GUIDELINES - The Endocrine Society

The Endocrine Society’sCLINICALGUIDELINESCase Detection, Diagnosis,and Treatment of Patientswith Primary Aldosteronism:An Endocrine Society Clinical Practice Guideline

Authors: John W. Funder, Robert M. Carey, Carlos Fardella, Celso E. Gomez-Sanchez, Franco Mantero, MichaelStowasser, William F. Young Jr, Jr., and Victor M. MontoriAffiliations: Prince Henry's Henry’s Institute of Medical Research (J.W.F.), Clayton; Australia; University of VirginiaHealth System (R.M.C.), Charlottesville, Virginia; Facultad de Medicina Pontificia Universidad Católica deChile (C.F.), Santiago; Chile; G.V. (Sonny) Montgomery VA Medical Center (C.E.G-S.), Jackson, Mississippi;University of Padova (F.M.), Padua; Italy; University of Queensland (M.S.), Brisbane; Australia; and Mayo Clinic(W.F.Y., V.M.M.), Rochester, Minnesota.Co-Sponsoring Associations: European Society of Endocrinology, European Society of Hypertension,International Society of Endocrinology, International Society of Hypertension, The Japanese Society ofHypertensionDisclaimer Statement: Clinical Practice Guidelines are developed to be of assistance to endocrinologists byproviding guidance and recommendations for particular areas of practice. The Guidelines should not be consideredinclusive of all proper approaches or methods, or exclusive of others. The Guidelines cannot guarantee any specificoutcome, nor do they establish a standard of care. The Guidelines are not intended to dictate the treatment of aparticular patient. Treatment decisions must be made based on the independent judgment of health care providersand each patient's individual circumstances.The Endocrine Society makes no warranty, express or implied, regarding the Guidelines and specificallyexcludes any warranties of merchantability and fitness for a particular use or purpose. The Society shall not beliable for direct, indirect, special, incidental, or consequential damages related to the use of the informationcontained herein.First published in the Journal of Clinical Endocrinology & Metabolism, September 2008, 93(9):3266–3281© The Endocrine Society, 2008

The Endocrine Society’sCLINICALGUIDELINESCase Detection, Diagnosis,and Treatment of Patientswith Primary Aldosteronism:An Endocrine Society Clinical Practice Guideline

Table of ContentsSummary of Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Methods of Development of Evidence-Based Recommendations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Definition and Clinical Significance of Primary Aldosteronism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Case Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Case Confirmation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Subtype Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Order Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Reprint Information, Questions & Correspondences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inside Back Cover

AbstractObjective: To develop clinical practice guidelines forthe diagnosis and treatment of patients with primaryaldosteronism.Participants: The Task Force comprised a chair,selected by the Clinical Guidelines Subcommittee(CGS) of The Endocrine Society, six additionalexperts, one methodologist, and a medical writer. TheTask Force received no corporate funding orremuneration.Evidence: Systematic reviews of available evidencewere used to formulate the key treatment andprevention recommendations. We used the Gradingof Recommendations, Assessment, Development,and Evaluation (GRADE) group criteria to describeboth the quality of evidence and the strengthof recommendations. We used ‘recommend’ forstrong recommendations and ‘suggest’ for weakrecommendations.Consensus Process: Consensus was guided bysystematic reviews of evidence and discussions duringone group meeting, several conference calls, andmultiple e-mail communications. The drafts preparedby the task force with the help of a medical writerwere reviewed successively by The EndocrineSociety’s CGS, Clinical Affairs Core Committee(CACC), and Council. The version approved by theCGS and CACC was placed on The EndocrineSociety's Web site for comments by members. Ateach stage of review, the Task Force received writtencomments and incorporated needed changes.Conclusions: We recommend case detection ofprimary aldosteronism be sought in higher risk groupsof hypertensive patients and those with hypokalemiaby determining the aldosterone-renin ratio understandard conditions, and that the condition beconfirmed/excluded by one of four commonly usedconfirmatory tests. We recommend that all patientswith primary aldosteronism undergo adrenalcomputed tomography (CT) as the initial study insubtype testing and to exclude adrenocorticalcarcinoma. We recommend the presence of aunilateral form of primary aldosteronism should beestablished/excluded by bilateral adrenal venoussampling by an experienced radiologist and,where present, optimally treated by laparoscopicadrenalectomy. We recommend that patients withbilateral adrenal hyperplasia, or those unsuitablefor surgery, optimally be treated medically bymineralocorticoid receptor antagonists.(J Clin Endocrinol Metab 93: 3266–3281, 2008)Abbreviations:APA, aldosterone-producing adenoma; ARR, plasma aldosterone: renin ratio;AVS, adrenal venous sampling; CT, computed tomography; DRC, direct renninconcentration; FST, fludrocortisone suppression testing; GRA,glucocorticoidremediable aldosteronism; IHA, idiopathic hyperaldosteronism;MR, mineralocorticoid receptor; MRI, magnetic resonance imaging; PA,primary aldosteronism; PAC, plasma aldosterone concentration; PRA, plasmarennin activity; SIT, saline infusion test; UAH, unilateral adrenal hyperplasiaCASE DETECTION, DIAGNOSIS, AND TREATMENT OF PA TIENTS WITH PRIMARY ALDOSTERONISM3

SUMMARY OFRECOMMENDATIONS3.2. We recommend that, when surgical treatment ispracticable and desired by the patient, the distinctionbetween unilateral and bilateral adrenal disease bemade by adrenal venous sampling (AVS) by anexperienced radiologist. (1| )THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES1.0.CASE DETECTION1.1. We recommend the case detection of primaryaldosteronism (PA) in patient groups with relativelyhigh prevalence of PA. (1| ) These includepatients with Joint National Commission (JNC)stage 2 (>160–179/100–109 mm Hg), stage 3(>180/110 mm Hg), or drug resistant hypertension;hypertension and spontaneous or diuretic-inducedhypokalemia; hypertension with adrenal incidentaloma;or hypertension and a family history of earlyonsethypertension or cerebrovascular accident at ayoung age (

METHOD OF DEVELOPMENT OFEVIDENCE-BASED GUIDELINESThe Clinical Guidelines Subcommittee of TheEndocrine Society deemed detection, diagnosis, andtreatment of patients with primary aldosteronism(PA) a priority area in need of practice guidelines andappointed a seven-member Task Force to formulateevidence-based recommendations. The Task Forcefollowed the approach recommended by the Gradingof Recommendations, Assessment, Development, andEvaluation group, an international group withexpertise in development and implementation ofevidence-based guidelines (1).The Task Force used the best available researchevidence that members identified to inform therecommendations and consistent language andgraphical descriptions of both the strength of arecommendation and the quality of evidence. In termsof the strength of the recommendation, strongrecommendations use the phrase “we recommend”and the number 1, and weak recommendations use thephrase “we suggest” and the number 2. Cross-filledcircles indicate the quality of the evidence, such thatdenotes very low quality evidence;, low quality; , moderate quality; and, high quality. The Task Force has confidencethat patients who receive care according to the strongrecommendations will derive, on average, more goodthan harm. Weak recommendations require morecareful consideration of the patient’s circumstances,values and preferences to determine the best course ofaction. A detailed description of this grading schemehas been published elsewhere (2).Linked to each recommendation is a description of theevidence, values that panelists considered in makingthe recommendation (when making these explicitwas necessary), and remarks, a section in whichpanelists offer technical suggestions for testingconditions, dosing and monitoring. These technicalcomments reflect the best available evidence appliedto a typical patient. Often, this evidence comes fromthe unsystematic observations of the panelists andshould, therefore, be considered suggestions.DEFINITION AND CLINICALSIGNIFICANCE OF PRIMARYALDOSTERONISMWhat is primary aldosteronism?Primary aldosteronism (PA) is a group of disordersin which aldosterone production is inappropriatelyhigh, relatively autonomous, and non-suppressibleby sodium loading. Such inappropriate productionof aldosterone causes cardiovascular damage,suppression of plasma renin, hypertension, sodiumretention, and potassium excretion that if prolongedand severe may lead to hypokalemia. PA is commonlycaused by an adrenal adenoma, by unilateral orbilateral adrenal hyperplasia, or in rare cases by theinherited condition of glucocorticoid-remediablealdosteronism (GRA).How common is PA?Most experts previously described PA in 10% ofhypertensive patients, both in general and in specialtysettings (10–18).How frequent is hypokalemia in PA?In recent studies, only a minority of patients withPA (9% to 37%) had hypokalemia (19). Thus,normokalemic hypertension constitutes the mostcommon presentation of the disease, with hypokalemiaprobably present in only the more severecases. Half the patients with an aldosteroneproducingadenoma (APA) and 17% of those withidiopathic hyperaldosteronism (IHA) had serumpotassium concentrations

