Adrenal Disorders
Medicine · Endocrinology · lean revision notes
Adrenal Disorders
The adrenal gland is a high-yield endocrine topic for NEET PG, anchored on three classic syndromes: Cushing syndrome (cortisol excess), Addison disease (primary adrenal insufficiency), and Conn syndrome (primary hyperaldosteronism). Mastering the biochemical localisation tests — overnight/high-dose dexamethasone suppression, ACTH levels, Synacthen test, aldosterone-to-renin ratio — is where most marks are won. Phaeochromocytoma and congenital adrenal hyperplasia round out the chapter.
Adrenal anatomy & hormone map
The adrenal cortex has three zones, each with a distinct product. The mnemonic GFR → "Salt, Sugar, Sex" (and the deeper you go, the sweeter it gets) captures this:
| Zone | Hormone | Regulation | Key clinical link |
|---|---|---|---|
| Zona Glomerulosa (outer) | Aldosterone (mineralocorticoid) | Renin-angiotensin, K⁺ | Conn syndrome |
| Zona Fasciculata (middle) | Cortisol (glucocorticoid) | ACTH/CRH | Cushing syndrome |
| Zona Reticularis (inner) | Androgens (DHEA, androstenedione) | ACTH | CAH, virilisation |
| Medulla (core) | Adrenaline, noradrenaline (catecholamines) | Sympathetic preganglionic | Phaeochromocytoma |
High-yield: The zona glomerulosa lacks 17α-hydroxylase, so it cannot make cortisol/androgens; the medulla uses cortisol draining from the cortex to induce PNMT (phenylethanolamine-N-methyltransferase), converting noradrenaline → adrenaline. This is why only adrenal medullary (not extra-adrenal) phaeochromocytomas secrete significant adrenaline.
Cushing syndrome (cortisol excess)
Definition & classification
Cushing syndrome = the clinical state of chronic glucocorticoid excess from any cause. Cushing disease = the specific subset caused by an ACTH-secreting pituitary adenoma (≈70% of endogenous cases). Classification splits cleanly into ACTH-dependent and ACTH-independent forms — this dichotomy drives the entire diagnostic algorithm.
| Type | Cause | ACTH level | Proportion |
|---|---|---|---|
| Exogenous (iatrogenic) | Therapeutic steroids | Low (suppressed) | Most common cause overall |
| ACTH-dependent | Pituitary adenoma (Cushing disease) | High/normal | ~70% of endogenous |
| ACTH-dependent | Ectopic ACTH (small cell lung Ca, carcinoid) | Very high | ~10% |
| ACTH-independent | Adrenal adenoma/carcinoma, nodular hyperplasia | Low (suppressed) | ~20% |
High-yield: The single most common cause of Cushing syndrome overall is iatrogenic (exogenous steroids). The most common endogenous cause is Cushing disease (pituitary). The most common cause of the most florid hypokalaemic alkalosis + rapid onset + hyperpigmentation picture is ectopic ACTH (classically small cell lung carcinoma).
Clinical features
Centripetal (truncal) obesity, moon facies, dorsocervical fat pad ("buffalo hump"), supraclavicular fat pads, proximal myopathy, thin skin with purple/violaceous striae >1 cm wide, easy bruising, hypertension, glucose intolerance/diabetes, osteoporosis, hirsutism, and psychiatric disturbance. The most discriminatory features (separating Cushing from simple obesity) are proximal myopathy, wide violaceous striae, easy bruising and facial plethora.
Diagnosis — a two-step logic
Step 1 — Establish hypercortisolism (any 2 of 3 abnormal):
- Overnight 1 mg dexamethasone suppression test (ODST) — give 1 mg at 11 pm, measure 8 am cortisol. Failure to suppress below 1.8 µg/dL (50 nmol/L) = positive screen.
- Late-night salivary cortisol (loss of diurnal nadir).
- 24-hour urinary free cortisol (≥ 3× upper limit is diagnostic).
Step 2 — Localise the source once excess is confirmed:
Measure plasma ACTH → if low/suppressed → ACTH-independent (adrenal) → CT adrenals. If normal/high → ACTH-dependent → high-dose DST + pituitary MRI ± inferior petrosal sinus sampling.
| Test | Cushing disease (pituitary) | Ectopic ACTH | Adrenal tumour |
|---|---|---|---|
| Plasma ACTH | High/normal | Very high | Low/suppressed |
| High-dose DST (8 mg) | Suppresses >50% | No suppression | No suppression |
| CRH stimulation | Exaggerated rise | No response | No response |
| Imaging | Pituitary MRI | CT chest/abdomen | CT adrenal |
High-yield: Pituitary corticotroph adenomas retain partial negative feedback, so high-dose (8 mg) dexamethasone suppresses cortisol by >50% in Cushing disease but NOT in ectopic ACTH or adrenal tumours. This is the classic single-best-answer discriminator.
