Endocrine

Primary aldosteronism: screening and workup

Clinical Overview and When to Suspect Primary Aldosteronism

— Bilateral adrenal hyperplasia (idiopathic hyperaldosteronism, IHA) — ~60–70%, managed medically.

— Aldosterone-producing adenoma (APA, Conn syndrome) — ~30–40%, potentially curable with unilateral adrenalectomy.

— Rarer: unilateral hyperplasia, familial hyperaldosteronism types I–IV, adrenocortical carcinoma.

— Sustained BP >150/100 on three measurements

— Hypertension resistant to 3 drugs including a diuretic, or controlled BP on ≥4 agents

— HTN + spontaneous or diuretic-induced hypokalemia

— HTN + adrenal incidentaloma

— HTN + sleep apnea

— HTN + family history of early HTN or CVA <40 years

— All first-degree relatives of patients with PA

Definition: Autonomous, renin-independent aldosterone secretion from one or both adrenal glands, leading to sodium retention, volume expansion, hypertension, and renin suppression — often (but not always) with hypokalemia.

Epidemiology: Most common cause of secondary hypertension; prevalence ~5–10% of all hypertensives and up to 20% in resistant hypertension clinics. Vastly underdiagnosed in primary care.

Two dominant subtypes:

Whom to screen (Endocrine Society 2016):

Why it matters for Step 3: Aldosterone excess causes cardiovascular and renal injury out of proportion to BP — increased LVH, atrial fibrillation, stroke, CKD, and metabolic syndrome compared to BP-matched essential hypertensives. Targeted therapy (MR antagonist or adrenalectomy) reverses much of this excess risk.

Step 3 management: In the ambulatory clinic, the index patient is often the 45-year-old on lisinopril, amlodipine, and HCTZ with BP 158/96 and K⁺ 3.2 — do not just add a fourth drug. Screen with ARR before escalating empirically.

Board pearl: Only ~30% of PA patients are hypokalemic; normokalemia does not exclude PA.

Presentation Patterns and Key History

— Often early-onset (<40 years) or abruptly worsening

— Resistant to multiple agents; paradoxically poor response to ACEi/ARB monotherapy (low renin)

— Strong response to spironolactone/eplerenone (a useful retrospective clue)

— Muscle weakness, cramps, fatigue

— Polyuria/polydipsia (hypokalemic nephrogenic DI)

— Palpitations, premature beats

— Constipation, ileus

— Rarely periodic paralysis, especially in Asian male patients

— Atrial fibrillation in a "young" hypertensive

— LVH on echo disproportionate to BP burden

— Obstructive sleep apnea co-existing with refractory HTN

— Adrenal incidentaloma on abdominal imaging done for other reasons

— MR antagonists (spironolactone, eplerenone) → falsely low ARR; hold 4–6 weeks

— Amiloride, triamterene, high-dose K-wasting diuretics → confound

— Beta-blockers → suppress renin more than aldosterone → false-positive ARR

— ACEi/ARB, DHP-CCBs → raise renin → false-negative ARR

— NSAIDs → suppress renin → false-positive

Hypertension features:

Hypokalemia symptoms (when present):

Metabolic alkalosis from K⁺ shifts and H⁺ excretion — mild but supportive

Non-specific but high-yield clues:

Family history: Early stroke <40, familial hyperaldosteronism, MEN syndromes

Medication history is critical — must be obtained meticulously because drugs alter aldosterone-to-renin ratio (ARR) testing:

Key distinction: Edema is rare in PA despite Na⁺ retention because of "aldosterone escape" via ANP and pressure natriuresis — its presence should redirect toward CHF, nephrotic syndrome, or cirrhosis.

Step 3 management: In a CCS-style ambulatory case, before ordering ARR, switch antihypertensives to verapamil SR, hydralazine, doxazosin, and/or moxonidine for 2 weeks — these minimally affect the renin-aldosterone axis.

Board pearl: Spontaneous (non-diuretic) hypokalemia in a hypertensive is PA until proven otherwise.

Physical Exam Findings and Hemodynamic Assessment

— Sustained hypertension, frequently stage 2 (≥140/90, often >160/100)

— Lack of nocturnal BP dipping on ambulatory monitoring

— Heart rate typically normal — tachycardia suggests pheochromocytoma instead

— Loud S4 from LVH

— Displaced PMI

— Possible irregularly irregular rhythm (afib)

— No peripheral edema in classic PA — its presence is a red flag for another diagnosis

— Diminished deep tendon reflexes

— Proximal muscle weakness

— Rarely flaccid paralysis or tetany (alkalosis-induced)

— Pheochromocytoma → episodic HTN, tachycardia, diaphoresis, headache

— Cushing → central obesity, striae, proximal weakness, glucose intolerance

— Renovascular HTN → abdominal bruit, flash pulmonary edema, AKI on ACEi

— Primary aldosteronism → boring exam, impressive labs

General appearance: Most patients look entirely well; PA is largely a lab- and BP-driven diagnosis, not a syndromic one. Cushingoid features, virilization, or buffalo hump should redirect to other adrenal pathology.

