• PA is the most common cause of secondary hypertension, accounting for approximately 5–13% of all hypertensive patients and up to 20% of patients with resistant hypertension (defined as BP uncontrolled on ≥3 antihypertensives including a diuretic) ^[1][2].
• Previously thought rare (~1%), but with widespread use of ARR screening, prevalence estimates have risen dramatically.
• In a Hong Kong context, PA is an important and underdiagnosed cause of secondary hypertension. Given HK's ageing population and high prevalence of hypertension (~20% of the population ^[3]), screening for PA in appropriate patients is clinically very relevant.

• Bilateral idiopathic adrenal hyperplasia (BAH): more common overall, typically presents in middle-aged adults (40–60 years), slight male predominance.
• Aldosterone-producing adenoma (APA / Conn's syndrome): tends to present at a younger age than BAH, with a female predominance (F:M ≈ 2:1). Younger patients with more profound hypokalaemia and higher BP should raise suspicion for APA ^[1].

• PA patients have higher cardiovascular morbidity and mortality compared to patients with essential hypertension matched for the same degree of BP elevation ^[1].
• This excess risk is due to the direct deleterious effects of aldosterone on the heart, vasculature, and kidneys — independent of blood pressure. Aldosterone causes:
  • Myocardial fibrosis → LVH, diastolic dysfunction, arrhythmias (especially AF)
  • Vascular inflammation and endothelial dysfunction → accelerated atherosclerosis
  • Renal fibrosis and proteinuria
• Therefore, identifying and specifically treating PA (rather than just treating BP with generic antihypertensives) is crucial.

The adrenal cortex has three zones, remembered by the mnemonic "GFR" (from outside in) = salt, sugar, sex:

PA arises from pathology in the zona glomerulosa.

Stimuli for aldosterone secretion ^[1]:

1. Angiotensin II (via RAAS) — the main stimulant
   • Triggered by: ↓glomerular perfusion pressure, ↓Na+ at macula densa → ↑renin → angiotensinogen → angiotensin I → (ACE) → angiotensin II → stimulates zona glomerulosa
2. Hyperkalaemia — directly stimulates zona glomerulosa (even small changes in K+ are potent stimuli)
3. ACTH — has a minor, short-term stimulatory effect (explains diurnal variation in aldosterone and is relevant in APA which may be partially ACTH-responsive)

Physiological factors modulating secretion ^[1]:

• ↑ Secretion: upright posture, exercise, Na deprivation, hypovolaemia, stress, diuretics
• ↓ Secretion: ↑age, Na loading, volume overload, autonomic failure

Aldosterone acts on the mineralocorticoid receptor (MR) in the principal cells of the distal convoluted tubule (DCT) and cortical collecting duct (CCD).

The key downstream effects:

1. Stimulates the epithelial sodium channel (ENaC) on the luminal membrane → ↑Na+ reabsorption from tubular lumen into cell
2. Stimulates the basolateral Na+/K+-ATPase → pumps Na+ into blood, K+ into cell
3. Net effect: Na+ retention + K+ secretion into the tubular lumen
4. The electrical gradient created by Na+ reabsorption also drives H+ secretion via H+-ATPase and H+/K+-ATPase in intercalated cells → metabolic alkalosis

Result of aldosterone excess: Hypokalaemic metabolic alkalosis ± hypernatraemia (though Na is often only at the upper end of normal due to "aldosterone escape" — see below) ^[1][2].

