Secondary Adrenal Insufficiency

Secondary adrenal insufficiency is cortisol deficiency from ACTH deficiency caused by pituitary disease. The adrenal glands are structurally normal, and mineralocorticoid production is preserved.

It affects roughly 150 to 280 people in each million. Causes are pituitary adenomas, pituitary surgery or radiotherapy, hypophysitis, apoplexy, Sheehan syndrome, head injury and infiltration. Isolated ACTH deficiency (including TBX19 variants) is rare.

It is part of hypopituitarism in most patients, and it can be the first deficiency. Untreated disease is life threatening in illness or surgery.

Pathophysiology.

Lack of ACTH causes adrenal atrophy and low cortisol and adrenal androgens. Aldosterone is controlled by the renin angiotensin system, so sodium and potassium handling are largely normal.

Cortisol deficiency impairs free water excretion and gluconeogenesis, giving hyponatraemia and hypoglycaemia.

• Fatigue, anorexia, weight loss, nausea, postural dizziness, hypoglycaemia, pallor and loss of axillary and pubic hair in women.
• No skin pigmentation and no salt craving. Hyperkalaemia is absent.
• Features of other pituitary deficiencies, or headache and visual loss with a tumour.

Red flags.

• Hypotension, vomiting, abdominal pain, confusion or collapse (adrenal crisis).
• New hypothyroidism treated without steroid cover.

• 8 to 9 am cortisol (after stopping hydrocortisone for 24 hours): under 100 nmol/L (3.6 micrograms/dL) confirms deficiency, and over 400 nmol/L (about 14.5 micrograms/dL) excludes it.
• Intermediate values: short tetracosactide test (250 micrograms), where a peak cortisol under about 450 nmol/L (assay dependent) indicates deficiency. In recent onset disease the adrenal may still respond, so the test can be falsely normal; use an insulin tolerance test or glucagon test if suspicion remains.
• ACTH low or inappropriately normal. Renin and aldosterone normal, potassium normal, sodium low.
• Pituitary MRI and tests of the other pituitary axes. Check thyroid function before starting thyroid hormone.

Differential diagnosis.

• Primary adrenal insufficiency (ACTH high, renin high, potassium high).
• Glucocorticoid induced adrenal suppression and critical illness.
• Hypothyroidism, hypoglycaemia from other causes and anorexia nervosa.

• Hydrocortisone 15 to 25 mg daily in two or three divided doses (for example 10 mg on waking, 5 mg at noon, 5 mg in the late afternoon). Fludrocortisone is not needed.
• Double the dose for fever or illness for the duration, and give hydrocortisone 100 mg intramuscularly or intravenously for vomiting or collapse. Provide a steroid alert card and emergency injection kit and teach the patient to use it.
• Adrenal crisis: hydrocortisone 100 mg intravenously at once, then 200 mg over 24 hours by infusion (or 50 mg every 6 hours), with intravenous 0.9% sodium chloride 1000 mL over the first hour and glucose if low.
• Surgery: hydrocortisone 100 mg intravenously at induction, then 200 mg over 24 hours.
• Start levothyroxine only after glucocorticoid cover. Replace sex steroids and growth hormone as needed.
• Avoid over replacement (weight gain, bone loss, diabetes). Use the lowest dose that controls symptoms.

Special groups. Pregnancy: increase hydrocortisone by about 20 to 40% in the third trimester, and give 100 mg intravenously at onset of labour then 200 mg over 24 hours. Older adults: the lowest effective dose.

Monitoring. Symptoms, weight and blood pressure at least yearly, with review of the sick day plan and bone density every 3 to 5 years. Cortisol levels are not used to adjust dose.

Referral and escalation. Endocrinology for all patients; same day review for adrenal crisis.