• Primary aldosteronism is the most common cause of secondary hypertension, accounting for 5–13% of all hypertensive patients (higher than the historically quoted 1–2%) ^[1][3]
• In resistant hypertension (uncontrolled BP despite ≥3 antihypertensive drugs at optimal doses), the prevalence of PA rises to ~15–20% ^[3]
• Previously massively underdiagnosed because the "classic" presentation of hypokalaemia is actually present in only ~30–50% of PA cases — most patients are normokalaemic ^[3]
• In Hong Kong, the prevalence mirrors international data; awareness has increased with the wider adoption of the aldosterone-to-renin ratio (ARR) as a screening tool

The Endocrine Society 2016/2024 guidelines recommend screening for PA in the following populations:

• Adrenal glands: paired retroperitoneal organs, each sitting on the superior pole of each kidney
• Right adrenal is pyramidal; left is semilunar/crescent-shaped
• Blood supply: superior (from inferior phrenic artery), middle (from aorta), inferior (from renal artery) suprarenal arteries
• Venous drainage: right adrenal vein → IVC directly (short, surgically significant); left adrenal vein → left renal vein (longer)

This anatomical asymmetry is critical during adrenal vein sampling (AVS) — cannulating the short right adrenal vein is technically more difficult and is a common cause of AVS failure.

The adrenal cortex has three concentric zones, remembered by the mnemonic "GFR makes Salt, Sugar, Sex":

Aldosterone is the principal mineralocorticoid. Its target is the mineralocorticoid receptor (MR) in the principal cells of the cortical collecting duct in the kidney.

Mechanism of action:

1. Aldosterone diffuses into the principal cell → binds cytoplasmic MR → translocates to nucleus
2. Upregulates expression of ENaC (epithelial sodium channel) on the apical (luminal) membrane → increases Na⁺ reabsorption
3. Upregulates basolateral Na⁺/K⁺-ATPase → pumps reabsorbed Na⁺ into the interstitium/blood
4. The lumen becomes relatively electronegative (as positive Na⁺ is removed) → this electrochemical gradient drives:
   • K⁺ secretion into the lumen via ROMK channels → kaliuresis
   • H⁺ secretion via H⁺-ATPase in intercalated cells → bicarbonatogenesis (metabolic alkalosis)

Why does aldosterone excess cause hypokalaemia AND metabolic alkalosis? Because the same electrochemical gradient that drives K⁺ secretion also drives H⁺ secretion. Losing both K⁺ and H⁺ in the urine simultaneously produces hypokalaemia and metabolic alkalosis. They are two sides of the same coin.

Biochemical factors that INCREASE aldosterone secretion ^[1]:

• Angiotensin II (most potent stimulator in normal physiology)
• ACTH (short-term stimulation only)
• Hyperkalaemia (direct effect on zona glomerulosa — so that you dump more K⁺)
• Hyponatraemia (so that you retain more Na⁺)

Physiological stimuli that INCREASE aldosterone ^[1]:

• Upright posture
• Exercise
• Sodium deprivation
• Hypovolaemia → reduced renal perfusion → macula densa signals JG cells → renin release
• Stress
• Diuretics

Stimuli that DECREASE aldosterone ^[1]:

• Increasing age
• Sodium loading
• Volume overload

The adrenal gland autonomously produces excess aldosterone, independent of the normal RAAS stimulation. Because aldosterone drives Na⁺ and water retention → volume expansion → negative feedback on JG cells → renin is suppressed.

^[1] Senior notes state: "Adrenal adenoma (Conn's syndrome) → 60-70%; Adrenal hyperplasia → 20-40%." Note that more recent large series (2020s) have shifted the prevalence: BAH is now considered the most common subtype (~60%), with APA at ~30-35%. The GC lecture slides and older notes may still quote adenoma as more common — for exam purposes, be aware of both framings but the current international consensus favours BAH as most common.

Familial Hyperaldosteronism — Important Subtypes

Here, the adrenal gland is responding appropriately to elevated renin. The problem is upstream — reduced effective circulating volume or renal perfusion.

These conditions present with hypertension, hypokalaemia, and metabolic alkalosis but with LOW aldosterone AND low renin — i.e., it's not aldosterone that's causing the problem, but another substance activating the MR or ENaC.

Primary hyperaldosteronism has no specific signs or symptoms ^[3]. The presentation is dominated by hypertension and its consequences. Hypokalaemia, which was historically considered the hallmark, is actually absent in the majority of PA patients (only ~30-50% are hypokalaemic at presentation). This is why PA was previously massively underdiagnosed.

