Adrenal Insufficiency: Diagnosis and Management (with Focus on Adrenal Crisis)

1. Overview and Classification

2. Causes

• Autoimmune adrenalitis (Addison disease) - isolated or part of polyglandular syndrome (type 1 or 2)
• Infections: tuberculosis, histoplasmosis, coccidioidomycosis, HIV-related (CMV, MAI)
• Bilateral metastases (lung, breast, kidney, gut) or lymphoma
• Adrenal hemorrhage (Waterhouse-Friderichsen syndrome in meningococcemia; anticoagulation; antiphospholipid syndrome)
• Drugs: ketoconazole, etomidate, rifampin
• Congenital: adrenoleukodystrophy (X-linked), congenital adrenal hyperplasia

• Long-term exogenous glucocorticoid use (most common overall cause)
• Pituitary tumor, surgery, or irradiation
• Pituitary apoplexy or traumatic brain injury
• Lymphocytic hypophysitis, infiltrative disease (sarcoid, TB)
• Empty sella syndrome
• ROSEN's Emergency Medicine, p. 815-831

3. Clinical Features

Primary vs. Secondary AI

4. Diagnosis

Biochemical Workup

• Serum cortisol (morning, 8 AM is ideal)
• Plasma ACTH
• Serum electrolytes: Na, K, glucose, creatinine
• CBC (may show eosinophilia, lymphocytosis)
• Renin and aldosterone (primary vs. secondary)
• ABG (mild metabolic acidosis from hypovolemia)

• > 18 mcg/dL (500 nmol/L): rules out AI in non-acutely ill patient
• < 3 mcg/dL (83 nmol/L): strongly suggests AI regardless of assay
• 3-18 mcg/dL: indeterminate - requires ACTH stimulation test
• In acute illness/shock, an "inappropriately normal" cortisol level in the setting of hypotension strongly suggests AI (stress cortisol should be >18 mcg/dL) - Goldman-Cecil Medicine, p. 4061

• Administer cosyntropin (synthetic ACTH 1-24) 250 mcg IV at any time of day
• Measure cortisol at 0, 30, and 60 minutes
• Normal response: cortisol rises to >18 mcg/dL (immunoassay with cross-reactivity) or >14 mcg/dL (specific assays like tandem mass spectrometry or monoclonal antibody-based)
• A significant rise (>18 mcg/dL) in secondary AI is also seen because the adrenal gland itself is intact and can respond to pharmacologic ACTH
• If urgent steroids are needed before the test: use dexamethasone (not hydrocortisone) as it has minimal cross-reactivity with cortisol in the assay
• Goldman-Cecil Medicine, p. 4065; Tintinalli's Emergency Medicine, p. 205

• HIGH ACTH → Primary AI (adrenal gland failure, no negative feedback)
• LOW or inappropriately normal ACTH → Secondary/tertiary AI

• Primary AI: 21-hydroxylase antibodies (positive in ~90% of autoimmune), VLFCA (C26:0) for adrenoleukodystrophy in males with negative antibodies
• CT/MRI abdomen: small adrenals in autoimmune; large/calcified in TB; hemorrhagic in Waterhouse-Friderichsen
• Secondary AI: MRI pituitary and hypothalamus; test other pituitary axes (TSH, gonadotropins, GH, prolactin)
• Goldman-Cecil Medicine, p. 4091-4097

5. Adrenal Crisis - Recognition and Emergency Management

What is Adrenal Crisis?

1. Acute infection (GI infections most common)
2. Surgery or invasive procedures
3. Extreme physical exertion
4. Trauma or severe burns
5. Cessation of glucocorticoid replacement therapy
6. Acute adrenal hemorrhage (Waterhouse-Friderichsen in sepsis)

Clinical Recognition

• Unexplained hypotension refractory to IV fluids and vasopressors
• Patient on chronic glucocorticoid therapy
• Known history of autoimmune disease, TB, HIV/AIDS
• History of chronic fatigue + hyperpigmentation
• Severe abdominal pain with hemodynamic instability (mimicking acute abdomen)
• CNS: confusion, disorientation, lethargy
• Fever without obvious source

• Hyponatremia + hyperkalemia + hypoglycemia = classic triad for primary AI crisis
• Draw serum cortisol BEFORE giving hydrocortisone (if possible)

Emergency Management of Adrenal Crisis

Do not delay treatment while waiting for lab results - if clinical suspicion is high, treat immediately.

Step 1 - IV Access and Immediate Blood Draw

• Draw cortisol (and ACTH if available) before giving steroids
• If ACTH stimulation test is planned: give dexamethasone (not hydrocortisone) to avoid interfering with cortisol assay

Step 2 - IV Fluids

• Normal saline (0.9% NaCl) 1-2 L rapidly for volume resuscitation
• If hypoglycemic: D5/NS (5% dextrose in normal saline)
• Correct electrolyte abnormalities (K, Na, Ca)

Step 3 - Steroids (PRIORITY)

• Tintinalli's Emergency Medicine, p. 220-224; Goldman-Cecil Medicine, p. 4105-4106

Step 4 - Vasopressors (only if fluids + steroids fail)

• Use only after steroid replacement in patients unresponsive to aggressive fluid resuscitation
• Choices: norepinephrine, dopamine, or phenylephrine
• Vasopressor resistance is often a direct consequence of cortisol deficiency (cortisol is needed for catecholamine sensitivity) - Tintinalli's Emergency Medicine, p. 238

Step 5 - Supportive Care

• Maintain airway, breathing, circulation
• Consider glucose (D50), thiamine, naloxone if altered mental status
• Treat the precipitating cause (antibiotics for infection, etc.)
• Admit to ICU

6. Chronic Maintenance Therapy

• Hydrocortisone 10-12 mg/m²/day in 1-3 divided doses
• Mimic diurnal rhythm: largest dose in morning (as soon as possible after waking), smaller dose in early afternoon (~4 PM)
• Alternatively: Prednisone 4-7 mg daily (longer half-life, helpful for afternoon fatigue)

• Fludrocortisone 50-300 mcg/day orally
• Titrate to normalize plasma renin activity
• Encourage adequate dietary salt

• Minor illness/fever: double or triple oral hydrocortisone dose
• Vomiting/unable to take oral meds: inject IM hydrocortisone 100 mg and go to ER
• Major surgery: stress-dose IV hydrocortisone (100 mg at induction, then 50-100 mg q6-8h for 24-48 h)
• Goldman-Cecil Medicine, p. 4111-4115

7. Quick Reference Summary

ADRENAL CRISIS TREATMENT MNEMONIC: "FAST-S"
F - Fluids: NS 1-2L IV stat (D5NS if hypoglycemic)
A - ACTH/cortisol: Draw blood BEFORE steroids
S - Steroids: Hydrocortisone 100 mg IV bolus NOW
T - Treat precipitant (infection, etc.)
S - Support: ICU, electrolytes, vasopressors if needed

Recent Evidence Note