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Clinical and Laboratory Assessment of Patients withSuspected Primary Aldosteronism
  JOHTN
SPECIAL SITUATIONS
Clinical and Laboratory Assessment of Patients with
Suspected Primary Aldosteronism
Richard J Auchus
Professor
Division of Metabolism, Endocrinology, and DiabetesDepartments of Pharmacology and Internal Medicine, Universityof Michigan, School of Medicine, Ann Arbor, Michigan, USA
Corresponding Author: Richard J Auchus, Professor, Divisionof Metabolism, Endocrinology, and Diabetes, Departments ofPharmacology and Internal Medicine, University of MichiganSchool of Medicine, Ann Arbor, Michigan, USA
Phone: +8645222261
e-mail: rauchus@med.umich.edu
 
ABSTRACT
Primary aldosteronism (PA) was described over 60 years ago,but the relevance of PA to the burden of hypertension has neverbeen greater. Best estimates from studies in a variety of settingsindicate that PA is present in 5 to 8% of all patients withhypertension and up to 20% of patients with resistant hypertension.Progress in our understanding of the pathogenesis of PAhelps to explain how PA can be so common and the genesisof bilateral hyperaldosteronism (BHA). Pitfalls in the evaluationof PA certainly exist, but these difficulties with the later stages ofthe evaluation should not impede liberal screening in groups ofpatients with a high prevalence of PA. In fact, the initial stagesof the evaluation are utterly simple, and screening can makean enormous impact on the care of these patients. This articlewill provide a practical review of the approach to the patientsuspected of having PA, which is by far the most common causeof secondary hypertension.
Keywords: Adrenal adenoma, Adrenal hyperplasia, Aldosterone,Hypertension, Hypokalemia, Ion channel, Primaryaldosteronism, Renin.
How to cite this article: Auchus RJ. Clinical and LaboratoryAssessment of Patients with Suspected Primary Aldosteronism.Hypertens J 2017;3(3):131-138.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

Throughout human history, the ability to conservesodium and thus to maintain plasma volume has beencritical for survival. Several defense mechanisms exist todefend against volume depletion from hemorrhage, environmentalstress, and sepsis. Both neural and humoralmechanisms cooperate to conserve sodium when necessary.On the contrary, we are not well designed to excreteexcess sodium, particularly if heart or kidney functionis impaired. This bias for sodium conservation helps toexplain the high prevalence of hypertension in developed countries with diets high in sodium. Furthermore, evenmild derangements in sodium conservation mechanismscan exacerbate the tendency for hypertension underconditions of sodium surfeit. One such mechanism is thegroup of conditions included under the diagnosis of PA.
 
SODIUM HOMEOSTASIS AND ALDOSTERONE

Central to the sodium conservation mechanisms is therenin-angiotensin (Ang)-aldosterone system. Reducedsodium delivery to the renal macula densa stimulates reninsynthesis, and renin cleaves angiotensinogen to AngI. Theconverting enzyme generates AngII from AngI, and AngIIboth acts as a vasoconstrictor and stimulates aldosteronesynthesis from the adrenal zona glomerulosa. Aldosteroneacts directly on the principal cells of the distal nephron toenhance resorption of the last 2% of filtered sodium. Whilethis small fraction might not seem like much, it is this lastbit of sodium that is critical for blood pressure regulation.Furthermore, aldosterone has direct actions on the brainto stimulate sympathetic nerve activity,1 and thus exertspressor activity via a second mechanism.2

For these reasons, the "normal range" of serumaldosterone must be defined in terms of volume statusand sodium intake, reflecting the dynamic nature ofaldosterone production to meet the need for sodiumconservation. In healthy individuals, plasma renin activity(PRA; alternatively, renin concentration) inverselyreflects plasma volume and sodium homeostasis; consequently,PRA and aldosterone normally rise and fall inparallel. The only other strong stimulus for aldosteroneproduction is hyperkalemia, and adrenocorticotropinelicits a moderate but transient rise in aldosterone. Ina salt-loaded society, most individuals have low PRAand therefore produce little aldosterone, with circulatingconcentrations < 4 ng/dL (< 0.1 nmol/L), among thelowest concentrations of any active steroid hormone inthe body. Unfortunately, this system leaves little roomfor error. Aldosterone is < 50% protein bound and thusmostly bioactive, and aldosterone has an affinity of ∼1nmol/L for the mineralocorticoid receptor (MR). Therefore,even mild aldosterone excess has the potential todrive MR activation, sodium retention, and hypertension.In turn, autonomous aldosterone excess will lower PRAvia volume expansion, and low PRA is a hallmark of allmineralocorticoid excess syndromes.