These are often the first clues that lead to investigation for PA:

In secondary hyperaldosteronism, the clinical features are dominated by the underlying disease:

In secondary hyperaldosteronism, oedema IS present because the aldosterone escape mechanism is overwhelmed by the underlying pathophysiology driving continued RAAS activation (unlike primary hyperaldosteronism).

Aldosterone excess causes organ damage disproportionate to the degree of blood pressure elevation — this is a critical concept. PA patients have worse cardiovascular outcomes than essential hypertension patients with the same BP level because aldosterone exerts:

• Direct cardiac effects: myocardial fibrosis, left ventricular hypertrophy (LVH), diastolic dysfunction
• Vascular effects: endothelial dysfunction, arterial stiffness, inflammation
• Renal effects: glomerular hyperfiltration, proteinuria (microalbuminuria), renal fibrosis
• Metabolic effects: insulin resistance, metabolic syndrome — PA patients have a higher rate of diabetes than essential HTN patients

This means that treating PA (whether surgically or medically) has benefits beyond BP control — it reverses the direct aldosterone-mediated organ damage.

The adrenal gland is autonomously pouring out aldosterone. Renin is suppressed by volume expansion (negative feedback on JG cells).

The GC 066 lecture ^[1] states: Adrenal adenoma (Conn's syndrome) → 60–70%; Adrenal hyperplasia → 20–40%; Dexamethasone-suppressible primary hyperaldosteronism → 1–2%; Adrenal carcinoma → very rare. Be aware that more recent large registries show BAH as more common (~60%) than APA (~30–35%), but for in-house exam framing, default to the GC slide figures if the question references them.

Here the adrenal is responding appropriately to an upstream stimulus — the real problem is reduced effective circulating volume or reduced renal perfusion.

These are the great mimics. The clinical picture is identical (HTN + hypokalaemia + metabolic alkalosis), but both renin AND aldosterone are suppressed. Something else is activating the mineralocorticoid receptor or ENaC.

Before jumping to hyperaldosteronism, exclude other causes of hypokalaemia ^[1]:

Senior notes ^[7]: "Discriminatory by comparing 9am and 1pm sample — BIAH: ↑ renin & aldosterone — sensitive to postural change (standing causes ↑ Ang II); Adenoma: paradoxical ↓ renin & aldosterone — aldosterone production becomes independent of RAAS but dependent on ACTH (highest in morning, fall afterwards)."

CT alone is insufficient to differentiate subtypes. Why?

• A unilateral adrenal nodule on CT may be a non-functioning incidentaloma in a patient who actually has bilateral hyperplasia (prevalence of adrenal incidentalomas increases with age — up to 5–7% of the population)
• Bilateral hyperplasia may appear normal on CT (the hyperplasia may be microscopic)
• Small APAs ( < 1 cm) may be missed on CT

This is why adrenal venous sampling (AVS) is the gold standard ^[7][10] for subtype differentiation in patients who are surgical candidates. The GC 153 lecture ^[10] and Endocrine Data Interpretation lecture ^[2] emphasise this point.

AVS Technical Details ^[7]:

• Blood cortisol & aldosterone sampled from upper, middle, lower IVC, right and left adrenal veins
• Adrenal vein to IVC cortisol > 10:1 = successful cannulation (confirms catheter is truly in the adrenal vein, not a lumbar vein)
• Calculate cortisol-corrected aldosterone ratio for each adrenal vein, then divide higher by lower side
• > 4:1 = lateralises to the higher side (unilateral → surgery); < 3:1 = bilateral (medical management)

The diagnostic approach to primary aldosteronism (PA) is fundamentally a three-step sequential process, moving from least invasive to most invasive. This principle is stressed repeatedly across the GC lectures and endocrine teaching ^[1][11][12]:

Endocrine is unique in that you need biochemistry before imaging → Resolution is too high with our imaging nowadays → so we might find benign lesions, which are not related to the condition ^[11]

The GC 066 lecture slide ^[1] states: "Diagnosis of primary aldosteronism includes biochemical tests as well as radiological images. Interpretation of biochemical tests can be difficult." This is a direct in-house exam-relevant point.

Before any dynamic biochemical testing, several precautions must be taken. These are non-negotiable because many drugs and conditions interfere with the RAAS axis and can produce false results.