Why is PA important?This condition is important not only because of itsprevalence, but also because PA patients have highercardiovascular morbidity and mortality than age- andsex-matched patients with essential hypertension andthe same degree of blood pressure elevation (21, 22).Furthermore, specific treatments are available thatameliorate the impact of this condition on patientimportantoutcomes.1.0. CASE DETECTION1.1. We recommend the case detection of primaryaldosteronism (PA) in patient groups with relativelyhigh prevalence of PA (listed in Table 1) (Figure 1).(1| ) These include patients with JointNational Commission (JNC) stage 2 (>160–179/100–109 mm Hg), stage 3 (>180/110 mm Hg), ordrug resistant hypertension; hypertension andspontaneous or diuretic-induced hypokalemia;hypertension with adrenal incidentaloma; orhypertension and a family history of early-onsethypertension or cerebrovascular accident at a youngage (180, DBP >110 (10).When systolic and diastolic blood pressures were in different categories, thehigher category was selected to classify the individual’s blood pressure status.Resistant hypertension, defined as SBP >140 and DBP >90 despite 17%–23%treatment with three hypertensive medications. The prevalence rates citedhere are from (26–31).Hypertensive patients with spontaneous or diureticinducedPA is hypokalemia.Specific prevalence figures are not available,but more frequently found in this group.Hypertension with adrenal incidentaloma (32–37), defined as an Median: 2% (range, 1.1%–10%)adrenal mass detected incidentally during imaging performed for extra- One retrospective study that excluded patientsadrenal reasons.with hypokalemia and severe hypertensionfound aldosterone-producing adenoma in 16of 1004 subjects (37).6

1.2.VALUESSimilar values underpin our recommendation totarget subjects in groups with documented highprevalence of PA and to test them by ARR. Inparticular, this recommendation acknowledges thecosts currently associated with ARR testing of allpatients with essential hypertension. Against thisrecommendation for selective testing, however,must be weighed the risk of missing or at leastdelaying the diagnosis of PA in some hypertensiveindividuals. The consequences of this may includethe later development of more severe and resistanthypertension resulting from failure to lower levels ofaldosterone or to block its actions. Furthermore,duration of hypertension has been reported by severalinvestigators to be a negative predictor of outcomefollowing unilateral adrenalectomy for aldosteroneproducingadenoma (46, 47), suggesting that delays indiagnosis may result in a poorer response to specifictreatment once PA is finally diagnosed.1.2. Remarks—technical aspects required for thecorrect implementation of recommendation 1.2.Testing conditions (Table 3 & 4)The ARR is most sensitive when used in patients fromwhom samples are collected in the morning after patientshave been out of bed for at least 2 hours, usually afterthey have been seated for 5–15 minutes. Ideally, patientsshould have unrestricted dietary salt intake prior totesting. In many cases the ARR can be confidentlyinterpreted with knowledge of the effect on the ARR ofcontinued medications or suboptimal conditions oftesting, avoiding delay and allowing the patient toproceed directly to confirmatory/exclusion testing.Washout of all interfering antihypertensive medicationsis feasible in patients with mild hypertension, but ispotentially problematic in others, and perhapsunnecessary in that medications with minimal effect onthe ARR can be used in their place (Table 2).Assay reliabilityAlthough newer techniques are evolving, we prefer touse validated immunometric assays for plasma reninactivity (PRA) or direct renin concentration (DRC);PRA takes into account factors (such as estrogencontainingpreparations) that affect endogenoussubstrate levels. Laboratories should use aliquots fromhuman plasma pools, carefully selected to cover thecritical range of measurements, rather than thelyophilized controls provided by the manufacturer tomonitor intra- and inter-assay reproducibility and longtermstability. Because the ARR is mathematicallyhighly dependent on renin (49), renin assays should besufficiently sensitive to measure levels as low as 0.2–0.3ng/mL/h (DRC 2 mU/L) (10, 16). For PRA, but notDRC, sensitivity for levels

TABLE 3. Measurement of the aldosterone-renin ratio: a suggested approachA. Preparation for aldosterone-renin ratio (ARR) measurement: agenda1. Attempt to correct hypokalemia, after measuring plasma potassium in blood collected slowly with a syringe andneedle [preferably not a Vacutainer to minimize the risk of spuriously raising potassium], avoiding fist clenchingduring collection, waiting at least 5 seconds after tourniquet release (if used) to achieve insertion of needle, andensuring separation of plasma from cells within 30 minutes of collection.2. Encourage patient to liberalize (rather than restrict) sodium intake.3. Withdraw agents that markedly affect the ARR (48) for at least 4 weeks:a. Spironolactone, eplerenone, amiloride, and triamtereneb. Potassium-wasting diureticsc. Products derived from liquorice root (e.g., confectionary licorice, chewing tobacco)4. If the results of ARR off the above agents are not diagnostic, and if hypertension can be controlled with relatively noninterferingmedications (see Table 2), withdraw other medications that may affect the ARR (48) for at least 2 weeks:a. Beta-adrenergic blockers, central alpha-2 agonists (e.g., clonidine, alpha-methyldopa), nonsteroidal antiinflammatorydrugsb. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, dihydropyridine calciumchannel antagonists5. If necessary to maintain hypertension control, commence other antihypertensive medications that have lesser effectson the ARR (e.g., verapamil slow-release, hydralazine [with verapamil slow-release, to avoid reflex tachycardia],prazosin, doxazosin, terazosin; see Table 2).6. Establish oral contraceptive (OC) and hormone replacement therapy (HRT) status, as estrogen-containing medicationsmay lower direct renin concentration (DRC) and cause false positive ARR when DRC (rather than plasma reninactivity) is measured. Do not withdraw OC unless confident of alternative effective contraception.B. Conditions for collection of blood1. Collect blood mid-morning, after the patient has been up (sitting, standing, or walking) for at least 2 hours andseated for 5-15 minutes.2. Collect blood carefully, avoiding stasis and hemolysis (see A.1 above).3. Maintain sample at room temperature (and not on ice, as this will promote conversion of inactive to active renin)during delivery to laboratory and prior to centrifugation and rapid freezing of plasma component pending assay.C. Factors to take into account when interpreting results (see Table 4)1. Age: in patients aged >65 years, renin can be lowered more than aldosterone by age alone, leading to a raised ARR2. Time of day, recent diet, posture, and length of time in that posture3 Medications4. Method of blood collection, including any difficulty doing so5. Level of potassium6. Level of creatinine (renal failure can lead to false positive ARR)incubation phase as suggested by Sealey and Laragh(50). Although most laboratories use radioimmunoassayfor plasma and urinary aldosterone,measured levels of standards have been shown to beunacceptably different in some instances (51). Tandemmass spectrometry is increasingly used and has provedto be much more consistent in performance (52).InterpretationThere are important and confusing differencesbetween laboratories in the methods and unitsused to report values of renin and aldosterone. Foraldosterone, 1 ng/dL converts to 27.7 pmol/L inSystème International [SI] units. For immunometricmethods of directly measuring renin concentration,a PRA level of 1 ng/mL/h (12.8 pmol/L/minin SI units) converts to a DRC of approximately8.2 mU/L (5.2 ng/L in traditional units) whenmeasured by either the Nichols Institute Diagnosticsautomated chemiluminescence immunoassay (previouslywidely used but recently withdrawn) or the Bio-RadRenin II radioimmunoassay. Because DRC assays arestill in evolution, these conversion factors maychange. For example, 1 ng/mL/h PRA converts to aCASE DETECTION, DIAGNOSIS, AND TREATMENT OF PA TIENTS WITH PRIMARY ALDOSTERONISM9

