Adrenal Disorders

Adrenal insufficiency — by mechanism

• Autoimmune adrenalitis: the leading primary cause in the US; anti-21-hydroxylase antibodies. Often part of autoimmune polyglandular syndrome type 2 (Addison + autoimmune thyroid disease ± type 1 diabetes) or type 1 (with chronic mucocutaneous candidiasis and hypoparathyroidism, AIRE mutation).
• Infectious/infiltrative: tuberculosis (dominant cause worldwide), disseminated histoplasmosis, HIV-associated CMV adrenalitis, sarcoid, metastases (lung, breast).
• Vascular: bilateral adrenal hemorrhage from meningococcemia (Waterhouse-Friderichsen), antiphospholipid syndrome, or anticoagulation.
• Iatrogenic (modifiable): abrupt withdrawal of supraphysiologic glucocorticoids is the single most common cause of secondary/tertiary insufficiency; also megestrol, opioids, checkpoint inhibitors (hypophysitis with CTLA-4 blockade), etomidate, ketoconazole.

Cortisol excess

• Exogenous glucocorticoids — the most common etiology overall and entirely modifiable.
• Endogenous: pituitary corticotroph adenoma (Cushing disease), ectopic ACTH (small cell lung carcinoma, bronchial carcinoid, medullary thyroid carcinoma), and adrenal adenoma/carcinoma. Smoking is the relevant modifiable risk factor for ectopic ACTH.

Catecholamine excess

• Germline mutations (non-modifiable) are now recognized in a substantially larger share of pheochromocytoma/paraganglioma than the classic rule of 10s implies: RET (MEN2A/2B), VHL, NF1, and SDHx subunits. The Endocrine Society recommends offering genetic testing to essentially all patients with pheochromocytoma or paraganglioma; SDHB carries the highest metastatic risk.

Aldosterone excess

• Bilateral idiopathic adrenal hyperplasia (most common) and unilateral aldosterone-producing adenoma (Conn syndrome); rarely glucocorticoid-remediable aldosteronism. Risk markers examiners plant: resistant hypertension, spontaneous or diuretic-induced hypokalemia, obstructive sleep apnea, adrenal incidentaloma, early-onset hypertension, or family history of stroke before age 40.

Adrenal Insufficiency (Hypoadrenalism)

• Primary insufficiency (Addison disease): Destruction or dysfunction of the adrenal cortex itself (>90% loss of parenchyma needed for symptoms), resulting in deficient cortisol, aldosterone, and ACTH stimulation. Common causes include autoimmune destruction (most common in developed countries), tuberculosis, infiltrative diseases (sarcoidosis, amyloidosis), hemorrhage (meningococcemia—Waterhouse-Friderichsen syndrome), medications (mitotane, ketoconazole), and genetic defects (21-hydroxylase deficiency in congenital adrenal hyperplasia).
• Secondary insufficiency: Pituitary or hypothalamic pathology (tumors, apoplexy, surgery, radiation, infiltration) reduces ACTH secretion, impairing adrenal cortisol production while preserving aldosterone (since the renin-angiotensin system remains intact).
• Tertiary insufficiency: Hypothalamic CRH deficiency blunts ACTH, leading to similar secondary-type deficiency.
• Loss of glucocorticoid and mineralocorticoid: Cortisol deficiency causes hypotension, hyponatremia, and inability to mount stress response; aldosterone loss in primary disease worsens hyperkalemia and sodium depletion.

