What is the diagnostic approach for adrenal insufficiency?

Diagnostic Approach for Adrenal Insufficiency

The diagnosis of adrenal insufficiency requires a two-step approach: first confirming cortisol deficiency through laboratory testing, then determining the etiology (primary vs. secondary) through additional specific tests. 1

Initial Diagnostic Evaluation

Step 1: Baseline Laboratory Testing

• Morning serum cortisol (8 AM):
  • <5 μg/dL (<140 nmol/L): Highly suggestive of adrenal insufficiency 2
  • 5-10 μg/dL (140-280 nmol/L): Intermediate, requires further testing

  • 10 μg/dL (>280 nmol/L): Usually rules out adrenal insufficiency

• Plasma ACTH level (measured simultaneously with morning cortisol)
  • Elevated ACTH with low cortisol: Primary adrenal insufficiency
  • Low or normal ACTH with low cortisol: Secondary adrenal insufficiency
• Additional baseline tests:
  • Electrolytes (hyponatremia, hyperkalemia common in primary AI)
  • Blood glucose (hypoglycemia may be present)
  • Complete blood count (anemia, mild eosinophilia may be present) 1

Step 2: Confirmatory Testing

• Cosyntropin (Synacthen) stimulation test:
  • Administration of 250 μg cosyntropin intramuscularly or intravenously
  • Measure serum cortisol at baseline, 30 and/or 60 minutes
  • Normal response: Peak cortisol >550 nmol/L (>20 μg/dL)
  • Test is highly specific but sensitivity varies (60-80%) 3
  • Low-dose (1 μg) test has similar diagnostic accuracy to standard dose 3

Etiologic Diagnosis

For Primary Adrenal Insufficiency

1. 21-hydroxylase antibodies (21OH-Ab):

   • Positive: Autoimmune adrenal insufficiency (85% of cases in Western countries) 1
   • Negative: Proceed to further testing

2. If 21OH-Ab negative:

   • CT scan of adrenal glands (to detect infiltration, hemorrhage, tumors)
   • Consider testing for tuberculosis (especially in endemic areas)
   • In males: Very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy
   • Consider genetic testing in children or with family history 1

For Secondary Adrenal Insufficiency

1. Evaluate other pituitary hormones:

   • TSH, free T4
   • LH, FSH, testosterone/estradiol
   • Prolactin

2. MRI of pituitary/hypothalamus:

   • Particularly important with multiple hormone deficiencies
   • Look for tumors, hemorrhage, infiltrative disease 1

Special Considerations

Glucocorticoid-Induced Adrenal Insufficiency

• Suspect in patients recently tapered off supraphysiological doses of glucocorticoids
• Testing challenging while on steroids; may need to wait until treatment can be discontinued 2

Immune Checkpoint Inhibitor-Related Adrenal Insufficiency

• May cause primary or secondary adrenal insufficiency
• Requires close monitoring during treatment
• May present with hypophysitis affecting multiple pituitary hormones 1, 4

Important Caveats

1. Never delay treatment for suspected adrenal crisis:

   • If adrenal crisis is suspected, administer hydrocortisone 100 mg IV immediately
   • Obtain blood for cortisol and ACTH before treatment if possible
   • Diagnosis can be established later 1

2. Factors affecting test interpretation:

   • Cortisol binding globulin alterations (pregnancy, estrogen therapy)
   • Time of day (cortisol has diurnal variation)
   • Recent glucocorticoid use
   • Assay variability (newer specific assays have lower cutoffs) 4

3. Pitfalls in diagnosis:

   • Nonspecific symptoms often lead to delayed diagnosis
   • Secondary AI often lacks mineralocorticoid deficiency (no electrolyte abnormalities)
   • Partial ACTH deficiency may be missed by standard testing 5

By following this structured diagnostic approach, clinicians can accurately diagnose adrenal insufficiency, determine its etiology, and initiate appropriate replacement therapy to prevent potentially life-threatening adrenal crises.