What is the appropriate diagnosis and treatment for adrenal insufficiency, particularly in relation to the ratio of Adrenocorticotropic hormone (ACTH) to cortisol?

Diagnosis and Management of Adrenal Insufficiency Based on ACTH to Cortisol Ratio

The diagnosis of adrenal insufficiency requires assessment of the relationship between ACTH and cortisol levels, with primary adrenal insufficiency characterized by high ACTH and low cortisol, while secondary adrenal insufficiency shows low ACTH with low cortisol. 1

Diagnostic Approach

Initial Assessment

• Morning (AM) measurements of both cortisol and ACTH are essential for initial evaluation 1
• In primary adrenal insufficiency:
  • Low morning cortisol with high ACTH levels 1
  • Often accompanied by hyponatremia (90% of cases) and hyperkalemia (50% of cases) 1
• In secondary adrenal insufficiency:
  • Low morning cortisol with low or inappropriately normal ACTH levels 1, 2
  • Caused by pituitary dysfunction affecting ACTH production 2

Confirmatory Testing

• For indeterminate results, perform ACTH stimulation test (Synacthen/cosyntropin test) 1, 3
• Standard protocol:
  • Administer 0.25 mg cosyntropin intravenously or intramuscularly 1, 3
  • Measure serum cortisol at baseline and 30-60 minutes post-administration 3
  • Peak cortisol <500 nmol/L (18 μg/dL) is diagnostic of adrenal insufficiency 1, 3
• Interpretation of baseline values:
  • Basal cortisol <250 nmol/L with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1, 3
  • Basal cortisol <400 nmol/L with elevated ACTH in acute illness raises strong suspicion 1, 3

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary Adrenal Insufficiency

• High ACTH, low cortisol pattern 1
• Additional testing:
  • Measure 21-hydroxylase autoantibodies to identify autoimmune etiology 1
  • If antibodies negative, perform adrenal CT imaging to evaluate for other causes 1
  • In males, consider very long-chain fatty acid testing for adrenoleukodystrophy 1
• Often presents with both glucocorticoid and mineralocorticoid deficiency 1

Secondary Adrenal Insufficiency

• Low ACTH, low cortisol pattern 1, 2
• Consider pituitary MRI with sellar cuts if multiple endocrine abnormalities are present 1
• May have additional pituitary hormone deficiencies (TSH, LH, FSH) 1
• No mineralocorticoid deficiency (aldosterone production preserved) 2

Treatment Based on Severity

Mild Symptoms (Grade 1)

• Replacement therapy with prednisone (5-10 mg daily) or hydrocortisone (10-20 mg morning, 5-10 mg afternoon) 1
• For primary adrenal insufficiency, add fludrocortisone (0.1 mg/day) for mineralocorticoid replacement 1
• Titrate dose according to symptoms 1

Moderate Symptoms (Grade 2)

• Initiate outpatient treatment at 2-3 times maintenance dose 1
• Prednisone 20 mg daily or hydrocortisone 20-30 mg morning, 10-20 mg afternoon 1
• Taper to maintenance doses over 5-10 days 1

Severe Symptoms/Adrenal Crisis (Grade 3-4)

• Immediate treatment with IV hydrocortisone 100 mg (or dexamethasone 4 mg if diagnosis not confirmed) 1
• Administer at least 2L normal saline IV 1
• Taper to maintenance doses over 7-14 days after discharge 1
• Treatment should never be delayed for diagnostic procedures if adrenal crisis is suspected 1, 3

Important Considerations

• All patients need education on stress dosing and should wear a medical alert bracelet 1
• Endocrine consultation is recommended prior to surgery or procedures for stress-dose planning 1
• Exogenous steroid use (oral, inhaled) can confound interpretation of cortisol levels 1, 3
• Patients with adrenal insufficiency should be prescribed injectable glucocorticoids for emergency use 2
• Low-dose ACTH (1 μg) test may be more sensitive than standard dose (250 μg) for diagnosing secondary adrenal insufficiency 4

Pitfalls to Avoid

• Don't rely solely on electrolyte abnormalities for diagnosis, as hyponatremia may be only marginally reduced and hyperkalemia is present in only about 50% of cases 1, 3
• Don't delay treatment of suspected adrenal crisis for diagnostic testing 1, 3
• When treating secondary adrenal insufficiency with concurrent hypothyroidism, always start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis 1
• Don't confuse adrenal insufficiency with SIADH, as both can present with similar laboratory findings of hyponatremia 3