This lecture addresses secondary hypertension caused by endocrine disorders — specifically conditions arising from the adrenal gland. While essential hypertension accounts for 92–94% of all hypertension in the general population, endocrine hypertension represents a small but critically important subset (0.3–0.4% of the general population, but up to 0.5–12% in specialist clinics) because these conditions are potentially curable if correctly identified ^[1].

The lecture systematically covers three major endocrine causes of hypertension:

1. Conn's syndrome (primary hyperaldosteronism)
2. Cushing's syndrome (glucocorticoid excess)
3. Phaeochromocytoma (catecholamine-secreting tumour)

For each condition, the lecture covers physiology → pathology → clinical features → biochemical investigation → localisation → management → surgical considerations.

This is a perennial favourite for summative exams — it integrates biochemistry (RAAS, cortisol axis, catecholamines), endocrinology, surgery (adrenalectomy), and pharmacology (spironolactone, phenoxybenzamine, metyrapone). Past papers consistently test:

• Recognising the clinical triad of phaeochromocytoma
• Interpreting dexamethasone suppression test results
• Differentiating adenoma vs. hyperplasia in primary aldosteronism
• Perioperative management of Cushing's and phaeochromocytoma
• Understanding why α-blockade must precede β-blockade

Aldosterone increases Na⁺ reabsorption in the distal renal tubule and ascending loop of Henle by exchanging Na⁺ for K⁺ and H⁺ ions. Excess aldosterone therefore leads to hypokalaemia and metabolic alkalosis. ^[1]

Why hypokalaemia? Because aldosterone drives the epithelial sodium channel (ENaC) in the collecting duct principal cells. As Na⁺ is reabsorbed, the lumen becomes more electronegative, which drives K⁺ and H⁺ secretion. More aldosterone = more Na⁺ reabsorbed = more K⁺ and H⁺ lost → hypokalaemic metabolic alkalosis.

Why hypertension? Na⁺ retention expands extracellular fluid volume → increased blood pressure. Additionally, aldosterone has direct vascular and cardiac pro-fibrotic effects.

Mineralocorticoid action: 30–40% from basal cortisol secretion, 50–60% from aldosterone. Controlled by the renin-angiotensin system. ^[1]

This is a crucial point: cortisol itself has mineralocorticoid activity. In normal physiology, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in the kidney converts cortisol → cortisone (which doesn't activate the mineralocorticoid receptor). In Cushing's syndrome, cortisol overwhelms this enzyme → mineralocorticoid effects → hypokalaemia. This also explains the mechanism of liquorice-induced hypertension (liquorice inhibits 11β-HSD2).

Angiotensinogen (liver) → [Renin from kidneys] → Angiotensin I → [ACE] → Angiotensin II → Vasoconstriction + Aldosterone secretion from adrenals → Na⁺ retention → ↑BP ^[1]

Physiological stimuli increasing aldosterone: upright posture, exercise, sodium deprivation, hypovolaemia, stress, diuretics. Decreasing: increasing age, sodium loading, volume overload. ^[1]

Why posture matters so much: Standing upright activates the RAAS (blood pools in lower extremities → relative hypovolaemia → renin release). This is the physiological basis of the postural test used to differentiate adenoma from hyperplasia (see below).

Primary hyperaldosteronism: adrenal adenoma (Conn's syndrome) 60–70%, adrenal hyperplasia 20–40%, dexamethasone-suppressible 1–2%, adrenal carcinoma — very rare. ^[1]

Secondary hyperaldosteronism: renal artery stenosis, congestive cardiac failure, cirrhosis, nephrotic syndrome, salt-losing states. ^[1]

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

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

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

Why Na⁺ intake matters: If the patient is on a low-sodium diet, less Na⁺ reaches the collecting duct for exchange with K⁺, so hypokalaemia may be masked. You need adequate Na⁺ delivery to "unmask" the K⁺-wasting effect of aldosterone.

Step 4: Stop diuretics, β-blockers and ACE inhibitors for at least 2 weeks before dynamic biochemical tests. ^[1]

Why stop these drugs?

• Diuretics: Cause hypokalaemia independently and activate RAAS → confound results
• β-blockers: Suppress renin release (renin is partly controlled by β₁-receptors on juxtaglomerular cells) → falsely low renin
• ACE inhibitors: Block Ang II formation → falsely low aldosterone, falsely high renin

The Aldosterone-to-Renin Ratio (ARR) is the initial screening test (from GC 153 and Block A notes) ^[3]. A high ARR ( > 30 with aldosterone in ng/dL and renin in ng/mL/h) suggests primary aldosteronism and warrants confirmatory testing.