In chronic aldosterone excess, you might expect massive sodium retention and severe oedema. However, this does NOT occur because of the "aldosterone escape" mechanism:

1. Initial aldosterone excess → Na+ and water retention → volume expansion
2. Volume expansion → ↑renal perfusion pressure → ↑GFR + ↑atrial natriuretic peptide (ANP) release
3. ANP + ↑GFR → pressure natriuresis — the kidney excretes the excess sodium despite ongoing aldosterone stimulation
4. Result: a new steady state is reached where sodium balance is restored but at a slightly expanded volume. This is why:
   • Oedema is rare in PA (unlike secondary hyperaldosteronism where RAAS is activated by true hypovolaemia)
   • Serum sodium is usually only at the upper end of normal (not overtly hypernatraemic)
   • Hypokalaemia persists because there is no equivalent "escape" for potassium — K+ secretion continues relentlessly

The relative frequency of APA vs BAH differs between sources ^[1][2]:

• Ryan Ho Endocrine notes ^[1]: BAH 60–70%, APA 30–40%
• Ryan Ho Fundamentals notes ^[2]: APA 60–70%, BAH 20–40%

Per the 2024 Endocrine Society Clinical Practice Guidelines and current literature, BAH is the most common cause (~60–70%) and APA accounts for ~30–40%. The Fundamentals note likely reflects older data when APA was thought to be more common (selection bias from surgical series). Use BAH > APA for exams in line with current guidelines.

• In APA: a monoclonal adenoma in the zona glomerulosa produces aldosterone independently of the normal RAAS regulatory feedback. Somatic mutations (commonly in KCNJ5, encoding the GIRK4 potassium channel) lead to constitutive activation of aldosterone synthesis.
• In BAH: bilateral hyperplasia of zona glomerulosa cells; the mechanism is less well understood, but aldosterone production remains partially responsive to angiotensin II (hence posture-sensitive).

1. ↑Na+ reabsorption → mild volume expansion → hypertension
2. ↑K+ secretion → hypokalaemia
3. ↑H+ secretion → metabolic alkalosis
4. Aldosterone escape limits Na+ retention (see above), but K+ and H+ loss continue

• Neuromuscular: muscle weakness, cramps, flaccid paralysis (K+ is critical for resting membrane potential of muscle cells; hypokalaemia hyperpolarizes cells → harder to depolarize → weakness)
• Cardiac: arrhythmias (U waves, prolonged QT, increased risk of VF), especially relevant given concurrent hypertension
• Renal: chronic hypokalaemia → vacuolar nephropathy of tubular cells → impaired concentrating ability → nephrogenic diabetes insipidus → polyuria, polydipsia, nocturia ^[2]
• Metabolic: impaired insulin secretion (K+ needed for pancreatic β-cell function) → glucose intolerance

• Alkalosis shifts the albumin-calcium equilibrium: more Ca²+ binds to albumin (albumin becomes more negatively charged in alkalotic pH) → ↓ionized Ca²+ → latent or overt tetany, paraesthesiae ^[2]
• Alkalosis also shifts the oxyhaemoglobin dissociation curve to the LEFT → ↓O₂ delivery to tissues (Bohr effect)

• Volume expansion (even modest) + direct vascular effects of aldosterone → sustained hypertension
• Aldosterone directly activates MR in cardiomyocytes, vascular smooth muscle, and fibroblasts → myocardial fibrosis, LVH, vascular remodelling, endothelial dysfunction
• These contribute to disproportionate target organ damage relative to degree of hypertension:
  • ↑LVH, ↑AF, ↑heart failure
  • ↑Stroke
  • ↑Proteinuria, ↑CKD progression
  • ↑Metabolic syndrome

This is the most important classification because it determines treatment:

Key point: Distinguishing unilateral from bilateral disease is the single most important step after confirming PA, because it dictates surgical vs medical management ^[1][4].

• Overt PA: classic presentation with hypertension + spontaneous hypokalaemia + ↑ARR + positive confirmatory test
• Normokalemic PA: increasingly recognized; PA WITHOUT hypokalaemia — this is actually the majority of cases! Only ~30–50% of PA patients have hypokalaemia at presentation. Do not rely on hypokalaemia to screen for PA.