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APPROACH TO THE PATIENT WITH
SUSPECTED PA


While the exact prevalence of PA in the hypertensivepopulation is debated, in part due to subtleties in definingPA, the prevalence is at least 5% and up to four timeshigher among those with resistant hypertension. Thejoint American College of Cardiology/American HeartAssociation hypertension guidelines3 list major criteriafor PA screening (Table 1). The Endocrine Society clinicalpractice guidelines add additional criteria,4 and theJapanese Society of Hypertension recommends screeningall patients with hypertension for PA.5 While the exactindications are debated, the concept is that patients withdifficult-to-control hypertension, early-onset hypertension,and hypertension with excessive potassium wastingare prime suspects for PA. In addition, the prevalence ofatrial fibrillation and congestive heart failure is muchhigher in patients with PA than in other forms of hypertension,6 which should also raise suspicion. Because PA isby far the most common cause of secondary hypertension,any hypertensive patient with a clinical course suggestiveof secondary hypertension should be screened for PA.

There are several reasons to screen patients withhypertension for PA. First, if the diagnosis is establishedand the patient has an aldosterone-producing adenoma(APA), localization and surgery can either cure the hypertensionor significantly improve blood pressure controloften with less medications. This objective assumesthat screening will be followed with the specializedsubsequent evaluation steps necessary to assure propermanagement. Second, making a diagnosis of PA thenshould remain in the patient's medical record to remindsubsequent providers that, if surgery is not an option,the patient should receive MR antagonist therapy at aminimum.

Contrary to widely held misconceptions, screeningfor PA is simple and can be performed in patients takingany hypertensive medications, as long as the principlesof screening are well understood. Primary aldosteronismscreening involves simultaneous measurement of PRA and serum aldosterone in a simple blood test, and it isbest to obtain a serum potassium as well. Based on thepreceding discussion, renin and aldosterone normallyrise and fall in parallel. Fundamentally, screening asksif aldosterone production persists when renin is low.For convenience, this assessment traditionally employsthe calculation of the aldosterone/renin ratio (ARR =aldosterone in ng/dL divided by PRA in ng/mL/h). Innormotensive individuals, the ARR is typically 2 to 7using these units.7 Rather than using a strict single ARRcut-off value to diagnose PA, the screening results shouldbe viewed as a continuum reflecting probability of thediagnosis. Furthermore, the individual values should beassessed systematically as described below.8

Table 1: Indications for PA screening
Clinical and Laboratory Assessment of Patients withSuspected Primary Aldosteronism
 
Plasma Renin Activity

Is it low (< 1), medium (1-5), or high (>5)? If the PRAis low, the screen can be interpreted, regardless of anymedications the patient might be taking. If the PRA ismedium, PA cannot be diagnosed, but if the patient istaking blood pressure medications, the result can bea false-negative. Most blood pressure medications areeither vasodilators or diuretics, which will tend to raisePRA and thus can obscure a low PRA in the absenceof these medications-particularly MR antagonists.While official recommendations are to wait up to6 weeks after stopping MR antagonists to screen for PA,most patients with PA will still have low PRA despitetypical doses of MR antagonists or require only 1 to2 weeks for the PRA to fall. Patients with PA rarely havehigh PRA despite any medications in the absence ofother concomitant illness. Beta-blockers tend to lowerPRA but lower aldosterone proportionately do not interferewith PA screening. Finally, many laboratories areconverting from PRA to renin mass or "direct renin"immunoassays. As a rule of thumb, the direct reninvalues in pg/mL are a factor of 10 higher than PRA inng/mL/h,7 and < 10 pg/mL should be considered lowand consistent with PA.