TABLE 4. Factors that may affect the aldosterone-renin ratio and thus lead to false positive or falsenegative resultsEffect onaldosterone Effect on Effect onFactor levels renin levels ARRMedicationsBeta-adrenergic blockers↑ ↑ ↑↑(FP)Central alpha-2 agonists(e.g., clonidine, alpha-methyldopa↑ ↑ ↑↑(FP)NSAIDs↑ ↑ ↑↑(FP)K+-wasting diuretics↑↑↑↑↑(FN)K+-sparing diuretics↑↑↑↑(FN)ACE inhibitors↑↑↑↑(FN)ARBs↑↑↑↑(FN)Ca2+ blockers (DHPs)↑↑↑↑(FN)Renin inhibitors ↑ * ↑ (FP)*↑ ↑↑(FN)*Potassium statusHypokalemia↑↑↑↑(FN)Potassium loading↑↑↑↑(FP)Dietary sodiumSodium restricted↑↑↑↑(FN)Sodium loaded↑ ↑ ↑↑(FP)Advancing age↑ ↑ ↑↑(FP)Other conditionsRenal impairment↑↑↑(FP)PHA-2↑↑↑(FP)Pregnancy↑↑↑↑(FN)THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINESRenovascular HTMalignant HTARR, aldosterone-renin ratio; NSAIDs, non-steroidal anti-inflammatory drugs; K+, potassium; ACE, angiotensin converting enzyme; ARBs, angiotensin II type 1receptor blockers; DHPs, dihydropyridines; PHA-2, pseudohypoaldosteronism type 2 (familial hypertension and hyperkalemia with normal glomerular filtrationrate); HT, hypertension; FP, false positive; FN, false negative.*Renin inhibitors lower plasma renin activity (PRA), but raise direct active renin concentrations (DRC). This would be expected to result in false positive ARRlevels for renin measured as PRA and false negatives for renin measured as DRC.DRC of approximately 12 mU/L (7.6 ng/L) whenmeasured by the recently introduced and alreadywidely used Diasorin automated chemiluminescenceimmunoassay. Here, we express aldosterone andPRA levels in conventional units (aldosterone innanograms per deciliter; plasma renin activity in↑↑↑↑↑↑(FN)(FN)nanograms per milliliter per hour) with SI units foraldosterone and DRC (using the 8.2 conversionfactor) given in parentheses. Lack of uniformity indiagnostic protocols and assay methods for ARRmeasurement has been associated with substantialvariability in cut-off values used by different groups↑↑10

anging from 20 to 100 (68 to 338) (11, 14, 15, 19, 29,53, 54). Most groups, however, use cut-offs of 20 to 40(68 to 135) when testing is performed in the morningon a seated ambulatory patient. Table 5 lists ARR cutoffvalues using some commonly expressed assay unitsfor plasma aldosterone concentration, plasma reninactivity, and direct measurement of plasma reninconcentration.Some investigators require elevated aldosterone levelsin addition to elevated ARR for a positive screeningtest for PA (usually aldosterone >15 ng/dL [416pmol/L]) (55). An alternative approach is to avoid aformal cut-off level for plasma aldosterone, but torecognize that the likelihood of a false positive ARRbecomes greater when renin levels are very low (11).Against a formal cut-off level for aldosterone are thefindings of several studies. In one study, seatedplasma aldosterone levels were 100) and showing failure of aldosterone to suppressduring fludrocortisone suppression testing (FST), andin four of 21 patients found by adrenal venoussampling (AVS) to have unilateral, surgicallycorrectable PA (56). Another study reported plasmaaldosterone levels of 9–16 ng/dL (250–440 pmol/L) in16 of 37 patients diagnosed with PA by FST (16).While it would clearly be desirable to provide firmrecommendations for ARR and plasma aldosteronecut-offs, the variability of assays between laboratoriesand the divided literature to date make it moreprudent to point out relative advantages anddisadvantages, leaving clinicians the flexibility tojudge for themselves.2.0. CASE CONFIRMATION2.1. Instead of proceeding directly to subtypeclassification, we recommend that patients with apositive ARR measurement undergo testing, by any offour confirmatory tests, to definitively confirm orexclude the diagnosis (Figure 1). (1| )2.1.EVIDENCEThe current literature does not identify a gold standardconfirmatory test for PA. Test performance has beenevaluated only retrospectively, in relatively small seriesof patients selected with high prior (pre-test)probability of PA, commonly in comparison with othertests rather than towards a conclusive diagnosis of PA.Some of these limitations are illustrated in thefollowing example. There is empirical evidence thatcase-control designs for establishing the accuracy ofdiagnostic tests overestimate their accuracy.Giacchetti et al. (57) used such a design including 61PA patients (26 with confirmed APA) and 157patients with essential hypertension. In this context,they found that a post-sodium infusion test with acut-off value for plasma aldosterone of 7 ng/dLTABLE 5. ARR cut-off values, depending on assay and based on whether PAC, PRA, and DRC aremeasured in conventional or SI unitsPRA PRA DRC a DRC a(measured in (measured in (measured in (measured inng/mL/h) pmol/L/min) mU/L) ng/L)PAC (as ng/dL) 20 1.6 2.4 3.830 b 2.5 3.7 5.740 3.1 4.9 7.7PAC (as pmol/L) 750 b 60 91 1441000 80 122 192ARR, Aldosterone-renin ratio; PAC, plasma aldosterone concentration; PRA, plasma renin activity; DRC, direct renin concentration; SI, Système International.a Values shown are on the basis of a conversion factor of PRA (ng/mL/h) to DRC (mU/L) of 8.2. DRC assays are still in evolution, and in a recently introducedand already commonly used automated DRC assay, the conversion factor is 12 (see text).b The most commonly adopted cut-off values are shown in bold: 30 for PAC and PRA in conventional units (equivalent to 830 when PAC is in SI units) and 750when PAC is expressed in SI units (equivalent to 27 in conventional units).CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PA TIENTS WITH PRIMARY ALDOSTERONISM11

THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINESshowed a sensitivity of 88% and a specificity of 100%when evaluated by ROC curve in the 76 cases withARR >40 ng/dL per ng/mL/h. In the prospectivePAPY study, analysis of sensitivity/specificity in the317 patients undergoing a saline infusion test (SIT)gave a best aldosterone cut-off value of 6.8 ng/dL. Thesensitivity and specificity, however, were moderate(respectively 83% and 75%), reflecting valuesoverlapping between patients with and withoutdisease; use of the aldosterone-cortisol ratio did notimprove the accuracy of the test (17, 58).Four testing procedures (oral sodium loading, salineinfusion, fludrocortisone suppression, and captoprilchallenge) are in common use, and there is currentlyinsufficient direct evidence to recommend one overthe others. While it is acknowledged that these testsmay differ in terms of sensitivity, specificity, andreliability, the choice of confirmatory test iscommonly determined by considerations of cost,patient compliance, laboratory routine, and localexpertise (Table 6). It should be noted thatconfirmatory tests requiring oral or intravenoussodium loading should be administered with cautionin patients with uncontrolled hypertension orcongestive heart failure. We recommend that thepharmacological agents with minimal or no effects onthe renin-angiotensin-aldosterone system shown inTable 2 be utilized to control blood pressure duringconfirmatory testing.2.1.VALUESConfirmatory testing places a high value on sparingindividuals with false-positive ARR tests costly andintrusive lateralization procedures.2.1.REMARKSFor each of the four confirmatory tests, procedures,interpretations, and concerns are described in Table 6.3.0. SUBTYPE CLASSIFICATION3.1. We recommend that all patients with PAundergo an adrenal computed tomography (CT) scanas the initial study in subtype testing and to excludelarge masses that may represent adrenocorticalcarcinoma (Figure 1). (1| )3.1.EVIDENCEThe findings on adrenal CT—normal-appearingadrenals, unilateral macroadenoma (>1 cm), minimalunilateral adrenal limb thickening, unilateralmicroadenomas (≤1 cm), or bilateral macro- or microadenomas(or a combination of the two)—are used inconjunction with AVS and, if needed, ancillary teststo guide treatment decisions in patients with PA.APA may be visualized as small hypodense nodules(usually 4 cm in diameter, but occasionallysmaller, and like most adrenocortical carcinomas havea suspicious imaging phenotype on CT (69).Adrenal CT has several limitations. Small APAs maybe interpreted incorrectly by the radiologist as “IHA”on the basis of CT findings of bilateral nodularity ornormal-appearing adrenals. Moreover, apparentadrenal microadenomas may actually represent areasof hyperplasia, and unilateral adrenalectomy would beinappropriate. In addition, nonfunctioning unilateraladrenal macroadenomas are not uncommon,especially in older patients (>40 years) (70) and areindistinguishable from APAs on CT. Unilateral UAHmay be visible on CT or the UAH adrenal may appearnormal on CT.In one study, CT contributed to lateralization in only59 of 111 patients with surgically proven APA; CTdetected fewer than 25% of the APAs that weresmaller than 1 cm in diameter (62). In another studyof 203 patients with PA who were evaluated with bothCT and AVS, CT was accurate in only 53% of patients(71). On the basis of CT findings, 42 patients (22%)would have been incorrectly excluded as candidates12