Per the Endocrine Society 2024 guidelines, screen for PA in:

1. Sustained BP > 150/100 mmHg (or > 140/90 on 3 occasions)
2. Resistant hypertension (uncontrolled on ≥3 drugs including diuretic)
3. Hypertension + spontaneous or diuretic-induced hypokalaemia ^[3]
4. Hypertension + adrenal incidentaloma
5. Hypertension + sleep apnoea (high co-prevalence)
6. Hypertension + family history of early-onset HTN or CVA at young age (< 40)
7. All first-degree relatives of PA patients
8. Hypertension with onset < 30 years (especially without obesity/family history)

Stop antihypertensives for ≥2 weeks before dynamic testing ^[2]:

• Diuretics → ↑renin (false ↓ARR — may mask PA)
• β-blockers → ↓renin (false ↑ARR — may overdiagnose PA)
• ACEI/ARB → ↓aldosterone and ↑renin (false ↓ARR)
• Spironolactone → must be stopped ≥6 weeks (long-acting metabolites)

Drugs that can be continued (minimal effect on ARR):

• α-blockers (e.g., doxazosin) — preferred antihypertensive during workup
• Non-dihydropyridine CCBs (e.g., verapamil slow-release) — acceptable alternative
• Hydralazine — acceptable

Ensure reasonable sodium intake ^[2]: ↓Na intake → protects against hypokalaemia by reducing tubular Na+ available for exchange → may mask the biochemical phenotype.

Correct hypokalaemia before testing — hypokalaemia suppresses aldosterone secretion, potentially causing a false-negative ARR.

• Screening tests: ONDST + spot ARR + 24h urine metanephrines (for adrenal incidentaloma workup) ^[5]
• For suspected PA specifically: Plasma aldosterone concentration (PAC) + Plasma renin activity (PRA) or Direct renin concentration (DRC) → calculate ARR

This is the single most powerful tool for differential diagnosis. Measure plasma renin and plasma aldosterone and plot the result:

This matrix is derived from first principles:

• ↓Renin + ↑Aldosterone: The adrenal is autonomously overproducing aldosterone → volume expansion suppresses renin via negative feedback → this IS primary hyperaldosteronism.
• ↑Renin + ↑Aldosterone: Something upstream is driving renin (e.g., renal hypoperfusion) → renin activates the cascade → aldosterone rises appropriately → this is secondary hyperaldosteronism.
• ↓Renin + ↓Aldosterone: Volume expansion (suppressing renin) from a NON-aldosterone mineralocorticoid source → aldosterone is also suppressed → this is non-aldosterone mineralocorticoid excess ^[2][8].

These conditions present with hypertension (sometimes) and hypokalaemia but the renin is HIGH — the aldosterone elevation is appropriate and driven by extra-adrenal RAAS activation ^[1][8].

Why does secondary hyperaldosteronism cause hypokalaemia? The same mechanism as PA — aldosterone acts on ENaC/Na⁺-K⁺-ATPase. The difference is that the DRIVER is renin (extra-adrenal), not autonomous adrenal production. Clinically, secondary causes usually have oedema (because the underlying condition involves true or effective hypovolaemia driving ongoing Na retention WITHOUT aldosterone escape — the kidney "thinks" it needs to retain salt).

These are the trickiest mimics. They cause the same clinical picture (HTN + hypokalaemia + metabolic alkalosis) but BOTH renin AND aldosterone are suppressed ^[2][8].

Differentiated by salt-loaded balance study (9am supine + 1pm erect) ^[4]:

The principle is based on the different regulatory drivers of APA vs BAH:

• APA is primarily ACTH-dependent → aldosterone follows the diurnal cortisol rhythm (peaks in early morning, falls by noon). Moving from supine to erect does NOT raise aldosterone because the adenoma is insensitive to angiotensin II.

  • Result: Paradoxical ↓aldosterone on standing (because ACTH naturally falls from 8am to 12 noon) ^[1][2][4]

• BAH is primarily angiotensin II-dependent → aldosterone rises briskly with upright posture (standing activates RAAS via reduced venous return → mild ↓renal perfusion → ↑renin → ↑Ang II).

  • Result: ↑Aldosterone on standing (exaggerated response to ↑angiotensin in erect posture) ^[1][2][4]

Adrenal venous sampling from femoral vein is the gold standard for lateralization ^[7]. It involves bilateral adrenal venous catheterization via the femoral vein, measuring aldosterone and cortisol levels from each adrenal vein and a peripheral vein.