Serum Aldosterone

If a normal serum aldosterone in a patient with low PRAis < 4 ng/dL, how much is too much? One should considerthe answer as a continuum from low-renin hypertensionto overt PA with intermediate results likely reflectingPA in evolution. As with all hormone excess syndromes,patients often progress through an early, mild, or "subclinical"stage before developing overt disease.9 With alow PRA, aldosterone values >20 ng/dL are essentiallydiagnostic, values 10 to 20 ng/dL are likely PA but requirefurther evaluation, and values 5 to 10 ng/dL are notstrictly normal but generally not high enough to pursue the workup further, because these patients might haveearly PA in evolution but not likely to have an APA withdominant aldosterone production from one adrenalgland. As will be discussed below, all other should betreated with MR antagonists if the blood pressure is notcontrolled in the absence of contraindications.
 
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Serum Potassium

Low potassium inhibits and high potassium stimulatesaldosterone production. An aldosterone >10 ng/dL inthe face of hypokalemia is almost certainly indicativeof aldosterone excess, because the aldosterone wouldbe higher if the potassium was normal. Conversely,hyperkalemia can raise aldosterone and cause a rarefalse-positive screen, but hyperkalemic patients are notusually evaluated for PA.

Aldosterone/Renin Ratio

Whereas a normal ARR is 2 to 7, we typically use acut-off of 20 for a positive screen, which is three timeshigher than normal. An important caveat is that as PRAfalls, the values approach zero, and since PRA is thedenominator of the ARR, the ARR approaches infinity.10In other words, if a PRA of 0.1 is used to calculate theARR, then patients with serum aldosterone as low as2 ng/dL would have an ARR >20-but they do nothave PA since the aldosterone is suppressed. Thus, PRAvalues not lower than 0.5 ng/mL/h should be used forcalculating the ARR, even if the laboratory reports thevalues lower.8

To summarize PA screening, medications can causefalse-negatives by raising the PRA, and for patients inwhom the index of suspicion for PA is high, removal ofmedications and rescreening is appropriate. The cluewill be that these patients still have a high ARR andvery high aldosterone (>20 ng/dL). Few false-positivesare encountered when screening for PA, primarilyhyperkalemia and the use of values PRA < 0.5 for calculatingARR. Thus, one should be more concerned aboutfalse-negatives than false-positives when screening forPA (Table 2).

Table 2: Pitfalls of screening
Clinical and Laboratory Assessment of Patients withSuspected Primary Aldosteronism
 
CONFIRMATORY TESTING AND
SUBTYPING STEPS


In a patient with hypokalemia, suppressed PRA, andserum aldosterone >20 ng/dL, a diagnosis of PA is madefrom screening alone.4 In patients without hypokalemiaand/or a serum aldosterone 10 to 20 ng/dL, confirmatorytesting is required to establish the diagnosis. Table 3lists common confirmatory tests and cut-off values todiagnose PA. In particular, the criterion of serum aldosterone>6 ng/dL for the fludrocortisone suppressiontest emphasizes what a fine line exists between normalaldosterone dynamics and PA. Whereas all providers whocare for patients with hypertension should screen for PA,confirmatory testing and later stages of the evaluation areusually performed after referral to an endocrinologist orhypertension specialist with experience in conductingand interpreting these tests.

Conceptually, PA has been dichotomized into unilateralPA (due to an APA) and BHA. This dichotomyis a slight oversimplification for two reasons. First, notall patients with unilateral PA have a single adenoma.Some have no identifiable neoplasm, and other mighthave more than one adenoma, though often one of theseaccounts for most of the aldosterone production, basedon staining for the aldosterone synthase (CYP11B2)enzyme.11 Conversely, patients with BHA were assumedto have hyperplasia of the zona glomerulosa, but in factthey might have different pathologies discussed below.Second, cases with an APA and unilateral dominance butsignificant aldosterone production from the nondominantadrenal are being increasingly recognized. Nevertheless,the evaluation subsequent to confirmatory testingendeavors to determine as completely as possible thesubtype of disease causing the PA and the contributionof each adrenal gland to the aldosterone production.

