Primary Adrenal Insufficiency (Addison Disease)
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
Overview
Insufficient adrenal cortical hormone production due to destruction or dysfunction of the adrenal cortex, resulting in deficiency of cortisol and (in primary disease) aldosterone. Adrenal crisis is the life-threatening acute decompensation.
Epidemiology
Prevalence ~100-140 per million in developed countries. Female predominance (autoimmune cases). Peak onset 30-50 for autoimmune Addison; can occur at any age. In developing regions, TB remains a leading cause. Bilateral hemorrhagic infarction (Waterhouse-Friderichsen) is a feared cause in meningococcemia.
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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 deficiencies
- Tertiary adrenal insufficiency (chronic glucocorticoid use) — Suppressed CRH/ACTH from exogenous steroids; aldosterone preserved
- Sepsis — Can precipitate adrenal crisis; cortisol may be inappropriately normal — consider relative adrenal insufficiency in refractory shock
- Acute gastroenteritis — Vomiting, weakness; check electrolytes — hyperkalemia and hyponatremia point to AI
- Hyperkalemia from CKD, ACE-i, K-sparing diuretics — Drug history, renal function
- Anorexia / malnutrition — Weight loss, fatigue; no hyperpigmentation; cortisol may be normal
- Hemochromatosis or amyloidosis affecting adrenals — Rare; ferritin, biopsy
Diagnostic 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 |
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
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