Endocrinology · PANCE / PANRE

Primary Adrenal Insufficiency (Addison Disease)

Written & clinically reviewed by Ryan Busch, PA-C · Updated August 2026 · Report an error

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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Question 1EndocrineMedium
A 45-year-old patient with type 1 diabetes mellitus and Addison disease reports several weeks of increasingly frequent and severe hypoglycemic episodes, including two that required assistance, despite no change in the insulin regimen, diet, or activity level. Deficiency of which of the following hormones best explains the increased risk of hypoglycemia?
  • AAldosterone
  • BThyroid hormone
  • CCortisol
  • DGrowth hormone
Reveal answer & full explanation
Correct answer: C — Cortisol
  • AAldosterone
  • BThyroid hormone
  • CCortisol✓
  • DGrowth hormone

Why Cortisol is correct

  • Cortisol is a key counter-regulatory hormone that stimulates hepatic gluconeogenesis and glycogenolysis and supports the glycemic response to falling glucose
  • In Addison disease the adrenal cortex fails, so cortisol deficiency removes this defense and blunts the counter-regulatory response to insulin-induced hypoglycemia
  • Combined with exogenous insulin in type 1 diabetes, this produces more frequent, severe, and prolonged hypoglycemia even when the insulin dose is unchanged
  • Worsening or unexplained hypoglycemia in a person with type 1 diabetes should prompt evaluation for concurrent adrenal insufficiency

Why the others are wrong

  • Aldosterone — the mineralocorticoid also lost in Addison disease, but it regulates sodium, potassium, and volume; its deficiency causes hyponatremia, hyperkalemia, and hypotension, not hypoglycemia; confused-with trap (right disease, wrong hormone)
  • Thyroid hormone — deficiency produces a hypometabolic state and is not deficient in this patient, so it does not explain the episodes; buzzword trap linking any endocrine deficiency to glucose
  • Growth hormone — a counter-regulatory hormone whose deficiency can cause hypoglycemia in young children, but it is not deficient in Addison disease and does not explain this picture; anchoring on 'counter-regulatory' without integrating the diagnosis
Question 2EndocrineEasy
A 35-year-old man with type 1 diabetes mellitus presents with weeks of fatigue, nausea, vomiting, and lightheadedness on standing. On examination he has hyperpigmentation of the palmar creases and buccal mucosa and is hypotensive. Laboratory studies show hyponatremia and hyperkalemia, and a cosyntropin (ACTH) stimulation test demonstrates an inadequate cortisol response. Which of the following is the most likely diagnosis?
  • APheochromocytoma
  • BPrimary adrenal insufficiency
  • CCushing's syndrome
  • DSecondary adrenal insufficiency
Reveal answer & full explanation
Correct answer: B — Primary adrenal insufficiency
  • APheochromocytoma
  • BPrimary adrenal insufficiency✓
  • CCushing's syndrome
  • DSecondary adrenal insufficiency

Why primary adrenal insufficiency is correct

  • Primary adrenal insufficiency (Addison disease) destroys the adrenal cortex, so both cortisol and aldosterone are lost.
  • Aldosterone deficiency produces hyponatremia, hyperkalemia, and hypotension, while loss of cortisol feedback raises ACTH/POMC and drives the hyperpigmentation of palmar creases and buccal mucosa.
  • A subnormal cortisol response to cosyntropin confirms the adrenal cortex cannot respond, localizing the defect to the gland itself.
  • Coexisting type 1 diabetes points to an autoimmune polyglandular process (autoimmune polyglandular syndrome type 2), and definitive treatment is glucocorticoid plus mineralocorticoid replacement.

Why the others are wrong

  • Pheochromocytoma — catecholamine excess causes episodic hypertension, palpitations, and hyperglycemia, not hypotension with hyponatremia and hyperkalemia (anchoring on an adrenal tumor).
  • Cushing's syndrome — cortisol excess causes hypertension, hypokalemia, and hyperglycemia, the opposite of this picture (confused-with the hypercortisol state).
  • Secondary adrenal insufficiency — pituitary ACTH deficiency spares the mineralocorticoid axis (so no hyperkalemia) and produces no hyperpigmentation because ACTH is low; the hyperkalemia and hyperpigmentation here exclude it.
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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

FeaturePrimary (Addison)Secondary (pituitary)Tertiary (steroid use)
ACTHHIGHLow / inappropriately normalLow
CortisolLowLowLow
Aldosterone / reninLow / HIGH reninNormalNormal
HyperpigmentationPresentAbsentAbsent
HyperkalemiaYesNoNo
HyponatremiaYes (volume + ADH)Mild (ADH)Mild
Common causeAutoimmune adrenalitisPituitary tumor / SheehanChronic 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

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Differentials & related conditions

Sepsis and Septic Shock

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