In general, a computed tomography (CT) scan withand without contrast of the adrenal glands is the imagingprocedure of choice for PA.4 A third set of images isalso obtained to measure contrast washout. Computedtomography has higher resolution than magnetic resonanceimaging and so can detect small tumors < 1 cm capable of causing PA; however, incidental nonfunctionaladrenal tumors are increasingly common with age andcannot be distinguished from APA by imaging criteriaalone. The major purpose of CT scanning is to screen forabnormal adrenal anatomy and to assess for large tumors.Adrenocortical carcinomas rarely cause PA but are easilyidentified as large heterogeneous masses on CT scan.More importantly, APAs often cosecrete cortisol,12 andin tumors >3 cm, this mixed hormone production caninterfere with subsequent testing.13 Unlike aldosteroneproduction in APAs, which correlates poorly with tumorsize, cortisol production generally tracts with tumorsize. Thus, a dexamethasone suppression test is oftenemployed in the evaluation of PA to screen for cortisolcosecretion, particularly in patients with a >2.5 cm tumoridentified on CT scan.

Table 3: Confirmatory testing options
Clinical and Laboratory Assessment of Patients withSuspected Primary Aldosteronism

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In a < 40-year-old patient with hypokalemia, an agerange in which adrenal adenomas are not common, a >1 cmadenoma with a clearly normal contralateral adrenal glandis sufficient to offer the patient adrenalectomy for the glandbearing the adenoma without further evaluation.4,14 Otherwise,the only way to definitively identify the source(s) ofaldosterone is adrenal vein sampling (AVS). Adrenal veinsampling is a technically challenging procedure, due to theanatomy of the right adrenal vein (RAV), which is a shortvessel connecting the right adrenal gland with the posteriorwall of the inferior vena cava (IVC). The left adrenalvein (LAV) meets with the superior wall of the left renalvein near the entry of the left inferior phrenic vein. Theradiologist obtains samples from the IVC, RAV, and LAV;cortisol and aldosterone are measured for these samples.Various procedures have been developed and adopted atcenters around the world, with the major variables beingthe use of basal samples or under cosyntropin infusion orbolus; simultaneous vs sequential sampling of the RAV andLAV, and use of superselective microcatheters to sampleregions within each adrenal.15

The interpretation of AVS data consists of threesteps.15 Because adrenal blood flow is so small relativeto the volume of the samples obtained, AV samplesalways contain a variable amount of mixed venousblood. Consequently, the first step is evaluation of thecortisol concentrations as a marker of AV blood. Cortisolconcentrations in the AV samples should be at least fourtimes higher than the mixed venous blood in the IVCwhen cosyntropin is used and at least two times withoutcosyntropin. These criteria are called the selectivity index,which assures that the AVs were successfully accessedand corrects for the variable dilution with mixed venousblood. Next, one calculates the aldosterone/cortisol (A/C)ratios (cortisol-corrected aldosterone values), which correctsthe aldosterone for the dilution of the AV samplewith mixed venous blood. Finally, the higher A/C ratio (dominant side) is divided by the lower A/C ratio (nondominantside), which yields the lateralization index (LI).With cosyntropin stimulation, LI values >4 confidentlylateralize aldosterone production to one adrenal gland,and these patients are offered adrenalectomy of thedominant side. LI values < 2 indicate bilateral disease, andthese patients are treated with MR antagonist. LI valuesof 2 to 4 are indeterminate but are uncommon. While notrequired to interpret an AVS study as lateralized whenthe LI is >4, the contralateral index (CI), which is thenondominant A/C ratio divided by the IVC A/C ratio,is helpful when the LI is 2 to 4. A CI value < 1, which iscalled "contralateral suppression," confidently indicatesthat the nondominant side is minor contributor to thetotal aldosterone production, and these patients are alsooffered adrenalectomy. Without cosyntropin stimulation,LI values >2 are consistent with lateralized aldosteroneproduction.

