Adrenal Insufficiency & Cushing Syndrome — Diagnosis & Management

Creator: Progress Note
Published: 2026-07-22
Keywords: adrenal insufficiency cortisol, Addison's disease symptoms, adrenal crisis treatment, Cushing syndrome dexamethasone suppression, cortisol ACTH

The 60-second version

Primary AI: low cortisol + HIGH ACTH + hyperkalemia + hyperpigmentation (Addison's)
Secondary AI: low cortisol + low/normal ACTH + NO hyperkalemia or hyperpigmentation
Adrenal crisis: IV hydrocortisone 100 mg stat + NS — do not wait for labs
Cushing's: exogenous steroids #1 cause; pituitary adenoma = #1 endogenous cause (Cushing's disease)
Diagnose Cushing's: overnight dexamethasone suppression test or 24h urine free cortisol

Adrenal Insufficiency: Primary vs Secondary

Primary (Addison's disease): destruction of adrenal glands → loss of cortisol AND aldosterone AND androgens. ACTH is HIGH (pituitary compensation → stimulates melanocortin receptors → hyperpigmentation of skin and mucosa). Causes: autoimmune (#1 in developed countries — anti-21-hydroxylase antibodies), TB (#1 worldwide), metastatic cancer, hemorrhage (Waterhouse-Friderichsen), adrenoleukodystrophy. Labs: low cortisol, high ACTH, hyponatremia, hyperkalemia, eosinophilia, low glucose. Secondary: insufficient ACTH from pituitary (tumor, surgery, radiation) → cortisol LOW, but aldosterone relatively preserved (regulated by RAAS not ACTH) → no hyperkalemia, no hyperpigmentation. Most common cause: exogenous steroid withdrawal (suppresses HPA axis). ACTH stimulation test: gold standard — give ACTH synthetic (cosyntropin) 250 mcg → cortisol should rise to >18–20 mcg/dL at 60 min; failure = adrenal insufficiency.

Adrenal Crisis

Precipitated by physiological stress (infection, surgery, trauma) in a patient with undiagnosed or undertreated adrenal insufficiency, OR abrupt steroid discontinuation. Presentation: severe hypotension (shock), fever, nausea/vomiting, severe abdominal pain, altered mental status. Labs: hyponatremia, hyperkalemia (if primary), hypoglycemia, eosinophilia. Treatment: DO NOT WAIT FOR CORTISOL LEVEL — TREAT EMPIRICALLY. Hydrocortisone 100 mg IV bolus, then 50–100 mg IV q6–8h (covers both glucocorticoid and mineralocorticoid needs at this dose). Normal saline for hypotension + dextrose for hypoglycemia. Fludrocortisone not needed acutely (high-dose hydrocortisone has sufficient mineralocorticoid activity). Long-term: hydrocortisone BID (morning higher dose, evening lower dose) + fludrocortisone for primary AI. Stress dosing: triple the maintenance dose during illness/surgery.

Cushing Syndrome

Excess cortisol. Causes: Exogenous steroids (#1 most common overall). Endogenous: Cushing's DISEASE = pituitary ACTH-secreting adenoma (#1 endogenous cause) → bilateral adrenal hyperplasia. Ectopic ACTH secretion (SCLC, carcinoid tumor) → very high ACTH, very high cortisol. Adrenal adenoma/carcinoma = low ACTH (autonomous cortisol production). Clinical features: central obesity (buffalo hump, moon facies, supraclavicular fat pads), purple striae, proximal muscle weakness, thin skin/easy bruising, osteoporosis, diabetes, hypertension, impaired immunity, hypokalemia (excess cortisol → mineralocorticoid activity → aldosterone-like effects). Diagnosis: 24-hour urine free cortisol (most reliable), late-night salivary cortisol (cortisol normally nadir at midnight — loss of diurnal rhythm in Cushing's), or 1mg overnight dexamethasone suppression test (normal → cortisol suppresses to <1.8 mcg/dL; Cushing's = failure to suppress). Then measure ACTH: low = adrenal source; high = pituitary or ectopic.

Test yourself

Quick check — 3 questions

1. A 38-year-old woman presents with fatigue, 20 lb weight loss, hypotension, and hyperpigmentation of her gums and palmar creases. Labs: Na 128, K 5.8, glucose 62. Which finding differentiates primary from secondary adrenal insufficiency?

2. A patient on chronic prednisone for RA undergoes emergency abdominal surgery. Which medication must be provided perioperatively?

3. A patient with Cushing syndrome has an overnight 1mg dexamethasone suppression test: morning cortisol 28 mcg/dL (normal <1.8). ACTH is undetectable (<5 pg/mL). The next step is:

Frequently asked questions

Why does primary adrenal insufficiency cause hyperpigmentation but secondary does not?

In primary adrenal insufficiency, the pituitary responds to low cortisol by massively upregulating ACTH production (negative feedback is lost). ACTH is derived from the same precursor peptide (POMC) as melanocyte-stimulating hormone (MSH). The excess ACTH/MSH stimulates melanocortin-1 receptors on melanocytes → hyperpigmentation, classically in sun-exposed areas, skin folds, scars, and buccal mucosa. In secondary AI, ACTH is LOW (pituitary failure is the problem), so there is no hyperpigmentation.

How do you distinguish Cushing's disease (pituitary) from ectopic ACTH (e.g., lung cancer)?

Both have elevated ACTH. Distinguish with: (1) High-dose dexamethasone suppression test: Cushing's disease (pituitary adenoma) suppresses cortisol by >50% (pituitary retains some sensitivity to feedback). Ectopic ACTH sources do NOT suppress. (2) CRH stimulation test: Cushing's disease responds with ACTH/cortisol rise; ectopic does not. (3) Inferior petrosal sinus sampling (IPSS): gold standard — direct measurement of ACTH in petrosal sinus vs periphery; ratio >2 at baseline or >3 after CRH = pituitary source. (4) Imaging: MRI pituitary (adenoma) vs CT chest/abdomen (carcinoid, SCLC).

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