Adrenal Disorders & Adrenalectomy

Surgical adrenal disease sits at the crossroads of endocrine physiology and operative judgement. NEET PG loves it because a single vignette can test biochemistry (VMA, aldosterone:renin ratio), pharmacology (alpha before beta), and surgical technique (laparoscopic vs open). Master the functional tumours, the incidentaloma algorithm, and the perioperative pitfalls.

Adrenal anatomy & functional zones — the foundation

The adrenal gland has a cortex (mesodermal) and a medulla (neural crest). The cortex follows the mnemonic GFR = "Salt, Sugar, Sex" and "The deeper you go, the sweeter it gets":

Zone	Layer	Hormone	Regulation
Zona Glomerulosa	Outer	Aldosterone (Salt)	Renin–angiotensin, K⁺
Zona Fasciculata	Middle	Cortisol (Sugar)	ACTH
Zona Reticularis	Inner	Androgens (Sex)	ACTH
Medulla	Core	Catecholamines	Sympathetic preganglionics

High-yield: The left adrenal vein drains into the left renal vein; the right adrenal vein drains directly into the IVC (short, friable — the surgical nightmare of right adrenalectomy). Arterial supply is from three sources: superior (inferior phrenic artery), middle (aorta), and inferior (renal artery).

PNMT (phenylethanolamine-N-methyltransferase), which converts noradrenaline to adrenaline, requires high cortisol concentrations delivered via the intra-adrenal portal system — which is why only the adrenal medulla (and organ of Zuckerkandl variably) makes significant adrenaline.

Phaeochromocytoma — the "10% tumour"

A catecholamine-secreting tumour of chromaffin cells. Paraganglioma is the extra-adrenal counterpart (commonest site = organ of Zuckerkandl near the aortic bifurcation; also carotid body, bladder).

The rule of 10s (classic)

• 10% extra-adrenal
• 10% bilateral
• 10% malignant
• 10% in children
• 10% familial (modern data: up to 30–40% have a germline mutation)
• 10% not associated with hypertension
• 10% calcify

Clinical features

The classic triad: Headache + Palpitations + Sweating (diaphoresis) — together >90% specific for phaeo in a hypertensive patient. Hypertension may be sustained or paroxysmal. Other clues: pallor (not flushing), anxiety/sense of impending doom, weight loss, orthostatic hypotension (volume depletion + desensitised receptors), and new-onset diabetes.

High-yield: Phaeo causes pallor, carcinoid causes flushing — a favourite discriminator. A hypertensive crisis precipitated by anaesthesia induction, micturition (bladder paraganglioma), or beta-blockade given first is the textbook trap.

Investigation of choice

1. Biochemical confirmation first, imaging later.
2. Best initial/most sensitive test = plasma free metanephrines or 24-hour urinary fractionated metanephrines & catecholamines. Metanephrines are continuously secreted by the tumour, so they outperform VMA.
3. Urinary VMA (vanillylmandelic acid) — older, less sensitive but still examined as the classic answer. Specificity is high; sensitivity lower than metanephrines.
4. Localisation: CT/MRI abdomen (phaeo is bright/high signal on T2 — "light-bulb sign"). For extra-adrenal/metastatic disease → ¹²³I-MIBG scintigraphy; functional ⁶⁸Ga-DOTATATE PET is increasingly preferred for paragangliomas.

Biochemical → anatomical → functional localisation is the logical flow: measure metanephrines → CT/MRI → MIBG/DOTATATE if needed.

Perioperative preparation — the most tested point

High-yield: ALWAYS alpha-block BEFORE beta-block. Giving a beta-blocker first leaves unopposed alpha-mediated vasoconstriction → catastrophic hypertensive crisis.

Sequence:

1. Alpha-blockade for 10–14 days pre-op: phenoxybenzamine (irreversible, non-selective) is the classic drug of choice; doxazosin/prazosin (selective α1) are alternatives.
2. Liberal salt and fluid intake to re-expand the contracted intravascular volume.
3. Beta-blockade added only after adequate alpha-blockade, to control reflex tachycardia (target HR ~60–80).
4. Goals (Roizen criteria): BP <160/90 seated, mild orthostatic hypotension acceptable, no ST/T changes, ≤1 PVC/5 min.

Intra-operative crisis drugs: sodium nitroprusside / phentolamine for surges; treat tumour-removal hypotension with fluids and noradrenaline. Ligate the adrenal vein early to stop the catecholamine surge.

Conn's syndrome — primary hyperaldosteronism

Autonomous aldosterone secretion. Two surgical-relevant causes dominate:

Feature	Aldosterone-producing adenoma (APA / Conn's)	Bilateral adrenal hyperplasia (IHA)
Proportion	~35%	~60% (commonest overall)
Treatment	Unilateral adrenalectomy (curative)	Medical (spironolactone/eplerenone)
Posture test	Aldosterone falls on standing	Aldosterone rises on standing

Clinical & biochemical picture

• Hypertension + hypokalaemia + metabolic alkalosis (though many are now normokalaemic).
• Muscle weakness, cramps, polyuria, tetany; no oedema (aldosterone escape via ANP).
• Best screening test = plasma Aldosterone-to-Renin Ratio (ARR) — elevated aldosterone with suppressed renin.
• Confirmation: salt-loading / saline infusion suppression test (aldosterone fails to suppress).
• Adrenal Venous Sampling (AVS) is the gold standard to lateralise before surgery — distinguishes a unilateral adenoma from bilateral hyperplasia, because CT can miss small adenomas or label a non-functioning nodule.

