Adrenal Cortical Insufficiency

Classification

Key threshold: Clinical adrenal insufficiency does not appear until at least 90% of the adrenal cortex has been destroyed. - Frameworks for Internal Medicine

1. Primary Adrenal Insufficiency (Addison Disease)

Etiology

• APS-1 (rare, autosomal recessive, AIRE gene mutation): adrenalitis + hypoparathyroidism + mucocutaneous candidiasis + ectodermal dystrophy
• APS-2 (more prevalent, starts 4th decade): adrenalitis + autoimmune thyroiditis ± type 1 diabetes
• APS-4: adrenalitis + other autoimmune phenomena (gastritis, vitiligo, alopecia) without thyroiditis or T1D

• Tuberculosis: hematogenous spread; was the dominant cause historically and remains common in developing countries (up to one-third of cases there). Recent infection shows bilateral adrenal enlargement on imaging; older infection shows calcification and atrophy.
• Fungal infections: Histoplasma, Coccidioides, Cryptococcus, Blastomyces, Paracoccidioides
• HIV/AIDS: up to one-fifth of hospitalized AIDS patients; due to opportunistic infections (CMV), malignancies (Kaposi sarcoma), or drugs (ketoconazole, rifampin)
• Bilateral adrenal hemorrhage: due to the adrenal gland's unique vascular anatomy (3 arteries in, 1 vein out - a "vascular dam"). Associated with anticoagulation, DIC, septicemia (Waterhouse-Friderichsen syndrome), critical illness surges in ACTH, and blunt trauma (right gland most common, compressed between liver and spine)
• Infiltrative: lymphoma, amyloidosis, sarcoidosis, hemochromatosis, metastatic carcinoma (lung and breast most common)
• Other: bilateral adrenalectomy (requires lifelong glucocorticoid + mineralocorticoid replacement), drugs inhibiting cortisol synthesis (ketoconazole) or accelerating its metabolism (phenytoin), adrenoleukodystrophy (X-linked, ABCD1 mutation - impaired peroxisomal β-oxidation of very long-chain fatty acids), congenital adrenal hypoplasia

Waterhouse-Friderichsen Syndrome

• Overwhelming bacterial septicemia - classically Neisseria meningitidis, also Rickettsia rickettsii, S. pneumoniae, Group A Strep, S. aureus
• Rapidly progressive hypotension and shock
• Widespread purpuric rash (DIC)
• Massive bilateral adrenal hemorrhage

Diffuse purpuric rash in a patient with Waterhouse-Friderichsen syndrome. (Robbins Pathology, Fig. 24.47)

2. Secondary and Tertiary Adrenal Insufficiency

• No hyperpigmentation (ACTH is low, not high) - skin may appear pale/alabaster
• No hyperkalemia (aldosterone secretion is relatively preserved, as it is primarily regulated by the renin-angiotensin system, not ACTH)
• ACTH levels are low or inappropriately normal

3. Pathophysiology and Clinical Features

Glucocorticoid (Cortisol) Deficiency

• Inability to maintain blood glucose between meals (impaired gluconeogenesis)
• Reduced protein and fat mobilization - generalized weakness
• Inability to mount adequate stress response - even mild illness can be fatal
• Loss of negative feedback on hypothalamus/pituitary → marked rise in ACTH and MSH → hyperpigmentation (especially lips, nipples, pressure areas, sun-exposed skin)
• Increased ADH release → hyponatremia (mimics SIADH)
• Mildly elevated TSH (normalizes with glucocorticoid replacement)

Mineralocorticoid (Aldosterone) Deficiency (primary only)

• Impaired Na+ reabsorption → sodium wasting, hyponatremia, volume depletion
• Impaired K+/H+ secretion → hyperkalemia and mild metabolic acidosis
• Plasma volume falls, hematocrit rises, cardiac output falls → shock; death in 4 days to 2 weeks without treatment

Classic Clinical Presentation (Addison Disease)