Vital signs:

Cardiovascular:

Neuromuscular (if K⁺ <3.0):

Funduscopic: Grade I–III hypertensive retinopathy from chronic HTN

Abdominal: No bruit (renovascular HTN typical mimic) and no palpable mass; adrenal tumors are rarely palpable

Skin: No striae, hyperpigmentation, or hirsutism — these point to Cushing, Addison, or adrenal carcinoma

Volume status: Euvolemic to mildly volume-expanded; JVP often normal because of aldosterone escape

Hemodynamic phenotype: High systemic vascular resistance, normal-to-mildly-elevated cardiac output, low renin "volume-expanded" hypertension

Key distinction:

Step 3 management: Document an in-office BP using standardized technique (rested 5 min, both arms, repeat) before labeling HTN as "resistant" — pseudoresistance from white-coat effect or poor technique inflates apparent prevalence and triggers unnecessary workup.

Board pearl: A normal exam in a patient with refractory HTN and low K⁺ is the most classic presentation of PA on Step 3.

Diagnostic Workup — Initial Labs and Screening (ARR)

— BMP: Na⁺ (often high-normal), K⁺ (low or low-normal), HCO₃⁻ (mildly elevated), Cr (CKD assessment)

— Urinalysis, urine albumin/creatinine

— TSH, fasting glucose/A1c, lipid panel

— ECG and echocardiogram if LVH suspected

— Measure plasma aldosterone concentration (PAC, ng/dL) and plasma renin activity (PRA, ng/mL/hr) or direct renin concentration (DRC)

— Positive screen (Endocrine Society): ARR >20–30 AND PAC ≥10 ng/dL (some labs use ≥15)

— Suppressed renin alone is suggestive; isolated renin suppression with low aldosterone suggests other low-renin HTN (Liddle, AME, Cushing, licorice)

— Correct hypokalemia first — hypokalemia suppresses aldosterone and yields false negatives

— Liberalize sodium intake to ≥100 mEq/day

— Draw mid-morning, after patient up and ambulatory ≥2 hours, seated 5–15 minutes

— Hold spironolactone/eplerenone/amiloride 4–6 weeks

— If feasible, transition to "renin-neutral" agents: verapamil SR, hydralazine, doxazosin (alpha-blocker), prazosin, moxonidine

— Continue beta-blockers and ACEi/ARB only if symptomatically necessary — interpret with caution

— Very low renin with modestly elevated aldosterone can yield extremely high ratios — always require minimum absolute PAC threshold

— Severe CKD, pregnancy, OCPs (raise renin substrate), and renovascular disease alter results

Foundation labs in any new resistant HTN:

Screening test: Plasma Aldosterone-to-Renin Ratio (ARR)

Pre-test optimization (critical for valid result):

Interpretation pitfalls:

Step 3 management: Order ARR + serum K⁺ + plasma metanephrines simultaneously when working up resistant HTN — covers PA and pheochromocytoma in one visit, efficient ambulatory workflow.

CCS pearl: Advance the clock 2 weeks after switching meds before redrawing ARR — premature labs are a classic test pitfall.

Diagnostic Workup — Confirmatory Testing and Subtype Imaging

— Oral sodium loading: 6 g NaCl/day × 3 days, then 24-hr urine aldosterone >12 mcg confirms PA

— IV saline infusion test: 2 L NS over 4 hr; PAC >10 ng/dL post-infusion = positive (>5 with seated protocol). Avoid in severe HTN, CHF, arrhythmia

— Fludrocortisone suppression test: Most sensitive but inpatient, rarely used in US

— Captopril challenge: Useful when volume loading unsafe — PAC fails to suppress >30% after 25–50 mg captopril

— Adrenal CT with thin cuts (2.5–3 mm) — first imaging study

— Identifies macroadenomas, bilateral hyperplasia, large masses concerning for ACC (>4 cm, irregular)

— Limitations: Misses microadenomas; nonfunctioning incidentalomas common after age 40; CT-PA correlation poor — agreement with AVS only ~50–60%

— Adrenal venous sampling (AVS) — gold standard for lateralization

— Indicated in all surgical candidates >35 years, or any age with equivocal CT

— Cosyntropin-stimulated bilateral catheterization; success requires cortisol-corrected aldosterone ratios

— Lateralization index >4 = unilateral disease → adrenalectomy

— <3 = bilateral → medical therapy

— Patients <35 with unilateral macroadenoma, normal contralateral, and classic biochemistry may proceed to surgery without AVS

Confirmatory testing (required after positive ARR unless spontaneous hypokalemia + PAC >20 + undetectable renin, which may bypass it):

Subtype differentiation — the pivotal next step:

Genetic testing: Consider in PA onset <20 years or family history of early stroke — screen for familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism, GRA) with FH-I genetic test; treatment is low-dose dexamethasone

Key distinction: CT identifies anatomy; AVS identifies physiology. Surgery decisions hinge on AVS.

Board pearl: A 2 cm adrenal nodule on CT with positive ARR does not justify surgery without AVS — the nodule may be a nonfunctioning incidentaloma while the contralateral gland is the secretor.