Cushing Syndrome (Hypercortisolism)

• ACTH-dependent (80%): Pituitary adenoma secreting ACTH (Cushing disease—accounts for ~70% of all Cushing syndrome) or ectopic ACTH secretion (small cell lung cancer, carcinoid tumors) causes excessive corticotropin stimulation.
• ACTH-independent (20%): Adrenal tumor (adenoma or carcinoma) produces cortisol autonomously, suppressing pituitary ACTH. Carcinomas carry poor prognosis.
• Iatrogenic: Excessive glucocorticoid administration (most common cause overall).
• Ectopic CRH: Rare; peripheral tumor produces CRH, stimulating pituitary ACTH.
• Pathologic mechanism: Chronic cortisol excess causes immunosuppression, insulin resistance, protein catabolism, lipolysis (with central redistribution), hypertension, osteoporosis, and psychiatric illness through widespread glucocorticoid receptor activation.

Pheochromocytoma (Catecholamine-Secreting Tumor)

• Neuroendocrine origin: Arises from chromaffin cells of the adrenal medulla (90%) or extra-adrenal paraganglia (10%); autonomously secretes epinephrine and norepinephrine.
• Rule of 10s: 10% bilateral, 10% extra-adrenal, 10% malignant, 10% hereditary (associated with MEN2A/2B, NF1, VHL, familial paraganglioma syndromes), 10% in children.
• Hypertension mechanism: Catecholamine-induced α1-adrenergic vasoconstriction, β-adrenergic myocardial stimulation, and renin-angiotensin activation; can cause paroxysmal (episodic) or sustained elevation.
• Catecholamine excess effects: Hyperglycemia, hypokalemia, orthostatic hypotension (due to intravascular volume depletion from catecholamine-induced peripheral pooling), cardiomyopathy (catecholamine-induced), and arrhythmias.

Adrenal Insufficiency

• Gradual onset insidious symptoms: Fatigue, weakness, anorexia, nausea, abdominal pain, weight loss, and depression evolving over weeks to months in primary disease.
• Hyperpigmentation (primary only): Due to elevated ACTH stimulating melanocortin receptors; classically seen on sun-exposed areas, buccal mucosa, and scars—absent in secondary insufficiency (low ACTH).
• Hyponatremia and hyperkalemia (primary disease): Sodium wasting and potassium retention from aldosterone deficiency cause muscle cramps, confusion, and cardiac arrhythmias. Secondary disease preserves aldosterone, so hyperkalemia is mild or absent.
• Orthostatic hypotension and cardiovascular collapse: Severe in primary disease due to combined cortisol and aldosterone loss; can present with shock during stressors (infection, surgery, trauma).
• Acute adrenal crisis: Life-threatening emergency with severe hypotension, severe hyponatremia, hyperkalemia, hypoglycemia, fever, and altered mental status precipitated by infection, trauma, or surgery in undiagnosed or undertreated patients.
• Vitiligo, other autoimmune features: Common in autoimmune primary adrenal insufficiency; concurrent thyroid disease, pernicious anemia frequent.
• Secondary insufficiency subtlety: Patients may present with only hypoglycemia or vague weakness; no hyperpigmentation or severe hypokalemia helps differentiate from primary.

Cushing Syndrome

• Classic appearance: Central obesity (buffalo hump and supraclavicular fat pads), moon facies, purple striae (>1 cm), easy bruising, and proximal muscle weakness reflecting catabolic state.
• Hypertension (60-80%): Present in majority; from mineralocorticoid effects and catecholamine sensitivity; often resistant to therapy.
• Diabetes and glucose intolerance: Cortisol antagonizes insulin; new-onset or worsening glycemic control.
• Psychiatric manifestations: Depression (most common, 50-80%), anxiety, psychosis, cognitive impairment; suicide risk elevated—critical to assess.
• Osteoporosis and pathologic fractures: Rapid bone loss, vertebral compression fractures in 10-20%; increased fracture risk even with mild hypercortisolism.
• Amenorrhea and sexual dysfunction: Hypogonadism from hypercortisolism; women may have hirsutism (if ACTH-secreting tumor coprodues androgens).
• Immunosuppression: Recurrent infections, including opportunistic organisms (PCP, tuberculosis reactivation).
• Hypokalemic metabolic alkalosis: Particularly with ectopic ACTH (oat cell cancer); profound hypokalemia dangerous.
• Iatrogenic variant: May lack classic stigmata but has metabolic derangements; suspect with new hypertension, diabetes, or osteoporosis on chronic steroids.

