What is the appropriate management for a patient with suspected adrenal insufficiency, given laboratory results including low morning cortisol, low salivary cortisol, elevated dexamethasone level after suppression, and a random morning cortisol within the normal range?

Diagnostic Interpretation: Exogenous Dexamethasone Suppression with Confounding Laboratory Results

This patient has laboratory evidence of exogenous glucocorticoid exposure (elevated dexamethasone level of 286) causing iatrogenic HPA axis suppression, which explains the low morning cortisol (<1.8) and low salivary cortisol values, but the random morning cortisol of 19.0 and elevated ACTH of 29 create a confusing picture that requires systematic interpretation.

Critical Laboratory Analysis

Exogenous Steroid Interference

• The elevated dexamethasone level of 286 indicates recent exogenous glucocorticoid exposure, which suppresses the HPA axis and makes all cortisol measurements unreliable for diagnosing endogenous adrenal insufficiency 1.
• Morning cortisol measurements in patients actively taking corticosteroids are not diagnostic because the assay measures both endogenous cortisol and therapeutic steroids, with cross-reactivity varying by assay 1.
• Laboratory confirmation of adrenal insufficiency should not be attempted in patients given corticosteroids until treatment is ready to be discontinued 1.

Interpreting the Contradictory Results

• The random morning cortisol of 19.0 (normal range) directly contradicts the AM cortisol <1.8, suggesting either:

  • Laboratory error or timing discrepancy between samples 1
  • Cross-reactivity of dexamethasone in the cortisol assay producing falsely elevated readings 1
  • Recovery of endogenous cortisol production between measurements 2

• The ACTH of 29 (mildly elevated) with suppressed morning cortisol creates an unusual pattern:

  • In iatrogenic secondary adrenal insufficiency from exogenous steroids, ACTH should be suppressed (low), not elevated 3, 1
  • Elevated ACTH with low cortisol typically indicates primary adrenal insufficiency 1, 3
  • This discordance suggests either assay interference, recovery phase, or possible underlying primary adrenal pathology 2

Salivary Cortisol Interpretation

• The low salivary cortisol values (AM 0.10, PM 0.04, second day AM 0.09, PM 0.08) are consistent with adrenal suppression 4.
• Normal salivary cortisol 60 minutes after ACTH stimulation should be >52.2 nmol/L, while patients with adrenal insufficiency have mean values of 7.5 nmol/L 4.
• Salivary cortisol measurements circumvent corticosteroid-binding globulin alterations and offer a practical approach to assess pituitary-adrenal function 4.

Immediate Management Approach

Do NOT Perform Diagnostic Testing Now

• Never attempt diagnostic testing while the patient has detectable exogenous dexamethasone in their system—this will yield false-positive results showing "adrenal insufficiency" that simply reflects expected HPA suppression 1.
• The dexamethasone suppression test predicts later development of impaired adrenal function, with patients having cortisol levels in the lowest quartile after dexamethasone having a 44% risk of developing suppressed adrenal function 5.

Clinical Assessment for Symptoms

• If the patient has symptoms of adrenal insufficiency (fatigue, nausea, weight loss, hypotension, orthostatic symptoms), treat empirically with glucocorticoid replacement rather than attempting diagnostic testing 3, 1.
• For mild symptoms: start hydrocortisone 15-20 mg in divided doses 6.
• For moderate symptoms: initiate 2-3 times maintenance dose, taper over 5-10 days 6.
• For severe symptoms with hypotension: immediate IV hydrocortisone 100 mg plus 0.9% saline infusion 6, 3.

If Patient is Asymptomatic

• Wait for complete washout of dexamethasone before performing any diagnostic testing 1.
• Dexamethasone has a longer half-life than hydrocortisone and requires adequate washout time before endogenous adrenal function can be accurately assessed 1.
• Consult endocrinology for a recovery and weaning protocol using hydrocortisone, rather than attempting abrupt discontinuation 1.

Definitive Diagnostic Plan After Dexamethasone Washout

Timing of Testing

• Wait at least 3 months after cessation of all exogenous glucocorticoids before performing definitive HPA axis testing 1.
• Laboratory confirmation should not be attempted until corticosteroid treatment is ready to be discontinued and sufficient washout time has elapsed 1.

Recommended Testing Sequence

1. Paired early morning (8 AM) serum cortisol and plasma ACTH measurements 3, 1:

   • Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency 1
   • Morning cortisol <250 nmol/L with low ACTH indicates secondary adrenal insufficiency 7, 3
   • Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH suggests secondary adrenal insufficiency 1

2. If morning cortisol is indeterminate (5-18 μg/dL), perform cosyntropin stimulation test 1, 3:

   • Administer 0.25 mg (250 mcg) cosyntropin IV or IM 1
   • Measure cortisol at baseline, 30 minutes, and 60 minutes 1
   • Peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 1, 3
   • Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes adrenal insufficiency 1

3. If primary adrenal insufficiency is confirmed, measure 21-hydroxylase autoantibodies 1:

   • Autoimmunity accounts for ~85% of primary adrenal insufficiency in Western populations 1
   • If autoantibodies are negative, obtain CT imaging of the adrenals 1

Critical Pitfalls to Avoid

• Never diagnose adrenal insufficiency based on cortisol measurements obtained while the patient has detectable exogenous glucocorticoids 1.
• Do not rely on a single random cortisol value—the random morning cortisol of 19.0 contradicts the other low values and suggests assay interference or timing issues 1.
• The elevated ACTH with suppressed cortisol in the presence of exogenous dexamethasone is an atypical pattern that warrants repeat testing after complete washout 2, 1.
• If treating empirically for suspected adrenal insufficiency while awaiting washout, use hydrocortisone (not dexamethasone) for replacement therapy 3, 6.
• All patients with confirmed adrenal insufficiency require education on stress dosing, medical alert bracelet, and emergency injectable hydrocortisone kit 3, 1.