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Reproductive & Endocrine Systems

Addison disease

Core Principle of Addison Disease
🧷 Addison disease is primary adrenal insufficiency — destruction of the adrenal cortex leads to deficiency of all three cortical zones: zona glomerulosa (aldosterone), zona fasciculata (cortisol), and zona reticularis (androgens).
🧷 The key pathophysiologic distinction is that primary insufficiency affects both glucocorticoid and mineralocorticoid production, while secondary/tertiary insufficiency (pituitary/hypothalamic) preserves aldosterone because the renin-angiotensin system remains intact.
🧷 Loss of negative feedback → sky-high ACTH → stimulation of melanocyte receptors → hyperpigmentation.
🧷 Board pearl: Primary = high ACTH with hyperpigmentation; Secondary = low ACTH without hyperpigmentation.
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Etiology and Epidemiology
📍 In developed countries: autoimmune adrenalitis accounts for 80-90% of cases, often associated with other autoimmune conditions (type 1 diabetes, thyroid disease, vitiligo).
📍 In developing countries: tuberculosis remains the most common cause — bilateral adrenal calcification on CT is pathognomonic.
📍 Other causes: adrenal hemorrhage (Waterhouse-Friderichsen syndrome with meningococcemia), metastases (lung, breast, melanoma), infections (CMV in AIDS, fungal), infiltrative diseases.
📍 Requires destruction of >90% of both adrenal glands before clinical insufficiency manifests.
📍 Board clue: Bilateral adrenal enlargement + primary insufficiency in HIV patient → think CMV or fungal infection.
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Clinical Presentation: The Insidious Onset
🔹 Chronic presentation: fatigue, weight loss, anorexia, salt craving, postural dizziness, nausea, vomiting, abdominal pain.
🔹 Hyperpigmentation: most specific sign — occurs in sun-exposed areas, pressure points, palmar creases, buccal mucosa, recent scars.
🔹 Vitiligo paradoxically coexists in autoimmune cases — patches of depigmentation alongside hyperpigmentation.
🔹 Women may report loss of axillary and pubic hair due to adrenal androgen deficiency.
🔹 Board pearl: A patient with "bronzing" of the skin + orthostatic hypotension + hyponatremia → think Addison disease until proven otherwise.
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Laboratory Findings: The Diagnostic Triad
⭐ Hyponatremia (90%): due to aldosterone deficiency → renal sodium wasting + ADH release from volume depletion.
⭐ Hyperkalemia (65%): aldosterone deficiency → impaired K⁺ secretion in collecting duct.
⭐ Hypoglycemia: cortisol deficiency → impaired gluconeogenesis, especially during stress or fasting.
⭐ Other findings: mild metabolic acidosis (type 4 RTA pattern), hypercalcemia (increased gut absorption when cortisol's inhibitory effect is lost), eosinophilia, lymphocytosis.
⭐ Board distinction: Hyponatremia + hyperkalemia + hypoglycemia = primary adrenal insufficiency; isolated hyponatremia = consider secondary.
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Morning Cortisol and ACTH: Initial Screening
✅ Morning cortisol <3 μg/dL: diagnostic of adrenal insufficiency.
✅ Morning cortisol >15 μg/dL: rules out adrenal insufficiency.
✅ Morning cortisol 3-15 μg/dL: indeterminate — requires dynamic testing.
✅ Simultaneous ACTH measurement distinguishes primary (ACTH >2× upper normal) from secondary (ACTH low/normal).
✅ Random cortisol levels are unreliable due to diurnal variation and stress response.
✅ Board pearl: Always draw cortisol before 9 AM; afternoon values cannot rule out insufficiency due to normal diurnal decline.
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Cosyntropin Stimulation Test: The Gold Standard
🧠 Administers 250 μg synthetic ACTH (cosyntropin) IV or IM, then measures cortisol at 30 and 60 minutes.
🧠 Normal response: cortisol rises to >18-20 μg/dL.
🧠 Primary insufficiency: low baseline, minimal rise (adrenals cannot respond).
🧠 Secondary insufficiency: may have normal response if recent onset (adrenals not yet atrophied) — low-dose test more sensitive.
🧠 Must be performed before starting steroids unless patient is in crisis.
🧠 Board pearl: A normal cosyntropin test does not rule out recent-onset secondary insufficiency — the adrenals haven't atrophied yet.
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Additional Diagnostic Tests
⚡ 21-hydroxylase antibodies: positive in 90% of autoimmune adrenalitis — most specific test for autoimmune etiology.
