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This is a clinician-written, evidence-based summary aligned to the USMLE Step 2 CK Content Outline. It is intended for medical students preparing for USMLE Step 2 CK. Management reflects current ACC/AHA, USPSTF, and APA guidelines. Always cross-reference with UpToDate, institutional protocols, and clinical judgment.
The Bottom Line
- Primary adrenal insufficiency = low cortisol + high ACTH + aldosterone deficiency; hyperkalemia and hyperpigmentation are classic
- Secondary adrenal insufficiency = low cortisol + low/inappropriately normal ACTH; aldosterone usually preserved
- Best diagnostic test: morning cortisol with ACTH, followed by cosyntropin stimulation when stable
- Adrenal crisis = hypotension/shock, vomiting, abdominal pain, hypoglycemia, hyponatremia +/- hyperkalemia — treat immediately
- Do not delay hydrocortisone for testing in suspected adrenal crisis
Overview
Adrenal insufficiency occurs when cortisol production is inadequate for physiologic needs. Primary adrenal insufficiency reflects adrenal cortex failure, most commonly autoimmune adrenalitis in the United States, and affects glucocorticoid and mineralocorticoid production. Secondary or tertiary adrenal insufficiency results from pituitary ACTH deficiency or hypothalamic suppression, commonly after chronic exogenous glucocorticoid therapy. Aldosterone secretion is usually preserved in secondary disease because it is primarily regulated by the renin-angiotensin-aldosterone system.
Epidemiology
Autoimmune adrenalitis accounts for most primary adrenal insufficiency in the United States and may coexist with autoimmune thyroid disease, type 1 diabetes, pernicious anemia, or premature ovarian insufficiency. Other causes include tuberculosis, fungal infection, adrenal hemorrhage, bilateral adrenal metastases, infiltrative disease, congenital adrenal hyperplasia, and medications such as ketoconazole, etomidate, rifampin, and immune checkpoint inhibitors. Secondary adrenal insufficiency is more common and frequently follows chronic steroid exposure.
Clinical Features
Symptoms
Chronic fatigue, weakness, anorexia, weight loss
Nausea, vomiting, abdominal pain, salt craving in primary disease
Orthostatic dizziness or syncope from hypotension
Hypoglycemic symptoms, especially in children or fasting adults
Acute severe abdominal pain, vomiting, confusion, or shock in adrenal crisis
Signs
Orthostatic hypotension, dehydration, tachycardia
Diffuse hyperpigmentation of skin creases, scars, palmar lines, and buccal mucosa in primary disease
Vitiligo or other autoimmune features
Hyperkalemia and salt wasting in primary adrenal insufficiency
Shock refractory to fluids and vasopressors until steroids are given
Investigations
First-line
8 AM serum cortisol and ACTHLow cortisol with high ACTH suggests primary adrenal insufficiency; low cortisol with low/normal ACTH suggests central disease
BMP and glucosePrimary disease often shows hyponatremia, hyperkalemia, metabolic acidosis, hypoglycemia, and prerenal azotemia
Cosyntropin stimulation testPeak cortisol response is inadequate in adrenal insufficiency; may be falsely normal early in acute secondary disease
Second-line
Plasma renin and aldosteroneHigh renin with low aldosterone supports mineralocorticoid deficiency in primary adrenal insufficiency
21-hydroxylase antibodiesSupports autoimmune Addison disease
TSH/free T4, HbA1c, B12Screen for autoimmune polyglandular syndrome when clinically appropriate
Specialist
Adrenal CTIf primary disease without autoimmune evidence, suspected infection, hemorrhage, malignancy, or infiltrative disease
Pituitary MRIIf central adrenal insufficiency or multiple pituitary hormone deficiencies
1
Adrenal crisis — treat first
- Draw cortisol and ACTH if immediately possible, but do not delay treatment
- Hydrocortisone 100 mg IV immediately, then scheduled stress-dose hydrocortisone
- Rapid isotonic saline resuscitation with dextrose if hypoglycemic
- Treat precipitant: infection, surgery, trauma, vomiting, missed steroids
2
Chronic primary adrenal insufficiency
- Glucocorticoid replacement: hydrocortisone in divided doses or equivalent
- Mineralocorticoid replacement: fludrocortisone, titrated to BP, electrolytes, edema, and renin
- Liberal salt intake may be needed in hot weather or heavy exercise
3
Secondary/tertiary adrenal insufficiency
- Glucocorticoid replacement without routine fludrocortisone because aldosterone is usually intact
- Evaluate and replace other pituitary axes when needed
- Taper chronic glucocorticoids slowly to allow HPA axis recovery
4
Patient safety education
- Sick-day rules: increase glucocorticoid dose during febrile illness or major physiologic stress
- Emergency injectable hydrocortisone and medical alert identification
- Stress-dose steroids before major surgery or severe illness
Complications
- Adrenal crisis: Life-threatening shock, hypoglycemia, hyponatremia, and hyperkalemia
- Autoimmune polyglandular syndrome: Association with type 1 diabetes, autoimmune thyroid disease, pernicious anemia, and gonadal failure
- Over-replacement: Weight gain, hypertension, hyperglycemia, osteoporosis, and Cushingoid features
- Under-replacement: Fatigue, weight loss, hypotension, salt craving, and crisis risk
- Central mass effects: Secondary disease from pituitary tumors may cause visual field defects or other hormone deficiencies
USMLE Step 2 CK Exam Tips
- 1Primary adrenal insufficiency: hyperpigmentation + hyperkalemia + hypotension = Addison disease
- 2Secondary adrenal insufficiency usually does NOT cause hyperkalemia because aldosterone is preserved
- 3Adrenal crisis: give hydrocortisone immediately; testing must not delay treatment
- 4Chronic steroids stopped abruptly = secondary adrenal insufficiency
- 5Cosyntropin stimulation confirms adrenal insufficiency in stable patients
- 6Hydrocortisone has both glucocorticoid and mineralocorticoid activity at stress doses
- 7Treat adrenal insufficiency before starting levothyroxine in combined pituitary disease to avoid precipitating crisis
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