• Fatigue, weakness, weight loss, anorexia
• Nausea, vomiting, abdominal pain
• Hypotension (orthostatic)
• Hyperpigmentation (primary AI only) - skin creases, buccal mucosa, pressure points, areolae
• Hyponatremia (88% at presentation), hyperkalemia (40-50% in primary AI, not seen in secondary)
• Eosinophilia (17% of patients)
• Hypoglycemia (rare in adults)
• Salt craving

4. Diagnosis

Initial Workup

• 18-20 mcg/dL: effectively excludes adrenal insufficiency

• <3 mcg/dL: confirms adrenal insufficiency
• Intermediate values require stimulation testing

Gold Standard: Short Cosyntropin (ACTH 1-24) Stimulation Test

• Give 250 mcg cosyntropin IV at any time of day
• Measure cortisol at 0 and 60 minutes
• Normal response: peak cortisol >18-20 mcg/dL (cutoff varies slightly by lab/assay)
• In primary disease: cortisol response is blunted (destroyed cortex cannot respond)
• In long-standing secondary disease: also blunted (atrophic cortex); may be normal in recent-onset secondary AI
• Dexamethasone does not cross-react with cortisol assays and can be given before testing if crisis is suspected

Additional Workup

• Autoimmune AI: screen for associated conditions - hypothyroidism, type 1 diabetes, B12 deficiency, premature ovarian failure
• Secondary AI confirmed: MRI of pituitary; evaluate other pituitary hormones
• Mineralocorticoid status: measure simultaneous plasma renin activity and serum aldosterone

5. Treatment

Adrenal Crisis (Emergency)

1. Hydrocortisone 100 mg IV bolus, then 200 mg/24 h (as 50 mg IV q6h, or continuous infusion)
   • Alternative: Dexamethasone 4 mg IV (preferred when cosyntropin stimulation test is still needed, as it does not interfere with cortisol assays)
2. IV fluid resuscitation - normal saline (often 1 L/h initially)
3. Pressor support and glucose as needed
4. Identify and treat the precipitating cause (infection, trauma, surgery, medication withdrawal)

Chronic Maintenance Therapy

• Hydrocortisone 15-25 mg/day in 2-3 divided doses
• Largest dose in the morning (mimics diurnal cortisol pattern; typically 2/3 AM, 1/3 afternoon)

• Fludrocortisone (9-α-fluorohydrocortisone) 50-200 mcg/day
• Dose titrated to blood pressure, serum Na+/K+, and plasma renin activity

• 50 mg/day may be considered in women with primary AI who have impaired well-being or decreased libido despite adequate glucocorticoid and mineralocorticoid replacement

Sick Day Rules (Stress Dosing)

• Minor illness/fever: double the usual daily hydrocortisone dose
• Major illness/surgery: hydrocortisone 100 mg IV (perioperative "stress dose")
• Patients should carry injectable hydrocortisone for emergencies and wear a medical alert bracelet
• Strenuous physical activity, pregnancy, and febrile illness all warrant dose increases

6. Secondary AI: Special Considerations

• The most common cause worldwide is exogenous glucocorticoid use (>20 mg prednisone equivalent/day for >5 days can suppress the HPA axis)
• Immune checkpoint inhibitors (cancer immunotherapy) can cause either primary AI (adrenalitis) or secondary AI (hypophysitis)
• Steroid tapering is required after chronic glucocorticoid use - no universally recommended protocol exists
• Radiation to the hypothalamic-pituitary region causes central AI in up to 50% of patients (median time to onset: 5 years)

Recent Evidence (2024-2026)

• Robbins & Cotran Pathologic Basis of Disease (Table 24.9, pp. 1035-1037)
• Frameworks for Internal Medicine (pp. 98-103)
• Harrison's Principles of Internal Medicine, 22E (Ch. 398)
• Guyton & Hall Textbook of Medical Physiology (pp. 956-957)
• Rosen's Emergency Medicine (Box 117.11)
• Symptom to Diagnosis: An Evidence-Based Guide, 4E
• Sabiston Textbook of Surgery, 21E

What's inside (14 slides):