Primary Adrenal Failure (Addison's disease)
- Autoimmune adrenal destruction - this is the most common cause in the developed world being responsible for approximately seventy five percent of cases.
- Adrenoleukodystrophy - possibly the next most common cause in males, occuring - in some series - in ten to twenty five percent of cases.
- Tuberculous adrenalitis - accounts for the majority of the remainder.
- Malignant infiltration
Iatrogenic primary adrenal failure is usually obvious from the history. While adrenal metastases are common, rarely and only when bilateral might they cause adrenal failure.
Secondary Adrenal Failure
- Exogenous glucocorticoids (and more rarely synthetic ACTH) are the commonest cause of secondary adrenal failure. It would seem reasonable to suppose thet most cases are formally undiagnosed with no clinical consequences. The steroids might have been prescribed orally, topically on the skin, dropped into the eyes, ears or nose, inhaled, gargled or injected; ACTH may be prescribed in courses for certain inflammatory conditions e.g. rheumatoid arthritis and multiple sclerosis. Often an over the counter preparation, herbal remedy or beauty product e.g. skin whitener, will contain glucocorticosteroids surreptitiously.
- Hypothalamo-pituitary damage
- Structural - secondary adrenal failure is most often due to structural pituitary or hypothalamic disease, or surgery to the region.
- Irradiation - either specifically to the hypothalamus and pituitary or to the whole cranium e.g. for prophylaxis in haemotological malignancy, which often results in corticotroph failure.
- Genetic - specific transcription factor defects may result in ACTH deficiency in a very small minority of patients.
Adrenal failure can be most protean in its presentation. Have a low threshold for measuring a 9 am corticol or doing a short synACTHen.
- Lethargy, malaise
- Hypotension and postural hypotension
- Weight loss
- Hyperpigmentation - buccal mucosa, hand creases, exposed areas
- Hypoglycaemic symptoms
Hyponatraemia Hyperkalaemia Raised urea Hypoglycaemia
- Basal endocrinology
- Primary adrenal failure. An elevated plasma ACTH together with a sub-normal cortisol can clinch the diagnosis without the need for further tests e.g. the Synacthen test. An elevated plasma ACTH with a cortisol in the normal range should raise the suspicion of primary adrenal failure (analagous to an elevated TSH alongside a 'normal' free serum thyroxine).
- Secondary adrenal failure. Usually requires a stimulation test to diagnose, ACTH will not be elevated. However, in the absence of any confounders, a 9 am serum cortisol < 100 nmol/L suggests adrenal failure and in the correct clinical situation require no further testing, a 9 am serum cortisol of > 500 nmol/L makes adrenal failure of any cause very unlikely. In cases of doubt the gold standard test is the cortisol response to insulin induced hypoglycaemia (insulin tolerance test) or if contraindicated the cortisol response to glucagon stimulation (glucagon tolerance test). The long synacthen test is an alternative but is limited in its utility as it does not test the integrity of the hypothalamo-pituitary-adrenal axis.
- Dynamic endocrinology - stimulation tests
- Insulin tolerance test (ITT). This is the gold standard test for the integrity of the hypothalamo-pituitary-adrenal axis. With appropriate hypoglycaemia (plasma glucose <2.2mmol/L) the serum cortisol should rise to over 580 nmol/L (some say 540 nmol/L).
- Glucagon tolerance test. Hypoglycaemia is not induced but the serum cortisol criteria are the same as for the ITT.
- ACTH stimulation tests (Tetracosactrin tests for adrenocortical insufficiency)
- Short SynACTHen test A very useful and cheap and easy screening test. 250 ug im of ACTH given and blood taken at 0,30 and 60 mins. If poor response then one can do...
- Long SynACTHen test Useful for confirmation (you can do this while patient on low dose prednisolone - although prednisolone interferes with many of the assays for cortisol that are commerically available). 1 mg synACTHen given.
- Hydrocortisone in a dose of 20-30 mg daily by mouth. Usually in two doses with a larger fraction on waking eg 20 mg on waking and 10 mg pm. Many centres would now split the second dose into two smaller doses at lunch and early evening, thus 10 mg on waking, 5 mg at lunch time and 5 mg in the early evening. The suitability of this regime can be assessed by performing a hydrocortisone day curve. At the very least, a pre morning dose serum cortisol must be undetectable in complete primary adrenal failure, if it is detectable then it is likely the patient has been overtreated at least overnight. The pre dose plasma ACTH can be measured and if undetectable strongly suggests either gross overtreatment or too much hydrocortisone too late in the evening.
- Cortisone acetate is used more commonly than hydrocortisone in the US. Cortisone acetate 25 mg on waking and 12.5 mg in the early evening is equivalent to hydrocortisone 20/10 mg.
- May be supplemented by fludrocortisone 30-300 mcg daily. The suitability of this dose can be checked by a critical appraisal of circulating volume supplemented by taking a plasma renin activity or plasma renin mass 120 minutes after the dose. If it is suppressed the dose is too high, if supraphysiological the dose is too low. Serum sodium and potassium are also helpful, hyponatraemia and hyperkalaemia suggests the dose is too small; hypokalaemia with or without hypernatraemia suggests the dose is too high.
- Crises - patient will need IM Hydrocortisone 100 mg 6 hrly
- Steroid cards must be carried at all times and a hydrocortisone emergency pack is advisable to have available
- Sick day rules - if unwell without a fever carry on with the normal replacement dose; if unwell with a fever double the dose of oral hydrocortisone, if taking double for more than 5 days seek medical attention at the next convenient opportunity; if there is vomiting or diarrhoea or any reason to suspect the dose of hydrocortisone is not being absorbed administer the 100 mg hydrocortisone injection im and seek medical attention immediately.