 
THERAPY FOR PA

As discussed above, patients who lateralization on AVSare offered surgery, and those with bilateral disease aretreated with MR antagonists. Patients with lateralizedAVS might also be managed with MR antagonists, particularlyif they are poor surgical candidates. Conversely,patients with BHA and inadequate control and/or sideeffects with MR antagonist might be offered unilateraladrenalectomy of the dominant side; however, the expectationsfor improvement are modest.16

How should patients be counseled about the effectivenessof surgery? The Primary Aldosteronism SurgicalOutcome (PASO) consortium sought to standardize thedefinition of complete or partial (and absent) biochemicaland clinical successes using the Delphi process.17 Thegroup then analyzed data from over 700 patients withPA treated with surgery after lateralized AVS. Completebiochemical success, meaning normal ARR and serumpotassium, occurred in 94% of patients, which atteststo the accuracy of AVS in guiding surgery. Completeclinical success, meaning normal blood pressure withoutany antihypertensive drugs, was achieved in only 37%.Partial clinical success, meaning lower blood pressurewith the same drugs and/or similar blood pressure usingfewer drugs, was achieved in 47%. Women and youngerpatients were most likely to experience complete orpartial clinical success, whereas higher preoperative useof antihypertensive medications was predictive of lowerlikelihood complete clinical success.17

Despite reduction or discontinuation of antihypertensivemedications postoperatively, two complications areseen following adrenalectomy. Because PA is in a hyperfiltrationstate, a small rise in serum creatinine is often seenafter surgery. Age, male sex, hypokalemia, large tumors, and high serum aldosterone concentrations are all riskfactors for impaired renal function and for a creatininerise after surgery.18,19 A second complication followingsurgery is prolonged hyperkalemia due to suppression ofthe contralateral zona glomerulosa, which occurs in 5%of cases.20 Impaired renal function preoperatively, a risein creatinine and/or microalbuminuria postoperatively,and contralateral suppression on AVS21 are all predictorsof hyperkalemia, which can persist up to 6 months andmight require fludrocortisone and/or dietary potassiumrestriction.
 
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A rise in serum creatinine and/or potassium isalso commonly observed with MR antagonist therapy,particularly in patients with impaired renal function.To avoid these complications, spironolactone should bestarted at a low dose of 12.5 to 25 mg/d with close monitoringof electrolytes and creatinine. The onset of bloodpressure reduction from spironolactone is much slowerthan most other antihypertensive drugs, so dosage adjustmentshould not be made more frequently than every4 to 6 weeks. Side effects of spironolactone, which aredose-dependent and rarely occur in the first 6 weeks or ondoses < 50 mg/d, include gynecomastia and sexual dysfunctionin men or breast tenderness and vaginal spottingin women. When these side effects limit spironolactoneuse, eplerenone might be substituted as a selective MRantagonists that lacks these limitations but is less potentthan spironolactone. Eplerenone should be started attwice the spironolactone dose and divided twice daily (50mg/d spironolactone = 50 mg BID eplerenone). The sameprinciples of subsequent dose titration for spironolactonealso apply for eplerenone. The most common error in theuse of spironolactone is advancing the dose too quickly.The most common error in the use of eplerenone is underdosingand not dosing twice daily.

The target of medical therapy for PA is not known, butnormalization of blood pressure and serum potassium isa minimal indication of adequate MR antagonist dosing.Monitoring of PRA is helpful for two reasons. The first isthat a rise in PRA to >1 indicates significant physiologicevidence of MR blockade, at least in the kidney. Thesecond reason is that when the blood pressure remainselevated despite a dose of MR antagonist sufficient to raisethe PRA to the normal range, higher doses of MR antagonistare not likely to lower the blood pressure further. Inthese cases, calcium channel blockers, beta-blockers, andeven loop diuretics might be added to normalize bloodpressure and serum potassium.