Risk Stratification and Management Logic

— Unilateral disease (APA or unilateral hyperplasia) → laparoscopic adrenalectomy

— Bilateral disease (IHA) or non-surgical candidate → lifelong mineralocorticoid receptor antagonist (MRA)

— GRA (FH-I) → low-dose glucocorticoid (dexamethasone or prednisone)

— Normalize BP (most need ongoing antihypertensives even post-surgery)

— Normalize serum K⁺ without supplementation

— Normalize plasma renin — best surrogate that MRA dose adequately blocks aldosterone effect; suppressed renin = undertreatment

— Reduce cardiovascular and renal end-organ damage

— Older age, longer HTN duration, multiple antihypertensives, higher BMI, male sex, and CKD predict persistent post-op HTN

— Use the Aldosteronoma Resolution Score (ARS) to counsel: ≤2 antihypertensives, BMI ≤25, female sex, HTN duration ≤6 yr — predicts complete BP cure

— Confirm diagnosis → image → AVS if surgical candidate → multidisciplinary discussion (endocrinology + endocrine surgery + interventional radiology)

— Set realistic expectations: only ~35–60% of surgical patients are fully cured of HTN; nearly all have biochemical cure and improved BP control

— Surgery: one-time procedure, potential cure, requires hospital stay, surgical risk

— Lifelong MRA: oral therapy, gynecomastia/menstrual side effects (spironolactone), simpler logistics

Once PA is biochemically confirmed and lateralized, treatment forks:

Goals of therapy (all subtypes):

Pre-surgical risk stratification:

Cardiovascular risk: PA patients have higher rates of MI, stroke, afib, CHF, and CKD than BP-matched essential HTN — aggressive lipid, glucose, and lifestyle management mandatory

Step 3 management:

Shared decision-making points:

CCS pearl: After adrenalectomy, taper antihypertensives carefully — postoperative hyperkalemia and hypotension are common, especially if the contralateral gland was chronically suppressed (transient hypoaldosteronism).

Pharmacotherapy — Mineralocorticoid Receptor Antagonists

— Start 12.5–25 mg daily, titrate q4–8 weeks to max 100 mg/day (rarely higher)

— Goals: BP control, K⁺ normalization without supplementation, renin de-suppression

— Nonselective MRA → also blocks androgen and progesterone receptors

— Side effects: gynecomastia (~10% at 50 mg, dose-dependent), erectile dysfunction, menstrual irregularities, breast tenderness, hyperkalemia, gastritis

— More selective for MR, far fewer endocrine side effects

— Start 25 mg BID, titrate to 50 mg BID (max 100 mg/day)

— Less potent than spironolactone (~50% on per-mg basis)

— Higher cost, shorter half-life requiring BID dosing

— Preferred in young men, premenopausal women, and patients intolerant of spironolactone

— Amiloride (5–20 mg/day): ENaC blocker, useful when MRAs intolerable; weaker BP effect

— Triamterene similar mechanism

— Add thiazide for residual HTN — synergistic since PA is volume-mediated

— DHP-CCB (amlodipine) as add-on

— Finerenone — nonsteroidal selective MRA, FDA-approved for DM2-CKD; emerging data in PA but not yet first-line

— Check K⁺ and Cr at 1 week, 1 month, then q3–6 months

— Renin should rise into the unsuppressed range when therapy is adequate

First-line agent: Spironolactone

Second-line: Eplerenone

Third-line / adjuncts:

Newer agents:

Monitoring:

Drug interactions: ACEi/ARB + MRA + NSAID = "triple whammy" hyperkalemia and AKI — avoid the combination in older or CKD patients

Step 3 management: In a patient with IHA + CKD stage 3b, start eplerenone 25 mg, recheck K⁺ in 5–7 days; if K⁺ ≥5.5, hold MRA and re-evaluate dietary K⁺ and concomitant RAAS blockade.

Board pearl: Gynecomastia developing in a man newly on a "diuretic" for resistant HTN — that drug is spironolactone, and the diagnosis worth questioning is primary aldosteronism.

Surgical Management — Laparoscopic Adrenalectomy

— Optimize BP with MRA + standard agents for 4–6 weeks preoperatively

— Normalize K⁺ before induction (hypokalemia → intraoperative arrhythmia)

— Liberalize sodium intake once on MRA to prevent volume depletion

— Continue MRA up to morning of surgery

— Anesthesia team aware of potential BP lability

— Avoid prolonged steroid coverage — unilateral adrenalectomy does not require stress-dose steroids (contralateral gland intact)

— Stop MRA and potassium supplements immediately

— Hold ACEi/ARB until K⁺ trend known

— Monitor K⁺ daily — transient hyperkalemia in ~5–15% from contralateral zona glomerulosa suppression; some require fludrocortisone short-term

— Re-measure ARR at 1–3 months: biochemical cure ~95–100% with successful AVS-guided surgery

— Clinical cure (no antihypertensives, normotensive) in ~35–60%; improvement in ~95%

Indication: Confirmed PA with AVS-proven unilateral aldosterone hypersecretion (lateralization index >4), or unequivocal unilateral macroadenoma on CT in a young patient (<35) with classic biochemistry.

Procedure: Laparoscopic (or robotic) unilateral total adrenalectomy — transabdominal or retroperitoneal approach. Subtotal adrenalectomy is generally not performed for PA (risk of residual disease).