• Why is this needed? CT/MRI can be misleading:
  • A non-functioning "incidentaloma" on one side may be mistaken for an APA
  • Small APAs (< 1 cm) may be missed on CT
  • BAH may cause asymmetric hyperplasia mimicking unilateral disease
• Interpretation: Lateralization ratio (aldosterone/cortisol ratio from one side vs the other) > 4:1 typically indicates unilateral disease → adrenalectomy appropriate

• APA: typically a small (< 2 cm), well-defined, lipid-rich unilateral adrenal nodule; low attenuation on non-contrast CT (< 10 HU)
• BAH: bilateral adrenal limb thickening or normal-appearing adrenals
• Adrenal carcinoma: large (> 4 cm), irregular, heterogeneous, high attenuation
• Limitation: imaging alone cannot reliably distinguish a functioning APA from a non-functioning incidentaloma, hence the need for AVS in patients > 35–40 years ^[1]

• For suspected FH Type I (GRA): test for the chimeric CYP11B1/CYP11B2 gene
• Indicated if: onset < 20 years, family history of PA, family history of stroke at young age (< 40)

Why? Hypokalaemia itself suppresses aldosterone secretion from the zona glomerulosa (K⁺ is a direct stimulus for aldosterone release). If K⁺ is low, aldosterone may be misleadingly low → false-negative ARR → you miss the diagnosis.

• Supplement K⁺ to > 4.0 mmol/L before testing
• Use oral KCl (slow-release preferred)

Stop antihypertensives for ≥2 weeks before dynamic testing (MRA for ≥6 weeks) ^[1]:

What to use for BP control during wash-out? α-blockers (doxazosin) and/or verapamil SR — these have minimal effect on the RAAS axis and are the preferred antihypertensives during PA workup ^[1][2].

Ensure reasonable Na intake ^[1][2]: ↓Na intake → ↓tubular Na available for exchange at the collecting duct → protects against K loss → may mask hypokalaemia. Low Na also stimulates RAAS → ↑renin → may lower ARR → false negative.

Advise patients to maintain a liberal salt diet (not low-salt) for at least 3 days before testing.

Exclude other causes of hypokalaemia: diuretics, GI loss, renal tubular acidosis ^[1][2]:

• Document excessive urinary K loss ^[2]: spot urine K > 20 mmol/L with concurrent hypokalaemia confirms inappropriate renal K wasting (normal kidneys should conserve K when plasma K is low)

The ARR = Plasma Aldosterone Concentration (PAC) ÷ Plasma Renin Activity (PRA) [or Direct Renin Concentration (DRC)].

This is a ratio test that exploits the fundamental pathophysiology: in PA, aldosterone is HIGH and renin is LOW (suppressed by volume expansion). The ratio amplifies this divergence.

• Timing: morning (ideally 8–10 am), after the patient has been seated for 5–15 minutes (not immediately after lying supine or after vigorous exercise)
• Conditions: as per pre-test precautions above (K corrected, interfering drugs stopped, liberal salt)
• Measure simultaneously: PAC (in ng/dL or pmol/L) + PRA (in ng/mL/hr) or DRC (in mU/L or ng/L)

Per the 2024 Endocrine Society guidelines, a positive screen requires BOTH:

1. Elevated ARR (> 30 if using PAC in ng/dL and PRA in ng/mL/hr)
2. Elevated PAC (≥ 10 ng/dL) — this absolute aldosterone threshold prevents false positives in patients with very low renin (e.g., elderly, salt-loaded) where the ratio could be high despite normal aldosterone

Why use a ratio? Imagine two scenarios:

• PA patient: PAC = 25 ng/dL, PRA = 0.3 ng/mL/hr → ARR = 83 (clearly abnormal)
• Normal patient on low-salt diet: PAC = 15 ng/dL, PRA = 3.0 ng/mL/hr → ARR = 5 (normal — both are appropriately elevated)
• False positive risk: Elderly patient with low renin: PAC = 8 ng/dL, PRA = 0.2 → ARR = 40 (ratio is high but PAC is < 10, so this is NOT true PA — the absolute PAC threshold catches this)

The hallmark of PA is that aldosterone production is autonomous — it does NOT suppress when you give the body a sodium/volume load (which should normally suppress RAAS and therefore aldosterone). Confirmatory tests exploit this by loading salt/volume and checking whether aldosterone appropriately falls.

