What is the diagnostic approach and treatment for adrenal insufficiency?

Diagnostic Approach and Treatment for Adrenal Insufficiency

The diagnosis of adrenal insufficiency requires paired measurement of early morning (8 AM) serum cortisol and plasma ACTH, with treatment initiated immediately if adrenal crisis is suspected—never delay treatment for diagnostic procedures. 1

Clinical Presentation: When to Suspect Adrenal Insufficiency

Suspect adrenal insufficiency in any patient presenting with unexplained collapse, hypotension, vomiting, or diarrhea. 1 The following clinical features increase suspicion:

• Hyperpigmentation in sun-exposed areas, skin creases, and mucous membranes (primary adrenal insufficiency only due to elevated ACTH) 2
• Salt craving due to aldosterone deficiency (specific to primary adrenal insufficiency) 2
• Hyponatremia (present in 90% of newly diagnosed cases) 3, 2
• Hyperkalemia (present in only 50% of cases—absence does NOT rule out diagnosis) 3, 2
• Hypoglycemia and acidosis 1
• Postural hypotension leading to dizziness or syncope 2

Critical pitfall: Do not rely on electrolyte abnormalities alone—10-20% of patients have mild hypercalcemia, and some present with normal electrolytes. 2

Diagnostic Algorithm

Step 1: Initial Laboratory Testing

Draw early morning (8 AM) serum cortisol, plasma ACTH, and DHEAS before initiating treatment (but never delay treatment if crisis suspected). 1, 2, 4

Interpretation of baseline values:

• Serum cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1, 3
• Serum cortisol <400 nmol/L (<14 μg/dL) with elevated ACTH in acute illness raises strong suspicion of primary adrenal insufficiency 1
• Serum cortisol <140 nmol/L (<5 μg/dL) suggests adrenal insufficiency and requires further testing 4, 5
• Low or inappropriately normal ACTH with low cortisol indicates secondary adrenal insufficiency 3, 4

Important caveat: Oral prednisolone, dexamethasone, and inhaled fluticasone may confound interpretation of low serum cortisol levels. 1

Step 2: Confirmatory Testing (When Baseline Results Are Equivocal)

The cosyntropin (Synacthen) stimulation test is the gold standard for confirming adrenal insufficiency when initial results are indeterminate. 1, 3

Test protocol:

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

Critical distinction: The high-dose (250 mcg) test is preferred over the low-dose (1 mcg) test due to easier administration, comparable diagnostic accuracy, and FDA approval. 3

Step 3: Etiologic Workup

Once adrenal insufficiency is confirmed, determine the underlying cause:

For primary adrenal insufficiency:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies first—positive in ~85% of cases in Western populations (autoimmune Addison's disease) 1, 3, 2
• If antibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative processes 1, 3, 2
• In male patients, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1, 3

For children and young adults with primary adrenal insufficiency:

• Consider APS-1 (autoimmune polyglandular syndrome type 1) if presenting with hypoparathyroidism and candidiasis 1
• Confirm with anti-interferon omega antibodies or AIRE gene mutational analysis 1

For secondary adrenal insufficiency:

• Evaluate for pituitary disease (tumors, hemorrhage, hypophysitis, sarcoidosis) 4
• Review medication history for opioids or other agents that suppress corticotropin production 4

Treatment

Acute Adrenal Crisis (Life-Threatening Emergency)

If adrenal crisis is suspected, treat immediately—do NOT wait for diagnostic test results. 1, 3, 2

Immediate management:

• Hydrocortisone 100 mg IV bolus immediately, followed by 100 mg IV every 6-8 hours until recovered 1, 2
• Isotonic (0.9%) sodium chloride solution at 1 L/hour until hemodynamic improvement 1, 2
• Identify and treat the underlying precipitant (infection, trauma, surgery) once treatment is initiated 1

Alternative if diagnosis uncertain and you need to perform ACTH stimulation testing: Use dexamethasone 4 mg IV instead of hydrocortisone, as it does not interfere with cortisol assays. 3, 6