⚡ CT abdomen: small atrophic adrenals (autoimmune), bilateral enlargement (infection, hemorrhage, metastases), calcification (TB, fungal).
⚡ PPD/QuantiFERON: screen for tuberculosis if clinical suspicion.
⚡ Very long chain fatty acids: elevated in X-linked adrenoleukodystrophy (young males with adrenal insufficiency + neurologic symptoms).
⚡ Board clue: Young male with Addison disease + behavioral changes or spastic paraparesis → check VLCFAs for adrenoleukodystrophy.
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Acute Adrenal Crisis: Life-Threatening Emergency
📌 Precipitated by stress (infection, surgery, trauma) in patients with undiagnosed or undertreated adrenal insufficiency.
📌 Presentation: profound hypotension/shock, fever, severe abdominal pain (may mimic acute abdomen), altered mental status, hypoglycemia.
📌 Laboratory: hyponatremia, hyperkalemia, hypoglycemia, azotemia, hypercalcemia, eosinophilia.
📌 Pathophysiology: cortisol deficiency → vascular collapse from loss of catecholamine responsiveness + mineralocorticoid deficiency → volume depletion.
📌 Board pearl: Unexplained shock + hyponatremia + hyperkalemia = adrenal crisis until proven otherwise — treat immediately!
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Emergency Management of Adrenal Crisis
📣 Do NOT delay treatment for diagnostic testing — draw cortisol and ACTH, then treat immediately.
📣 IV hydrocortisone 100 mg bolus, then 50-100 mg q6-8h (provides both glucocorticoid and mineralocorticoid activity at high doses).
📣 Aggressive IV normal saline for volume resuscitation — often require 2-3 L in first few hours.
📣 Dextrose for hypoglycemia.
📣 Treat precipitating illness (antibiotics for infection).
📣 Board pearl: Dexamethasone 4 mg can be used initially if cosyntropin testing planned — doesn't interfere with cortisol assay, but lacks mineralocorticoid activity.
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Chronic Replacement Therapy
🔸 Glucocorticoid: hydrocortisone 15-25 mg daily in divided doses (2/3 morning, 1/3 afternoon) to mimic diurnal rhythm, or prednisone 5-7.5 mg daily.
🔸 Mineralocorticoid: fludrocortisone 0.05-0.2 mg daily — titrate to normalize BP, K⁺, and plasma renin activity.
🔸 DHEA replacement controversial — may improve well-being in women.
🔸 Monitor: electrolytes, BP (supine and standing), symptoms of over/under-replacement.
🔸 Board pearl: Secondary adrenal insufficiency does NOT require fludrocortisone — aldosterone production remains intact via RAA axis.
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Stress Dose Steroids: Preventing Crisis
🧷 Minor illness/stress: double or triple daily dose for 2-3 days.
🧷 Major surgery/severe illness: hydrocortisone 100 mg IV q8h, taper as stress resolves.
🧷 Unable to take oral meds (vomiting): must use parenteral steroids.
🧷 Patient education critical — wear medical alert bracelet, carry emergency injection kit, never abruptly stop steroids.
🧷 Board pearl: A patient with Addison disease presenting for elective surgery needs stress-dose steroids perioperatively — typically hydrocortisone 100 mg IV before induction.
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Autoimmune Polyglandular Syndromes
📍 APS-1: rare, childhood onset, mucocutaneous candidiasis + hypoparathyroidism + Addison disease (2 of 3 needed). AIRE gene mutation.
📍 APS-2: common, adult onset, Addison disease + autoimmune thyroid disease and/or type 1 diabetes. HLA-associated.
📍 Screen Addison patients for associated conditions: TSH, glucose, calcium.
📍 Screen family members of APS patients — 50% develop autoimmune endocrinopathy.
📍 Board pearl: Adult with Addison disease + hypothyroidism + type 1 diabetes = APS-2 (Schmidt syndrome).
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Addison vs Secondary Adrenal Insufficiency
🔹 Addison: ↑ACTH, hyperpigmentation, hyperkalemia, volume depletion, affects all three adrenal zones.
🔹 Secondary: ↓ACTH, no hyperpigmentation, normal potassium, euvolemic (intact aldosterone), only glucocorticoid deficiency.
🔹 Most common cause of secondary: chronic exogenous steroid use → HPA axis suppression.
🔹 Other secondary causes: pituitary tumors, surgery, radiation, infiltrative diseases, Sheehan syndrome.