High-yield: When pituitary MRI is equivocal or to distinguish pituitary from ectopic source, the gold standard is bilateral inferior petrosal sinus sampling (IPSS) — a central:peripheral ACTH ratio >2 at baseline or >3 after CRH confirms a pituitary source.
Management / drug of choice
- Cushing disease → trans-sphenoidal selective adenomectomy (treatment of choice). Second line: pituitary radiotherapy, bilateral adrenalectomy.
- Adrenal adenoma → unilateral adrenalectomy.
- Ectopic ACTH → resect the tumour; control cortisol medically.
- Medical control (pre-op or unresectable): ketoconazole, metyrapone, osilodrostat (steroidogenesis inhibitors); mifepristone (glucocorticoid receptor antagonist, useful with hyperglycaemia); pasireotide (somatostatin analogue) and cabergoline for pituitary disease.
High-yield: Nelson syndrome — after bilateral adrenalectomy for Cushing disease, loss of cortisol feedback drives a pre-existing corticotroph adenoma to enlarge → very high ACTH, hyperpigmentation, mass effect/visual field defects.
Complications
Osteoporotic fractures, diabetes, hypertension/cardiovascular events, opportunistic infections (immunosuppression), venous thromboembolism, and psychiatric morbidity. Adrenal carcinoma carries a poor prognosis.
Addison disease (primary adrenal insufficiency)
Definition & etiology
Addison disease = primary failure of the adrenal cortex with deficiency of both cortisol AND aldosterone (and adrenal androgens). Because the gland itself fails, ACTH is high (loss of feedback) → the cause of hyperpigmentation.
- Worldwide (developing countries / India): tuberculosis remains a leading cause.
- Developed world: autoimmune (≈70–90%) — anti-21-hydroxylase antibodies; may be part of autoimmune polyendocrine syndromes (APS-1: Addison + hypoparathyroidism + mucocutaneous candidiasis, AIRE gene; APS-2/Schmidt: Addison + autoimmune thyroid ± type 1 DM).
- Others: adrenoleukodystrophy, metastases, bilateral haemorrhage (Waterhouse-Friderichsen in meningococcaemia), HIV, amyloidosis, drugs (ketoconazole, etomidate).
High-yield: Secondary vs primary — secondary adrenal insufficiency (pituitary ACTH deficiency, e.g. exogenous steroid withdrawal) has LOW ACTH → no hyperpigmentation, and aldosterone is preserved (renin-angiotensin intact) → no significant hyperkalaemia. Hyponatraemia can still occur (cortisol deficiency → SIADH-like water retention).
Clinical features
Chronic: fatigue, weight loss, anorexia, postural hypotension, salt craving, hyperpigmentation (palmar creases, buccal mucosa, scars, pressure points — driven by ACTH/MSH from the POMC precursor), GI upset. In women, loss of adrenal androgens → reduced axillary/pubic hair, low libido.
Addisonian (adrenal) crisis: acute hypotension/shock, vomiting, abdominal pain, hyponatraemia, hyperkalaemia, hypoglycaemia — often precipitated by infection, surgery, or abrupt steroid withdrawal. A medical emergency.
Biochemistry — the classic pattern
| Parameter | Primary (Addison) | Secondary |
|---|---|---|
| Sodium | ↓ (hyponatraemia) | ↓ (milder) |
| Potassium | ↑ (hyperkalaemia) | Normal |
| ACTH | ↑↑ | ↓/normal |
| Aldosterone | ↓ | Normal |
| Pigmentation | Present | Absent |
| Other | Hypoglycaemia, metabolic acidosis, eosinophilia, mild hypercalcaemia | — |
Diagnosis — investigation of choice
Short Synacthen (ACTH stimulation) test is the confirmatory test of choice: measure baseline cortisol → give 250 µg synthetic ACTH (tetracosactide/cosyntropin) IM/IV → measure cortisol at 30 and 60 min. A peak cortisol <18 µg/dL (500 nmol/L) = inadequate response → adrenal insufficiency.