Chronic Replacement Therapy

For primary adrenal insufficiency (requires both glucocorticoid and mineralocorticoid replacement):

Glucocorticoid replacement:

• Hydrocortisone 15-25 mg daily in split doses (first dose immediately after waking, last dose at least 6 hours before bedtime) 1, 2, 7
• Alternative: Cortisone acetate 18.75-31.25 mg daily 1
• In children: 6-10 mg/m² body surface area 1
• Use the lowest dose compatible with health and sense of well-being 1

Mineralocorticoid replacement:

• Fludrocortisone 50-200 µg as a single daily dose 1, 2, 8
• Children and younger adults may require higher doses 1
• If essential hypertension develops, reduce (but do not stop) fludrocortisone 1
• Advise patients to take salt and salty foods ad libitum and avoid liquorice and grapefruit juice 1

For secondary adrenal insufficiency:

• Glucocorticoid replacement only (mineralocorticoid production is usually intact) 4, 5
• Hydrocortisone 15-25 mg daily or prednisone 3-5 mg daily 4

Important caveat: There is insufficient evidence to recommend routine replacement of adrenal androgens (DHEA). 1

Stress Dosing and Special Situations

During minor illness with fever:

• Double or triple the usual glucocorticoid dose 2

For major surgery:

• Hydrocortisone 100 mg IM before anesthesia, followed by 100 mg IM every 6 hours until able to take oral medications 2
• Surgery and invasive procedures often require IV or IM hydrocortisone and increased oral doses 1

During pregnancy:

• Small adjustments to hydrocortisone and fludrocortisone may be needed, particularly during the last trimester 1
• Parenteral hydrocortisone should be given during delivery 1

Critical warning when treating concurrent hypothyroidism:

• Start corticosteroids several days BEFORE initiating thyroid hormone replacement to prevent precipitating adrenal crisis 3

Patient Education and Safety Measures

All patients with adrenal insufficiency must:

• Wear medical alert identification jewelry and carry a steroid alert card 1, 2
• Receive education on managing daily medications and stress dosing during minor to moderate concurrent illnesses 1, 2
• Be provided with supplies for self-injection of parenteral hydrocortisone (100 mg IM) and know how to administer it 1, 2
• Increase glucocorticoid doses during intercurrent illness, vomiting, injuries, or other stressors 2

Follow-Up and Monitoring

Annual follow-up should include:

• Assessment of health, well-being, weight, and blood pressure 1, 2
• Serum sodium, potassium, glucose, and HbA1c 1, 2
• Complete blood count to screen for anemia 1, 2
• Thyroid function tests (TSH, FT4, TPO antibodies) to screen for autoimmune hypothyroidism 1, 2
• Vitamin B12 levels to screen for autoimmune gastritis 1, 2
• Bone mineral density every 3-5 years to assess for complications of glucocorticoid therapy 1

In patients with frequent diarrhea: Screen for celiac disease with tissue transglutaminase 2 autoantibodies and total IgA. 1

In women of reproductive age: Inform about the possibility of premature ovarian insufficiency, especially if side-chain cleavage enzyme autoantibodies are present. 1

Critical Pitfalls to Avoid

• Never delay treatment of suspected adrenal crisis for diagnostic procedures—mortality is high if untreated 1, 3, 2
• Do not rely on the absence of hyperkalemia to rule out adrenal insufficiency—it is present in only 50% of cases 3, 2
• Under-replacement with mineralocorticoids is common and can predispose to recurrent adrenal crises 2
• Hyponatremia in adrenal insufficiency can be indistinguishable from SIADH—always perform cosyntropin stimulation testing to rule out adrenal insufficiency before diagnosing SIADH 3
• TSH levels may be mildly elevated (4-10 IU/L) in primary adrenal insufficiency due to lack of cortisol's inhibitory effect on TSH production—this does not necessarily indicate hypothyroidism 1