TABLE 6. Primary aldosteronism confirmatory testsConfirmatorytest Procedure Interpretation ConcernsOral sodiumloading testPatients should increase theirsodium intake to >200 mmol (~6g) per day for 3 days, verified by24-hour urine sodium content.Patients should receive adequateslow-release potassium chloridesupplementation to maintainplasma potassium in the normalrange. Urinary aldosterone ismeasured in the 24-hour urinecollection from the morning of day3 to the morning of day 4.PA is unlikely if urinaryaldosterone is lowerthan 10 mcg/24-hr(27.7 nmol/day) in theabsence of renal diseasewhere PA may co-existwith lower measuredurinary aldosteronelevels. Elevated urinaryaldosterone excretion(>12 mcg/24-hr[>33.3 nmol/d] at theMayo Clinic, >14 mcg/24-hr (38.8 nmol/d) atthe Cleveland Clinic)makes PA highly likely.This test should not be performed in patientswith severe uncontrolled hypertension, renalinsufficiency, cardiac insufficiency, cardiacarrhythmia, or severe hypokalemia. 24-hoururine collection may be inconvenient.Laboratory-specific poor performance of theradio-immunoassay for urinary aldosterone(aldosterone 18-oxo-glucuronide or acidlabilemetabolite) may blunt diagnosticaccuracy—a problem obviated by thecurrently available HPLC-tandem massspectrometry methodology (52). Aldosterone18-oxo-glucuronide is a renal metabolite, andits excretion may not rise in patients with renaldisease.Salineinfusion testPatients stay in the recumbentposition for at least 1 hour beforeand during the infusion of 2 litersof 0.9% saline i.v. over 4 hours,starting at 8:00–9.30 a.m. Bloodsamples for renin, aldosterone,cortisol, and plasma potassiumare drawn at time zero and after4 hours, with blood pressure andheart rate monitored throughoutthe test.Post-infusion plasmaaldosterone levels 10 ng/dLare a very probable signof PA. Values between 5and 10 ng/dL areindeterminate (57-60).This test should not be performed in patientswith severe uncontrolled hypertension, renalinsufficiency, cardiac insufficiency, cardiacarrhythmia, or severe hypokalemia.Fludrocortisonesuppression testCaptoprilchallenge testPatients receive 0.1 mg oralfludrocortisone every 6 hours for4 days, together with slow-releaseKCI supplements (every 6 hours atdoses sufficient to keep plasmaK+, measured 4 times a day, closeto 4.0 mmol/L), slow-release NaClsupplements (30 mmol three timesdaily with meals) and sufficientdietary salt to maintain a urinarysodium excretion rate of at least 3mmol/kg body weight. On day 4,plasma aldosterone and PRA aremeasured at 10 a.m. with thepatient in the seated posture, andplasma cortisol is measured at 7a.m. and 10 a.m.Patients receive 25–50 mg ofcaptopril orally after sitting orstanding for at least 1 hour. Bloodsamples are drawn formeasurement of PRA, plasmaaldosterone, and cortisol at timezero and at 1 or 2 hours afterchallenge, with the patientremaining seated during thisperiod.Upright plasmaaldosterone >6 ng/dL onday 4 at 10 a.m.confirms PA, providedPRA is 30%). Inpatients with PA itremains elevated andPRA remains suppressed.Differences may be seenbetween patients withAPA and those with IHA,in that some decrease ofaldosterone levels isoccasionally seen in IHA(23, 64–66).While some centers (10, 16) conduct this testin the outpatient setting (provided that patientsare able to attend frequently to monitor theirpotassium), in other centers several days ofhospitalization are customary.Most of the data available come from theBrisbane group (42, 43, 56, 61-63) who haveestablished, on the basis of a very large seriesof patients, a cut-off of a plasma aldosteroneconcentration of 6 ng/dL at 10 a.m. in anambulatory patient on day 4.Proponents of the FST argue that (1) it is themost sensitive for confirming PA, (2) it is a lessintrusive method of sodium loading than SITand therefore less likely to provoke non-renindependentalterations of aldosterone levels, (3)it allows for the potentially confounding effectsof potassium to be controlled, and for ACTH(via cortisol) to be monitored and detected,and (4) it is safe when performed byexperienced hands.There are reports of a substantial number offalse negative or equivocal results (67, 68).CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PA TIENTS WITH PRIMARY ALDOSTERONISM13

THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINESfor adrenalectomy, and 48 (25%) might have hadunnecessary or inappropriate surgery (71). In a recentstudy, AVS was performed in 41 patients with PA, andconcordance between CT and AVS was only 54%(72). Therefore, AVS is essential to direct appropriatetherapy in patients with PA who seek a potentialsurgical cure. CT is particularly useful, however,for detecting larger lesions (e.g., >2.5 cm) that maywarrant consideration for removal based on malignantpotential and also for localizing the right adrenal veinas it enters into the inferior vena cava, thus aidingcannulation of the vein during AVS (73, 74).3.1.REMARKSMagnetic resonance imaging (MRI) has no advantageover CT in subtype evaluation of primary aldosteronism,being more expensive and having lessspatial resolution than CT.3.2. We recommend that, when surgical treatment ispracticable and desired by the patient, the distinctionbetween unilateral and bilateral adrenal diseasebe made by AVS by an experienced radiologist(Figure 1). (1| )3.2.EVIDENCELateralization of the source of the excessivealdosterone secretion is critical to guide themanagement of PA. Distinguishing betweenunilateral and bilateral disease is important becauseunilateral adrenalectomy in patients with APA orunilateral adrenal hyperplasia (UAH) results innormalization of hypokalemia in all; hypertension isimproved in all and cured in 30% to 60% (46, 75, 76).In bilateral IHA and GRA, unilateral or bilateraladrenalectomy seldom corrects the hypertension(77–81), and medical therapy is the treatment ofchoice (82). Unilateral disease may be treatedmedically if the patient declines or is not a candidatefor surgery.Imaging cannot reliably visualize microadenomas ordistinguish incidentalomas from aldosteroneproducingadenomas with confidence (71), makingAVS the most accurate means of differentiatingunilateral from bilateral forms of PA. AVS isexpensive and invasive, and so it is highly desirable toavoid this test in patients who do not have PA (83).Since ARR testing can be associated with falsepositives, confirmatory testing should eliminate thepotential for patients with false positive ARR toundergo AVS.The sensitivity and specificity of AVS (95% and100%, respectively) for detecting unilateral aldosteroneexcess are superior to that of adrenal CT(78% and 75%, respectively) (62, 71, 72).Importantly, CT has the potential to be franklymisleading by demonstrating unilateral nodules inpatients with bilateral disease and thereby to lead toinappropriate surgery.AVS is the reference standard test to differentiateunilateral (APA or UAH) from bilateral disease(IHA) in patients with PA (62, 71). Although AVScan be a difficult procedure, especially in terms ofsuccessfully cannulating the right adrenal vein(which is smaller than the left and usually emptiesdirectly into the inferior vena cava rather than therenal vein), the success rate usually improves quicklyas the angiographer becomes more experienced.According to a review of 47 reports, the success ratefor cannulating the right adrenal vein in 384 patientswas 74% (82). With experience, the success rateincreased to 90%–96% (71, 73, 74, 84). The additionof rapid intraprocedural measurement of adrenal veincortisol concentrations has facilitated improvedaccuracy of catheter placement in AVS (85). Somecenters perform AVS in all patients who have thediagnosis of PA (62), and others advocate its selectiveuse (e.g., AVS may not be needed in patients youngerthan age 40 with solitary unilateral apparent adenomaon CT scan) (71, 86).At centers with experienced AVS radiologists, thecomplication rate is 2.5% or lower (71, 73). The riskof adrenal hemorrhage can be minimized byemploying a radiologist skilled in the technique, andby avoiding adrenal venography and limiting use ofcontrast to the smallest amounts necessary to assessthe catheter tip position (74).Where there is aclinical suspicion of a pro-coagulant disorder, the riskof thrombo-embolism may be reduced by performingtests for such conditions before the procedure and14

