What are the differential diagnoses for a low morning (6‑8 am) cortisol level and how should it be evaluated?

Differential Diagnosis and Evaluation of Low Morning Cortisol

A low morning (6–8 AM) cortisol requires immediate paired ACTH measurement to distinguish primary adrenal insufficiency (high ACTH, low cortisol) from secondary/central adrenal insufficiency (low or inappropriately normal ACTH, low cortisol), with cosyntropin stimulation testing reserved for indeterminate cortisol values between 5–18 µg/dL. 1

Primary Differential Diagnoses

Primary Adrenal Insufficiency (High ACTH, Low Cortisol)

• Autoimmune adrenalitis accounts for ~85% of cases in Western populations and is confirmed by positive 21-hydroxylase autoantibodies 2, 1
• Congenital adrenal hyperplasia should be considered, particularly in younger patients with ambiguous genitalia or family history 3
• Infectious causes including tuberculosis, fungal infections (histoplasmosis, coccidioidomycosis), HIV-related opportunistic infections, and cytomegalovirus 2, 3
• Adrenal hemorrhage from anticoagulation, trauma, sepsis (Waterhouse-Friderichsen syndrome), or antiphospholipid syndrome 2, 1
• Metastatic disease to the adrenals (lung, breast, melanoma, lymphoma) requires >90% bilateral destruction to cause insufficiency 2, 1
• Pharmacologic adrenal inhibition from high-dose azole antifungals (ketoconazole, fluconazole), etomidate, mitotane, or abiraterone 2, 3
• Adrenoleukodystrophy should be screened in males with negative autoantibodies by measuring very long-chain fatty acids 2
• Bilateral adrenalectomy for Cushing's disease or other indications 1

Secondary (Central) Adrenal Insufficiency (Low ACTH, Low Cortisol)

• Pituitary adenomas causing mass effect and ACTH deficiency, or post-surgical hypopituitarism 4, 3
• Pituitary hemorrhage (Sheehan syndrome postpartum, apoplexy) or infarction 4, 3
• Inflammatory/infiltrative disorders including hypophysitis (particularly from immune checkpoint inhibitors), sarcoidosis, hemochromatosis, Langerhans cell histiocytosis 4, 3
• Pituitary radiation therapy with delayed onset of hypopituitarism (months to years post-treatment) 4, 3
• Traumatic brain injury with pituitary stalk disruption 4
• Hypothalamic tumors (craniopharyngioma, glioma, metastases) or infiltrative disease 4
• Medications suppressing ACTH including chronic opioid therapy, megestrol acetate, or progestins 3

Iatrogenic (Glucocorticoid-Induced) Adrenal Insufficiency

• Oral glucocorticoids at doses ≥20 mg/day prednisone equivalent for ≥3 weeks cause HPA axis suppression 2, 4
• Inhaled corticosteroids particularly fluticasone at high doses (>500 µg/day) can suppress the HPA axis 2, 4
• Topical corticosteroids applied to large surface areas or under occlusion 4
• Intra-articular or epidural steroid injections with systemic absorption 2
• Recent glucocorticoid discontinuation after prolonged use, with HPA axis recovery taking 3–12 months 2

Diagnostic Algorithm

Step 1: Morning Paired ACTH and Cortisol (8 AM Sample)

• Cortisol <250 nmol/L (<9 µg/dL) with ACTH >300 pg/mL is diagnostic of primary adrenal insufficiency without further testing 2, 1
• Cortisol <400 nmol/L (<14 µg/dL) with elevated ACTH in acute illness raises strong suspicion for primary adrenal insufficiency 2
• Cortisol 140–275 nmol/L (5–10 µg/dL) with low or inappropriately normal ACTH indicates secondary adrenal insufficiency 1, 4
• Cortisol >550 nmol/L (>18–20 µg/dL) effectively rules out adrenal insufficiency 2, 1
• Cortisol 140–500 nmol/L (5–18 µg/dL) requires cosyntropin stimulation testing for definitive diagnosis 1

Step 2: Basic Metabolic Panel

• Hyponatremia occurs in 90% of newly diagnosed adrenal insufficiency cases but may be absent in secondary forms 2, 1, 4
• Hyperkalemia is present in only ~50% of primary adrenal insufficiency cases; its absence does not exclude the diagnosis 2, 4
• Hypoglycemia may occur, particularly in children and during fasting 2
• Mild hypercalcemia is seen in 10–20% of cases 2
• Elevated creatinine from prerenal azotemia due to volume depletion 2

Step 3: Cosyntropin Stimulation Test (When Cortisol 5–18 µg/dL)