High-yield: A hypertensive, hypokalaemic patient with a low renin and a unilateral adrenal nodule → confirm lateralisation with AVS before adrenalectomy. Pre-op spironolactone normalises K⁺ and BP.

Cushing's syndrome — surgical causes

Cushing's syndrome = chronic glucocorticoid excess (any cause). Cushing's disease = pituitary ACTH-secreting adenoma specifically.

Surgically relevant causes

• ACTH-independent (adrenal): adrenal adenoma, adrenocortical carcinoma, bilateral macronodular/PPNAD hyperplasia → treated by adrenalectomy.
• ACTH-dependent: pituitary adenoma (Cushing's disease, ~70% — trans-sphenoidal surgery) and ectopic ACTH (small-cell lung cancer, bronchial/thymic carcinoid).

Features

Central obesity, moon facies, buffalo hump, purple striae (>1 cm), proximal myopathy, easy bruising, hypertension, hyperglycaemia, osteoporosis, hirsutism. Ectopic ACTH classically presents with rapid onset, marked hyperpigmentation, severe hypokalaemic alkalosis and weight loss (cancer) rather than the chronic cushingoid habitus.

Diagnostic flow

Step 1 — Establish hypercortisolism (any two): late-night salivary cortisol, 24-h urinary free cortisol, overnight 1 mg dexamethasone suppression (fails to suppress). Step 2 — Measure plasma ACTH: low/suppressed → adrenal cause (do CT adrenals); normal/high → ACTH-dependent. Step 3 — High-dose (8 mg) dexamethasone + pituitary MRI ± inferior petrosal sinus sampling: suppression suggests pituitary; no suppression with high ACTH suggests ectopic.

Test	Pituitary (disease)	Adrenal tumour	Ectopic ACTH
Plasma ACTH	High/normal	Low/suppressed	Very high
High-dose dex	Suppresses	No suppression	No suppression
Pigmentation	Mild	Absent	Marked

High-yield: After bilateral adrenalectomy for Cushing's disease, watch for Nelson's syndrome — an aggressive, hyperpigmenting pituitary corticotroph tumour from loss of cortisol feedback.

Adrenocortical carcinoma (ACC)

A rare, aggressive cortical malignancy with a bimodal age distribution (<5 yrs and 4th–5th decade). Often large (>4–6 cm) at presentation.

• ~60% are functional — usually mixed Cushing's + virilisation (rapid hirsutism/virilisation in a woman is a red flag); pure feminising/aldosterone-secreting variants are rarer.
• Associated syndromes: Li-Fraumeni (p53), Beckwith-Wiedemann, MEN1.
• Imaging suspicious features: size >4 cm, irregular margins, heterogeneity, CT attenuation >10 HU, low washout, calcification, local invasion, IVC tumour thrombus.
• Weiss score (≥3 of 9 histological criteria) defines malignancy on histology.
• Staging via CT chest/abdomen; FDG-PET for mets.

Management

• Treatment of choice = complete open en-bloc R0 resection (open, NOT laparoscopic — see below). Avoid capsular rupture (tumour seeding worsens prognosis).
• Adjuvant mitotane (adrenolytic, inhibits steroidogenesis) ± etoposide/doxorubicin/cisplatin for advanced disease.
• Prognosis poor; stage and complete resection are the key determinants.

Adrenal incidentaloma — the algorithm examiners love

An adrenal mass ≥1 cm found on imaging done for another reason (prevalence rises with age). Two questions must be answered:

(1) Is it functional? (2) Is it malignant?

Functional workup for every incidentaloma:

1. 1 mg overnight dexamethasone suppression (autonomous cortisol).
2. Plasma metanephrines (rule out phaeo before any biopsy/surgery).
3. ARR — only if hypertensive or hypokalaemic.
4. DHEAS / sex steroids if virilising features or suspected ACC.

Malignancy assessment by imaging:

• <10 HU on non-contrast CT = lipid-rich → benign adenoma.
• High absolute/relative washout (>60%/>40% at 15 min) favours adenoma even if lipid-poor.
• Size cut-offs: >4 cm raises ACC suspicion; >6 cm → strongly consider resection.

High-yield: NEVER biopsy an adrenal mass until phaeochromocytoma is biochemically excluded — biopsy can trigger a fatal hypertensive crisis, and adrenal FNA rarely changes management anyway. Biopsy is reserved for suspected metastasis/lymphoma with a known primary, after excluding phaeo.