0.9% normal saline IV (500 mL/h) for 4 hours — i.e. 2L in 4 hours, sitting or recumbent. Monitor pulse and BP and watch for signs of fluid overload. Measure renin/aldosterone post salt loading. Normal response: suppression of renin and aldosterone levels. Primary aldosteronism: failure or inadequate suppression. ^[1]

Why this works: In a normal person, sodium loading expands blood volume → suppresses RAAS → aldosterone falls. In primary aldosteronism, the adrenal is autonomously producing aldosterone, so it does not suppress despite volume expansion.

Postural test: Measure supine/erect plasma renin and aldosterone. Supine at 8am after 8 hours overnight recumbence. Erect at 12 noon after 4 hours of ambulation. Normal response: supine to upright posture activates RAA with a rise in renin and aldosterone. ^[1]

Adenoma is very sensitive to ACTH. Hyperplasia responds excessively to angiotensin II but not to ACTH. ^[1]

Early morning supine position — ACTH drive is high and angiotensin drive is low. Lunchtime erect position — ACTH drive has fallen and angiotensin drive is high. ^[1]

The reasoning:

• Adenoma cells are ACTH-responsive. In the early morning (supine), ACTH is at its peak (diurnal rhythm), so adenoma aldosterone is high. By noon (erect), ACTH has fallen, and even though angiotensin rises from standing, the adenoma doesn't respond well to angiotensin → aldosterone paradoxically falls on standing.
• Hyperplasia cells are angiotensin-responsive. Standing activates RAAS → angiotensin II rises → hyperplastic glands respond excessively → aldosterone rises exaggeratedly on standing.

This is the gold standard for lateralisation. A CT may show a nodule, but incidentalomas are common (especially in older patients), so you cannot rely on imaging alone. AVS catheterises both adrenal veins and measures aldosterone:cortisol ratios bilaterally. A lateralisation ratio > 4:1 confirms unilateral disease → surgical candidate ^[1][2].

Spironolactone: competitive antagonist to aldosterone. Amiloride or triamterene: direct actions on distal renal tubules blocking Na⁺ reabsorption and K⁺ excretion independent of aldosterone. Surgery in adrenal adenoma. Medical treatment in adrenal hyperplasia. ^[1]

Why spironolactone? It directly blocks the mineralocorticoid receptor (MR), reversing Na⁺ retention, K⁺ wasting, and BP elevation. Side effects include gynaecomastia (because spironolactone also has anti-androgenic activity) — in male patients, eplerenone (a more selective MR antagonist) may be preferred.

Why amiloride? It blocks ENaC directly, so it works downstream of aldosterone. Useful as an alternative or adjunct when spironolactone side effects are intolerable.

ACTH-dependent: Cushing's disease (pituitary/hypothalamic) → ACTH ↑, cortisol ↑. Ectopic ACTH (malignant or benign non-endocrine tumour) → ACTH ↑, cortisol ↑. ^[1]

Non-ACTH-dependent: Adrenal adenoma → ACTH suppressed, cortisol ↑. Adrenal carcinoma → ACTH suppressed, cortisol ↑. Iatrogenic (steroid administration) → ACTH suppressed, cortisol decreased (exogenous steroids not measured as cortisol). ^[1]

From the 2021 past paper minicase, students were asked to "list physical signs which suggest glucocorticoid excess" ^[10]. Key features include:

• Central obesity with thin limbs (cortisol promotes visceral fat deposition while causing peripheral muscle wasting)
• Moon face and buffalo hump (fat redistribution)
• Purple striae (> 1cm wide, on abdomen, thighs, breasts — cortisol weakens collagen)
• Easy bruising and thin skin (collagen and vascular fragility)
• Proximal myopathy (cortisol is catabolic to muscle)
• Hypertension (cortisol has mineralocorticoid activity + potentiates catecholamines)
• Glucose intolerance/diabetes (cortisol is diabetogenic — gluconeogenesis, insulin resistance)
• Hypokalaemic metabolic alkalosis (mineralocorticoid effect)
• Osteoporosis (cortisol inhibits osteoblasts, promotes osteoclasts)
• Depression/psychosis (neuropsychiatric effects of cortisol)
• Hirsutism and acne (adrenal androgen excess in adrenal causes)

CXR, MRI pituitary, CT adrenals, CT body scans. Venous sampling for ACTH — Inferior Petrosal Sinus Sampling (IPSS). ^[1]

IPSS is the gold standard for confirming pituitary source. Catheters are placed in both inferior petrosal sinuses, and ACTH is measured centrally vs peripherally before and after CRH stimulation. A central:peripheral ratio > 2 (basal) or > 3 (post-CRH) confirms pituitary source. This is crucial because pituitary microadenomas are often too small to see on MRI ^[1][2].

