How should a patient with a suspected adrenal gland disorder, such as Cushing's syndrome or Addison's disease, be diagnosed and treated?

Diagnosis and Management of Adrenal Gland Disorders

Diagnostic Approach: Establishing the Diagnosis

For suspected adrenal insufficiency (Addison's disease), obtain early morning (8 AM) serum cortisol and plasma ACTH as the first-line diagnostic tests. 1, 2

Initial Laboratory Evaluation

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency and requires no further testing 1, 3
• Morning cortisol 250-400 nmol/L (9-14 μg/dL) with elevated ACTH raises strong suspicion and warrants confirmatory testing 3
• Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH suggests secondary adrenal insufficiency 3
• Include basic metabolic panel (sodium, potassium, glucose) to assess for hyponatremia and hyperkalemia, though hyperkalemia is present in only 50% of primary adrenal insufficiency cases 3

Confirmatory Testing: Cosyntropin Stimulation Test

When morning cortisol is indeterminate, perform the standard ACTH stimulation test 1, 2:

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 3
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 1, 3
• Peak cortisol <500-550 nmol/L (<18-20 μg/dL) is diagnostic of adrenal insufficiency 1, 3
• Peak cortisol >550 nmol/L (>20 μg/dL) excludes adrenal insufficiency 1, 3

Critical pitfall: If acute adrenal crisis is suspected clinically (hypotension, collapse, severe vomiting), never delay treatment for diagnostic testing—give 100 mg IV hydrocortisone immediately and draw blood for cortisol/ACTH before treatment if possible 1, 3

Etiologic Diagnosis

Once adrenal insufficiency is confirmed, determine the underlying cause 1:

• Measure 21-hydroxylase autoantibodies first, as autoimmunity accounts for 85% of primary adrenal insufficiency in Western populations 1, 3
• If autoantibodies are negative, obtain non-contrast CT of the adrenals to evaluate for hemorrhage, tuberculosis (calcifications), tumors, or metastatic disease 1, 3
• In males with negative autoantibodies, measure very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 1, 3

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Diagnosis of Cushing's Syndrome

For suspected Cushing's syndrome, screen with 24-hour urinary free cortisol (UFC), late-night salivary cortisol, and/or 1 mg dexamethasone suppression test. 4, 5

Screening Tests

• 1 mg dexamethasone suppression test: Give 1 mg dexamethasone orally at midnight, measure plasma cortisol at 8 AM—normal suppression is <80 nmol/L (<3 μg/dL) 5
• 24-hour urinary free cortisol: Markedly elevated in clinically apparent Cushing's syndrome, proportionally higher than plasma cortisol 5
• Late-night salivary cortisol: Loss of normal circadian rhythm 4

Differential Diagnosis After Positive Screening

Once hypercortisolism is confirmed, differentiate between pituitary (70%), adrenal (20%), and ectopic ACTH (10%) causes 4, 5:

• Measure plasma ACTH: suppressed in adrenal Cushing's, elevated in ACTH-dependent causes 5
• High-dose dexamethasone suppression test (8 mg) to distinguish pituitary from ectopic sources 5
• Corticotropin-releasing hormone (CRH) stimulation test with ACTH/cortisol measurements 5

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Treatment of Primary Adrenal Insufficiency (Addison's Disease)

All patients with primary adrenal insufficiency require lifelong glucocorticoid and mineralocorticoid replacement therapy. 1, 2

Glucocorticoid Replacement

• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) to mimic physiological cortisol secretion 1, 2
• Alternative regimens: 15+5 mg, 10+10 mg, or 10+5+5 mg depending on individual response 1, 3
• Cortisone acetate 25-37.5 mg daily in divided doses is an acceptable alternative 1, 3
• Prednisolone 4-5 mg daily may be used in select patients with marked energy fluctuations on hydrocortisone 3
• Avoid dexamethasone for chronic replacement therapy 3

Mineralocorticoid Replacement

• Fludrocortisone 50-200 μg daily as a single morning dose (younger adults may require higher doses) 1, 3
• Monitor adequacy by assessing salt cravings, orthostatic blood pressure, serum electrolytes, and peripheral edema 1, 3
• Advise unrestricted salt intake and salty foods 1, 3
• Avoid liquorice and grapefruit juice, which interfere with hydrocortisone metabolism 3

Monitoring Glucocorticoid Replacement

Plasma ACTH and serum cortisol are not useful for dose adjustment—rely on clinical assessment 1:

• Signs of over-replacement: weight gain, insomnia, peripheral edema 1
• Signs of under-replacement: lethargy, nausea, poor appetite, weight loss, increased pigmentation 1, 3
• Fine-tune dosing by detailed questioning about energy levels, daytime somnolence, and timing of symptom dips 1

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Stress Dosing and Special Situations

Surgery and Medical Procedures

Patients require increased hydrocortisone doses during surgery based on procedure severity 1:

• Major surgery: 100 mg hydrocortisone IM immediately before anesthesia, then 100 mg IM every 6 hours until able to eat/drink, then double oral dose for 48+ hours before tapering 1
• Minor surgery/major dental procedures: 100 mg hydrocortisone IM before anesthesia, then double oral dose for 24 hours 1
• Dental procedures: Extra morning dose 1 hour prior, then double oral dose for 24 hours 1

