Lucan · Conditions

Addison's / primary adrenal insufficiency

Australian guidance: eTG Endocrinology — Adrenal Insufficiency

1. Definition and epidemiology

Primary adrenal insufficiency (Addison's disease) is a condition of inadequate production of cortisol and, in most cases, aldosterone due to destruction or dysfunction of the adrenal cortex itself, distinguishing it from secondary (pituitary ACTH deficiency) and tertiary (hypothalamic CRH deficiency) forms. In Australia the prevalence is estimated at approximately 100 to 140 per million population, with autoimmune adrenalitis accounting for around 80 to 90% of cases in developed-country settings. Women are affected approximately twice as frequently as men, and onset is most common in the third to fifth decades.

2. Pathophysiology

Per Robbins Ch 24, the adrenal cortex must lose more than 90% of its functional mass before overt adrenal insufficiency becomes manifest. In autoimmune Addison's disease, autoreactive T lymphocytes target steroidogenic enzymes, most commonly 21-hydroxylase (CYP21A2), with circulating anti-21-hydroxylase antibodies detectable in approximately 90% of autoimmune cases. Progressive cortical destruction reduces glucocorticoid (cortisol) and mineralocorticoid (aldosterone) output from the zona fasciculata and zona glomerulosa respectively, while androgen production from the zona reticularis falls correspondingly. Loss of cortisol removes negative feedback at the pituitary and hypothalamus, driving compensatory ACTH and pro-opiomelanocortin (POMC) hypersecretion. The MSH moieties cleaved from POMC bind melanocortin-1 receptors in melanocytes, producing characteristic hyperpigmentation in sun-exposed areas, pressure points, buccal mucosa, and palmar creases. Mineralocorticoid deficiency causes urinary sodium wasting, volume depletion, and hyperkalaemia via failed aldosterone-mediated sodium-potassium exchange in the collecting duct. Cortisol deficiency impairs gluconeogenesis, reduces vascular tone, and sensitises the vasculature to catecholamines, predisposing to haemodynamic collapse under physiological stress. In tuberculosis-related disease (the most common infective cause) and other granulomatous causes, bilateral adrenal enlargement with subsequent calcification may be visible on imaging.

3. Clinical presentation and diagnostic criteria

The onset of primary adrenal insufficiency is typically insidious. Cardinal symptoms include profound fatigue, weakness, weight loss, anorexia, nausea, vomiting, and postural dizziness. Hyperpigmentation is the clinical hallmark of primary disease and distinguishes it from secondary and tertiary forms; it is particularly evident on gingival mucosa, areolae, recent scars, and skin creases. Salt craving is common and reflects mineralocorticoid deficiency. Examination may reveal postural hypotension, hyperpigmentation, and evidence of associated autoimmune conditions (vitiligo, autoimmune thyroid disease, type 1 diabetes mellitus), collectively termed autoimmune polyglandular syndrome (APS) type 2. Adrenal crisis presents as cardiovascular collapse with fever, severe abdominal pain, and altered consciousness, often precipitated by intercurrent illness, surgery, or missed glucocorticoid doses. Biochemical findings typically include hyponatraemia, hyperkalaemia, hypoglycaemia, and a mild normocytic anaemia with eosinophilia and lymphocytosis.

4. Investigations and AU-specific cutoffs

Diagnosis is confirmed by a standard-dose (250 micrograms intravenous) synthetic ACTH (tetracosactide) stimulation test. A peak serum cortisol of less than 500 nmol/L at 30 or 60 minutes is consistent with adrenal insufficiency across most Australian laboratory reference ranges, though some centres use a threshold of 550 nmol/L; the eTG Endocrinology module specifies a cut-off of 500 nmol/L when using high-specificity immunoassay platforms. A random serum cortisol of less than 100 nmol/L in the context of appropriate symptoms is strongly suggestive and may allow empirical treatment while confirmatory testing is arranged, particularly in the setting of haemodynamic compromise. ACTH (plasma, collected in chilled EDTA on ice) should be measured simultaneously with the morning cortisol: a frankly elevated ACTH (typically greater than 50 pmol/L) in the context of a low cortisol confirms primary disease. Autoimmune aetiology is supported by detection of anti-21-hydroxylase antibodies. Electrolytes, blood glucose, and renal function should be checked. CT of the adrenal glands is indicated when autoimmune aetiology is not established, to exclude infiltrative, granulomatous, haemorrhagic, or metastatic disease. Adrenal gland calcification on CT supports prior tuberculosis or other granulomatous infection.