Preoperative preparation:

Intraoperative considerations:

Postoperative course:

Complications: Bleeding (~1%), conversion to open (~3%), adrenal insufficiency (rare, only if both glands compromised), hypoaldosteronism with hyperkalemic acidosis

CCS pearl: Order postoperative K⁺ daily × 3 days, taper antihypertensives based on home BP log; arrange endocrinology follow-up at 6–8 weeks with repeat ARR and metabolic panel.

Key distinction: Persistent post-op HTN ≠ failed surgery if K⁺ and renin normalize — patient likely has concomitant essential HTN, which is common given the typical demographic.

Board pearl: A patient with bilateral adrenal hyperplasia gains nothing from bilateral adrenalectomy except iatrogenic Addison disease — medical therapy only.

Special Populations — Elderly and Renal/Hepatic Impairment

— Prevalence of PA underestimated; many labeled "essential HTN" or "diuretic-induced hypokalemia"

— Adrenal incidentalomas common (~7% over age 70) — must distinguish functioning from nonfunctioning

— Screening still indicated for resistant HTN, spontaneous hypokalemia, or new HTN with incidentaloma

— Surgical decision-making: weigh life expectancy, frailty, anesthetic risk; many elderly with unilateral disease still benefit from adrenalectomy, but medical management with low-dose MRA is reasonable

— Start spironolactone at 12.5 mg in elderly — risk of orthostasis, hyperkalemia, AKI

— PA accelerates CKD; conversely, CKD complicates MRA use (hyperkalemia)

— Eplerenone preferred over spironolactone in CKD due to dosing flexibility and side-effect profile, but both require caution

— Avoid MRA when eGFR <30 unless under close specialty supervision

— Finerenone is FDA-approved for DM2-associated CKD with proteinuria — useful adjunct in PA + diabetic CKD

— Renin interpretation tricky in advanced CKD — use direct renin concentration

— Spironolactone undergoes hepatic metabolism — active metabolite canrenone accumulates in cirrhosis

— Paradox: cirrhotics often need spironolactone for ascites despite hepatic clearance issues

— Eplerenone — CYP3A4 metabolism; contraindicated with strong inhibitors (ketoconazole, clarithromycin)

— Spironolactone + digoxin → falsely elevated digoxin levels

— MRA + trimethoprim → severe hyperkalemia

— MRA + NSAID → AKI + hyperkalemia

Elderly patients (>65 yr):

Chronic kidney disease:

Hepatic impairment:

Drug interactions to flag in older polypharmacy patients:

Step 3 management: In a 78-year-old with PA, eGFR 38, on amlodipine + losartan + HCTZ, K⁺ 3.3 — discontinue losartan, start eplerenone 25 mg daily, recheck BMP in 5–7 days, target BP <130/80 cautiously to avoid orthostatic falls.

Board pearl: Trimethoprim has structural similarity to amiloride and blocks ENaC — combined with an MRA in an elderly PA patient, it can produce life-threatening hyperkalemia within days.

Special Populations — Pregnancy, Pediatrics, and Familial Forms

— PA in pregnancy is rare but high-risk: severe HTN, preeclampsia, IUGR, preterm birth, abruption

— Screening complicated — pregnancy physiologically raises renin and aldosterone; ARR interpretation unreliable

— Confirmatory salt-loading and AVS contraindicated/avoided

— Spironolactone contraindicated in pregnancy (antiandrogenic, feminization of male fetus)

— Eplerenone: Category B; case reports of safe use, but limited data

— Mainstays: methyldopa, labetalol, nifedipine ER, hydralazine

— Definitive workup and surgery deferred until postpartum

— Postpartum: discontinue breastfeeding if planning AVS or surgery, then re-evaluate

— PA before age 20 strongly suggests familial hyperaldosteronism

— Refer to pediatric endocrinology and genetics

— Glucocorticoid-remediable aldosteronism may present in infancy with severe HTN

— FH-I (GRA): CYP11B1/CYP11B2 chimeric gene; ACTH-regulated aldosterone; treat with low-dose dexamethasone (0.125–0.25 mg qHS) or prednisone; consider MRA adjunct; high stroke risk before age 40

— FH-II: CLCN2 mutations; clinically indistinguishable from sporadic PA

— FH-III: KCNJ5 germline; severe early-onset, often requires bilateral adrenalectomy

— FH-IV: CACNA1H; variable severity

— PA diagnosis <20 years

— Family history of PA or stroke <40 years

— Bilateral macronodular hyperplasia in young patient

Pregnancy:

Pediatrics and adolescents:

Familial hyperaldosteronism subtypes:

Genetic screening indications:

Key distinction: GRA is the only PA subtype where dexamethasone is curative — never forget it in the young hypertensive with family history of intracerebral hemorrhage.

Step 3 management: A 16-year-old with HTN 165/105, K⁺ 3.0, and a maternal uncle who died of stroke at 32 — order ARR, then genetic testing for FH-I before adrenal imaging.

Board pearl: A pregnant woman with newly worsening HTN and hypokalemia → defer ARR/AVS; control BP with labetalol or nifedipine, and complete workup postpartum.