Principles when investigating a case of potential Conn's syndrome ^[1]:

1. Exclude other causes of hypokalaemia ^[1]:

   • Diuretics (most common cause of hypoK)
   • GI loss (diarrhoea, vomiting)
   • Renal tubular acidosis (type 1 to 3) ^[1]

2. Document excessive urinary potassium loss ^[1]:

   • Spot or 24-hour urine K⁺ — if urine K⁺ > 30 mmol/day (or spot urine K⁺ > 25 mmol/L) in the setting of hypokalaemia, this is inappropriate kaliuresis → points to a renal cause of K⁺ wasting

3. Ensure a reasonable Na intake because low Na intake may protect against hypokalaemia by decreasing tubular Na available for exchange ^[1]:

   • Why? Aldosterone drives K⁺ secretion by first reabsorbing Na⁺ through ENaC. If Na⁺ delivery to the collecting duct is low (from Na⁺-restricted diet), there is less Na⁺ to reabsorb, less lumen electronegativity, and therefore less K⁺ secretion. This can mask the hypokalaemia.

4. Stop interfering medications before dynamic biochemical tests:

The ARR is the ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA) (or direct renin concentration, DRC). It exploits the principle that in PA, aldosterone is autonomously elevated while renin is suppressed by volume expansion — creating a disproportionately high ratio.

• Collect blood in the morning in a seated posture ^[7] — the patient should sit quietly for 15–30 minutes before the sample is taken
• Stop MRA ± diuretics before testing ^[7]
• Ideally, correct hypokalaemia first — severe hypoK directly suppresses aldosterone secretion (K⁺ is a stimulus for aldosterone release from zona glomerulosa), which can cause a false-negative ARR
• Draw for: PAC, PRA (or DRC), and serum K⁺ simultaneously

The GC lecture and senior notes ^[1][7][13] define a positive screen as:

Senior notes ^[7]: "Primary hyperaldosteronism: plasma renin activity < 1 ng/mL/hour, plasma aldosterone conc. ≥ 20 ng/dL. Now use less aldosterone:renin ratio (ARR) [Grand round]."

Ryan Ho Endocrine ^[13]: "1° hyperaldosteronism: ↓ basal PRA ( < 1), ↑ basal aldosterone (≥ 10), ARR > 30 (90% Sens, 90% Spec). 2° hyperaldosteronism: ↑ basal PRA, ↑ basal aldosterone, ARR < 10. Non-aldosterone mineralocorticoid excess: ↓ basal PRA, ↓ basal aldosterone."

Method ^[7][13]:

• IV normal saline 0.9% at 500 mL/hour for 4 hours (total 2 L) in sitting/recumbent position
• Monitor BP, pulse, and watch out for signs of fluid overload (especially if underlying HF) ^[13]
• Draw PAC and PRA before and after the infusion

Rationale: Volume loading expands plasma volume → suppresses renin → in a normal person, aldosterone falls. In PA, the adrenal is autonomous → aldosterone remains inappropriately elevated.

Findings ^[7][13]:

• Normal: suppression of both renin and aldosterone after saline loading
• Primary hyperaldosteronism: failure or inadequate suppression (aldosterone still ≥ 10 ng/dL or ≥ 277 pmol/L post-infusion) ^[7]
• Post-infusion PAC < 5 ng/dL → PA excluded
• Post-infusion PAC 5–10 ng/dL → indeterminate — consider further testing

Contraindications ^[7]:

• Uncontrolled hypertension
• Congestive heart failure
• Risk of cardiac arrhythmia (from rapid volume shift + existing hypoK)

Method ^[7]:

• PO NaCl 1800 mg TDS for 5 days (± K supplement: prevent hypoK due to increased Na intake) ^[7]
• Admit on Day 5: confirm spot urine Na ≥ 100 mmol/L (to ensure adequate salt loading was achieved) → administer IV saline if inadequate ^[7]
• Collect 24-hour urinary aldosterone on Day 3–5

Interpretation:

• 24h urinary aldosterone > 12 μg/day (> 33 nmol/day) after adequate salt loading → confirms PA
• < 10 μg/day → PA unlikely
• This test is used in certain centres where IV saline infusion is not feasible

• Oral fludrocortisone 0.1 mg QID for 4 days + NaCl supplementation
• At the end, if PAC remains elevated → confirms PA
• Considered the most reliable confirmatory test but rarely used because of logistical complexity and risk (prolonged mineralocorticoid loading in already hypertensive/hypokalaemic patients)

• 25–50 mg captopril PO; measure PAC and PRA at baseline, 1h, and 2h
• Captopril blocks ACE → Ang II falls → in normal subjects, aldosterone falls
• In PA, aldosterone remains non-suppressed
• Less commonly used; some centres use as alternative when saline loading is contraindicated

The GC 066 lecture ^[1] and senior notes ^[7] emphasise this as a key discriminatory tool.

