What is the appropriate management for a patient with low Adrenocorticotropic hormone (ACTH) and normal cortisol levels, suggesting potential adrenal insufficiency?

Low ACTH with Normal Cortisol: Diagnostic Approach and Management

Low ACTH with normal cortisol most commonly represents early or partial secondary adrenal insufficiency, exogenous glucocorticoid suppression of the HPA axis, or a physiologic state where cortisol demand is being met despite reduced ACTH reserve—and requires cosyntropin stimulation testing to determine if clinically significant adrenal insufficiency exists. 1

Understanding the Pattern

This biochemical pattern creates diagnostic uncertainty because:

• Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH is the classic presentation for secondary adrenal insufficiency 1
• The normal cortisol suggests preserved basal adrenal function, but the low ACTH indicates impaired pituitary reserve that may fail during stress 1
• Secondary adrenal insufficiency is characterized by low ACTH with low cortisol, but early in the disease process, basal cortisol may remain normal while stress response is already impaired 2

Immediate Diagnostic Algorithm

Step 1: Verify the Pattern and Exclude Exogenous Steroids

• Repeat morning (8 AM) paired ACTH and cortisol measurements to confirm the pattern 1
• Obtain detailed medication history including oral, inhaled (particularly fluticasone), topical, and injected corticosteroids—any patient taking ≥20 mg/day prednisone or equivalent for at least 3 weeks can develop HPA axis suppression 1
• Check for dexamethasone use, which suppresses ACTH but doesn't cross-react with cortisol assays, potentially creating this exact pattern 1
• If the patient is actively taking corticosteroids, morning cortisol measurements are not diagnostic due to assay cross-reactivity, and testing should be deferred until adequate washout time has elapsed 2

Step 2: Assess Clinical Context and Associated Findings

• Obtain basic metabolic panel—hyponatremia occurs in 90% of adrenal insufficiency cases but can be absent in secondary AI, and hyperkalemia is typically absent (unlike primary AI) 1
• Look for symptoms: fatigue (50-95%), nausea/vomiting (20-62%), anorexia and weight loss (43-73%), morning nausea, orthostatic symptoms 3
• Consider immune checkpoint inhibitor therapy, which commonly causes hypophysitis leading to secondary adrenal insufficiency 1
• Assess for pituitary disease risk factors: history of traumatic brain injury, pituitary tumors, cranial irradiation/surgery, lymphocytic hypophysitis 4, 5

Step 3: Evaluate Other Pituitary Axes

• Measure TSH, free T4, LH, FSH, testosterone/estradiol, and prolactin to assess for multiple pituitary hormone deficiencies 1
• If multiple hormone deficiencies are present, new severe headaches, or vision changes occur, obtain MRI brain with pituitary/sellar cuts 1

Step 4: Perform Cosyntropin Stimulation Test

This is the definitive test to determine if clinically significant adrenal insufficiency exists:

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 2, 6
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 2, 6
• Peak cortisol <500-550 nmol/L (<18-20 μg/dL) at either 30 or 60 minutes is diagnostic of adrenal insufficiency 2, 6, 1
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes clinically significant adrenal insufficiency 2, 1

Management Based on Test Results

If Adrenal Insufficiency is Confirmed (Peak Cortisol <500-550 nmol/L):

Initiate glucocorticoid replacement therapy:

• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5-5 mg at 4:00 PM) 2, 7, 3
• Alternative: prednisone 3-5 mg daily or cortisone acetate 25-37.5 mg daily 2, 3
• Mineralocorticoid replacement (fludrocortisone) is NOT required for secondary adrenal insufficiency, as the renin-angiotensin-aldosterone system remains intact 2, 5

Critical patient education:

• Instruct patients to double or triple their usual dose during illness, fever, or physical stress 2, 3
• Prescribe hydrocortisone 100 mg IM injection kit with self-injection training for emergency use 2, 3
• All patients must wear a medical alert bracelet indicating adrenal insufficiency 2, 6, 3
• Arrange endocrine consultation for optimization and long-term management 1

If Concurrent Hypothyroidism Exists:

When initiating both glucocorticoid and thyroid hormone replacement, always start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis 2, 1, 7

If Adrenal Insufficiency is Excluded (Peak Cortisol >550 nmol/L):

• The low ACTH with normal cortisol and adequate stress response likely represents a benign variant or subclinical pituitary dysfunction without clinical significance 1
• No glucocorticoid replacement is needed 1
• Consider periodic reassessment if symptoms develop 5

Critical Pitfalls to Avoid

• Do not rely on electrolyte abnormalities alone—hyponatremia may be mild or absent in secondary AI, and hyperkalemia is typically not present 2, 1
• Never delay treatment for diagnostic testing if adrenal crisis is suspected—give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion at 1 L/hour 2, 1
• Do not attempt diagnostic testing while the patient is on corticosteroids or immediately after stopping—this will yield false results reflecting expected HPA suppression 2
• Never discontinue glucocorticoid replacement therapy once confirmed adrenal insufficiency is diagnosed—this is lifelong treatment 2

Long-Term Monitoring

• Patients with confirmed secondary adrenal insufficiency require annual review with assessment of health, well-being, weight, blood pressure, and serum electrolytes 2
• Screen periodically for new autoimmune disorders, particularly hypothyroidism 2
• Monitor bone mineral density every 3-5 years to assess for complications of glucocorticoid therapy 2