Complications and Adverse Outcomes

— Compared to BP-matched essential HTN patients, PA patients have:

— 2–4× risk of stroke

— 2–6× risk of atrial fibrillation

— 2× risk of MI and heart failure

— Higher LVH, diastolic dysfunction, and arterial stiffness

— Mechanism: direct MR-mediated cardiac fibrosis, endothelial dysfunction, sympathetic activation — independent of BP

— Hyperfiltration initially masks renal injury — eGFR may drop after starting MRA (revealing true GFR)

— Long-term: proteinuria, CKD progression

— Aldosterone escape in CHF and CKD contributes to fibrosis

— Insulin resistance and type 2 diabetes (~2× risk)

— Metabolic syndrome clustering

— Osteoporosis — aldosterone increases urinary calcium and magnesium loss; bone mineral density improves with MRA or adrenalectomy

— Cardiac arrhythmias (PVCs, afib, torsades when severe)

— Rhabdomyolysis (rare, with K⁺ <2.5)

— Nephrogenic DI → polyuria, nocturia

— Glucose intolerance from impaired insulin release

Cardiovascular morbidity (the headline harm of PA):

Renal complications:

Metabolic complications:

Hypokalemia-related:

Adrenal venous sampling complications: Adrenal vein rupture (<1%), hematoma, contrast reaction, failed cannulation (centers <20% success early; experienced centers >95%)

Post-adrenalectomy: Transient hypoaldosteronism with hyperkalemia, hypotension, contralateral adrenal insufficiency (rare)

Mental health: Higher rates of depression and anxiety, often improving with treatment

Step 3 management: Every newly diagnosed PA patient warrants baseline echocardiogram, ECG, lipid panel, A1c, urine ACR, and DXA in selected patients — these aren't optional adjuncts; they're disease-specific risk stratification.

Board pearl: Aldosterone causes cardiac and renal damage directly, not just via BP — even normotensive PA (rare entity) shows end-organ harm. This is why treatment targets renin normalization, not just BP.

When to Escalate Care — Consult, Inpatient, and Specialty Triage

— Positive ARR requiring confirmatory testing

— Subtype determination and AVS coordination

— Familial PA suspicion → genetics referral

— Atypical biochemistry (e.g., PA with normal renin, mixed Cushing-PA)

— AVS-confirmed lateralization

— Adrenal mass >4 cm or imaging features concerning for carcinoma (irregular margins, heterogeneity, high Hounsfield units, washout <50% on contrast)

— Performing AVS — outcomes are operator-dependent; refer to high-volume centers

— Severe hypokalemia (K⁺ <2.5) with ECG changes or arrhythmias — IV repletion, telemetry

— Hypertensive emergency (BP >180/120 with end-organ damage) — ICU, IV antihypertensives (labetalol, nicardipine), avoid hydralazine if reflex tachycardia concerning

— Hypokalemic periodic paralysis with respiratory weakness

— Acute heart failure or arrhythmia attributable to PA

— Hypertensive encephalopathy, ICH, aortic dissection

— Refractory arrhythmias with electrolyte derangement

— Stroke <40 years

— New afib in young hypertensive

— Severe HTN + hypokalemia in pregnancy

Endocrinology referral — essentially always:

Endocrine surgery referral:

Interventional radiology:

Inpatient admission criteria:

ICU triage:

Outpatient red flags requiring expedited workup:

CCS pearl: For a patient admitted with K⁺ 2.2 and BP 220/130, immediate actions: IV access, telemetry, IV potassium chloride 10 mEq/hr (max 20 with central line), magnesium repletion, IV labetalol or nicardipine drip, neuro and cardiac monitoring — then in parallel, draw aldosterone, renin, and metanephrines before any spironolactone is started.

Key distinction: Once spironolactone or eplerenone is given, ARR becomes uninterpretable for 4–6 weeks — preserve diagnostic windows by drawing baseline labs before MRA initiation, even when clinically appropriate to start it acutely.

Step 3 management: Always document the indication and timing of any RAAS-active drug — downstream clinicians depend on it to correctly interpret follow-up labs.

Key Differentials — Other Causes of Mineralocorticoid Excess

— Renovascular hypertension — renal artery stenosis (atherosclerotic in older, fibromuscular dysplasia in young women); abdominal bruit, AKI with ACEi

— Renin-secreting tumor (reninoma) — rare juxtaglomerular cell tumor; severe HTN, hypokalemia, very high renin and aldosterone

— Malignant/accelerated hypertension — pressure-induced renin secretion

— Diuretic use, volume depletion, CHF, cirrhosis, nephrotic syndrome — physiologic activation

— Coarctation of aorta — differential upper/lower extremity BP

— Cushing syndrome — high cortisol overwhelms 11β-HSD2, activating MR; look for stigmata, do 24-hr UFC or overnight DST

— Apparent mineralocorticoid excess (AME) — congenital 11β-HSD2 deficiency or acquired (chronic licorice ingestion, chewing tobacco, carbenoxolone); cortisol acts as mineralocorticoid

— Liddle syndrome — autosomal dominant constitutive ENaC activation; presents like PA but ARR is low (low aldo); treat with amiloride/triamterene, not spironolactone

— Congenital adrenal hyperplasia — 11β- or 17α-hydroxylase deficiency; DOC excess

— Geller syndrome — activating MR mutation; severe HTN exacerbated by pregnancy or spironolactone (paradoxical agonism)

— Young hypertensive + hypokalemia + low aldo + low renin → think Liddle, AME, CAH

— Young hypertensive + hypokalemia + high aldo + low renin → primary aldosteronism

— Hypertensive + hypokalemia + high aldo + high renin → secondary (RAS, reninoma)

Secondary hyperaldosteronism (high renin, high aldosterone):

Low-renin, low-aldosterone mineralocorticoid excess (mimics):

Pseudohyperaldosteronism patterns to recognize:

Board pearl: A patient with refractory HTN, hypokalemia, and suppressed aldosterone and renin who responds to amiloride but not spironolactone has Liddle syndrome until proven otherwise.