Procedure ^[7]:

• Performed during the same admission, usually the day after saline infusion
• PO NaCl 1800 mg TDS for 5 days + K⁺ supplement ^[7] — patient is salt-loaded
• PRA and aldosterone measured at:
  • 9 AM supine (after 8 hours of overnight recumbence)
  • 1 PM erect (after 4 hours of ambulation) ^[7]
• Collect 24-hour urinary aldosterone ^[7]

Physiological Basis ^[1][13]:

Interpretation ^[7][13]:

Senior notes ^[1] elaborate: "Adrenal hyperplasia is more sensitive to Ang II drive, but not ACTH. Hence, at 8 AM in the morning, the supine aldosterone will be lowest since that is when ACTH drive is predominant. However, upon standing for 4 hours + activation of RAAS, there is less ACTH drive and more Ang II drive → as hyperplasia is sensitive to Ang II drive, there is an excessive RISE in aldosterone compared to the morning supine level (in 90% of cases)."

The investigation sequence ^[11]: "Use the simple screening tests first, before moving on to imaging → and if that still doesn't work, then think of invasive testing."

Imaging characteristics to assess ^[2]:

• Irregular border, Hounsfield units (the higher, the more worrying; the lower = the more fat, less worrying) ^[2]
• Size: > 4 cm raises concern for adrenal carcinoma ^[2]
• Constitutional symptoms + large irregular mass → consider adrenal carcinoma or metastatic deposit (primary adrenal neoplasm uncommon, more common for it to be a metastatic adrenal neoplasm) ^[2]

Critical pitfall: CT alone is insufficient ^[1] —

• Adrenal incidentalomas are common (prevalence 3–7% in general population), especially in older patients → a unilateral nodule may be a non-functioning incidentaloma coexisting with bilateral hyperplasia
• Small APAs ( < 1 cm) may be below CT resolution
• Bilateral macronodular hyperplasia can mimic bilateral adenomas

The gold standard test used to differentiate between adenoma and hyperplasia as a cause of primary aldosteronism is adrenal venous sampling ^[1][7]

Indications ^[7][13]:

• All patients with confirmed PA who are surgical candidates (age < 40 with clear unilateral adenoma on CT may be an exception — see algorithm below)
• Discordant postural test and CT findings
• Bilateral adrenal nodules on CT where lateralisation needs to be confirmed

Procedure ^[7]:

• Percutaneous, done by interventional radiology ^[1]
• Catheter placed in both adrenal veins via femoral vein approach ^[10]
• Blood cortisol and aldosterone sampled from: upper, middle, lower IVC, right and left adrenal veins ^[7]

Confirming successful cannulation ^[7]:

• Adrenal vein to IVC cortisol ratio > 10:1 = successful cannulation ^[7]
• Why cortisol? Because cortisol is produced by both adrenal glands equally and in large quantities. If the catheter is truly in the adrenal vein (not a lumbar or phrenic vein), cortisol will be massively concentrated compared to peripheral IVC blood. This serves as an internal quality control.
• Right adrenal vein is technically more difficult to cannulate because it is short and drains directly into the IVC (anatomical point from Section 3 of these notes)

Interpreting lateralisation ^[7]:

• Calculate cortisol-corrected aldosterone ratio for each adrenal vein: i.e., Aldosterone/Cortisol for the left and right adrenal veins
• Divide the higher side by the lower side to obtain the lateralisation index:
  • > 4:1 = lateralises to the higher side → unilateral disease → surgery ^[7]
  • < 3:1 = bilateral → no lateralisation → medical management ^[7]
  • 3:1–4:1 = equivocal — requires clinical judgement

Why correct for cortisol? Because the catheter position and dilution effects vary between the two sides. By dividing aldosterone by cortisol, you normalise for any differences in catheter position and blood flow dilution — you're comparing the relative aldosterone output from each gland.