PATHOGENESIS OF PA

Clues to the pathogenesis of PA have derived fromrare genetic forms of PA, the familial hyperaldosteronism(FHA) syndromes types 1 to 3. The FHA1 is also called dexamethasone-suppressible or glucocorticoidremediablealdosteronism. The FHA1 derives from ahybrid gene, which places the adrenocorticotropinresponsivepromoter of the CYP11B1 (11-hydroxylase)gene upstream of the CYP11B2 (aldosterone synthase)gene.22 This hybrid gene drives the adrenocorticotropindependentexpression of an enzyme with aldosteronesynthase activity in the zona glomerulosa. One featureof this disease is production of hybrid steroids, specifically18-hydroxycortisol and 18-oxo-cortisol.23 TheFHA2 is probably a mixture of diseases without aknown genetic defect. The molecular basis of FHA3was elucidated in 201124 as autosomal dominant gainof-function mutations in the KCNJ5 gene encoding theKir3.4 or GIRK4 potassium channel, which maintainsthe resting hyperpolarization of zona glomerulosa cells.The mutations modify the selectivity filter, allowing thechannel to conduct sodium as well as potassium. Thisalteration leads to chronic depolarization, increasedintracellular calcium, and autonomous aldosteroneproduction. While only a few families with germlineKCNJ5 mutations have been identified, many studieshave now shown that somatic KCNJ5 mutations arecommonly observed in APAs and are likely a majorcomponent of their pathogenesis.25 Curiously, patientswith FHA3 and APAs bearing KCNJ5 mutations alsoproduce excess 18-hydroxycortisol and 18-oxo-cortisol,26which illustrates that these diseases are not simplyovergrowths of normal zona fasciculata cells.

 
Following the identification of KCNJ5 mutationsin APAs, mutations in other ion channels and pumpswere also found in APAs, including the ATP1A1gene27 encoding a sodium/potassium ATPase, theATP2B3 gene27 encoding a calcium ATPase, and theCACNA1D28,29 and CACNA1H30,31 genes encodingL-type Cav1.3 and T-type Cav3.2 calcium channelsrespectively (Fig. 1). These mutations function via thefinal common pathway: Increased intracellular calcium,calmodulin activation, and increased expression of theenzymes and other proteins necessary for aldosteroneproduction.

If ion channels and pumps are involved in the pathogenesisof APAs, what causes BHA? Recently, severalgroups have identified a clue from normal adrenal glandsof adults. Using an antibody specific for aldosteronesynthase, these investigators found not a continuouszona glomerulosa as found in adrenals from childrenand rodents but rather isolated small clusters of aldosteronesynthase-positive cells scattered under the adrenalcapsule.32 Using laser-capture microdissection, theystudied the molecular signatures of these aldosteroneproducingcell clusters (APCCs) and found the mutationsfound in APAs, primarily CACNA1D but also ATP1A1 and ATP2B3-yet not in KCNJ5. The prevalence and sizeof APCCs increase with age, such that most adrenalsfrom adults age 50 or older contain one or more APCCs.32It is possible that accumulation of these APCCs overtime causes BAH, and it is also possible that APCCs areprecursors for at least some APAs following additionalmolecular alterations.
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Clinical and Laboratory Assessment of Patients withSuspected Primary Aldosteronism
Fig. 1: Germline and somatic gene mutations implicated in primary aldosteronism. Gain-of-functionmutations in the KCNJ5 (GIRK4, Kir3.4) potassium channel, which is normally inhibited upon AngIIbinding to its receptor (ATR1), are commonly found in APA. Mutations in the sodium/potassiumATPase ATP1A1 prevent the maintenance of hyperpolarization. Mutations in the calcium ATPaseATP2B3 or L-type CACNA1D and T-type CACNA1H calcium channels elevate intracellular calcium,which activates calmodulin and its kinase (Cam, CamK) to drive aldosterone production

CONCLUDING REMARKS

Primary aldosteronism is the most common cause ofsecondary hypertension, and screening for PA shouldbe a routine part of hypertension practice. Screeningis simple and can be performed without stopping anymedications. The latter stages of the evaluation shouldbe reserved for specialists and centers with experiencein interpreting dynamic testing, performing AVS, andusing minimally invasive adrenal surgery. The pathogenesisof PA is being unraveled, and the common occurrenceof APCCs in adult adrenal glands might explainwhy PA is so common. We have much more to learnabout the pathophysiology and management of PA. Inthe meantime, screening for PA is simple and routinelyavailable but underutilized. Given the profound benefita diagnosis of PA can make for an individual, screeningshould be considered routinely (Table 1). Even in thosewho cannot progress to the latter stages of the evaluationor who screen negative, MR antagonist therapy islikewise an underutilized tool in hypertension care and,as shown in the ASCOT33 and PATHWAY-234 studies,extremely effective in patients with all forms of lowreninhypertension.

 
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