4th April 2024

Addison’s Disease

Pathophysiology

Addison’s disease, or primary adrenal insufficiency, is a rare condition whereby the adrenal glands are not able to secrete enough adrenocortical hormones to sustain normal bodily functions. It is usually an autoimmune condition where the individual’s immune system destroys healthy adrenal tissue. In normal health, these hormones – mainly cortisol, aldosterone and dehydroepiandrosterone (DHEA) – are vital in maintaining various balances within the body as well as responding to acute demands placed on the body in day-to-day life.

An understanding of the role of each of these hormones is useful in recognising the symptoms and signs in a patient presenting with Addison’s disease (see Table 1).

In addition to the symptoms and signs elicited directly from the hormone deficiencies, the adrenal gland’s place within the hypothalamic-pituitary-adrenal axis results in the classical sign of Addison’s disease: hyperpigmentation. This is because the low levels of adrenal hormones (specifically cortisol) are detected and lead to increased secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland via a negative feedback loop. The pituitary gland continues to secrete more and more ACTH in an attempt to stimulate the damaged adrenal gland. The high levels of ACTH have a stimulant effect on melanocytes to produce melanin, leading to hyperpigmented or ‘bronzed’ skin.

The onset of Addison’s disease is usually prolonged over several months of gradually progressive symptoms. In rare cases, the initial presentation may be an Addisonian crisis, where the levels of adrenal hormones (mainly cortisol) are so low as to be life-threatening. Addisonian crisis presents more commonly in patients with established Addison’s disease who experience an acute physiological stress, e.g., infection or abrupt removal of steroids.  Patients will commonly have reduced GCS, be hypotensive and have significant electrolyte disturbances.

Diagnosis

The signs and symptoms of Addison’s disease can be vague but a detailed history and examination, as well as simple blood tests such as urea and electrolytes, can raise suspicion. Some findings which are indicative of Addison’s disease include:

• Hyponatraemia and hyperkalaemia (due to low aldosterone levels)
• Hypoglycaemia (due to low cortisol)
• Uraemia
• Normocytic anaemia

If Addison’s disease is suspected a morning cortisol level should be taken and further investigations depending on the result:

• <83 nmol/L is highly suggestive of adrenal insufficiency
• >497 nmol/L makes adrenal insufficiency highly unlikely
• 83-497 nmol/L warrants further testing to determine if there is adrenal insufficiency

The diagnostic test for Addison’s disease is an ACTH suppression test, also called the short Synacthen test. This involves measuring baseline serum cortisol followed by administration of synthetic ACTH (Synacthen) to the patient after which cortisol levels are rechecked at 30- and 60-minute intervals. In an individual with healthy adrenal tissue, administration of ACTH will lead to a rise in cortisol but in Addison’s disease, the adrenal glands will not be able to mount a response. Cortisol levels below 497 nmol/L after synthetic ACTH indicate probable adrenal insufficiency and these patients will require further evaluation by an endocrinologist to confirm the diagnosis.

Management

This consists of glucocorticoid and mineralocorticoid replacement with hydrocortisone and fludrocortisone, respectively. During times of stress e.g., infection or surgery, there will be greater physiological demand for cortisol and patients should be educated to double their glucocorticoid dose. Medical alert bracelets detailing Addison’s disease can be helpful in ensuring prompt treatment is administered in the event of an Addisonian crisis.

Management of the Addisonian crisis involves replacing cortisol with IV hydrocortisone. Further treatment may involve fluid resuscitation, blood glucose control, optimisation of blood pressure and replacement of electrolytes and adrenal hormones. This may require admission to an intensive care unit and care must be taken to avoid rapid fluid shifts as patients are likely to be hyponatremic on presentation.

References

• Adrenal cortex and Cushing’s syndrome & Addison’s disease (adrenal insufficiency). Oxford handbook of clinical medicine. 9ᵗʰ edition
• Addison’s disease. BMJ Best Practice. Last reviewed 17ᵗʰ Jan 2022