Pregnancy

• Increase hydrocortisone by 2.5-10 mg daily during third trimester due to rising free cortisol levels 1
• Fludrocortisone dose often needs increase during late pregnancy due to progesterone's anti-mineralocorticoid effects 1
• During delivery: 100 mg hydrocortisone IM at onset of labor, repeat every 6 hours if needed 1
• Double oral dose for 24-48 hours postpartum 1

Physical Activity

• Regular, accustomed exercise requires no dose adjustment 1
• For intense/prolonged exercise (e.g., marathon): take extra 5 mg hydrocortisone before activity 1
• Increase fluid and salt intake during hot conditions or intense activity 1

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Adrenal Crisis: Emergency Management

Adrenal crisis is a life-threatening emergency requiring immediate treatment—even mild gastrointestinal upset can precipitate crisis as patients cannot absorb oral medication. 1

Immediate Treatment Protocol

• 100 mg hydrocortisone IV or IM bolus immediately, repeat every 6-8 hours until recovered 1, 3
• 0.9% saline infusion at 1 L/hour initially (at least 2L total) until hemodynamic improvement 3
• Draw blood for cortisol and ACTH before treatment if possible, but never delay treatment for diagnostic procedures 1, 3
• Identify and treat precipitating cause (infection, trauma, surgery) 1

Patient Education and Prevention

All patients must receive comprehensive education to prevent adrenal crisis 1, 3:

• Wear medical alert bracelet or necklace indicating adrenal insufficiency 1, 3
• Carry steroid emergency card with treatment instructions 1
• Prescribe injectable hydrocortisone 100 mg IM kit with self-injection training 3
• Instruct to double or triple oral dose during illness, fever, or physical stress 3
• Educate on warning signs of impending crisis: severe fatigue, nausea, vomiting, dizziness 3

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Treatment of Cushing's Syndrome

First-line therapy for all causes of endogenous Cushing's syndrome is surgical resection of the causative tissue. 4

Surgical Management

• Pituitary Cushing's disease: Transsphenoidal resection of corticotroph adenoma 4
• Adrenal Cushing's syndrome: Unilateral adrenalectomy for adenoma, bilateral adrenalectomy for bilateral disease 4
• Ectopic ACTH syndrome: Resection of ectopic tumor if localized 4
• Minimally invasive surgery should be performed when feasible 1

Medical Management (Second-Line)

• Steroidogenesis inhibitors (e.g., metyrapone, ketoconazole) for any cause when surgery is not possible or unsuccessful 4
• Pituitary radiation therapy (with or without steroidogenesis inhibitors) for persistent Cushing's disease 4
• Bilateral adrenalectomy as definitive treatment for ACTH-dependent Cushing's when other therapies fail 4

Important consideration: Metyrapone may induce acute adrenal insufficiency in patients with reduced adrenal reserve—ability of adrenals to respond to exogenous ACTH should be demonstrated before use 6

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Follow-Up and Screening for Associated Conditions

Patients with primary adrenal insufficiency require annual follow-up with systematic screening for autoimmune comorbidities. 1

Annual Monitoring

• Assessment of health, well-being, weight, blood pressure, and serum electrolytes 1
• Thyroid function tests (TSH, FT4) and thyroid peroxidase antibodies to screen for autoimmune thyroid disease 1, 3
• Plasma glucose and HbA1c to screen for diabetes mellitus 1
• Complete blood count to screen for anemia 1
• Vitamin B12 levels to detect autoimmune gastritis 1
• Tissue transglutaminase antibodies and total IgA if episodic diarrhea present (celiac disease screening) 1
• Bone mineral density every 3-5 years to assess for glucocorticoid-related osteoporosis 1

Special Considerations

• Women of reproductive age should be informed about risk of premature ovarian insufficiency, especially if side-chain cleavage enzyme autoantibodies (SCC-Ab) are present 1
• Patients with 21-hydroxylase autoantibodies without overt adrenal insufficiency should undergo periodic cosyntropin testing to detect evolving disease 1

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Management of Adrenal Incidentalomas

All patients with adrenal incidentalomas should undergo functional testing to exclude hormone hypersecretion, regardless of imaging appearance. 1

Hormonal Screening

• Screen all patients for autonomous cortisol secretion with 1 mg dexamethasone suppression test 1
• Screen patients with hypertension and/or hypokalemia for primary aldosteronism with aldosterone-to-renin ratio 1
• Screen for pheochromocytoma with plasma or 24-hour urinary metanephrines if mass >10 HU on non-contrast CT or signs/symptoms of catecholamine excess 1
• Test for excess androgens if virilization present or adrenocortical carcinoma suspected 1

Imaging Protocol

• Non-contrast CT is first-line imaging to distinguish benign lesions (≤10 HU) from indeterminate masses 1
• Indeterminate masses require second-line imaging with washout CT or chemical-shift MRI 1
• Adrenal biopsy should not be performed routinely for incidentaloma workup 1

Surgical Indications

• Unilateral adrenalectomy for: clinically apparent Cushing's syndrome, aldosterone-secreting adenomas, pheochromocytomas 1
• Consider adrenalectomy for younger patients with mild autonomous cortisol secretion and progressive metabolic comorbidities after shared decision-making 1
• Minimally invasive surgery preferred when feasible 1

Follow-Up Imaging

• No further imaging needed for: benign non-functional adenomas <4 cm, myelolipomas, masses with macroscopic fat 1
• Non-functional lesions ≥4 cm but radiologically benign: repeat imaging in 6-12 months 1
• Consider adrenalectomy if growth >5 mm/year after repeating functional workup 1
• No further follow-up needed if growth <3 mm/year 1