How to investigate a patient with a low 8 AM cortisol level?

Diagnostic Approach for Low Morning Cortisol (0.4 mcg/dl)

A morning cortisol of 0.4 mcg/dl (4 nmol/L) is diagnostic of adrenal insufficiency and requires immediate evaluation for the underlying cause and prompt hormone replacement therapy.

Initial Diagnostic Workup

• Measure ACTH level immediately to differentiate between primary adrenal insufficiency (elevated ACTH) and secondary adrenal insufficiency (low or inappropriately normal ACTH) 1
• Obtain basic metabolic panel to check for electrolyte abnormalities (hyponatremia, hyperkalemia) 1
• Assess for other pituitary hormone deficiencies: TSH, FT4, LH, FSH, testosterone/estradiol 1, 2
• Consider MRI of the brain with pituitary/sellar cuts if multiple pituitary hormone deficiencies are present 1, 2

Interpretation of Morning Cortisol Results

• Morning cortisol <108 nmol/L (<3.9 mcg/dL) is highly sensitive (83%) and specific (99%) for central adrenal insufficiency 3
• A value of 0.4 mcg/dl (4 nmol/L) is well below this threshold and confirms adrenal insufficiency 4, 5
• Further dynamic testing with ACTH stimulation is unnecessary with such a low value 5

Treatment Algorithm

Immediate Management

• Initiate hormone replacement with hydrocortisone 20 mg in the morning and 10 mg in early afternoon for mild symptoms 1
• For moderate symptoms, consider higher initial dosing: hydrocortisone 20-30 mg in the morning and 10-20 mg in the afternoon 1
• If signs of adrenal crisis are present (hypotension, severe weakness, confusion), administer IV normal saline and IV hydrocortisone 100 mg immediately 2, 1

Important Considerations

• If multiple hormone deficiencies are present, always start corticosteroids first before thyroid hormone replacement to prevent precipitating adrenal crisis 1, 6
• When both glucocorticoid and thyroid replacement are needed, start glucocorticoids at least 3-7 days before initiating thyroid replacement 6
• Testosterone or estrogen replacement should be considered only after cortisol replacement is established 7, 6

Long-term Management

• Maintenance therapy with hydrocortisone 15-20 mg total daily dose (typically 2/3 in morning, 1/3 in afternoon) 6
• Educate patient on stress dosing (doubling or tripling doses during illness, surgery, or significant stress) 1
• Provide medical alert bracelet for adrenal insufficiency 1, 2
• Consider endocrine consultation for optimization of therapy and management of other potential hormone deficiencies 1

Special Considerations

Monitoring and Follow-up

• For secondary adrenal insufficiency, periodic evaluation of other pituitary hormones is necessary 1
• If the patient is on thyroid hormone replacement, follow FT4 for dose titration as TSH may not be accurate 1
• ACTH stimulation can give false-negative results early in hypophysitis as adrenal reserve declines slowly after pituitary stimulation is lost 2

Common Pitfalls to Avoid

• Never start thyroid hormone replacement before establishing adequate cortisol replacement, as this can precipitate adrenal crisis 1, 6
• Morning cortisol in a patient already on corticosteroids is not diagnostic as the measurement of therapeutic steroids in the assay for cortisol varies 2
• Hydrocortisone needs to be held for 24 hours and other steroids for longer before endogenous function can be assessed 2

By following this systematic approach to evaluating and managing a patient with a very low morning cortisol, you can ensure appropriate diagnosis and treatment while avoiding potentially dangerous complications.