Pheochromocytoma

• Episodic hypertension and headache: Sudden severe headache during catecholamine surge; classic triad (headache, diaphoresis, palpitations) present in <50% but highly specific.
• Paroxysmal symptoms: Sudden attacks of anxiety, tremor, chest/abdominal pain, pallor alternating with flushing lasting minutes to hours; triggered by physical activity, Valsalva, micturition (especially bladder tumors), abdominal palpation, or foods high in tyramine/sympathomimetics (in patients on MAOI inhibitors).
• Persistent hypertension or resistant hypertension: 60% have sustained elevation; may be paroxysmal in 30%.
• Cardiovascular complications: Takotsubo cardiomyopathy (stress-induced, mimics acute MI), arrhythmias including atrial fibrillation, acute coronary syndrome, or sudden cardiac

Adrenal insufficiency

• Initial test: 8 AM serum cortisol with simultaneous plasma ACTH. A clearly low morning cortisol with a markedly elevated ACTH establishes primary disease; low/inappropriately normal ACTH indicates secondary or tertiary.
• Confirmatory (gold standard): cosyntropin (ACTH1-24) stimulation test, 250 mcg IV/IM with cortisol at 30 and 60 minutes. Per the Endocrine Society, a peak cortisol below roughly 18 mcg/dL (assay-dependent) confirms insufficiency. Chronic secondary disease also fails because the atrophic cortex cannot respond.
• Supporting findings: hyponatremia, hyperkalemia with non-anion-gap acidosis, hypoglycemia, eosinophilia; elevated renin with low aldosterone in primary disease. Check 21-hydroxylase antibodies; if negative, image the adrenals and consider very-long-chain fatty acids in young men (adrenoleukodystrophy).

• Then localize: plasma ACTH. Suppressed ACTH → adrenal CT. Normal/elevated ACTH → pituitary MRI; high-dose (8 mg) dexamethasone suppression and CRH stimulation favor a pituitary source (partial suppression, ACTH response), while ectopic tumors typically do neither.
• Inferior petrosal sinus sampling is the definitive test when ACTH is dependent and the MRI is non-diagnostic or the lesion is small.

Adrenal crisis — treat before confirming

• Hydrocortisone: 100 mg IV bolus followed by continuous infusion or divided dosing; at stress doses it provides both glucocorticoid and mineralocorticoid activity, so fludrocortisone is unnecessary acutely.
• Volume and glucose: aggressive isotonic saline with dextrose corrects hypovolemia, hyponatremia, and hypoglycemia. Treat the precipitant (usually infection).
• If diagnosis is unconfirmed, dexamethasone may be substituted because it does not cross-react in the cortisol immunoassay, allowing a subsequent cosyntropin test.

• Alpha blockade first: phenoxybenzamine (irreversible) or a selective agent such as doxazosin, started roughly one to two weeks preoperatively, with a high-sodium diet and liberal fluids to re-expand the contracted plasma volume.
• Beta blockade second, only after adequate alpha blockade, to control reflex tachycardia. Giving a beta blocker first is contraindicated — unopposed alpha stimulation precipitates hypertensive crisis.
• Definitive: laparoscopic adrenalectomy; intraoperative crises are managed with IV phentolamine or nitroprusside.

