What are the diagnostic and treatment approaches for a patient with suspected adrenal insufficiency presenting with symptoms such as fatigue, weight loss, hypotension, and electrolyte imbalances?

Diagnostic and Treatment Approach for Suspected Adrenal Insufficiency

Immediate Clinical Assessment

If the patient presents with severe symptoms (unexplained collapse, profound hypotension, intractable vomiting, altered mental status, or shock), immediately administer IV hydrocortisone 100 mg bolus plus 0.9% saline infusion at 1 L/hour—never delay treatment for diagnostic procedures. 1, 2, 3

• Draw blood for serum cortisol and plasma ACTH before giving hydrocortisone if possible, but do not wait for results to treat 2, 3
• If you need to treat but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 2, 3
• Continue hydrocortisone 100 mg IV every 6-8 hours until the patient stabilizes 3

Diagnostic Algorithm for Stable Patients

Step 1: Obtain Early Morning (8 AM) Laboratory Tests

Measure paired serum cortisol and plasma ACTH as the first-line diagnostic test—this often establishes the diagnosis without further testing. 1, 2, 3, 4

• Also obtain: basic metabolic panel (sodium, potassium, CO2, glucose), DHEAS, and plasma renin activity 1, 2
• Hyponatremia is present in 90% of newly diagnosed cases, but hyperkalemia occurs in only ~50% of patients—absence of hyperkalemia does not rule out adrenal insufficiency 1, 2, 5, 4
• Between 10-20% of patients have mild or moderate hypercalcemia at presentation 1

Step 2: Interpret Initial Results

Primary adrenal insufficiency (PAI):

• Serum cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic 1, 2, 3
• Serum cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion 1, 2
• Low DHEAS and elevated plasma renin activity support the diagnosis 1

Secondary adrenal insufficiency:

• Low or intermediate cortisol (140-275 nmol/L or 5-10 μg/dL) with low or inappropriately normal ACTH 2, 4
• DHEAS is typically low or low-normal 4

Step 3: Confirmatory Testing for Equivocal Cases

For intermediate morning cortisol values (140-400 nmol/L or 5-14.5 μg/dL), perform the cosyntropin stimulation test to definitively confirm or exclude adrenal insufficiency. 1, 2, 3, 4

Cosyntropin stimulation test protocol:

• Administer 0.25 mg (250 μg) cosyntropin (tetracosactide) intramuscularly or intravenously 1, 2, 3
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 1, 2, 3
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 2, 3, 4
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is normal and excludes adrenal insufficiency 2, 3

Critical pitfall: Do not perform this test in patients taking exogenous steroids (prednisolone, dexamethasone, inhaled fluticasone)—these medications suppress the HPA axis and cause false results 1, 2

Etiologic Workup After Diagnosis Confirmed

For Primary Adrenal Insufficiency:

Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmunity accounts for ~85% of PAI cases in Western populations. 1, 2, 3

• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumors, tuberculosis, fungal infections, or other structural abnormalities 1, 2, 3
• In male patients with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1, 2
• Consider APS-1 (autoimmune polyendocrine syndrome type 1) in children and young adults presenting with PAI plus hypoparathyroidism or candidiasis 1

For Secondary Adrenal Insufficiency:

• Evaluate for pituitary lesions, tumors, hemorrhage, inflammatory conditions (hypophysitis, sarcoidosis), or history of pituitary surgery/radiation 4, 6
• Screen for other pituitary hormone deficiencies 2
• Review medication history for opioids or other drugs that suppress ACTH production 4

Treatment Approach

Chronic Maintenance Therapy

For primary adrenal insufficiency, prescribe both glucocorticoid and mineralocorticoid replacement:

• Glucocorticoid: Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at 12 PM, 2.5-5 mg at 4 PM) 1, 2, 3, 4
  • Alternative: Prednisone 3-5 mg daily 2, 4
  • Avoid dexamethasone for chronic replacement 2
• Mineralocorticoid: Fludrocortisone 0.05-0.2 mg daily (range 0.05-0.3 mg daily) 1, 2, 3, 7, 4
  • Monitor adequacy by assessing salt cravings, orthostatic blood pressure, peripheral edema, and plasma renin activity 2
  • Doses up to 500 μg daily may be needed in younger adults 2

For secondary adrenal insufficiency, prescribe glucocorticoid replacement only (mineralocorticoid not needed as the renin-angiotensin-aldosterone system remains intact): 2

• Hydrocortisone 15-25 mg daily or prednisone 3-5 mg daily 2, 4

Stress Dosing and Sick Day Management

All patients must be educated on stress dosing to prevent adrenal crisis: 1, 2, 3, 4, 6

• Minor stress (mild illness, fever): Double the usual daily dose for 1-2 days 2
• Moderate stress (moderate illness, dental procedures): Hydrocortisone 50-75 mg daily or prednisone 20 mg daily 2
• Major stress (severe illness, major surgery): Hydrocortisone 100-150 mg daily 2
• Vomiting or inability to take oral medications: Use emergency injectable hydrocortisone 100 mg IM immediately and seek medical attention 2, 3, 4, 6

Mandatory Patient Education and Safety Measures

Every patient with adrenal insufficiency must receive: 1, 2, 3, 4, 6

• Medical alert bracelet or necklace indicating adrenal insufficiency 1, 2, 3, 6
• Steroid emergency card 1, 6
• Injectable hydrocortisone 100 mg IM kit with self-injection training 2, 3, 4, 6
• Written instructions on stress dosing and sick day management 1, 2, 6

Critical Pitfalls to Avoid

• Never rely solely on electrolyte abnormalities for diagnosis—hyponatremia may be only marginally reduced and hyperkalemia is present in only ~50% of cases 1, 5
• Never delay treatment of suspected adrenal crisis for diagnostic testing—mortality is high if untreated 1, 2, 3, 6
• When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 2
• Do not attempt diagnostic testing in patients actively taking corticosteroids—wait until the patient has been weaned off steroids for at least 3 months before performing HPA axis testing 2
• Recognize that patients taking ≥20 mg/day prednisone or equivalent for ≥3 weeks who develop unexplained hypotension should be presumed to have adrenal insufficiency until proven otherwise 2, 5

Drug Interactions and Monitoring

Medications that increase hydrocortisone requirements: 2

• Anti-epileptics (phenytoin, barbiturates), rifampin, antifungals, etomidate, topiramate

Medications that interfere with fludrocortisone: 2, 7

• Diuretics, NSAIDs, acetazolamide, liquorice

Avoid grapefruit juice and liquorice as they decrease hydrocortisone requirements 2

Monitor regularly: 1, 7

• Blood pressure (supine and standing) to assess mineralocorticoid adequacy 2
• Serum electrolytes (sodium, potassium) 1, 7
• Plasma renin activity to guide fludrocortisone dosing 2

Annual Screening for Associated Conditions

In patients with primary adrenal insufficiency, screen annually for associated autoimmune conditions: 3

• Thyroid function tests 3
• Plasma glucose (diabetes screening) 3
• Complete blood count (pernicious anemia) 3
• Vitamin B12 levels 3
• Tissue transglutaminase antibodies (celiac disease) 3