Adrenal tumours — surgery. Pituitary tumours — transsphenoidal surgery. Medical treatment essential to reduce hypercortisolism prior to surgery. ^[1]

Metyrapone: blocks cortisol synthesis at the final 11β-hydroxylase step. Ketoconazole: inhibits cortisol and androgen secretion — hepatotoxicity is a potential problem. ^[1]

Why reduce cortisol before surgery? Hypercortisolaemia causes:

• Poor wound healing
• Immunosuppression → infection risk
• Hyperglycaemia
• Hypertension
• Thromboembolic risk

Operating on a hypercortisolaemic patient without pre-treatment dramatically increases surgical morbidity and mortality.

Control and correct: blood pressure, diabetes, hypokalaemia. Prophylaxis: steroid cover, antibiotics, deep vein thrombosis. ^[1]

The biosynthetic pathway for catecholamines is almost identical in adrenal medulla and sympathetic neurons. An additional phenylethanolamine-N-methyltransferase (PNMT) step converts noradrenaline → adrenaline in the adrenal medulla. ^[1]

Pathway: Tyrosine → DOPA (tyrosine hydroxylase, rate-limiting) → Dopamine → Noradrenaline → Adrenaline (PNMT, only in adrenal medulla)

Noradrenaline: α₁ and β₁ receptors. 95% from peripheral sympathetic nerve endings, remainder from adrenal medulla. Adrenaline: β₁ and β₂ receptors, weak α₁ actions — represents true secretion from adrenal medulla. Dopamine: released during intense adrenal medullary activity; most circulating dopamine is of renal origin. ^[1]

Metabolised predominantly extraneuronally by catecholamine-O-methyltransferase (COMT) to O-methylated derivatives. COMT found mainly in liver and kidney. Methylated catecholamines are then deaminated and finally oxidised to vanillylmandelic acid (VMA) which is excreted in urine. ^[1]

Clinical relevance: This is why we measure urinary VMA, urinary metanephrines (normetanephrine and metanephrine), and urinary catecholamines for diagnosis. Plasma free metanephrines have the highest sensitivity (~99%) and are the preferred initial screening test in current guidelines, though the lecture emphasises urinary measurements ^[1][3].

Arises from chromaffin cells of adrenal medulla. Rule of 10 no longer valid. 20% extra-adrenal. 24% familial (MEN II, neurofibromatosis). Up to 36% malignant. ^[1]

Extra-adrenal tumours tend to produce noradrenaline whereas adrenal tumours usually produce both [noradrenaline and adrenaline]. ^[1]

Why? Extra-adrenal chromaffin tissue (paraganglia) lacks PNMT, the enzyme that converts noradrenaline → adrenaline. Only the adrenal medulla expresses PNMT (which requires high local cortisol concentrations from the adrenal cortex for induction). Hence, pure noradrenaline production suggests extra-adrenal or paraganglioma.

• MEN 2A: Medullary thyroid carcinoma + phaeochromocytoma + primary hyperparathyroidism (RET mutation)
• MEN 2B: Medullary thyroid carcinoma + phaeochromocytoma + mucosal neuromas/marfanoid habitus (RET mutation)
• Neurofibromatosis type 1 (NF1)
• Von Hippel-Lindau (VHL) syndrome
• Succinate dehydrogenase (SDH) mutations — especially paragangliomas

Hypertension (paroxysmal or sustained), headache, palpitations, hyperhydrosis, dizziness, anxiety, pallor, weight loss, hypermetabolism, pyrexia, angina, cardiac failure, stroke, glucose intolerance, diabetes. ^[1]

Why pallor (not flushing)? Catecholamines cause α₁-mediated vasoconstriction of cutaneous vessels → pallor. This distinguishes phaeochromocytoma from carcinoid syndrome (which causes flushing).