Key distinction: Renin level is the single most useful divider — high renin redirects you toward secondary causes (RAS), low renin keeps PA and mimics on the table.

Key Differentials — Other Causes of Resistant Hypertension

— Episodic HTN, headache, palpitations, diaphoresis, pallor

— Screen with plasma free metanephrines or 24-hr urinary fractionated metanephrines

— Always screen with PA — both can coexist (very rare) and both are commonly missed

— Central obesity, striae, proximal myopathy, glucose intolerance

— 24-hr UFC, late-night salivary cortisol, low-dose DST

— Frequently comorbid with PA; treating one improves the other

— Polysomnography for any resistant HTN

— Hyperthyroidism → systolic HTN, tachycardia

— Hypothyroidism → diastolic HTN

Step 3 expects systematic exclusion of all secondary HTN causes before, alongside, or after PA workup:

Pheochromocytoma/paraganglioma:

Cushing syndrome:

Obstructive sleep apnea:

Thyroid disorders:

Hyperparathyroidism: Hypercalcemia → HTN; check PTH and Ca²⁺

Acromegaly: Coarse features, ring/shoe size change; check IGF-1

Renovascular disease: Bruit, flash pulmonary edema, AKI on ACEi; CTA or Doppler

Drug-induced HTN: NSAIDs, decongestants, OCPs, stimulants, cocaine, glucocorticoids, calcineurin inhibitors, EPO, VEGF inhibitors, MAOI + tyramine, herbals (licorice, ephedra), excess sodium, heavy alcohol

Pseudoresistance: Nonadherence, white-coat HTN, improper cuff size — confirm with ambulatory or home BP monitoring before extensive workup

Aortic coarctation: Differential BP, radial-femoral delay, rib notching

CKD-driven volume HTN: Most common secondary cause in elderly

Step 3 management: In the ambulatory clinic, an efficient "resistant HTN panel" includes BMP, TSH, UA, urine ACR, plasma metanephrines, ARR, lipid panel, A1c, and an ambulatory BP recording — ordered together at the index visit.

Board pearl: Always screen for pheochromocytoma before adrenal surgery, even when PA is confirmed — operating on an unsuspected pheo can be fatal.

Long-Term Plan, Secondary Prevention, and Discharge Medications

— Confirm and document subtype, lateralization status, and treatment modality

— Set explicit BP and K⁺ goals; share home BP log with patient

— Tobacco cessation, weight optimization, DASH diet (~moderate sodium restriction even on MRA), aerobic exercise

— Treat dyslipidemia per ACC/AHA ASCVD risk; statin if 10-yr risk ≥7.5–10%

— Treat diabetes per ADA; address insulin resistance

— Sleep apnea evaluation and CPAP adherence

— Stop MRA and K⁺ supplements immediately postop

— Continue background antihypertensives initially, then taper sequentially based on home BP

— Recheck ARR, K⁺, Cr at 6–8 weeks → confirms biochemical cure

— If renin still suppressed and BP still elevated → residual ipsilateral or contralateral disease, re-evaluate

— Spironolactone 25–100 mg daily or eplerenone 25–50 mg BID

— Continue or add CCB, thiazide as needed

— Discontinue oral K⁺ once MRA stable and K⁺ in mid-normal range

— Patient counseling: report breast tenderness/gynecomastia, leg cramps, or signs of hyperkalemia (weakness, palpitations)

— Lowest effective glucocorticoid dose

— Monitor for iatrogenic Cushing features and bone health

— Often adjunctive MRA used to minimize steroid exposure

— Annual basic metabolic panel, lipid, A1c

— Periodic echocardiogram and ambulatory BP

— Adrenal CT only if symptoms or biochemistry change post-medical-therapy initiation

Post-diagnosis longitudinal plan:

Post-adrenalectomy regimen:

Medical management discharge regimen (IHA):

GRA-specific discharge plan:

Secondary prevention end-organ surveillance:

CCS pearl: Schedule the 6–8-week post-op or post-medication-initiation visit before the patient leaves — capturing renin normalization is the metric that defines treatment success.

Board pearl: Persistent suppressed renin on MRA therapy means underdosed — uptitrate; do not just add a thiazide.

