Adrenal Disorders (Clinical)

Cushing syndrome

Cortisol excess head to toe. Central obesity, moon facies, a dorsocervical fat pad, wide purple striae, proximal muscle weakness, hypertension, hyperglycemia, easy bruising, and osteoporosis. The most common cause overall is exogenous glucocorticoids, so take a careful medication history (including inhaled, topical, and injected steroids) before any testing.

Screen, then confirm. For suspected endogenous Cushing, there are three screening tests: 24-hour urinary free cortisol, late-night salivary cortisol (loss of the normal nighttime nadir), and the low-dose (1 mg) overnight dexamethasone suppression test (failure to suppress morning cortisol). Two abnormal results are needed to confirm hypercortisolism before localizing. Obesity, depression, and heavy alcohol use can cause mild false positives ("pseudo-Cushing").

ACTH splits the differential. Once hypercortisolism is confirmed, measure plasma ACTH. Low ACTH means ACTH-independent disease (adrenal adenoma or carcinoma). High or inappropriately normal ACTH means ACTH-dependent disease: pituitary Cushing disease or ectopic ACTH. High-dose dexamethasone suppresses a pituitary source but not an ectopic one, and inferior petrosal sinus sampling confirms a pituitary origin.

After a cortisol-secreting adenoma is removed, the suppressed opposite adrenal cannot keep up, so glucocorticoid coverage is needed until the axis recovers.

Adrenal insufficiency

Primary adrenal insufficiency (Addison) destroys the cortex, losing BOTH cortisol and aldosterone: fatigue, weight loss, salt craving, hypotension, hyponatremia, hyperkalemia, and hyperpigmentation of skin creases and mucosa from high ACTH (its precursor POMC also yields MSH). Autoimmune adrenalitis is the most common cause in developed countries and TB worldwide; adrenal hemorrhage and metastases are others.

Autoimmune Addison can cluster with other endocrinopathies as autoimmune polyglandular syndrome (e.g., Hashimoto thyroiditis, type 1 diabetes).

Secondary adrenal insufficiency (pituitary ACTH deficiency) lowers cortisol but leaves aldosterone INTACT, because renin-angiotensin rather than ACTH controls it. There is no hyperkalemia and no hyperpigmentation (ACTH is low), though hyponatremia can still occur. The most common central cause is abrupt withdrawal of chronic glucocorticoids, which suppresses hypothalamic CRH (tertiary adrenal insufficiency) and gives the same pattern.

Cosyntropin confirms the diagnosis. Start with a morning cortisol, then give cosyntropin (synthetic ACTH): in adrenal insufficiency, cortisol fails to rise above ~18 mcg/dL. Primary AI has high ACTH and low cortisol; secondary AI has low ACTH and low cortisol. Replace with hydrocortisone and add fludrocortisone only in primary AI. Teach stress dosing: higher glucocorticoid doses during illness and parenteral doses for surgery.

Adrenal crisis

Fluids and hydrocortisone now. Adrenal crisis presents with hypotension or shock, nausea, vomiting, and often hyponatremia, hyperkalemia, and hypoglycemia, precipitated by stress or infection in a patient with known or unrecognized adrenal insufficiency. Treat immediately with IV hydrocortisone and aggressive normal saline (with dextrose if hypoglycemic); do NOT delay for confirmatory testing. High-dose hydrocortisone covers both glucocorticoid and mineralocorticoid needs, so fludrocortisone is unnecessary acutely.

If you must preserve diagnostic testing, dexamethasone does not interfere with the cortisol assay, but never delay treatment. Bilateral adrenal hemorrhage in meningococcal sepsis (Waterhouse-Friderichsen syndrome) is a classic cause of crisis.

Primary hyperaldosteronism

Conn syndrome. Autonomous aldosterone from a unilateral adenoma or bilateral adrenal hyperplasia causes hypertension with spontaneous or diuretic-induced hypokalemia and metabolic alkalosis, though many patients are normokalemic. Edema is absent because of aldosterone escape. The 2025 Endocrine Society guideline suggests screening all adults with hypertension; it is most likely with resistant hypertension, hypertension plus hypokalemia, or hypertension with an adrenal incidentaloma.

Pheochromocytoma and the adrenal incidentaloma

Paroxysms and metanephrines. Pheochromocytoma, a chromaffin-cell tumor, secretes catecholamines in bursts: episodic Pressure (hypertension), Pain (headache), Palpitations, Perspiration, and Pallor. Diagnose with plasma free metanephrines or 24-hour urinary metanephrines, then localize with CT or MRI. The rule of 10s describes bilateral, extra-adrenal, malignant, pediatric, and familial tumors, although genetic testing shows the hereditary share is higher. Associations are MEN2A/2B, von Hippel-Lindau, and neurofibromatosis type 1.

Starting a β-blocker first leaves α vasoconstriction unopposed and can precipitate a catastrophic hypertensive crisis.

Adrenal incidentaloma. Every incidentally found adrenal mass raises two questions: is it functional, and could it be malignant?

• Function: 1 mg dexamethasone suppression test for cortisol in every patient (cortisol above 1.8 mcg/dL suggests mild autonomous cortisol secretion), plasma metanephrines unless the mass is homogeneous and ≤10 HU, and the aldosterone-to-renin ratio if hypertensive or hypokalemic.
• Malignancy risk: imaging phenotype first; a homogeneous mass with low attenuation (≤10 HU) on noncontrast CT is a benign lipid-rich adenoma at any size and needs no further imaging. Higher HU or heterogeneity is indeterminate, and size >4 cm adds concern.
• Disposition: resect functional masses and those with suspicious imaging (an indeterminate mass >4 cm usually goes to surgery); size alone with benign imaging is not an indication (ESE/ENSAT 2023). Nonfunctional, benign-appearing masses need no imaging follow-up.

Rule out pheochromocytoma biochemically before any adrenal biopsy or surgery.