administering heparin after the procedure in patientsat risk.3.2.VALUESOur recommendation to pursue AVS in the subtypeevaluation of the patient with PA who is a candidatefor surgery places a high value on avoiding the risk ofan unnecessary unilateral adrenalectomy based onadrenal CT and a relatively low value on avoiding thepotential complications of AVS.3.2.REMARKSA radiologist experienced with and dedicated to AVSis needed to implement this recommendation.There are three protocols for AVS: a) unstimulatedsequential or simultaneous bilateral AVS, b)unstimulated sequential or simultaneous bilateralAVS followed by bolus cosyntropin-stimulatedsequential or simultaneous bilateral AVS, and c)continuous cosyntropin infusion with sequentialbilateral AVS. Simultaneous bilateral AVS is difficultto perform and is not used at most centers. Manygroups advocate the use of continuous cosyntropininfusion during AVS a) to minimize stress-inducedfluctuations in aldosterone secretion duringnonsimultaneous (sequential) AVS, b) to maximizethe gradient in cortisol from adrenal vein to inferiorvena cava and thus confirm successful sampling of theadrenal vein, and c) to maximize the secretion ofaldosterone from an APA (71, 81, 84, 87) and thusavoid the risk of sampling during a relativelyquiescent phase of aldosterone secretion.The criteria used to determine lateralization ofaldosterone hypersecretion depend on whether thesampling is done under cosyntropin administration.Dividing the right and left adrenal vein plasmaaldosterone concentrations (PACs) by theirrespective cortisol concentrations corrects fordilutional effects of the inferior phrenic vein flowinginto the left adrenal vein and, if suboptimallysampled, of IVC flow into the right adrenal vein.These are termed “cortisol-corrected aldosteroneratios.” With continuous cosyntropin administration,a cut-off of the cortisol-corrected aldosterone ratiofrom high-side to low-side more than 4:1 is used toindicate unilateral aldosterone excess (71); a ratio lessthan 3:1 is suggestive of bilateral aldosteronehypersecretion (71). With these cut-offs, AVS fordetecting unilateral aldosterone hypersecretion (APAor UAH) has a sensitivity of 95% and specificity of100% (71). Patients with lateralization ratiosbetween 3:1 and 4:1 may have either unilateral orbilateral disease, and the AVS results must beinterpreted in conjunction with the clinical setting,CT scan, and ancillary tests.Some investigators consider a cortisol-correctedaldosterone lateralization ratio (high to low side) ofmore than 2:1 in the absence of cosyntropin asconsistent with unilateral disease (83). Othergroups rely primarily on comparing the adrenalvein aldosterone-cortisol ratios to those in asimultaneously collected peripheral venous sample(62). When the aldosterone-cortisol ratio from anadrenal vein is significantly (usually at least 2.5 times)greater than that the peripheral vein (cubital fossa orIVC), and the aldosterone-cortisol ratio in thecontralateral adrenal vein is no higher thanperipheral (indicating contralateral suppression), theratio is considered to show lateralization, anindication that unilateral adrenalectomy should cureor improve the hypertension.Cosyntropin useIf cosyntropin infusion is not used, AVS should beperformed in the morning hours following overnightrecumbency. This approach avoids the confoundingeffects of changes in posture on aldosterone levels inpatients with angiotensin II-responsive varieties ofPA and takes advantage of the effect of high earlymorning endogenous ACTH levels on aldosteroneproduction in all subtypes of PA (74).If cosyntropin infusion is used, it may be continuousor bolus. For continuous cosyntropin, an infusion of50 µg of cosyntropin per hour is begun 30 minutesbefore adrenal vein catheterization and continuedthroughout the procedure (71, 81, 84). The boluscosyntropin technique involves AVS before and afterthe intravenous administration of 250 µg ofcosyntropin. However, some groups have suggestedthat when given as a bolus injection and when theCASE DETECTION, DIAGNOSIS, AND TREATMENT OF PA TIENTS WITH PRIMARY ALDOSTERONISM15

THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINESadrenal veins are sampled simultaneously,cosyntropin administration does not improve thediagnostic accuracy of AVS and that cosyntropin mayin fact increase secretion from the non-adenomatousgland to a greater degree than from the APA (88).CatheterizationThe adrenal veins are catheterized through thepercutaneous femoral vein approach, and the positionof the catheter tip is verified by gentle injection of asmall amount of nonionic contrast medium andradiographic documentation (73). Blood is obtainedfrom both adrenal veins and a peripheral vein, e.g.,cubital fossa or iliac vein, and labeled peripheral andassayed for aldosterone and cortisol concentrations. Tobe sure there is no cross-contamination, the“peripheral” sample should be obtained from a cubitalor iliac vein. The venous sample from the left sidetypically is obtained with the catheter tip at thejunction of the inferior phrenic and left adrenal vein.The right adrenal vein may be especially difficult tocatheterize because it is short and enters the IVC at anacute angle (84). The cortisol concentrations from theadrenal veins and peripheral vein are used to confirmsuccessful catheterization. The adrenal/peripheral veincortisol ratio is typically more than 10:1 with thecontinuous cosyntropin infusion protocol (71) andmore than 3:1 without the use of cosyntropin (43).Unsuccessful adrenal venous samplingWhen both adrenal veins are not successfullycatheterized, the clinician may (1) repeat AVS; (2)treat the patient with MR antagonsist; (3) considersurgery based the findings of other studies (e.g.,adrenal CT). Additional studies that may guide theclinician in this setting include posture stimulationtest and iodocholesterol scintigraphy.Posture stimulation test. In patients with unsuccessfulAVS and with a CT scan showing a unilateral adrenalmass, some experts use the posture stimulation test.This test, developed in the 1970s, was based on thefinding that the PAC in patients with APA showeddiurnal variation and was relatively unaffected bychanges in angiotensin II levels, whereas IHA wascharacterized by enhanced sensitivity to a smallchange in angiotensin II that occurred with standing(89). In a review of 16 published reports, the accuracyof the posture stimulation test was 85% in 246patients with surgically verified APA (82). The lackof accuracy is explained by the fact that some APAsare sensitive to angiotensin II and some patients withIHA have diurnal variation in aldosterone secretion(90). Thus, the posture stimulation test—particularlyif it shows lack of responsiveness (consistent withangiotensin II–unresponsive APA or familialhyperaldosteronism type I (FH-I), with the latterreadily confirmed or excluded by genetic testing)—may serve an ancillary role, for example, in thosepatients for whom AVS was unsuccessful and CTshows a unilateral adrenal mass (91, 92).Iodocholesterol scintigraphy. [131I]-19-iodocholesterolscintigraphy was first used in the early 1970s (93), andan improved agent, [6β-131I]iodomethyl-19-norcholesterol (NP-59), was introduced in 1977 (94).The NP-59 scan, performed with dexamethasonesuppression, had the putative advantage of correlatingfunction with anatomical abnormalities. However,the sensitivity of this test depends heavily on the sizeof the adenoma (95, 96). Because tracer uptake waspoor in adenomas smaller than 1.5 cm in diameter,this method often is not helpful in interpretingmicronodular findings obtained with high-resolutionCT (97) and rarely plays a role in subtype evaluation.Currently it is no longer used in most centers.18-Hydroxycorticosterone levels. 18-Hydroxycorticosterone(18-OHB) is formed by 18-hydroxylation ofcorticosterone. Patients with APA generally haverecumbent plasma 18-OHB levels greater than 100ng/dL at 8:00 a.m., whereas patients with IHA havelevels that are usually less than 100 ng/dL (98).However, this test lacks the accuracy needed to guidethe clinician in the subtype evaluation of PA (82).3.3. In patients with onset of confirmed PA earlierthan at 20 years of age and in those who have a familyhistory of PA or of strokes at young age, we suggestgenetic testing for GRA (Figure 1). (2| )16

3.3.EVIDENCETesting for familial forms of PA: FH-I [GRA]The FH-I syndrome is inherited in an autosomaldominant fashion and is responsible for fewer than1% of cases of PA (99). GRA presentation is highlyvariable, with some patients presenting with normalblood pressure and some characterized by aldosteroneexcess, suppressed PRA, and hypertension of earlyonset that is usually severe and refractory toconventional antihypertensive therapies.Some studies suggest a high pretest probability forGRA in children or young adults with severe orresistant hypertension and a positive family history ofearly onset hypertension and/or prematurehemorrhagic stroke (100, 101). In the study by Dluhyand colleagues (100), 50% of children under 18years of age with GRA had moderate or severehypertension (blood pressure >99th percentile for ageand sex) at diagnosis. Moreover, Litchfield et al.(101) reported in 376 patients from 27 geneticallyproven GRA pedigrees that 48% of all GRApedigrees and 18% of all GRA patients hadcerebrovascular complications, with the mean age atthe time of the initial event being 32 ± 11.3 years.Seventy percent of events were hemorrhagic strokeswith an overall case fatality rate of 61% (101). Thestudy design used in these reports does not allowestimation of the yield of new GRA patients that casedetection could have in such populations.Genetic testing by either Southern blot (102) or longpolymerase chain reaction (103) techniques issensitive and specific for GRA and obviates the needto measure the urinary levels of 18-oxocortisol and18-hydroxy-cortisol or to perform dexamethasonesuppression testing, both of which may be misleading(104). Genetic testing for GRA should be consideredfor PA patients with a family history of PA or ofstrokes at a young age (101, 105), or with an onset ata young age (e.g.,

THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES(76). Other factors have been reported to predictcure, but have only been evaluated by univariateanalysis or when the cut-off for blood pressureresolution was

contralateral gland) to assess whether the PA hasbeen cured from a biochemical perspective (123).4.2. In patients with PA due to bilateral adrenaldisease, we recommend medical treatment withan MR antagonist (1| ); we suggestspironolactone as the primary agent with eplerenoneas an alternative. (2| ) (Figure 1)4.2.EVIDENCEBilateral adrenal disease includes idiopathic adrenalhyperplasia, bilateral APA, and GRA. In 99 surgicallytreated patients with IHA reported in the literature,the hypertension cure rate was only 19% afterunilateral or bilateral adrenalectomy (77-81). Norandomized placebo-controlled trials have evaluatedthe relative efficacy of drugs in the treatment of PA.However, the pathophysiology of PA due to bilateraladrenal hyperplasia and longstanding clinicalexperience suggest several pharmacological targets.MR antagonistsMR antagonists appear to be effective at controllingblood pressure and to provide blood pressureindependenttarget organ protection.SpironolactoneFor more than 4 decades, the MR antagonistspironolactone has been the agent of choice in themedical treatment of PA. Several observationalstudies in patients with IHA (combined N=122) havereported a mean reduction in systolic blood pressureof 25% and diastolic blood pressure of 22% inresponse to spironolactone 50–400 mg per day for 1 to96 months (124-130). In a study of 28 hypertensivesubjects with an ARR >750 pmol/l (27 ng/dl) perng/mL per hour who failed to suppress their PAC aftersalt loading and without evidence of adenoma onadrenal CT scan, spironolactone therapy (25–50mg/day) reduced the need for antihypertensive drugsby -0.5 (from a mean of 2.3 to 1.8 drugs) drugs, as wellas reducing systolic blood pressure by -15 mm Hg(from a mean of 161 to 146 mm Hg) and diastolicblood pressure by -8 mm Hg (from a mean of 91 to 83mm Hg); 48% of subjects achieved a blood pressure

THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINESin patients with PA and is generally well tolerated,lacking the sex steroid-related side effects ofspironolactone, but without the beneficial effects onendothelial function (138, 139).Calcium channel blockers, ACE inhibitors, andangiotensin receptor blockers have been evaluated invery few patients with PA, and in general they areantihypertensive without a major effect on aldosteroneexcess. Supportive studies are small andmethodologically weak, and have not measuredpatient-important outcomes. Aldosterone synthaseinhibitors may play a role in the future.4.2.VALUESThis recommendation places a relatively higher valueon reduction of blood pressure normalization of serumpotassium concentrations and abrogation of thevascular, cardiac, and renal effects of aldosterone withthe minimum number of pharmacological agents, anda relatively lower value on side effects such asgynecomastia and erectile dysfunction in men andmenstrual irregularities in women. Eplerenone, givenits selectivity and despite its cost, is an alternative if theside effects of spironolactone prove difficult to tolerate.4.2.REMARKSThe starting dose for spironolactone should be 12.5 to25 mg daily in a single dose. The lowest effective doseshould be found by very gradually titrating upward ifnecessary to a maximum dose of 100 mg per day. Thestarting dose for eplerenone is 25 mg once or twicedaily. In patients with stage III chronic kidney disease(i.e., GFR

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Arch Surg 129:291–636. Kim HY, Kim SG, Lee KW, Seo JA, Kim NH, Choi KM,Baik SH, Choi DS 2005 Clinical study of adrenalincidentaloma in Korea. Korean J Intern Med 20:303–937. Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM,Ali A, Giovagnetti M, Opocher G, Angeli A 2000 Asurvey on adrenal incidentaloma in Italy. Study Group onAdrenal Tumors of the Italian Society of Endocrinology. JClin Endocrinol Metab 85:637–4438. Rossi GP, Sacchetto A, Visentin P, Canali C, GranieroGR, Palatini P, Pessina AC 1996 Changes in leftventricular anatomy and function in hypertension andprimary aldosteronism. Hypertension 27:1039–4539. Montori VM, Young WF, Jr. 2002 Use of plasmaaldosterone concentration-to-plasma renin activity ratio asa screening test for primary aldosteronism. A systematicreview of the literature. Endocrinol Metab Clin North Am31:619–32, xi40. Hiramatsu K, Yamada T, Yukimura Y, Komiya I,Ichikawa K, Ishihara M, Nagata H, Izumiyama T 1981 Ascreening test to identify aldosterone-producing adenomaby measuring plasma renin activity. Results in hypertensivepatients. Arch Intern Med 141:1589–9341. McKenna TJ, Sequeira SJ, Heffernan A, Chambers J,Cunningham S 1991 Diagnosis under random conditions ofall disorders of the renin-angiotensin-aldosterone axis,including primary hyperaldosteronism. J Clin EndocrinolMetab 73:952–742. Stowasser M, Gordon RD, Gunasekera TG, Cowley DC,Ward G, Archibald C, Smithers BM 2003 High rate ofdetection of primary aldosteronism, including surgicallytreatable forms, after ‘non-selective’ screening ofhypertensive patients. J Hypertens 21:2149–5743. Gordon RD 1995 Primary aldosteronism. J EndocrinolInvest 18:495–51144. Stowasser M, Gordon RD 2004 The aldosterone-reninratio for screening for primary aldosteronism. TheEndocrinologist 14:267–7645. Tanabe A, Naruse M, Takagi S, Tsuchiya K, Imaki T,Takano K 2003 Variability in the renin/aldosterone profileunder random and standardized sampling conditions inprimary aldosteronism. J Clin Endocrinol Metab88:2489–9446. Celen O, O’Brien MJ, Melby JC, Beazley RM 1996Factors influencing outcome of surgery for primaryaldosteronism. Arch Surg 131:646–5047. Streeten DH, Anderson GH, Jr., Wagner S 1990 Effect ofage on response of secondary hypertension to specifictreatment. Am J Hypertens 3:360–548. Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F,Chiandussi L, Veglio F 2002 Drug effects onaldosterone/plasma renin activity ratio in primaryaldosteronism. Hypertension 40:897–90249. Montori VM, Schwartz GL, Chapman AB, Boerwinkle E,Turner ST 2001 Validity of the aldosterone-renin ratioused to screen for primary aldosteronism. Mayo Clin Proc76:877–8250. Sealey JE, Laragh JH 1975 Radioimmunoassay of plasmarenin activity. Semin Nucl Med 5:189–20251. Schirpenbach C, Seiler L, Maser-Gluth C, Beuschlein F,Reincke M, Bidlingmaier M 2006 Automatedchemiluminescence-immunoassay for aldosterone duringdynamic testing: comparison to radioimmunoassays withand without extraction steps. Clin Chem 52:1749–5552. Guo T, Taylor RL, Singh RJ, Soldin SJ 2006Simultaneous determination of 12 steroids by isotopedilution liquid chromatography-photospray ionizationtandem mass spectrometry. Clin Chim Acta 372:76–8253. Tiu SC, Choi CH, Shek CC, Ng YW, Chan FK, Ng CM,Kong AP 2005 The use of aldosterone-renin ratio as adiagnostic test for primary hyperaldosteronism and its testcharacteristics under different conditions of bloodsampling. J Clin Endocrinol Metab 90:72–822

54. Young WF, Jr. 1997 Primary aldosteronism: update ondiagnosis and treatment. The Endocrinologist 7:213–2155. Young WF 2007 Primary aldosteronism: renaissance of asyndrome. Clin Endocrinol (Oxf) 66:607–1856. Stowasser M, Gordon RD 2004 Primary aldosteronism—careful investigation is essential and rewarding. Mol CellEndocrinol 217:33–957. Giacchetti G, Ronconi V, Lucarelli G, Boscaro M,Mantero F 2006 Analysis of screening and confirmatorytests in the diagnosis of primary aldosteronism: need for astandardized protocol. J Hypertens 24:737–4558. Rossi GP, Belfiore A, Bernini G, Desideri G, Fabris B,Ferri C, Giacchetti G, Letizia C, Maccario M, MallamaciF, Mannelli M, Montemurro D, Palumbo G, Rizzoni D,Rossi E, Semplicini A, Agabiti-Rosei E, Pessina AC,Mantero F 2007 Prospective evaluation of the salineinfusion test for excluding primary aldosteronism due toaldosterone-producing adenoma. J Hypertens 25:1433–4259. Holland OB, Brown H, Kuhnert L, Fairchild C, Risk M,Gomez-Sanchez CE 1984 Further evaluation of salineinfusion for the diagnosis of primary aldosteronism.Hypertension 6:717–2360. Kem DC, Weinberger MH, Mayes DM, Nugent CA 1971Saline suppression of plasma aldosterone in hypertension.Arch Intern Med 128:380–661. Gordon RD 1994 Mineralocorticoid hypertension. Lancet344:240–362. Gordon RD 2001 Diagnostic investigations in primaryaldosteronism. In: Zanchetti A (ed) Clinical medicineseries on hypertension. McGraw-Hill International,Maidenhead, UK; pp 101–11163. Gordon RD, Stowasser M, Klemm SA, Tunny TJ 1994Primary aldosteronism and other forms of mineralocorticoidhypertension. In: Swales J (ed) Textbook of hypertension.Blackwell Scientific, London; pp 865–89264. Agharazii M, Douville P, Grose JH, Lebel M 2001Captopril suppression versus salt loading in confirmingprimary aldosteronism. Hypertension 37:1440–365. 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Ann Intern Med 90:386–9582. Young WF, Jr., Klee GG 1988 Primary aldosteronism.Diagnostic evaluation. Endocrinol Metab Clin North Am17:367–9583. Rossi GP, Sacchetto A, Chiesura-Corona M, De Toni R,Gallina M, Feltrin GP, Pessina AC 2001 Identification ofthe etiology of primary aldosteronism with adrenal veinsampling in patients with equivocal computed tomographyand magnetic resonance findings: results in 104 consecutivecases. J Clin Endocrinol Metab 86:1083–9084. Doppman JL, Gill JR, Jr. 1996 Hyperaldosteronism:sampling the adrenal veins. Radiology 198:309–1285. Mengozzi G, Rossato D, Bertello C, Garrone C, Milan A,Pagni R, Veglio F, Mulatero P 2007 Rapid cortisol assayduring adrenal vein sampling in patients with primaryaldosteronism. Clin Chem 53:1968–71CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PA TIENTS WITH PRIMARY ALDOSTERONISM23

THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES86. Tan YY, Ogilvie JB, Triponez F, Caron NR, Kebebew EK,Clark OH, Duh QY 2006 Selective use of adrenal venoussampling in the lateralization of aldosterone-producingadenomas. World J Surg 30:879–8587. Carr CE, Cope C, Cohen DL, Fraker DL, Trerotola SO2004 Comparison of sequential versus simultaneousmethods of adrenal venous sampling. J Vasc Interv Radiol15:1245–5088. Rossi GP, Ganzaroli C, Miotto D, De Toni R, PalumboG, Feltrin GP, Mantero F, Pessina AC 2006 Dynamictesting with high-dose adrenocorticotrophic hormone doesnot improve lateralization of aldosterone oversecretion inprimary aldosteronism patients. J Hypertens 24:371–989. Ganguly A, Dowdy AJ, Luetscher JA, Melada GA 1973Anomalous postural response of plasma aldosteroneconcentration in patients with aldosterone-producingadrenal adenoma. J Clin Endocrinol Metab 36:401–490. 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Sarkar SD, Cohen EL, Beierwaltes WH, Ice RD, CooperR, Gold EN 1977 A new and superior adrenal imagingagent, 131I-6beta-iodomethyl-19-nor-cholesterol (NP-59):evaluation in humans. J Clin Endocrinol Metab 45:353–6295. Hogan MJ, McRae J, Schambelan M, Biglieri EG 1976Location of aldosterone-producing adenomas with 131I-19-iodocholesterol. N Engl J Med 294:410–496. Nomura K, Kusakabe K, Maki M, Ito Y, Aiba M, DemuraH 1990 Iodomethylnorcholesterol uptake in analdosteronoma shown by dexamethasone-suppressionscintigraphy: relationship to adenoma size and functionalactivity. J Clin Endocrinol Metab 71:825–3097. Mansoor GA, Malchoff CD, Arici MH, Karimeddini MK,Whalen GF 2002 Unilateral adrenal hyperplasia causingprimary aldosteronism: limitations of I-131 norcholesterolscanning. Am J Hypertens 15:459–6498. Biglieri EG, Schambelan M 1979 The significance ofelevated levels of plasma 18-hydroxycorticosterone inpatients with primary aldosteronism. J Clin EndocrinolMetab 49:87–9199. McMahon GT, Dluhy RG 2004 Glucocorticoidremediablealdosteronism. Cardiol Rev 12:44–8100. Dluhy RG, Anderson B, Harlin B, Ingelfinger J, Lifton R2001 Glucocorticoid-remediable aldosteronism is associatedwith severe hypertension in early childhood. J Pediatr138:715–20101. Litchfield WR, Anderson BF, Weiss RJ, Lifton RP,Dluhy RG 1998 Intracranial aneurysm and hemorrhagicstroke in glucocorticoid-remediable aldosteronism.Hypertension 31:445–50102. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S,Ulick S, Lalouel JM 1992 A chimaeric 11 betahydroxylase/aldosteronesynthase gene causesglucocorticoid-remediable aldosteronism and humanhypertension. Nature 355:262–5103. Jonsson JR, Klemm SA, Tunny TJ, Stowasser M, GordonRD 1995 A new genetic test for familialhyperaldosteronism type I aids in the detection of curablehypertension. Biochem Biophys Res Commun 207:565–71104. Fardella CE, Pinto M, Mosso L, Gomez-Sanchez C, JalilJ, Montero J 2001 Genetic study of patients withdexamethasone-suppressible aldosteronism without thechimeric CYP11B1/CYP11B2 gene. J Clin EndocrinolMetab 86:4805–7105. Gates LJ, Benjamin N, Haites NE, MacConnachie AA,McLay JS 2001 Is random screening of value in detectingglucocorticoid-remediable aldosteronism within ahypertensive population? J Hum Hypertens 15:173–6106. So A, Duffy DL, Gordon RD, Jeske YW, Lin-Su K, NewMI, Stowasser M 2005 Familial hyperaldosteronism type IIis linked to the chromosome 7p22 region but also showspredicted heterogeneity. J Hypertens 23:1477–84107. Gordon RD, Stowasser M, Tunny TJ, Klemm SA, FinnWL, Krek AL 1991 Clinical and pathological diversity ofprimary aldosteronism, including a new familial variety.Clin Exp Pharmacol Physiol 18:283–6108. Stowasser M, Gordon RD 2003 Primary aldosteronism:from genesis to genetics. Trends Endocrinol Metab14:310–7109. Lafferty AR, Torpy DJ, Stowasser M, Taymans SE, LinJP, Huggard P, Gordon RD, Stratakis CA 2000 A novelgenetic locus for low renin hypertension: familialhyperaldosteronism type II maps to chromosome 7 (7p22).J Med Genet 37:831–5110. Blumenfeld JD, Sealey JE, Schlussel Y, Vaughan ED, Jr.,Sos TA, Atlas SA, Muller FB, Acevedo R, Ulick S,Laragh JH 1994 Diagnosis and treatment of primaryhyperaldosteronism. Ann Intern Med 121:877–85111. Harris DA, Au-Yong I, Basnyat PS, Sadler GP, WheelerMH 2003 Review of surgical management of aldosteronesecreting tumours of the adrenal cortex. Eur J Surg Oncol29:467–74112. Rossi H, Kim A, Prinz RA 2002 Primaryhyperaldosteronism in the era of laparoscopicadrenalectomy. Am Surg 68:253–6; discussion 256–7113. Stowasser M, Klemm SA, Tunny TJ, Storie WJ,Rutherford JC, Gordon RD 1994 Response to unilateraladrenalectomy for aldosterone-producing adenoma: effect24