Localise primary vs secondary → measure plasma ACTH and renin/aldosterone: high ACTH + high renin/low aldosterone = primary. Then anti-21-hydroxylase antibodies (autoimmune) or CT adrenals (TB, haemorrhage, metastasis — bilateral enlargement/calcification suggests TB).
High-yield: In a crisis, do NOT delay treatment for test results. Draw a random cortisol + ACTH, then immediately give hydrocortisone; confirm later with Synacthen.
Management / drug of choice
- Chronic replacement: hydrocortisone (glucocorticoid; ~15–25 mg/day split, larger morning dose) PLUS fludrocortisone (mineralocorticoid) in primary disease. Secondary disease needs glucocorticoid only.
- Sick-day rules: double the glucocorticoid dose during intercurrent illness; switch to parenteral if vomiting.
- Addisonian crisis → IV hydrocortisone 100 mg STAT then 100 mg q6–8h (or infusion) + aggressive IV normal saline (often with dextrose for hypoglycaemia) + treat precipitant. At high hydrocortisone doses, separate fludrocortisone is unnecessary (hydrocortisone has intrinsic mineralocorticoid activity).
- Patients should carry a steroid emergency card and ideally a hydrocortisone IM kit.
Differentials
Other causes of hyperpigmentation (haemochromatosis), hyponatraemia (SIADH, diuretics), fatigue/weight loss (malignancy, depression), and shock (sepsis, hypovolaemia).
Conn syndrome (primary hyperaldosteronism)
Definition & etiology
Primary hyperaldosteronism (PA) = autonomous aldosterone overproduction independent of renin — now recognised as the commonest secondary, potentially curable cause of hypertension (up to 5–10% of hypertensives). Causes:
- Bilateral idiopathic adrenal hyperplasia (≈60%) — the most common cause.
- Aldosterone-producing adenoma (Conn adenoma, ≈30%) — surgically curable.
- Rare: unilateral hyperplasia, adrenal carcinoma, glucocorticoid-remediable aldosteronism (GRA) — CYP11B1/CYP11B2 chimeric gene, autosomal dominant, suppressed by dexamethasone.
Clinical features
Hypertension + hypokalaemia is the textbook picture, though many are normokalaemic. Hypokalaemia causes muscle weakness, cramps, polyuria (nephrogenic DI), and metabolic alkalosis. Notably no oedema ("aldosterone escape"). Suspect PA in: resistant/early hypertension, hypertension with spontaneous or diuretic-induced hypokalaemia, adrenal incidentaloma with hypertension, or hypertension + family history of early stroke.
Diagnosis — investigation of choice
Screening: plasma Aldosterone-to-Renin Ratio (ARR) — an elevated ARR with high aldosterone + suppressed renin is the screening test of choice. (Stop interfering drugs: spironolactone/eplerenone for 4–6 weeks; β-blockers raise ARR falsely, ACEi/ARB/diuretics lower it.)
Flow: High ARR (screen +) → confirmatory test (saline infusion / oral salt loading / fludrocortisone suppression — failure to suppress aldosterone confirms PA) → CT adrenals → adrenal vein sampling (AVS) to lateralise → surgery vs medical.
High-yield: Adrenal vein sampling (AVS) is the gold standard for lateralisation before adrenalectomy — CT alone misclassifies because of non-functioning incidentalomas and small adenomas. AVS distinguishes a unilateral adenoma (→ surgery) from bilateral hyperplasia (→ medical).
Management / drug of choice
- Unilateral adenoma/unilateral hyperplasia → laparoscopic adrenalectomy (cures hypokalaemia, improves/cures hypertension).
- Bilateral hyperplasia → mineralocorticoid receptor antagonist — spironolactone (drug of choice) or eplerenone (fewer anti-androgenic effects: less gynaecomastia).
- GRA → low-dose dexamethasone.
Differentials & comparison
| Feature | Primary HA (Conn) | Secondary HA | Liddle / apparent MC excess |
|---|---|---|---|
| Aldosterone | High | High | Low |
| Renin | Low | High | Low |
| Example | Adenoma/hyperplasia | Renal artery stenosis, CHF, cirrhosis | Liddle (ENaC), liquorice |
High-yield: Bartter (loop, like furosemide) and Gitelman (DCT, like thiazide — also hypomagnesaemia + hypocalciuria) syndromes give hypokalaemic alkalosis but with normal/low BP and HIGH renin & aldosterone — opposite renin pattern to Conn.