Why glucose intolerance? Catecholamines:

• Stimulate hepatic glycogenolysis and gluconeogenesis (β₂ and α₁ effects)
• Inhibit insulin secretion (α₂ effect on pancreatic β-cells)
• Promote insulin resistance

Urinary VMA. Urinary catecholamines and their metabolites (metanephrine and normetanephrine). Beware of drug and dietary interference (e.g. β-blocker, methyldopa). Measurement of plasma catecholamines available in some centres. ^[1]

Practical points for investigation:

• Collect 24-hour urine for catecholamines, metanephrines, and VMA
• The patient should avoid certain foods (bananas, chocolate, coffee, vanilla) and drugs that can cause false positives
• Plasma free metanephrines are increasingly used as the first-line screening test due to superior sensitivity (~96–99%)

CT scan / MRI. Contrast injection may induce a pressor crisis → patients should be prepared with complete adrenoceptor blockade. MIBG scan: taken up by chromaffin tissue, labelled with radioactive iodine, produces adrenomedullary images 24–48 hours after injection. ^[1]

MIBG scan: Meta-iodobenzylguanidine is structurally similar to noradrenaline and is taken up by chromaffin cells via the noradrenaline transporter. When labelled with ¹²³I or ¹³¹I, it produces functional imaging of catecholamine-producing tissue. Useful for:

• Detecting extra-adrenal phaeochromocytomas/paragangliomas
• Identifying metastatic disease
• Post-surgical surveillance

Surgery. Full α and β blockade before surgery or any procedures to prevent crisis. Initially α-blockade with phenoxybenzamine, then β-blockade with propranolol. Important to institute α-blockade first. If β-blocker administered first, vasoconstriction due to unopposed α-adrenoceptor activity may occur and exacerbate hypertension. ^[1]

Perioperative protocol:

1. α-blockade (phenoxybenzamine 10–20mg BD–TDS, titrated over 1–2 weeks) → aim for postural hypotension (sign of adequate blockade)
2. Liberal salt and fluid intake to re-expand contracted intravascular volume (chronic catecholamine excess causes volume contraction)
3. β-blockade (propranolol) added ONLY after adequate α-blockade → controls tachycardia
4. Intraoperative: IV phentolamine (short-acting α-blocker) or sodium nitroprusside for acute hypertensive surges during tumour manipulation
5. Post-tumour removal: Watch for hypotension (loss of catecholamine drive + volume depletion) → IV fluids

Conventional open techniques: anterior transabdominal, lateral extraperitoneal, posterior lumbar. Choice depends on: size, location, concomitant procedure, surgical expertise, pathology. ^[1]

Advantages: safety, efficacy, shortened hospital stay, reduced analgesic requirement, hastened return to normal activities, improved overall patient satisfaction. ^[1]

Laparoscopic adrenalectomy is now the standard of care for most benign adrenal tumours < 6 cm. Open surgery is reserved for large tumours ( > 6–8 cm), suspected adrenal carcinoma (due to need for en-bloc resection), or when laparoscopic approach is technically unfeasible.

Intraoperative haemorrhage (adrenal capsular, vena cava), splenic injury, liver injury, pneumothorax, loss of adrenal tissue. Others: hypertensive crisis, acute adrenal insufficiency, electrolyte disturbance. ^[1]

1. MCQ: "A patient presents with paroxysmal hypertension, headache, palpitations, and sweating. What is the most likely diagnosis?" → Phaeochromocytoma ^[8]

2. SAQ: "Describe the investigation pathway for suspected Cushing's syndrome, including how to differentiate pituitary from ectopic ACTH" → Use the DST algorithm + CRH test ^[1]

3. Minicase: Incidental adrenal mass + hypokalaemia → systematic exclusion of phaeochromocytoma, Conn's, Cushing's ^[10]

4. SAQ: "Why must α-blockade precede β-blockade in phaeochromocytoma?" → Standard explanation of unopposed α-activity ^[1]

5. SAQ/Minicase: "How do you differentiate an aldosterone-producing adenoma from bilateral adrenal hyperplasia?" → Postural test, AVS, CT, response to standing ^[1]

• For phaeochromocytoma triad: "Paroxysmal hypertension with episodic headache, palpitations, and diaphoresis"
• For Conn's biochemistry: "Elevated aldosterone with suppressed renin (high aldosterone-to-renin ratio), failure of aldosterone suppression with salt loading"
• For DST interpretation: State: "Low-dose DST fails to suppress in all causes of Cushing's syndrome. High-dose DST suppresses in pituitary Cushing's disease but not in ectopic ACTH or adrenal causes"