Follow-Up, Monitoring Parameters, and Counseling

— 1 week: BMP — K⁺, Cr trend

— 1 month: BMP, BP review, side-effect screen

— 3 months: Renin (target unsuppressed), aldosterone, BP, K⁺, weight

— 6 months and thereafter: Every 3–6 months if stable; annually once steady

— DXA at baseline in postmenopausal women or men >50 with prolonged untreated PA

— Annual echo if LVH at baseline; ECG yearly

— POD #1–3: daily K⁺, BP, hold MRA

— 6–8 weeks: ARR, BMP — confirm biochemical cure

— 6 and 12 months: BP, A1c, lipids, weight

— Annual thereafter: BP, BMP, lifestyle reinforcement

— Validated upper-arm cuff, twice daily (morning, evening), two readings each, for 7 days monthly

— Target <130/80 (most), individualized in elderly/frail

— Sodium ≤2.3 g/day even on MRA — reduces residual BP

— Aerobic exercise 150 min/week

— Alcohol moderation (≤1–2 drinks/day)

— Weight loss ~5–10% reduces BP meaningfully

Monitoring cadence after starting MRA:

Monitoring after adrenalectomy:

Home BP monitoring:

Lifestyle counseling:

Side-effect counseling (spironolactone): breast tenderness, gynecomastia, menstrual changes — discuss switching to eplerenone if bothersome

Drug-drug awareness: Patients must inform any new provider about MRA before being prescribed trimethoprim, NSAIDs, or ACEi/ARB combinations

Cardiac rehab consideration: For PA patients with MI, HF, or stroke history

Vaccination and routine prevention: Influenza, pneumococcal, COVID — standard; PA per se does not change vaccine recommendations

Step 3 management: Use shared visit summaries with primary care to coordinate ongoing BP titration — fragmented care is the most common cause of treatment failure in PA outpatients.

Board pearl: Renin de-suppression is the molecular target of adequate MRA therapy — not symptomatic improvement, not BP alone.

Ethical, Legal, and Patient Safety Considerations

— Discuss procedural success rates (operator-dependent), adrenal vein rupture risk (<1%), contrast nephropathy, and the possibility of nondiagnostic study requiring repeat

— Disclose that surgical decision-making hinges on AVS result — a non-diagnostic study delays therapy

— Realistic counseling on biochemical cure (~95–100%) vs clinical cure of HTN (~35–60%) — many patients still need antihypertensives

— Risk of transient hypoaldosteronism, hyperkalemia

— Surgical risks: bleeding, infection, conversion to open

— Patients discharged on spironolactone + ACEi/ARB + NSAID PRN are at high risk of life-threatening hyperkalemia; medication reconciliation at each transition is mandatory

— Verbal handoff between endocrinology, surgery, and PCP should explicitly include the timing for resuming or stopping MRA and K⁺ monitoring plan

— A common Step 3 pitfall: ED clinician restarts spironolactone post-adrenalectomy on a patient with K⁺ 4.9 → hyperkalemic arrest

— AVS available only at experienced centers; rural and underserved patients disproportionately undertreated

— Cost of eplerenone can be a barrier; advocate for formulary alternatives

— Avoid ordering ARR while patient is on MRA — wasteful and misleading; counsel and reschedule

— Document medication washout in the chart

— Counsel implications for first-degree relatives (cascade screening) and consider GINA protections; pediatric testing for FH-I has implications for family members

— Document and communicate adrenal incidentaloma findings to the PCP — failure to act on incidental findings is a leading malpractice claim

Informed consent for AVS:

Informed consent for adrenalectomy:

Transition-of-care risk (high-yield Step 3 theme):

Disparities and access:

Diagnostic stewardship:

Genetic testing ethics:

Mandatory communication:

Step 3 management: Before any discharge involving an MRA, generate a clear medication list with K⁺ monitoring schedule and a "do not combine" list (NSAIDs, trimethoprim, ACEi/ARB without checks) — and ensure follow-up within 1–2 weeks.

Board pearl: The riskiest moment in PA care is the transition between inpatient and outpatient — medication errors here cause more harm than the disease itself.

High-Yield Associations and Rapid-Fire Clinical Facts

PA prevalence: ~5–10% of all HTN; up to 20% of resistant HTN

Only ~30% of PA patients have hypokalemia — normokalemia does not rule out PA

ARR positive: ARR >20–30 AND PAC ≥10–15 ng/dL

Confirmatory tests: oral salt loading, IV saline infusion, fludrocortisone suppression, captopril challenge

Bilateral hyperplasia (IHA) > APA in frequency

AVS lateralization index >4 = unilateral; <3 = bilateral

AVS success rate at experienced centers >95%; novice centers <60%

Surgical biochemical cure ~95–100%; clinical HTN cure ~35–60%

Spironolactone side effect: gynecomastia (dose-dependent); switch to eplerenone

Eplerenone dosed BID; less potent per mg than spironolactone

Triamterene, amiloride: alternative ENaC blockers when MRA intolerable

Finerenone: nonsteroidal MRA, DM2-CKD indication

Liddle syndrome: low aldo, low renin; amiloride works, spironolactone does not

AME: chronic licorice ingestion → low aldo, low renin, HTN, hypokalemia

GRA (FH-I): chimeric CYP11B1/CYP11B2; treat with dexamethasone

FH-III: severe early-onset, KCNJ5 mutation, often bilateral adrenalectomy

PA increases stroke, MI, afib, CHF, CKD, DM2 risk beyond BP-matched essential HTN