Phaeochromocytoma (medulla) — quick reference
Catecholamine-secreting tumour of chromaffin cells. Rule of 10s (classic but dated): 10% extra-adrenal (paraganglioma), 10% bilateral, 10% malignant, 10% familial, 10% in children. Now ≈40% are hereditary (MEN 2A/2B, VHL, NF-1, SDHx).
- Features: episodic headache, palpitations, sweating (the classic triad) + paroxysmal/sustained hypertension, pallor, anxiety.
- Investigation of choice: plasma free metanephrines (or 24-h urinary fractionated metanephrines) — most sensitive; then CT/MRI, MIBG scan for localisation/metastases.
- Management: surgical resection after α-blockade FIRST (phenoxybenzamine) for 10–14 days, then β-blockade to control reflex tachycardia.
High-yield: Never give a β-blocker before adequate α-blockade — unopposed α-vasoconstriction precipitates hypertensive crisis. "Alpha before beta."
Adrenal incidentaloma & CAH (high-yield extras)
- Incidentaloma: adrenal mass found on imaging done for another reason. Work-up = (1) functional screen — ODST, plasma metanephrines, ARR (if hypertensive); (2) malignant potential — size >4 cm and HU >10 on non-contrast CT raise suspicion.
- Congenital adrenal hyperplasia (CAH): 21-hydroxylase deficiency (>90%) — ↓cortisol & ↓aldosterone, shunting to androgens → salt-wasting crisis + virilisation/ambiguous genitalia in females; ↑17-hydroxyprogesterone is diagnostic. 11β-hydroxylase deficiency → hypertension (11-deoxycorticosterone excess) + virilisation. 17α-hydroxylase deficiency → hypertension + lack of sexual development.
High-yield mnemonic for CAH and BP: "1 and 7 = hypertension; 21 = hypotension (salt wasting)." (11β- and 17α-hydroxylase → high BP; 21-hydroxylase → low BP.)
Recently asked / exam angle
- High-dose DST suppresses in pituitary Cushing disease but not ectopic/adrenal — repeatedly tested SBA.
- Best test to localise pituitary vs ectopic ACTH → inferior petrosal sinus sampling.
- Synacthen test cut-off (cortisol <18 µg/dL / 500 nmol/L) as confirmatory for Addison.
- Hyperpigmentation present in primary but absent in secondary adrenal insufficiency (ACTH/POMC).
- ARR as screening, adrenal vein sampling as gold-standard lateralisation for Conn.
- Eplerenone over spironolactone when avoiding gynaecomastia.
- Alpha-blockade before beta-blockade in phaeochromocytoma.
- 17-hydroxyprogesterone elevation → 21-hydroxylase-deficiency CAH; Gitelman → hypocalciuria + hypomagnesaemia.
- Drug of choice in Addisonian crisis = IV hydrocortisone (not dexamethasone — though dexamethasone is used if you must not interfere with a pending Synacthen test).
Rapid revision
- Adrenal cortex GFR = Salt, Sugar, Sex (aldosterone, cortisol, androgens); medulla = catecholamines.
- Commonest Cushing cause overall = exogenous steroids; endogenous = pituitary (Cushing disease).
- ODST screens, ACTH localises, 8 mg DST splits pituitary (suppresses) from ectopic/adrenal (no suppression).
- IPSS confirms a pituitary ACTH source when MRI is equivocal.
- Trans-sphenoidal surgery = treatment of choice for Cushing disease; Nelson syndrome follows bilateral adrenalectomy.
- Addison = ↓cortisol + ↓aldosterone, ↑ACTH → hyperpigmentation, hyponatraemia + hyperkalaemia + hypoglycaemia.
- Confirm Addison with short Synacthen test (peak cortisol <18 µg/dL = positive); TB and autoimmune are leading causes.
- Addisonian crisis → IV hydrocortisone 100 mg + IV saline immediately; double steroids on sick days.
- Secondary adrenal insufficiency: low ACTH, no pigmentation, aldosterone preserved (no hyperkalaemia).
- Conn = hypertension + hypokalaemia + metabolic alkalosis, high aldosterone, suppressed renin; screen with ARR, lateralise with adrenal vein sampling.
- Adenoma → adrenalectomy; bilateral hyperplasia → spironolactone/eplerenone; GRA → dexamethasone.
- Phaeochromocytoma → plasma metanephrines, alpha-blockade before beta-blockade; CAH 21-hydroxylase → ↑17-OHP + salt wasting.