Additional finding — Contralateral suppression ^[13]:

• If the contralateral (non-dominant) adrenal vein shows an aldosterone/cortisol ratio lower than the IVC ratio, this confirms suppression of the normal gland by the autonomous side → further supports unilateral disease

When PA is discovered in the context of an adrenal incidentaloma, the questions to ask are ^[2]:

1. Is it malignant or benign?

   • Imaging characteristics → irregular border, Hounsfield units ^[2]
   • Size > 4 cm → higher malignancy risk
   • Constitutional symptoms ^[2]

2. Is it functional or not? — Must screen for THREE hormonal syndromes ^[2]:

   • Morning cortisol (if low, confirm exogenous) → if high, followed by suppression testing → subclinical Cushing's ^[2]
   • ARR ratio → PA ^[2]
   • 24-hour urine for steroid profiling → for CA adrenals ^[2]
   • Plasma metanephrines → pheochromocytoma ^[2]

There is no single universally agreed "diagnostic criterion" in the way that, say, the Jones criteria define rheumatic fever. Instead, PA is diagnosed through a sequential biochemical algorithm. The Endocrine Society 2016 Clinical Practice Guideline (updated 2024) defines PA as:

Primary aldosteronism is confirmed when there is:

1. A positive screening test (elevated ARR with PAC ≥ 10–15 ng/dL)
2. AND a positive confirmatory test (failure of aldosterone to suppress on salt/volume loading — post-infusion PAC ≥ 10 ng/dL)

The HKU/PWH salt-loaded balance study protocol ^[7] combines confirmatory and discriminatory steps:

• Confirmatory: 9 AM plasma renin activity < 1 ng/mL/hour, plasma aldosterone conc. ≥ 10 ng/dL (≥ 277 pmol/L) ^[7]
• Discriminatory by comparing 9 AM and 1 PM sample ^[7] → separates adenoma from hyperplasia as described above

The entire management strategy hinges on one question: Is the disease unilateral or bilateral?

• Unilateral disease (adenoma, unilateral hyperplasia) → surgery via unilateral adrenalectomy — the localised pathology can be excised ^[1]
• Bilateral disease (bilateral idiopathic adrenal hyperplasia, BIAH) → medical treatment — the generalised pathology cannot be removed without causing adrenal crisis ^[1][7]

GC 066 lecture ^[1]: The reason we do "so many tests to differentiate between adrenal adenoma and hyperplasia" is because there are "implications on management" — adenoma is surgical, hyperplasia is medical. This is the single most important management decision point.

Adrenal adenoma → surgery via unilateral adrenalectomy ^[1]. This applies to:

• Aldosterone-producing adenoma (Conn's syndrome) — the most common indication
• Unilateral adrenal hyperplasia — behaves like adenoma, confirmed by AVS lateralisation > 4:1 ^[7]

This is a critical phase. You cannot simply take a hypokalaemic, hypertensive patient straight to theatre.

Remember to pre-medicate to optimize electrolyte balance before surgery ^[1]

Laparoscopic adrenalectomy ^[1][14]:

• Laparoscopic trans-peritoneal approach (lateral decubitus, ipsilateral side up): for mass < 6 cm ^[14]
• Open approach: preferred if mass > 6 cm or malignant ^[14]
• Minimally invasive laparoscopic approach is standard for benign APAs (which are typically < 2 cm)

Younger patients, shorter duration of HTN, fewer antihypertensive drugs pre-op, and absence of a family history of HTN predict better BP outcomes after surgery.

Adrenal hyperplasia → medical ^[1]. Bilateral adrenalectomy is not performed because:

• Generalized pathology, cannot remove all ^[1]
• Bilateral adrenalectomy → complete adrenal insufficiency → lifelong glucocorticoid + mineralocorticoid replacement → risk of adrenal crisis → far worse than the disease itself

Medical management is also indicated for:

• Patients with unilateral disease who decline or are unfit for surgery
• While awaiting surgery (pre-operative optimisation)
• FH-I (GRA) — managed medically with dexamethasone ± MRA

Amiloride / triamterene → second line if patient can't tolerate spironolactone, and cannot afford eplerenone ^[1]

If BP is not at target with MRA alone (common, as aldosterone-mediated vascular remodelling may persist), add:

Management is directed at the underlying cause, not at the aldosterone itself:

• Hyperkalaemia: same mechanism as spironolactone, though may be slightly less common at equivalent doses
• Significantly fewer anti-androgenic effects due to selective MR binding
• More expensive ^[1] — a practical limitation, especially in public hospital settings in Hong Kong

• Hyperkalaemia: direct ENaC blockade → reduced K⁺ secretion. Same monitoring and management as above
• No anti-androgenic effects (non-steroidal structure)