What is the differential diagnosis for a patient with low Adrenocorticotropic hormone (ACTH) and normal cortisol levels?

Differential Diagnosis: Low ACTH with Normal Cortisol

Low ACTH with normal cortisol most commonly represents either early/partial secondary adrenal insufficiency with preserved basal cortisol production, exogenous glucocorticoid suppression of the HPA axis, or a physiologic state where cortisol demand is being met despite reduced ACTH reserve. 1, 2

Primary Differential Considerations

1. Early or Partial Secondary Adrenal Insufficiency

• Patients with subnormal ACTH but normal cortisol responses have decreased ACTH secretory reserve but may not yet have clinically significant adrenal insufficiency. 3
• The normal ACTH increment during stress testing is greater than necessary to stimulate adequate cortisol production—patients can maintain normal basal cortisol with reduced ACTH levels until the reserve is exhausted. 3
• These patients often have additional pituitary hormone deficiencies, suggesting evolving pituitary disease. 3
• Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH is the classic pattern for secondary adrenal insufficiency. 1

2. Exogenous Glucocorticoid Suppression

• Any patient taking ≥20 mg/day prednisone or equivalent for at least 3 weeks can develop HPA axis suppression with low ACTH and variable cortisol levels. 1
• Inhaled corticosteroids (particularly fluticasone) and topical steroids can also suppress the HPA axis and confound testing. 1
• Dexamethasone suppresses ACTH but does not cross-react with cortisol assays, potentially creating this pattern. 1

3. Hypophysitis or Pituitary Disease

• Immune checkpoint inhibitor therapy commonly causes hypophysitis leading to secondary adrenal insufficiency. 4, 2
• Lymphocytic hypophysitis, pituitary adenomas, or infiltrative diseases can selectively impair ACTH secretion while preserving basal cortisol production initially. 5
• Consider MRI brain with pituitary/sellar cuts in patients with multiple endocrine abnormalities, new severe headaches, or vision changes. 4, 2

4. Isolated ACTH Deficiency (IAD)

• Rare disorder characterized by secondary adrenal insufficiency with low/absent ACTH, normal other pituitary hormones, and no structural pituitary defects. 5
• Can occur after traumatic injury, lymphocytic hypophysitis (autoimmune), or have genetic origins in neonatal/childhood cases. 5
• Patients may fare well during unstressed periods until acute stress precipitates adrenal crisis. 5

5. Technical/Assay Considerations

• Cortisol assays can vary by as much as 110 nmol/L between different immunoassays for the same sample, potentially affecting interpretation of "normal" cortisol. 6
• Oral contraceptives elevate total cortisol 2-fold but lower calculated free cortisol, creating discordant results. 6
• Nephrotic syndrome lowers total cortisol but maintains similar free cortisol levels. 6

Critical Diagnostic Algorithm

Step 1: Confirm the Pattern

• Repeat morning (8 AM) paired ACTH and cortisol measurements to verify the pattern. 1, 2
• Obtain basic metabolic panel—hyponatremia occurs in 90% of adrenal insufficiency but can be absent in secondary AI. 1

Step 2: Assess for Exogenous Steroid Exposure

• Detailed medication history including oral, inhaled, topical, and injected corticosteroids. 1
• If recent steroid exposure confirmed, this explains the pattern and requires assessment of HPA axis recovery over time.

Step 3: Determine Clinical Significance with ACTH Stimulation Testing

• If basal cortisol ≥450 nmol/L (≥16 μg/dL), the negative predictive value to rule out clinically significant AI is 98.7%—formal testing may not be needed. 7
• If basal cortisol ≤100 nmol/L (≤3.6 μg/dL), the positive predictive value for AI is 93.2%—diagnosis is essentially confirmed. 7
• For intermediate values (100-450 nmol/L), perform high-dose (250 μg) cosyntropin stimulation test. 7, 8
• Peak cortisol <500-550 nmol/L (<18-20 μg/dL) at 30 or 60 minutes is diagnostic of adrenal insufficiency. 1, 7

Step 4: Evaluate for Pituitary Disease

• Assess other pituitary axes: TSH, free T4, LH, FSH, testosterone/estradiol, prolactin. 4, 2
• If multiple hormone deficiencies present or new severe headaches/vision changes, obtain MRI brain with pituitary/sellar cuts. 4, 2

Step 5: Consider Autoimmune Workup

• In suspected isolated ACTH deficiency, consider evaluation for lymphocytic hypophysitis (autoimmune markers). 5

Key Clinical Pitfalls to Avoid

• Never assume normal basal cortisol excludes adrenal insufficiency—patients with reduced ACTH reserve can maintain normal basal levels but fail during stress. 3
• Do not rely on electrolyte abnormalities alone—hyperkalemia is absent in secondary AI, and hyponatremia may be mild or absent. 1
• If treating suspected adrenal crisis, never delay treatment for diagnostic testing—give IV hydrocortisone 100 mg immediately. 1, 9
• When initiating both glucocorticoid and thyroid hormone replacement, always start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis. 2, 9
• Be aware that oral contraceptives dramatically alter cortisol measurements and should be discontinued before definitive testing. 6

Management Implications

If secondary adrenal insufficiency is confirmed:

• Initiate hydrocortisone 10-20 mg in the morning and 5-10 mg in early afternoon for mild symptoms. 2, 9
• Fludrocortisone is NOT required in secondary AI as mineralocorticoid production is preserved. 5
• Provide education on stress dosing (doubling/tripling doses during illness) and medical alert identification. 2, 9
• Arrange endocrine consultation for optimization and long-term management. 2