Aldosterone causes direct cardiac and renal fibrosis via MR

Hold spironolactone/eplerenone 4–6 weeks before ARR

"Renin-neutral" drugs during workup: verapamil SR, hydralazine, doxazosin, prazosin, moxonidine

Always screen for pheochromocytoma before adrenal surgery

Trimethoprim + MRA = severe hyperkalemia

Post-adrenalectomy transient hyperkalemia — stop MRA, sometimes need fludrocortisone

Adrenal mass >4 cm, irregular, HU >20, washout <50% → concern for adrenocortical carcinoma

PA in pregnancy: avoid spironolactone; use methyldopa, labetalol, nifedipine

Genetic testing if PA <20 yr or family history of stroke <40 yr

Board pearl: The Step 3 stem giveaway: "resistant HTN + spontaneous hypokalemia + adrenal mass on incidental imaging" = order ARR, then CT, then AVS.

Board Question Stem Patterns

— 45-yr-old on lisinopril, amlodipine, HCTZ; BP 162/102; K⁺ 3.1; eGFR 85. Best next step?

— Answer: Plasma aldosterone-to-renin ratio (after stabilizing K⁺ and adjusting interfering meds)

— CT abdomen for nephrolithiasis shows 1.8-cm left adrenal nodule; patient has HTN on three drugs and K⁺ 3.4. Next step?

— Answer: ARR; also rule out pheochromocytoma (metanephrines) and Cushing (DST)

— Confirmatory test (oral salt loading or saline suppression) → then adrenal CT → then AVS if surgical candidate

— Answer: Spironolactone or eplerenone, 4–6 weeks before testing

— 1.5-cm right adrenal adenoma on CT in a 52-yr-old with confirmed PA — proceed to surgery?

— Answer: No — perform AVS first; CT-AVS discordance is common

— 17-yr-old, BP 170/110, K⁺ 2.9, mother died of ICH at 35 → think GRA; treat with dexamethasone

— Hypokalemic alkalotic hypertensive with low aldosterone and low renin that improves on amiloride but not spironolactone → Liddle syndrome

— POD #2 after right adrenalectomy for APA, K⁺ 5.6 → transient hypoaldosteronism; stop K⁺ supplements, discontinue ACEi temporarily; sometimes fludrocortisone

— Known PA, now 8 weeks pregnant on spironolactone → discontinue spironolactone, switch to labetalol/nifedipine; defer surgery to postpartum

— Patient on spironolactone develops UTI; PCP prescribes TMP-SMX → presents with K⁺ 6.8 → recognize TMP-induced hyperkalemia with MRA

Classic stem 1 — Resistant HTN with hypokalemia:

Stem 2 — Adrenal incidentaloma + HTN:

Stem 3 — Post-positive ARR, next step:

Stem 4 — Which drug to discontinue before ARR?

Stem 5 — Lateralization decision:

Stem 6 — Young patient with PA and family stroke history:

Stem 7 — Liddle vs PA:

Stem 8 — Post-op hyperkalemia:

Stem 9 — Pregnancy:

Stem 10 — Drug interaction:

Step 3 management: When in doubt on a vignette: secure airway/circulation if acute, identify offending drug, draw labs before giving an MRA, and screen for both PA and pheochromocytoma in any resistant HTN.

Board pearl: "Spontaneous hypokalemia + HTN" virtually demands ARR on the exam.

One-Line Recap

Primary aldosteronism is the most common — and most underdiagnosed — curable secondary hypertension; screen any patient with resistant HTN, spontaneous hypokalemia, HTN with adrenal incidentaloma, or HTN with OSA using a plasma aldosterone-to-renin ratio, confirm autonomy with salt loading or saline suppression, image with adrenal CT, lateralize with adrenal venous sampling, and treat unilateral disease with laparoscopic adrenalectomy or bilateral disease with lifelong mineralocorticoid receptor antagonist therapy targeting normalized potassium and de-suppressed renin.

Screen broadly: ARR in all resistant HTN, spontaneous hypokalemia, HTN + adrenal mass, HTN + OSA, HTN + family history of early stroke; ~30% of PA patients are normokalemic, so do not rely on K⁺ alone.

Confirm before committing: Positive ARR (>20–30 with PAC ≥10) requires confirmatory salt-loading or saline suppression unless spontaneous hypokalemia with markedly elevated PAC and undetectable renin; only then move to subtyping.

Lateralize before operating: Adrenal CT identifies anatomy but discordance with functional studies is ~40%; AVS is the gold standard for surgical candidates, particularly >35 years or with bilateral/ambiguous imaging.

Treat to renin, not just BP: Surgery cures biochemistry in ~95–100% but HTN in only ~35–60%; medical therapy with spironolactone or eplerenone should be uptitrated until plasma renin de-suppresses, the surrogate that aldosterone-mediated end-organ damage is being neutralized.

Step 3 management: The exam-defining sequence is identify → screen with ARR → confirm → subtype → AVS → definitive therapy → renin-guided monitoring, with careful medication reconciliation at every transition to prevent hyperkalemia and to preserve diagnostic accuracy.

Board pearl: If you remember nothing else — resistant hypertension plus low potassium equals aldosterone-to-renin ratio, and spironolactone plus trimethoprim equals danger.