of potassium levels and angiotensin responsiveness. ClinExp Pharmacol Physiol 21:319–22114. Young WF, Jr. 2003 Minireview: primary aldosteronism--changing concepts in diagnosis and treatment.Endocrinology 144:2208–13115. Lo CY, Tam PC, Kung AW, Lam KS, Wong J 1996Primary aldosteronism. Results of surgical treatment. AnnSurg 224:125–30116. Proye CA, Mulliez EA, Carnaille BM, Lecomte-HouckeM, Decoulx M, Wemeau JL, Lefebvre J, Racadot A, ErnstO, Huglo D, Carre A 1998 Essential hypertension: firstreason for persistent hypertension after unilateraladrenalectomy for primary aldosteronism? Surgery124:1128–33117. Jacobsen NE, Campbell JB, Hobart MG 2003Laparoscopic versus open adrenalectomy for surgicaladrenal disease. Can J Urol 10:1995–9118. Rutherford JC, Stowasser M, Tunny TJ, Klemm SA,Gordon RD 1996 Laparoscopic adrenalectomy. World JSurg 20:758–60; discussion 761119. Ishidoya S, Ito A, Sakai K, Satoh M, Chiba Y, Sato F,Arai Y 2005 Laparoscopic partial versus totaladrenalectomy for aldosterone producing adenoma. J Urol174:40–3120. Ghose RP, Hall PM, Bravo EL 1999 Medical managementof aldosterone-producing adenomas. Ann Intern Med131:105–8121. Sywak M, Pasieka JL 2002 Long-term follow-up and costbenefit of adrenalectomy in patients with primaryhyperaldosteronism. Br J Surg 89:1587–93122. Mattsson C, Young WF, Jr. 2006 Primary aldosteronism:diagnostic and treatment strategies. Nat Clin Pract Nephrol2:198–208123. Rutherford JC, Taylor WL, Stowasser M, Gordon RD1998 Success of surgery for primary aldosteronism judged byresidual autonomous aldosterone production. World J Surg22:1243–5124. Brown JJ, Davies DL, Ferriss JB, Fraser R, Haywood E,Lever AF, Robertson JI 1972 Comparison of surgery andprolonged spironolactone therapy in patients withhypertension, aldosterone excess, and low plasma renin. BrMed J 2:729–34125. 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AcknowledgmentsIn addition to the members of the Task Force, there have been a number of people whose contribution to theseguidelines has been invaluable. First, we would like to thank Dr. Robert Vigersky, the members of the ClinicalGuidelines Subcommittee, the Clinical Affairs Core Committee, and the Council of The Endocrine Society fortheir careful reading of and very useful suggestions for improving the guidelines. Second, we thank the membersof The Endocrine Society at large for their input when the draft guidelines were posted on the Society’s website;all the responses received were considered by the authors, and many incorporated. Third, we thank the membersof our sister societies around the world for their enthusiastic involvement in reading the draft guidelines, and inoffering their support for this publication. Fourth, we thank Lisa Marlow of The Endocrine Society, who hasprovided first-class administrative and logistic back-up, without which such a geographically disperse task forcewould have faced considerable difficulty in operating. Last, but very much not least, the authors are indebted toDr. Patricia A. Stephens, medical writer, for her unfailing patience, her meticulous checking of both text andreferences, and most importantly her ability to meld half a dozen disparate writing styles into a seamless whole.Financial Disclosure of Task ForceTHE ENDOCRINE SOCIETY’S CLINICAL GUIDELINESJohn W. Funder, MD, PhD (chair)—Financial or Business/Organizational Interests: Schering-Plough, Daiichi-Sankyo, Pfizer, Cancer Institute of N.S.W, Speedel, Garnett Passe and Rodney Williams Memorial Foundation,Merck, Eli Lilly, P3 Panel (Commonwealth of Australia); Significant Financial Interest or Leadership Position:Schering-Plough, Pfizer, Daiichi-Sankyo and Cancer Institute of N.S.W. Robert M. Carey, MD—Financial orBusiness/Organizational Interests: Novartis, Pfizer, Daiichi-Sankyo; Significant Financial Interest or LeadershipPosition: none declared. Carlos Fardella, MD—Financial or Business/Organizational Interests: National Fund forScientific and Technological Development (Fondo Nacional de Desarrollo Científico y Tecnológico[FONDECYT]); Significant Financial Interest or Leadership Position: none declared. Celso E. Gomez-Sanchez,MD—Financial or Business/Organizational Interests: American Heart Association; Significant Financial Interestor Leadership Position: Associate Editor for the journal Hypertension. Franco Mantero, MD, PhD—Financial orBusiness/Organizational Interests: none declared; Significant Financial Interest or Leadership Position: ExecutiveCommittee of the International Society of Endocrinology. Michael Stowasser, MBBS, FRACP, PhD—Financialor Business/Organizational Interests: none declared; Significant Financial Interest or Leadership Position: nonedeclared. William F. Young Jr., MSc, MD—Financial or Business/Organizational Interests: none declared;Significant Financial Interest or Leadership Position: Mayo Clinic, Clinical Endocrinology. *Victor M. Montori,MD—Financial or Business/Organizational Interests: KER Unit (Mayo Clinic); Significant Financial Interest orLeadership Position: none declared.*Evidence-based reviews for this guideline were prepared under contract with The Endocrine Society.26

THE ENDOCRINE SOCIETYGUIDELINE ORDER FORM(Single reprint request for orders of 100 and less)8401 Connecticut Avenue, Suite 900Chevy Chase, MD 20815-5817Phone 301.941.0210; Fax 301.941.0257societyservices@endo-society.orgFEIN 73-0521256PRODUCTS QTY. PRICE (USD) SUBTOTALMemberNon-MemberAndrogen Therapy in Women: $15.00 $20.00An Endocrine Society Clinical Practice GuidelineCase Detection, Diagnosis, and Treatment of Patients with Primary $15.00 $20.00Aldosteronism: An Endocrine Society Clinical Practice GuidelineThe Diagnosis of Cushing’s Syndrome: $15.00 $20.00An Endocrine Society Clinical Practice GuidelineEvaluation & Treatment of Adult Growth Hormone Deficiency: $15.00 $20.00An Endocrine Society Clinical Practice GuidelineEvaluation & Treatment of Hirsutism in Premenopausal Women: $15.00 $20.00An Endocrine Society Clinical Practice GuidelineManagement of Thyroid Dysfunction during Pregnancy and Executive Summary Executive SummaryPostpartum: An Endocrine Society Clinical Practice Guideline (MMTD07)—$10.00 (MMTD07)—$15.00Guideline (MTSD07)— Guideline (MTSD07)—$10.00 $15.00Testosterone Therapy in Adult Men with Androgen Deficiency $15.00 $20.00Syndromes: An Endocrine Society Clinical Practice GuidelineMiscellaneousTOTAL All prices include sales tax $PAYMENT INFORMATION: ❍ Check ❍ MasterCard ❍ VisaCard NumberExpiration DateBilling AddressSignatureAre you a member of The Endocrine Society? ❍ Yes ❍ NoIf you are a member and you know your member ID, please provide: ___________________________________________________________Prefix: First Name (Given): Middle: Last (Surname):Institution/Company:Dept/Div:Street/PO:City: State/Province: Zip/Mail Code: Country:Telephone: Fax: Email:Degree(s) that you would like listed after your name: Professional Title: Date of Birth: Gender:❍ Male❍ FemaleWhich of the following best describes your primary professional role?Race or Ethnic Affiliation (voluntary)(Please mark only one)❍ African American, Black❍ Administrator ❍ Retired ❍ Asian❍ Basic Researcher ❍ Teacher/Educator ❍ Hispanic❍ Clinical Practitioner ❍ Fellow (Clinical) ❍ Native American, Eskimo, Aleut❍ Clinical Researcher ❍ Fellow (Postdoctoral/Research) ❍ Pacific Islander❍ Industry/Corporate Professional ❍ Student ❍ White, Caucasian❍ Nurse/Healthcare Professional ❍ Other___________________________________ ❍ Other___________________________________

What goes into ourClinical Guidelinesis a story worth tellingThe extensive process that goes into creating The EndocrineSociety’s Clinical Guidelines not only provides validation andassurance, but also raises the standard for the development ofguidelines everywhere.The guidelines are developed using a multi-step process that reflectsthe standards of excellence embraced by The Endocrine Society.Endocrine Society Clinical Guidelines Now Available:Evaluation and Treatment ofAdult Growth Hormone DeficiencyTestosterone Therapy in Adult Men withAndrogen Deficiency SyndromesAndrogen Therapy in WomenManagement of Thyroid Dysfunction duringPregnancy and PostpartumEvaluation and Treatment of Hirsutism inPremenopausal WomenThe Diagnosis of Cushing’s SyndromeCase Detection, Diagnosis, and Treatment of Patientswith Primary AldosteronismEndocrine Society Clinical GuidelinesComing Soon:• Primary Prevention of CardiovascularDisease and Type 2 Diabetes in Patientsat Metabolic Risk• Prevention and Treatment of PediatricObesity• Evaluation and Management of AdultHypoglycemic Disorders• Endocrine Treatment of Adolescent & AdultTranssexuals• Vitamin D & Bone• Managing Patients Post-Bariatric Surgery• Continuous Glucose Monitoring• Congenital Adrenal Hyperplasia• Lipids (with an endocrine focus)• Pituitary IncidentalomaTo purchase the available guidelines visit:www.endo-society.org/guidelines/Current-Clinical-Practice-Guidelines.cfm.To view patient guides (companion pieces to the clinical guidelines), visitThe Hormone Foundation’s Web site at www.hormone.org/public/patientguides.cfm.

Commercial Reprint InformationFor information on reprint requests of more than 101 and commercial reprints contact:Heather EdwardsReprint Sales SpecialistCadmus Professional CommunicationsPhone: 410.691.6214Fax: 410.684.2789Email: endoreprints@cadmus.comSingle Reprint InformationFor information on reprints of 100 and fewer, complete the guideline order form and return using one of thefollowing methods:Mail:The Endocrine Societyc/o Bank of AmericaP.O. Box 630721Baltimore, MD 21263-0736Fax: 301.941.0257Email: Societyservices@endo-society.orgQuestions & CorrespondencesThe Endocrine SocietyAttn: Government & Public Affairs Department8401 Connecticut Avenue, Suite 900Chevy Chase, MD 20815Phone: 301.941.0200Email: govt-prof@endo-society.orgWeb: www.endo-society.orgFor more information on The Endocrine Society’s Clinical Practice Guidelines or to download the completeversion of this guideline, visit http://www.endo-society.org/guidelines/index.cfm.PPA08

The Endocrine Society8401 Connecticut Avenue, Suite 900Chevy Chase, MD 20815301.941.0200www.endo-society.org