia, The non-selectiveactionofspironolactonecancause receptor andagonistactivitytotheprogesteronereceptor. and displaysbothantagonistactivitytotheandrogen aldosterone foritsreceptor, theMR.Itisnon-selective canrenoate ( patients followinglong-termtreatmentwithpotassium followingdiagnosis( at 10.8and12.9 years (2 of 37 patients treated with spironolactone (5.4%) PA afterlong-termtreatmentwithMRantagonistsin remission havebeenreportedinpatientswithbilateral for surgery. Casesofspontaneouscompletebiochemical rather thansurgicalmanagementorthosewhoareunfit arethosewithunilateralPAcategory whooptformedical spironolactone ( treated medicallywithanMRantagonist,usually patients ( normalization oftheARR)wasachievedin94%699 –and (correction ofhypokalemia–ifpresentpre-surgery a further47%( pressure andantihypertensivemedicationresponse)in and substantiallyimprovedtheclinicaloutcome(blood normalized bloodpressurein37%of705patientswithPA an international cohort study, unilateral adrenalectomy and the resolution of excess aldosterone production. In of bloodpressureremissionorclinicalimprovement with unilateralPA, adrenalectomyoffersthepossibility Review < A longitudinalstudythatincluded602patients Spironolactone is a competitive inhibitor of Patients with bilateral PA are most effectively 50 mg/day to52%at 48 ). < 56 1 ). μ 58 g/L perh)onMRantagonists. Thestudy 48 54 , ). Asuccessfulbiochemicaloutcome 59 ). Otherpatientsincludedinthis ). InJapan,eplerenoneisapproved > gdy ( 150 mg/day T AWilliamsandMReincke 57 < 6.9% atadose ). Eplerenone 60 55 ). Patients )) andin typesII andIV( AVS shouldbeperformed in patientswithfamilial relatives andprovidestimely treatmentwhenappropriate. the possibilityofanearly diagnosisofasymptomatic Genetic testingofpatients in thesetargetgroupsoffers for thepresenceofhybrid long-term complications. antagonists toblocktheMRmoreeffectivelyandreduce studies raise the question of uptitrating the dose of MR higher riskofatrialfibrillation( treatment butnotadrenalectomywasassociatedwitha for PA andforessentialhypertension.MRantagonist 11.2 years, wassimilarinpatientstreated overallsurvival 88.8% with essential hypertension. After a median of BAH andstandardmedicaltreatmentintheremaining APA, MRantagonisttreatment(6.4%)inpatientswith results: unilateraladrenalectomy(4.8%)inpatientswith screened forPA andtreatedaccordingtobiochemical cardiovascular outcomesandmortalityin1125patients with PA ( to avoidtheexcesscardiovascularriskassociated control wouldbeamoreeffectivetherapeuticapproach to MR antagonist therapy instead of blood pressure mutations inthe a diagnosisofPA (forexample, that causesFHtypeI( ofPAa familyhistory orstrokeatayoungage( with adiagnosisofearly-onsetPA ( Guideline ( antagonists. Therefore,inaccordancewiththeESSociety latter istreatedbybilateraladrenalectomyorwithMR with glucocorticoids (such as )and the type III)( hyperaldosteronism typesIandIII(FHtypeFH procedure ofAVS inpatientswithfamilial isunnecessary cause rarefamilialformsofPA ( macrolide antibioticsasselectiveinhibitors( patients with an APA carrying a highprobabilityofhavinganAPA ( with bilateraldiseasebyselectionofthosepatients may lieinsteroidprofilingtocircumvent AVS inpatients been firmlyestablishedalthoughapotentialfutureuse in patientswithAPAs ( channels andtransportersthatdrivethealdosteroneexcess A numberofsomaticmutationshavebeenidentifiedinion Genetic formsofPA aldosteronism Management ofprimary Germline variantshavealsobeenidentifiedthat 66 3 60 , ), genetictestingisrecommendedinpatients 67 ). ThePAPY studyanalyzedlong-term ) becausetheformeriseffectivelytreated KCNJ5 66 62 genethatcauseFHtypeIII( ) and in very youngpatientswith ) andinvery Downloaded fromBioscientifica.com at09/27/202105:58:35AM , 63 ). Noclinicalapplicationhas CYP11B1 KCNJS < 61 0 years)forgermline 20 62 < ). Insummary, both 20 years old)orwith 20 years 179 , 69 64 63 mutations using www.eje-online.org :1 , ) orbyselecting 70 ). Theinvasive / CYP11B2 , 65 71 ). < ) because 40 years) R25 gene 68 via freeaccess ). European Journal of Endocrinology www.eje-online.org The excellentartworkofFrancescaWilliams isgratefullyacknowledged. Acknowledgements (2013_A182 and2015_A171toMR). of theGermanConnsRegistry-Else-KrönerHyperaldosteronismRegistry RE 752/20-1toMR)andtheElseKröner-Fresenius Stiftunginsupport Adrenal: Central Relay in Health and Disease’ to M R and T A W; and grant Forschungsgemeinschaft (DFG)(withintheCRC/Transregio 205/1‘The programme (grantagreementNo(694913)toMR)andbytheDeutsche under theEuropeanUnion’s Horizon2020researchandinnovation This workwassupportedbytheEuropeanResearchCouncil(ERC) Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcould be Declaration ofinterest and diagnosisforPA. enable timely, cost-effective and patient-friendly screening excess. However, simplifiedproceduresarerequiredto minimize orreversetheadverseeffectsofaldosterone early diagnosisandindicatesthatspecifictreatmentscan accumulating evidencehighlightstheimportanceofan an alternative to ease the subtyping of PA. In summary, of PA, suchasCXCR4PET-CT imaging( results. Inaddition, novel functional imaging methods commentaries will resolve the issue of the validity of the trial whichtakesintoaccountthecriticismsofmany exception istheSPARTACUS studybutanindependent diagnostic andtherapeuticalgorithmoftheguideline.An treatment ofPA. Ingeneral,thesedataconfirmthe of thegenetics,diagnosis,subtypedifferentiationand several high-qualityreportshaveadvancedourknowledge Since the publication of the ES guideline on PA in 2016, Conclusions cause ofearly-onsetPA. secretion. Thesefindingsestablish expression ofaldosteronesynthaseand conductance at restingpotentialsresultinginincreased channels showgainoffunctionwithincreasedchloride is expressedinadrenalglomerulosacells,andthemutated patients withsporadicchildhood-onsetPA ( gene, havebeenidentifiedinfamilieswithFH-IIand gated chloridechannelCIC-2,encodedbythe adrenalectomy aswellwithMRantagonists( these patientshavebeentreatedsuccessfullybyunilateral Review Germline heterozygous mutations in thevoltage- T AWilliamsandMReincke CLCN2 74 mutationsasa 72 ), couldoffer , 73 62 ). CIC-2 ). CLCN2

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