Indications for adrenalectomy in an incidentaloma

Functioning tumour → OR → Size >4 cm → OR → Imaging features suspicious for malignancy → OR → Documented growth on follow-up.

Laparoscopic adrenalectomy — operative principles

High-yield: Laparoscopic adrenalectomy is the gold standard for benign functioning tumours (Conn's adenoma, cortisol-secreting adenoma) and most phaeochromocytomas. Open surgery is reserved for ACC and large/invasive tumours because of the need for en-bloc resection and to avoid capsular rupture/seeding.

Key points:

• Approaches: lateral transperitoneal (most common, good working space) and posterior retroperitoneoscopic (PRA — direct, avoids prior abdominal adhesions, good for bilateral disease in prone position).
• Cortical-sparing (partial) adrenalectomy is preferred in bilateral phaeo / MEN-2 to preserve cortical function and avoid lifelong steroid replacement.
• Right side is harder due to the short right adrenal vein and IVC proximity.
• Convert to open if uncontrollable bleeding, invasion, or strong malignancy suspicion.

Post-operative care

• After resection of a cortisol-secreting adenoma, the contralateral gland is suppressed → post-op glucocorticoid replacement with taper is mandatory; failure → adrenal (Addisonian) crisis.
• After bilateral adrenalectomy → lifelong gluco- + mineralocorticoid replacement and emergency steroid education.
• Post-phaeo resection: monitor for hypotension and hypoglycaemia (catecholamine withdrawal, persistent beta-blockade).

Familial / syndromic associations (frequently tested)

Syndrome	Gene	Adrenal lesion
MEN 2A / 2B	RET	Phaeochromocytoma (bilateral) + medullary thyroid Ca (+ parathyroid in 2A)
VHL	VHL	Phaeo + RCC + haemangioblastoma
NF-1	NF1	Phaeochromocytoma
Hereditary paraganglioma	SDHB/C/D	Para/phaeo (SDHB → malignant)
Conn's (familial type I)	—	Glucocorticoid-remediable aldosteronism (responds to dexamethasone)
Li-Fraumeni	TP53	Adrenocortical carcinoma

High-yield: In MEN-2, treat the phaeochromocytoma BEFORE the medullary thyroid carcinoma / parathyroids — operating on the thyroid first in an unblocked phaeo can precipitate a lethal crisis.

Key differentials

• Phaeo vs essential hypertension vs hyperthyroidism vs panic disorder — metanephrines settle it.
• Conn's vs renal artery stenosis vs Liddle/Bartter — Conn's: low renin, high aldosterone; renovascular: high renin, high aldosterone; Liddle: low renin, low aldosterone (responds to amiloride, not spironolactone).
• Cushing's vs pseudo-Cushing's (alcohol, depression, obesity) — late-night salivary cortisol/dexamethasone-CRH test.
• Adenoma vs ACC vs metastasis on imaging — HU, washout, size, growth.

Recently asked / exam angle

• Why alpha before beta in phaeo and the drug of choice (phenoxybenzamine) — a perennial single-best-answer.
• Investigation of choice for phaeo (urinary/plasma metanephrines; VMA as the classic older answer) and the T2 light-bulb MRI sign.
• AVS as gold standard to lateralise primary hyperaldosteronism before surgery.
• Open surgery for ACC (not laparoscopic) and the Weiss score.
• Nelson's syndrome after bilateral adrenalectomy; Zuckerkandl as commonest extra-adrenal paraganglioma site.
• "Do not biopsy before excluding phaeo" in an incidentaloma vignette.
• Drainage anatomy: right adrenal vein → IVC, left → renal vein.
• Pallor (phaeo) vs flushing (carcinoid) discriminator.
• Cortisol replacement after unilateral cortisol-secreting adenoma removal (contralateral suppression).

Rapid revision

1. Alpha-block (phenoxybenzamine) 10–14 days, then beta-block — never reverse the order in phaeo.
2. Best phaeo test = plasma/urinary metanephrines; VMA is the classic older answer; T2 MRI = light-bulb.
3. Rule of 10s; commonest extra-adrenal site = organ of Zuckerkandl.
4. Phaeo = pallor; carcinoid = flushing.
5. Conn's = hypertension + hypokalaemia + low renin + high aldosterone (high ARR); lateralise with AVS.
6. Unilateral aldosteronoma → adrenalectomy; bilateral hyperplasia → spironolactone/eplerenone.
7. Cushing's screen: 1 mg overnight dexamethasone, late-night salivary cortisol, 24-h urinary free cortisol; then ACTH.
8. Suppressed ACTH = adrenal cause; do CT adrenals.
9. Nelson's syndrome follows bilateral adrenalectomy for Cushing's disease.
10. ACC: open en-bloc resection + mitotane; Weiss score ≥3; size >4 cm and HU >10 are red flags.
11. Incidentaloma: <10 HU = benign adenoma; never biopsy before excluding phaeo.
12. Right adrenal vein drains into the IVC; ligate the adrenal vein early in phaeo surgery; replace steroids after cortisol-adenoma removal.