• Protocol: Administer 0.25 mg (250 µg) cosyntropin IV or IM after obtaining baseline cortisol; measure serum cortisol at exactly 30 and 60 minutes post-administration 2, 1
• Interpretation: Peak cortisol <500 nmol/L (<18 µg/dL) at 30 or 60 minutes confirms adrenal insufficiency 2, 1
• Normal response: Peak cortisol >550 nmol/L (>18–20 µg/dL) excludes adrenal insufficiency 2, 1
• Assay-specific thresholds: For Abbott Architect assay, use 366.5 nmol/L at 30 minutes and 418.5 nmol/L at 60 minutes for >95% sensitivity 5
• Timing: Preferably performed in the morning, though not strictly necessary 2

Step 4: Etiologic Workup for Primary Adrenal Insufficiency

• Measure 21-hydroxylase autoantibodies first; positive in ~85% of autoimmune Addison's disease 2, 1
• If autoantibodies negative: Obtain contrast-enhanced CT scan of adrenals to evaluate for hemorrhage, metastases, tuberculosis, infiltrative disease, or structural abnormalities 2, 1
• In males with negative autoantibodies: Measure very long-chain fatty acids to screen for X-linked adrenoleukodystrophy 2
• Measure renin and aldosterone to assess mineralocorticoid deficiency 2

Step 5: Etiologic Workup for Secondary Adrenal Insufficiency

• Assess other pituitary axes: Measure TSH, free T4, LH, FSH, testosterone/estradiol, prolactin, and IGF-1 to detect additional hormone deficiencies 1, 4
• Obtain pituitary MRI with contrast if multiple hormone deficiencies are present, new severe headaches develop, or visual field defects occur 1, 4
• Measure DHEA-S: Low levels support adrenal insufficiency diagnosis but do not distinguish primary from secondary forms 4, 3

Critical Pitfalls to Avoid

Do Not Delay Treatment in Suspected Adrenal Crisis

• Immediate therapy: Administer 100 mg IV hydrocortisone bolus plus 0.9% saline infusion at 1 L/hour without waiting for diagnostic test results 2, 1
• Blood sampling: Obtain cortisol and ACTH before steroid administration if feasible, but never delay treatment 2, 1
• Clinical triggers: Unexplained hypotension, collapse, severe vomiting/diarrhea, altered mental status, or refractory shock warrant immediate empiric treatment 2

Do Not Rely on Electrolyte Abnormalities Alone

• Hyperkalemia is absent in ~50% of primary adrenal insufficiency cases 2, 4
• Hyponatremia may be mild or absent in secondary adrenal insufficiency 4
• Between 10–20% of patients have normal electrolytes at presentation 2

Do Not Test Cortisol in Patients on Exogenous Steroids

• Morning cortisol measurements are unreliable in patients taking prednisone, prednisolone, hydrocortisone, or inhaled fluticasone due to assay cross-reactivity 2, 4
• Wait until corticosteroids have been discontinued with adequate washout time (hydrocortisone 24 hours, prednisone/prednisolone longer) before performing definitive HPA axis testing 2
• Exception: Dexamethasone 4 mg IV can be used for emergent treatment when diagnosis is uncertain, as it does not interfere with cortisol assays 2

Do Not Start Thyroid Hormone Before Glucocorticoids

• In patients with both adrenal insufficiency and hypothyroidism, initiate glucocorticoid replacement several days before starting thyroid hormone to prevent precipitating adrenal crisis 2, 1, 4

Do Not Use Afternoon Cortisol Without Validated Thresholds

• For Abbott Architect assay, afternoon (12 PM–6 PM) cortisol >234 nmol/L excludes adrenal insufficiency with 100% sensitivity 5
• Afternoon cortisol <250 nmol/L requires cosyntropin stimulation testing 6
• Morning (8 AM–12 PM) cortisol >275 nmol/L excludes adrenal insufficiency with 96.2% sensitivity 6

Additional Diagnostic Considerations

Alternative Morning Cortisol Thresholds

• Morning cortisol >13 µg/dL (360 nmol/L) reliably rules out adrenal insufficiency 7
• Morning cortisol >375 nmol/L predicts adrenal sufficiency with 95% specificity 8
• Morning cortisol <100 nmol/L makes cosyntropin stimulation testing unnecessary to confirm adrenal insufficiency 8

High-Dose vs. Low-Dose Cosyntropin Testing

• The high-dose (250 µg) test is recommended over the low-dose (1 µg) test due to easier practical administration, comparable diagnostic accuracy, and FDA approval 2
• The low-dose test requires dilution of the commercial preparation at bedside, making it less practical for routine clinical use 2

Special Populations

• Critically ill patients: Total cortisol <10 µg/dL (276 nmol/L) or delta cortisol <9 µg/dL (248 nmol/L) after ACTH stimulation defines critical illness-related corticosteroid insufficiency (CIRCI) 2
• Patients with cirrhosis and refractory shock: Consider screening for adrenal insufficiency or empiric hydrocortisone 50 mg IV q6h 2
• Patients on chronic opioids: High risk for secondary adrenal insufficiency due to ACTH suppression 3