Emergencies

• Adrenal crisis: cortisol deficiency removes permissive support for vascular catecholamine responsiveness, producing hypotension refractory to fluids and pressors. Signalled by shock plus hyponatremia, hyperkalemia, and hypoglycemia in a patient with intercurrent illness or a missed steroid dose. Give hydrocortisone immediately.
• Pheochromocytoma hypertensive crisis: massive catecholamine release — during anesthetic induction, tumor manipulation, or after an unopposed beta blocker — causes stroke, aortic dissection, or catecholamine (Takotsubo-pattern) cardiomyopathy with pulmonary edema.
• Post-resection hypotension: abrupt loss of catecholamine tone in a chronically vasoconstricted, volume-depleted patient; also post-resection hypoglycemia from rebound hyperinsulinemia.
• Severe hypokalemia with ectopic ACTH: cortisol overwhelms 11β-HSD2 and floods the mineralocorticoid receptor, producing hypokalemic metabolic alkalosis and arrhythmia.

Disease complications

• Chronic hypercortisolism: osteoporotic vertebral fractures, avascular necrosis of the femoral head, poorly healing wounds, venous thromboembolism (a leading cause of perioperative death), and opportunistic infection including Pneumocystis.
• Untreated hyperaldosteronism: myocardial and vascular fibrosis with left ventricular hypertrophy, atrial fibrillation, and stroke out of proportion to blood pressure.
• Malignant transformation: adrenocortical carcinoma and metastatic paraganglioma, especially with SDHB mutations.

Treatment complications

• Over-replacement of hydrocortisone/fludrocortisone: iatrogenic Cushing features, hypertension, hypokalemia, edema.
• Nelson syndrome: after bilateral adrenalectomy for Cushing disease, loss of feedback drives corticotroph tumor growth — hyperpigmentation, headache, visual field loss.
• Steroidogenesis inhibitors: ketoconazole causes hepatotoxicity and QT prolongation; metyrapone shunts precursors to 11-deoxycorticosterone and androgens (hypertension, hirsutism); osilodrostat and mitotane cause adrenal insufficiency. Mifepristone masks cortisol-based monitoring.
• Spironolactone: antiandrogen effects (gynecomastia, erectile dysfunction) and hyperkalemia.
• Glucocorticoid withdrawal syndrome: after cure of Cushing syndrome, patients feel unwell despite adequate replacement while the axis recovers.

• Hyperpigmentation localizes the lesion: it requires high ACTH, so it occurs in primary insufficiency only. Hyperkalemia likewise implies primary disease — secondary insufficiency spares the renin-angiotensin-aldosterone axis.
• In suspected adrenal crisis, the single best next step is glucocorticoid, not a test. If you must preserve diagnostic accuracy, give dexamethasone: it does not cross-react with the cortisol immunoassay, so cosyntropin testing can follow.
• Alpha before beta, always. Giving a beta blocker first in pheochromocytoma leaves alpha-mediated vasoconstriction unopposed and can precipitate hypertensive crisis and pulmonary edema. The same logic explains why cocaine-associated chest pain avoids unopposed beta blockade.
• Never biopsy an adrenal mass until pheochromocytoma is biochemically excluded — needle puncture can trigger a catecholamine storm.
• The classic ectopic ACTH stem: a smoker with weight loss, marked hypokalemic metabolic alkalosis, hyperpigmentation, and dark skin but few Cushingoid body-habitus features — the syndrome evolves too fast for striae and moon facies.
• Screen for primary aldosteronism in resistant hypertension, hypertension with spontaneous or diuretic-provoked hypokalemia, adrenal incidentaloma, or sleep apnea (Endocrine Society). Note that many patients are normokalemic — absence of hypokalemia does not rule it out, a favorite distractor.
• Common false-positive traps: the 1 mg dexamethasone suppression test fails in pseudo-Cushing states (alcohol use disorder, major depression, obesity), with CYP3A4 inducers, and with estrogen-containing contraceptives that raise cortisol-binding globulin. Metanephrine testing is confounded by tricyclics, labetalol, and levodopa.
• The association examiners love: pheochromocytoma plus medullary thyroid carcinoma and hyperparathyroidism = MEN2A; add mucosal neuromas and a marfanoid habitus = MEN2B. Always rule out pheochromocytoma before thyroidectomy.