Exception: spontaneous hypokalaemia with Ald ≥ 20 ng/dL → practically diagnostic ^[1] — in this scenario, the pre-test probability is so high that confirmatory testing adds little value and you can proceed directly to subtyping.

1. You infuse 2 litres of normal saline over 4 hours → massive volume expansion
2. Volume expansion → ↑renal perfusion → ↓renin secretion from JGA + ↑ANP release
3. In a normal person: ↓renin → ↓Ang II → ↓aldosterone (aldosterone suppresses appropriately)
4. In PA: the adrenal is producing aldosterone autonomously → aldosterone remains elevated despite the volume/salt load → failure or inadequate suppression (Ald still > 10 ng/dL) ^[1][2]

Normal:     2L NS → ↓renin → ↓Ang II → ↓aldosterone (<5 ng/dL)      ✓ Suppressed
PA:         2L NS → ↓renin → ↓Ang II → aldosterone STILL HIGH (>10)  ✗ Not suppressed
Grey zone:  Ald 5-10 ng/dL → indeterminate → clinical judgement or repeat

Purpose: Anatomical assessment of adrenal glands — detect mass, determine side, assess malignancy risk.

Limitations of CT alone (why you cannot rely on imaging):

• Up to 25% of adults > 40 have non-functioning adrenal incidentalomas → a visible nodule may NOT be the source
• Small APAs (< 1 cm) can be missed
• Unilateral incidentaloma + contralateral BAH → imaging misleading
• Therefore, CT alone is insufficient for lateralization in most patients

When can CT alone suffice without AVS? Per the 2024 Endocrine Society guidelines:

• Patient < 35 years with spontaneous hypokalaemia, marked aldosterone elevation, AND a clear unilateral adenoma > 1 cm on CT with a normal contralateral adrenal → can proceed to surgery without AVS (very high pre-test probability; incidentalomas rare in this age group)

Differentiated by salt-loaded balance study (9am supine + 1pm erect) ^[4]:

Protocol ^[1][2]:

1. Patient admitted overnight, lying supine from midnight
2. 8 am (supine): Draw blood for PRA and aldosterone (and cortisol)
   • At this time: ACTH is HIGH (early morning cortisol peak); Ang II is LOW (supine = no RAAS activation)
3. Patient then ambulates (walks around) for 4 hours
4. 12 noon (erect): Draw blood again for PRA and aldosterone (and cortisol)
   • At this time: ACTH is LOWER (natural diurnal decline); Ang II is HIGHER (upright posture activates RAAS)

Interpretation ^[1][2]:

Why the paradoxical fall in APA?

• The adenoma's aldosterone production is driven primarily by ACTH (not Ang II, because the adenoma has lost normal Ang II responsiveness)
• ACTH follows a diurnal rhythm: peaks early morning, falls by noon
• When the patient stands up, Ang II rises but the adenoma doesn't respond to it
• Meanwhile, ACTH is falling → aldosterone falls too
• Net result: paradoxical FALL in aldosterone despite upright posture

Caveat: considered not reliable enough in differentiating between adenoma and hyperplasia ^[1] — the postural test has about 70–85% accuracy and should be supplemented by AVS in equivocal cases.

Adrenal venous sampling: bilateral adrenal venous catheterization → venous sampling to measure aldosterone level ^[2][7]

Principle: Directly sample the effluent blood from each adrenal vein (via femoral vein catheterization) and compare the aldosterone concentration from each side. This tells you which adrenal is over-producing.