🔹 Board distinction: Hyperkalemia and hyperpigmentation are unique to primary insufficiency — their presence excludes secondary causes.
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Drug-Induced Adrenal Insufficiency
⭐ Ketoconazole: inhibits multiple steps in steroidogenesis — used therapeutically for Cushing syndrome.
⭐ Rifampin: induces hepatic enzymes → increased cortisol metabolism → may precipitate crisis in marginal reserve.
⭐ Etomidate: single dose can suppress adrenal function for 24 hours — avoid in suspected insufficiency.
⭐ Chronic opioids: suppress HPA axis → secondary insufficiency.
⭐ Megestrol (progesterone analog): glucocorticoid activity suppresses ACTH.
⭐ Board pearl: New diagnosis of adrenal insufficiency in patient on antifungals → check if taking ketoconazole.
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Special Populations: Pregnancy
✅ Pregnancy increases cortisol-binding globulin → total cortisol rises but free cortisol normal.
✅ Diagnosis challenging — use trimester-specific cortisol ranges.
✅ Hydrocortisone dose may need 20-40% increase in third trimester.
✅ Labor/delivery = major stress → requires stress-dose steroids (hydrocortisone 100 mg q8h).
✅ Fludrocortisone requirements may decrease due to progesterone's mineralocorticoid activity.
✅ Board pearl: Pregnant woman with known Addison disease in labor → immediate stress-dose steroids regardless of symptoms.
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Subclinical Adrenal Insufficiency
🧠 Partial adrenal dysfunction — normal baseline cortisol but inadequate response to stress.
🧠 Often discovered incidentally when screening patients with nonspecific symptoms.
🧠 Abnormal cosyntropin stimulation test but no overt clinical insufficiency.
🧠 Management controversial — some advocate treatment only during stress, others recommend full replacement.
🧠 High risk of progression to overt insufficiency, especially with autoimmune etiology.
🧠 Board pearl: Patient with borderline cosyntropin test undergoing surgery → provide perioperative stress-dose steroids.
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Adrenal Hemorrhage and Waterhouse-Friderichsen
⚡ Acute bilateral adrenal hemorrhage → sudden onset adrenal insufficiency.
⚡ Waterhouse-Friderichsen syndrome: adrenal hemorrhage due to meningococcemia — presents with shock, purpura, DIC.
⚡ Other causes: anticoagulation (especially with underlying stress/sepsis), HIT, antiphospholipid syndrome, trauma.
⚡ CT shows bilateral adrenal enlargement with high attenuation (blood).
⚡ High mortality — requires immediate recognition and treatment.
⚡ Board pearl: Septic shock + purpuric rash + bilateral flank pain → suspect Waterhouse-Friderichsen syndrome.
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Monitoring and Complications of Treatment
📌 Overreplacement: weight gain, hypertension, hyperglycemia, osteoporosis, psychiatric symptoms.
📌 Underreplacement: persistent fatigue, hypotension, electrolyte abnormalities, hyperpigmentation.
📌 Monitor: clinical symptoms, BP, electrolytes, plasma renin activity (for fludrocortisone adjustment).
📌 Annual screening: bone density (glucocorticoid effect), glucose, lipids.
📌 Quality of life often remains impaired despite adequate biochemical replacement.
📌 Board pearl: Persistent hypertension + hypokalemia in treated Addison patient → excessive fludrocortisone dose.
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Board Question Stem Patterns
📣 Hyperpigmentation + orthostatic hypotension + hyponatremia + hyperkalemia → primary adrenal insufficiency.
📣 HIV patient + bilateral adrenal enlargement + fever → CMV adrenalitis.
📣 Young male + neurologic symptoms + adrenal insufficiency → adrenoleukodystrophy.
📣 Septic shock + purpura + DIC → Waterhouse-Friderichsen syndrome.
📣 Post-steroid withdrawal + hypotension + normal potassium → secondary adrenal insufficiency.
📣 TB exposure + adrenal calcifications + chronic symptoms → tuberculous Addison disease.
📣 Type 1 diabetes + hypothyroidism + new hyperpigmentation → APS-2 with developing Addison disease.
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One-Line Recap
🔸 Addison disease is primary adrenal insufficiency causing cortisol and aldosterone deficiency, presenting with hyperpigmentation, orthostatic hypotension, hyponatremia, and hyperkalemia, diagnosed by elevated ACTH with failed cosyntropin stimulation, treated with hydrocortisone plus fludrocortisone replacement, and requiring stress-dose steroids during illness to prevent life-threatening adrenal crisis.
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