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?
ACortisol
BGrowth hormone
CAldosterone
DThyroid hormone
ECorticotropin
Reveal answer & full explanation
Correct answer: A — Cortisol
ACortisol✓
BGrowth hormone
CAldosterone
DThyroid hormone
ECorticotropin
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
Corticotropin — the pituitary hormone that drives cortisol secretion, so its deficiency in secondary adrenal insufficiency can also cause hypoglycemia, but in Addison disease the adrenal cortex itself fails and corticotropin (ACTH) is elevated, not deficient; confused-with trap (primary vs secondary adrenal insufficiency).
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?
AHypoaldosteronism
BEctopic ACTH syndrome
CHemochromatosis
DSecondary adrenal insufficiency
EPrimary adrenal insufficiency
Reveal answer & full explanation
Correct answer: E — Primary adrenal insufficiency
AHypoaldosteronism
BEctopic ACTH syndrome
CHemochromatosis
DSecondary adrenal insufficiency
EPrimary 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
Hypoaldosteronism — isolated aldosterone deficiency, such as the hyporeninemic hypoaldosteronism that is common in diabetes, causes hyperkalemia and volume depletion but leaves cortisol secretion intact, so the cosyntropin response would be normal and there would be no hyperpigmentation.
Hemochromatosis — iron overload causes diffuse bronze skin with diabetes, not pigment concentrated in the palmar creases and buccal mucosa, and it does not produce hyperkalemia or a subnormal cortisol response to cosyntropin.
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.
Ectopic ACTH syndrome — ACTH excess also darkens the skin, but ectopic ACTH secretion, classically from small cell lung cancer, drives cortisol excess with hypertension, hypokalemia, and hyperglycemia, the opposite of the hypotension and hyperkalemia here, and the overstimulated adrenal glands are producing excess cortisol rather than failing to respond to cosyntropin.
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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. Cortisol deficiency removes a key counter-regulatory hormone (less gluconeogenesis and glycogenolysis), causing hypoglycemia, and contributes to hypotension (reduced vascular response to catecholamines) and to hyponatremia (loss of cortisol's inhibition of ADH). In a patient with T1DM, new frequent hypoglycemia or falling insulin requirements should prompt testing for adrenal insufficiency (APS-2).
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 (about 14-15 mcg/dL with newer monoclonal immunoassays or LC-MS/MS; use the lab's assay-specific cutoff)
Plasma renin (high) and aldosterone (low) in primary
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)
European consensus 2014 — Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency (Husebye et al., J Intern Med 2014;275:104-115)
Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA or PAEA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants; End of Rotation™ is a program of the Physician Assistant Education Association.