Destruction of the adrenal cortex with deficiency of cortisol AND aldosterone; hyperpigmentation distinguishes from secondary.
Also known as: Addison disease, primary adrenal insufficiency, adrenal failure, adrenal crisis, autoimmune adrenalitis
🔒 Free preview limit reached
Keep reading — start your free trial
You've read your 2 free diagnosis previews. Create your free account to unlock the full Primary Adrenal Insufficiency (Addison Disease) outline — plus all 514 diagnoses , 3,500+ board-style questions, flashcards, and an AI tutor. Your 7-day free trial includes everything, and there's no credit card required.
Free to start · No credit card · Cancel anytime
Risk factors Autoimmune adrenalitis (most common in developed world, ~80-90%); often part of APS-1 or APS-2 Infections: tuberculosis, HIV (CMV, MAC), histoplasmosis, blastomycosis Bilateral adrenal hemorrhage: anticoagulation, sepsis, antiphospholipid syndrome, Waterhouse-Friderichsen (meningococcal) Metastasis (lung, breast, melanoma), lymphoma, primary adrenal carcinoma Drugs: ketoconazole, etomidate, mitotane, abiraterone, immune-checkpoint inhibitors Genetic: adrenoleukodystrophy (ALD; check very-long-chain fatty acids in boys), congenital adrenal hyperplasia, adrenal hypoplasia congenita Bilateral adrenalectomy Pathophysiology Destruction of >90% of adrenal cortex produces deficiency of all three corticosteroid lineages (cortisol, aldosterone, adrenal androgens). Low cortisol releases negative feedback, raising CRH and ACTH (which drives hyperpigmentation via MSH from POMC cleavage). Aldosterone deficiency produces hyperkalemia, hyponatremia (volume depletion stimulates ADH), and metabolic acidosis.
Clinical presentation Symptoms Insidious: fatigue, weakness, anorexia, weight loss, nausea, vague abdominal pain Salt craving (mineralocorticoid deficiency) Postural dizziness, syncope Hyperpigmentation: palmar creases, knuckles, oral mucosa, scars, areolae Vitiligo (autoimmune association) Signs / physical exam Orthostatic hypotension, tachycardia Hyperpigmentation of sun-exposed and pressure areas (primary only) Vitiligo, alopecia Adrenal crisis: hypotension/shock refractory to fluids, fever, confusion, abdominal pain Classic findings Hyperpigmented palmar creases + hyponatremia + hyperkalemia + fatigue + orthostasis = Addison disease until proven otherwise.
Differential diagnosis Secondary adrenal insufficiency (pituitary) — Cortisol low, ACTH low; aldosterone preserved (no hyperkalemia or marked hypovolemia); NO hyperpigmentation; often coexisting pituitary deficienciesTertiary adrenal insufficiency (chronic glucocorticoid use) — Suppressed CRH/ACTH from exogenous steroids; aldosterone preservedSepsis — Can precipitate adrenal crisis; cortisol may be inappropriately normal — consider relative adrenal insufficiency in refractory shockAcute gastroenteritis — Vomiting, weakness; check electrolytes — hyperkalemia and hyponatremia point to AIHyperkalemia from CKD, ACE-i, K-sparing diuretics — Drug history, renal functionAnorexia / malnutrition — Weight loss, fatigue; no hyperpigmentation; cortisol may be normalHemochromatosis or amyloidosis affecting adrenals — Rare; ferritin, biopsyDiagnostic workup Diagnostic criteria Failed cosyntropin stim (peak cortisol <18) + elevated ACTH + low aldosterone + elevated renin = primary AI.
Labs 8 AM serum cortisol — <3 mcg/dL strongly suggests AI; >18 mcg/dL excludes Plasma ACTH — elevated in primary, low in secondary/tertiary Cosyntropin (ACTH 1-24) stimulation test — 250 mcg IV/IM, measure cortisol at 30 and 60 min; peak <18 mcg/dL = AI Plasma renin (high) and aldosterone (low) in primary BMP — hyponatremia, hyperkalemia, mild metabolic acidosis, mild hypercalcemia, hypoglycemia Adrenal autoantibodies (21-hydroxylase antibody) Very-long-chain fatty acids in males to screen for adrenoleukodystrophy TSH (often coexisting autoimmune thyroid) QuantiFERON or PPD if TB suspected Imaging Adrenal CT — enlarged glands in TB, infection, hemorrhage, or infiltration; small/atrophic in autoimmune Pituitary MRI if secondary AI suspected Diagnostic algorithm Feature Primary (Addison) Secondary (pituitary) Tertiary (steroid use) ACTH HIGH Low / inappropriately normal Low Cortisol Low Low Low Aldosterone / renin Low / HIGH renin Normal Normal Hyperpigmentation Present Absent Absent Hyperkalemia Yes No No Hyponatremia Yes (volume + ADH) Mild (ADH) Mild Common cause Autoimmune adrenalitis Pituitary tumor / Sheehan Chronic glucocorticoid taper
Distinguishing primary, secondary, and tertiary adrenal insufficiency. Complications Adrenal crisis (mortality ~6% per episode) Hypoglycemia, severe hyperkalemia, dysrhythmia Hypothyroidism (Schmidt syndrome / APS-2) Premature ovarian insufficiency, T1DM, pernicious anemia, vitiligo, celiac (autoimmune cluster) Osteoporosis from over-replacement Iatrogenic Cushing if over-replaced Reduced quality of life, lifelong replacement burden PANCE pearls Hyperpigmentation = PRIMARY adrenal insufficiency (high ACTH stimulates MSH). Secondary/tertiary AI does NOT have hyperpigmentation. Aldosterone is preserved in secondary/tertiary AI (regulated by RAAS, not ACTH) — so hyperkalemia is a primary disease finding. Adrenal crisis: treat FIRST, confirm later. Hydrocortisone 100 mg IV + saline. Do not wait for labs. Stress-dose steroids: double for minor illness, triple/IV for surgery, trauma, severe illness. Patients must be educated to self-administer IM hydrocortisone (100 mg IM emergency kit) when vomiting or unable to tolerate oral doses. Bilateral adrenal hemorrhage in a septic anticoagulated patient = Waterhouse-Friderichsen until proven otherwise. References Endocrine Society 2016 — Diagnosis and Treatment of Primary Adrenal Insufficiency (Bornstein et al., J Clin Endocrinol Metab 2016)ESE 2018 — European Society of Endocrinology Guideline on Adrenal Insufficiency in Adults (Husebye et al., Eur J Endocrinol 2018)Adrenal Crisis Statement 2019 — Adrenal Crisis: Still a Deadly Event in the 21st Century (Allolio, Eur J Endocrinol 2015) and consensus statements
Practice Endocrinology questions on FirstPassPA
Turn this outline into retention. 3,500+ board-style questions with an AI tutor that explains every answer — free to start, no card required.
Start studying free →
Browse all 514 diagnoses