5. Management

Glucocorticoid replacement is the cornerstone of treatment. Hydrocortisone is the preferred agent in Australia because its pharmacokinetics most closely mirror physiological cortisol secretion. Per eTG Endocrinology guidance on adrenal insufficiency, the typical total daily dose is 15 to 25 mg given in divided doses, with the larger morning dose (10 to 15 mg) taken immediately on waking to replicate the cortisol circadian peak and a smaller afternoon dose (5 to 10 mg) taken approximately 4 to 6 hours later. A third small evening dose of 2.5 to 5 mg may be added when fatigue persists into the late afternoon, but must be timed before 4 pm to avoid sleep disturbance. Mineralocorticoid replacement with fludrocortisone 50 to 200 micrograms orally once daily is required in primary disease; secondary adrenal insufficiency does not typically require fludrocortisone because the renin-angiotensin-aldosterone axis remains intact. Dose adequacy is monitored clinically by postural blood pressure, salt craving, and ankle oedema, and biochemically by plasma renin activity (target mid-normal). All patients must receive a sick-day rule card and wear a medical alert bracelet. The sick-day rule (also called steroid stress dosing) requires doubling or trebling the glucocorticoid dose for febrile illness, vomiting, or injury; parenteral hydrocortisone 100 mg intramuscularly or intravenously is required if oral intake is not possible, and patients should carry an emergency injection kit. Adrenal crisis is a medical emergency treated with intravenous hydrocortisone 100 mg as a bolus followed by 200 mg per 24 hours by continuous infusion or 50 mg 6-hourly, alongside aggressive intravenous normal saline resuscitation and correction of hypoglycaemia.

6. Pharmacology and AU PBS notes

Hydrocortisone (cortisol) is the first-line glucocorticoid. Available as Hydrocortisone tablets 5 mg and 20 mg. Listed on the PBS under Section 85 for adrenal insufficiency; prescriptions for adrenal insufficiency qualify for the General Schedule (no streamlined code required for this indication in standard chronic use). Fludrocortisone acetate 100 microgram tablets (brand name Florinef) are available in Australia and listed on the PBS for primary adrenal insufficiency. Prednisolone or dexamethasone may be used as alternatives in patients who cannot tolerate hydrocortisone but both lack mineralocorticoid activity and dexamethasone has a prolonged action that increases suppression risk; these are second-line choices only. Dehydroepiandrosterone (DHEA) replacement is not routinely recommended in Australian guidelines but may be considered for women with primary adrenal insufficiency experiencing reduced libido or persistent fatigue despite optimised cortisol and aldosterone replacement, as an unlisted medicine.

7. Complications and monitoring

Undertreated adrenal insufficiency risks recurrent adrenal crises, haemodynamic instability, and death. Overtreated glucocorticoid replacement risks weight gain, hypertension, osteoporosis, glucose intolerance, and HPA axis suppression. Monitoring should include annual clinical assessment of symptoms, body weight, and blood pressure, alongside electrolytes, blood glucose, and bone mineral density (dual-energy X-ray absorptiometry at baseline then every two years). Thyroid function and coeliac serology should be checked at diagnosis and periodically thereafter given the association with autoimmune polyglandular syndrome. Annual screening for associated autoimmune conditions (type 1 diabetes, autoimmune thyroid disease, primary ovarian insufficiency in women) is recommended. All patients should be enrolled in an endocrinology shared-care model and educated to adjust doses during illness, elective surgery, and pregnancy, as pregnancy significantly increases glucocorticoid requirements particularly in the third trimester.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.