Protocol:

1. Interventional radiologist catheterizes both adrenal veins (via femoral vein approach) ^[7]
2. Blood is drawn from:
   • Right adrenal vein (drains into IVC directly — technically more difficult to cannulate)
   • Left adrenal vein (drains into left renal vein — easier)
   • Peripheral (IVC) as a reference
3. Measure aldosterone and cortisol from all three sites
4. Cortisol is used to confirm successful cannulation — adrenal venous cortisol should be much higher than peripheral cortisol (selectivity index ≥ 2–3:1 without ACTH stimulation, ≥ 5:1 with ACTH stimulation)

Interpretation — Lateralization Index (LI):

$\text{LI} = \frac{\text{Aldo/Cortisol ratio (dominant side)}}{\text{Aldo/Cortisol ratio (non-dominant side)}}$

Additionally, the contralateral suppression index (non-dominant adrenal Aldo/Cortisol divided by peripheral Aldo/Cortisol < 1) suggests the contralateral gland is suppressed by the dominant adenoma, further supporting unilateral disease.

Why use the Aldo/Cortisol ratio rather than absolute aldosterone?

• Cortisol secretion is roughly symmetric from both adrenals
• Using cortisol as a denominator corrects for:
  • Differences in blood flow between the two adrenal veins
  • Dilution effects (e.g., if one catheter tip is further from the gland)
  • Ensures valid comparison between the two sides

When is AVS indicated?

• All confirmed PA patients ≥ 35 years who are potential surgical candidates (to prevent inappropriate surgery on a non-functioning incidentaloma)
• Can be omitted in patients < 35 years with classic clinical/biochemical picture + clear unilateral CT lesion

Complications: Rare (< 2.5%), but include adrenal vein rupture, adrenal haemorrhage, contrast reactions. Right adrenal vein cannulation is technically challenging (success rate 74–96%).

• Administer dexamethasone 0.5 mg q6h × 2–4 days
• In FH Type I: aldosterone suppresses (because production is ACTH-dependent in zona fasciculata)
• In sporadic PA: aldosterone does NOT suppress
• Confirmatory: long-range PCR for the chimeric gene (gold standard)

• ↑↑ 18-hydroxycortisol (> 100 nmol/day in urine): highly suggestive of APA or FH Type I
• Less specific for BAH
• Not widely available; primarily a research/confirmatory tool

Adrenalectomy is indicated for: ^[5]

• Functional adenoma (Conn's syndrome) — confirmed unilateral APA or unilateral hyperplasia on AVS ^[5]
• Adrenal incidentaloma meeting resection criteria (functional, > 4 cm, or growing > 0.5 cm in 6 months) ^[5]
• Adrenal malignancy (adrenocortical carcinoma — extremely rare in PA) ^[5]

This is a critical step that is frequently examined.

Pre-op preparation for primary aldosteronism: correct electrolyte imbalance, e.g. K+ ^[5]

Why specifically spironolactone for pre-op?

• It simultaneously addresses BOTH problems: blocks MR → ↓Na+ reabsorption → ↓volume/BP AND ↓K+ secretion → corrects hypokalaemia
• It also begins to reverse the direct aldosterone-mediated cardiac and vascular damage
• Usually a few weeks of medical Tx beforehand to normalize whole-body electrolyte balance ^[1][2]

Laparoscopic trans-peritoneal approach (lateral decubitus, ipsilateral side up): for mass < 6 cm ^[5]

• This is the standard approach for APA — most adenomas are small (< 2 cm)
• Patient positioned in lateral decubitus with the affected side up
• Advantages: smaller incisions, faster recovery, less post-op pain, shorter hospital stay
• Open approach: preferred if mass > 6 cm or malignant ^[5] (e.g., suspected adrenocortical carcinoma)

Complications — Intra-op: ^[5]

• Adrenal insufficiency (Conn's): IV hydrocortisone upon removal of adrenal gland ^[5]

  • Why? The contralateral zona glomerulosa has been chronically suppressed by the autonomous aldosterone from the adenoma (negative feedback via volume expansion → ↓renin → ↓Ang II → contralateral atrophy). Upon removal of the adenoma, there is a transient period of relative hypoaldosteronism until the contralateral gland recovers.
  • Note: glucocorticoid axis (zona fasciculata) is generally preserved in PA, so unlike Cushing's surgery, you do NOT typically need long-term cortisol replacement. However, IV hydrocortisone at physiological doses also has some mineralocorticoid activity and provides a safety net.

