What is the best approach to diagnosing and managing adrenal insufficiency?

Workup of Adrenal Insufficiency

When adrenal insufficiency is suspected, immediately draw early-morning (8 AM) serum cortisol, ACTH, and DHEAS before initiating treatment, but never delay emergency treatment if adrenal crisis is clinically suspected—the diagnosis can always be established later. 1, 2

Initial Diagnostic Approach

Clinical Suspicion Triggers

Suspect adrenal insufficiency in patients presenting with:

• Unexplained collapse, hypotension, or postural dizziness 1, 3
• Persistent fatigue (50-95% of cases), anorexia, and unintentional weight loss (43-73%) 2, 4
• Nausea, vomiting (20-62%), or abdominal pain 2, 3
• Salt craving (specific for primary adrenal insufficiency) 1
• Hyperpigmentation in sun-exposed areas, skin creases, and mucous membranes 1, 3

Laboratory Red Flags

• Hyponatremia (present in ~90% of newly presenting cases) 1, 3
• Hyperkalemia (present in ~50% of primary adrenal insufficiency cases) 1, 3
• Mild hypercalcemia (10-20% of cases) 1, 3

Biochemical Diagnosis

First-Line Testing

Draw early-morning (8 AM) blood samples for: 1, 2

• Serum cortisol: <5 µg/dL (<138 nmol/L) strongly suggests adrenal insufficiency; <250 nmol/L with elevated ACTH is diagnostic of primary adrenal insufficiency 1, 2
• ACTH: Elevated in primary adrenal insufficiency, low or inappropriately normal in secondary/tertiary adrenal insufficiency 2, 5
• DHEAS: Low in primary adrenal insufficiency, low or low-normal in secondary adrenal insufficiency 2
• Serum sodium, potassium, glucose, creatinine 1, 3

Confirmatory Testing When Initial Results Are Equivocal

If morning cortisol is intermediate (5-10 µg/dL or 138-276 nmol/L): 2, 5

• Perform cosyntropin (Synacthen) stimulation test: Administer 0.25 mg (250 µg) cosyntropin intramuscularly or intravenously, then measure serum cortisol at 30 and 60 minutes 6, 5
• Normal response: Cortisol should exceed 550 nmol/L (20 µg/dL) at 30 or 60 minutes 6
• Abnormal response: Failure to reach this threshold confirms adrenal insufficiency 6

Critical pitfall: The cosyntropin test can give false-normal results in secondary adrenal insufficiency, particularly early in the disease course. If secondary adrenal insufficiency is strongly suspected despite a normal cosyntropin test, consider insulin hypoglycemia test or metyrapone test (though these are rarely needed in routine practice). 5

Etiologic Workup

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary adrenal insufficiency pattern: 2, 1

• Low cortisol (<5 µg/dL)
• High ACTH (typically >2-fold upper limit of normal)
• Low DHEAS
• Hyponatremia and hyperkalemia common
• Hyperpigmentation present

Secondary/tertiary adrenal insufficiency pattern: 2, 6

• Low or intermediate cortisol (5-10 µg/dL)
• Low or inappropriately normal ACTH
• Low or low-normal DHEAS
• Hyponatremia may be present, but hyperkalemia is absent
• No hyperpigmentation

Determining the Cause of Primary Adrenal Insufficiency

Step 1: Test for 21-hydroxylase autoantibodies (21OH-Ab) 6

• If positive: Diagnosis is autoimmune Addison's disease (accounts for ~85% of cases in Western Europe) 6, 1
• No further etiologic testing needed if 21OH-Ab positive 6

Step 2: If 21OH-Ab negative, obtain CT scan of the adrenals 6, 1

• Evaluate for adrenal hemorrhage, tumors, tuberculosis, or infiltrative processes 6, 1

Step 3: Consider additional testing based on clinical context: 6

• Very long chain fatty acids (VLCFA) if adrenoleukodystrophy suspected (especially in males with neurological symptoms) 6, 3
• Interferon-omega or IL-22 autoantibodies and AIRE gene mutation analysis if autoimmune polyglandular syndrome type 1 (APS-1) suspected (young patients with hypoparathyroidism, chronic mucocutaneous candidiasis, or other APS-1 features) 6

Determining the Cause of Secondary Adrenal Insufficiency

Evaluate for: 2, 4

• Pituitary or hypothalamic disease: Obtain MRI of the pituitary with sellar cuts if multiple pituitary hormone deficiencies, severe headaches, or visual changes are present 6
• Exogenous glucocorticoid use: Most common cause of secondary adrenal insufficiency; review medication history for any glucocorticoid exposure (oral, inhaled, topical, intra-articular) 2, 7
• Opioid use: Chronic opioid therapy can suppress ACTH production 2

Screening for Associated Autoimmune Conditions (Primary Adrenal Insufficiency Only)

Annual screening should include: 6, 1

• Thyroid function tests (TSH, free T4, TPO antibodies) to detect autoimmune thyroid disease 6, 1
• Plasma glucose and HbA1c to screen for diabetes mellitus 6, 1
• Complete blood count to screen for anemia 6, 1
• Vitamin B12 levels to detect autoimmune gastritis 6, 1
• Tissue transglutaminase 2 autoantibodies and total IgA if episodic diarrhea present (to screen for celiac disease) 6
• Counsel women of reproductive age about risk of premature ovarian insufficiency, especially if side-chain cleavage enzyme autoantibodies (SCC-Ab) are present 6

Critical Management Principles During Workup

If adrenal crisis is suspected clinically: 6, 1, 3

• Administer hydrocortisone 100 mg IV bolus immediately without waiting for laboratory confirmation 6, 1, 3
• Start rapid IV infusion of 0.9% normal saline at 1 L over the first hour 1, 3
• Draw blood for cortisol and ACTH before treatment if possible, but never delay treatment to obtain samples 6, 1
• The diagnosis can always be established later, even after treatment has been initiated 6

Common pitfall: Physicians often delay treatment waiting for diagnostic confirmation. This increases mortality. When clinical suspicion is high, treat first and diagnose later. 6, 1, 3

Special Considerations

Glucocorticoid-Induced Adrenal Insufficiency

• Most prevalent form of adrenal insufficiency but often unrecognized 7
• During ongoing oral glucocorticoid treatment or initially after withdrawal, ~50% of patients have adrenal insufficiency, yet <1% have documented testing 7
• Suspect in any patient who has recently tapered or discontinued supraphysiological glucocorticoids 2, 7
• Diagnosis requires cosyntropin stimulation test, as baseline cortisol and ACTH are often suppressed and unreliable 7

Pediatric Considerations

• In children <2 years: Hypoglycemia, dehydration, and convulsions are common presentations; virilization in young girls suggests congenital adrenal hyperplasia 5
• Circadian cortisol rhythm is not established until after 4 months of age; cosyntropin test is the only feasible diagnostic test in infants 5
• In children >2 years: Signs and diagnostic methods are the same as in adults 5