• Injury to surroundings: ^[5]

  • Right adrenalectomy: IVC, right lobe of liver ^[5] (the right adrenal sits between the IVC and right kidney, nestled against the liver)
  • Left adrenalectomy: pancreatic tail, spleen ^[5] (the left adrenal sits above the left kidney, near the tail of pancreas and spleen)

• Haemodynamic instability — less of a concern in PA than in phaeochromocytoma, but can occur with fluid shifts

Predictors of post-operative BP cure (i.e., factors favouring complete resolution of HTN):

• Younger age at surgery
• Shorter duration of hypertension pre-operatively
• Fewer antihypertensive medications pre-operatively
• Female sex
• Absence of target organ damage (no LVH, no CKD)
• Higher pre-op responsiveness to spironolactone (if BP normalizes on spironolactone pre-op, it is more likely to normalize post-op)

• Bilateral idiopathic adrenal hyperplasia (BIAH): medical treatment ^[4]
• Bilateral adrenalectomy would lead to adrenal crisis ^[4] — this is why you NEVER perform bilateral adrenalectomy for BAH (you would lose ALL adrenal function → Addisonian crisis)
• Unilateral disease in patients who are unfit for surgery (e.g., severe comorbidities, advanced age) or who decline surgery
• FH Type I (GRA) — treated with low-dose dexamethasone rather than MRA

K-sparing diuretics (2nd line), e.g. amiloride, triamterene ^[1][2]

Why are ENaC blockers considered second-line? Because they block the downstream EFFECT of aldosterone (the channel) but NOT the receptor itself. Aldosterone's deleterious effects on the heart, vessels, and kidneys are mediated through MR activation in those tissues — ENaC blockers do nothing to prevent this extra-renal damage. MRAs (spironolactone/eplerenone) block the MR everywhere → cardiovascular protection on top of electrolyte/BP correction ^[1].

Many patients on MRA alone will not achieve BP targets. Additional agents can be added:

• < 130/80 mmHg (per 2024 Endocrine Society and ESC/ESH guidelines) — PA patients are at very high cardiovascular risk
• Lifestyle modifications: dietary Na restriction (< 2g/day), weight management, exercise, alcohol moderation ^[3]

• Extremely rare (< 1% of PA)
• Suspect if: adrenal mass > 4 cm, irregular margins, high attenuation on CT (> 10 HU), heterogeneous enhancement, rapid growth
• Management: Open adrenalectomy (not laparoscopic — need complete excision with wide margins ± lymph node dissection) ^[5]
• Often co-secretes cortisol and androgens → mixed biochemical picture
• May require adjuvant mitotane ± chemotherapy

• Spironolactone is contraindicated in pregnancy (Category D — anti-androgen effect risks feminization of male fetus)
• Eplerenone: limited data; generally avoided
• Preferred agents: α-methyldopa, labetalol, nifedipine for BP control; amiloride may be considered (Category B)
• Definitive management (surgery) usually deferred to post-partum unless severe

Per cardiology guidelines, PA should be specifically sought in resistant hypertension. If confirmed:

• Adding spironolactone 25–50 mg/day to existing triple therapy (ACEI/ARB + CCB + thiazide) is the most effective "fourth drug" for resistant HTN
• The PATHWAY-2 trial (2015) demonstrated that spironolactone was superior to bisoprolol, doxazosin, and placebo as add-on therapy for resistant hypertension — this is partly because a significant proportion of "resistant HTN" patients have undiagnosed PA