Addison Disease

Addison disease refers to primary adrenal insufficiency, resulting from destruction or dysfunction of the adrenal cortex itself, causing deficiency of both glucocorticoid (cortisol) and mineralocorticoid (aldosterone) production, distinguishing it from secondary adrenal insufficiency, which arises from inadequate pituitary ACTH stimulation and, given the different regulatory pathway, generally spares mineralocorticoid production.

• Autoimmune adrenalitis is the most common cause in high income settings, and may occur in isolation or as part of an autoimmune polyglandular syndrome alongside other autoimmune endocrine conditions, including autoimmune thyroid disease and type 1 diabetes.

• Tuberculosis remains an important cause globally, particularly in endemic regions, historically the leading cause worldwide, and other infectious causes include disseminated fungal infection and, in the context of HIV, cytomegalovirus adrenalitis.

• Other causes include bilateral adrenal hemorrhage (classically in the context of severe meningococcal sepsis, termed Waterhouse-Friderichsen syndrome), bilateral adrenal metastasis, and adrenoleukodystrophy.

A critically important and distinct cause of adrenal insufficiency in everyday clinical practice is suppression of the hypothalamic pituitary adrenal axis from prolonged exogenous corticosteroid use, which, while technically causing a form of secondary rather than primary adrenal insufficiency, is highly relevant to recognize given how commonly it is encountered, and the specific risk it creates around abrupt steroid withdrawal or during periods of physiological stress such as intercurrent illness or surgery.

Chronic, insidious presentation is typical, and includes fatigue, weakness, anorexia and weight loss, nausea and vomiting, and postural dizziness from the associated hypotension.

Hyperpigmentation, particularly of the skin creases, buccal mucosa, and pressure areas, is a distinctive feature of primary adrenal insufficiency specifically, resulting from the markedly elevated ACTH (and the related peptide, melanocyte stimulating hormone, cleaved from the same precursor molecule) that occurs in an attempt to stimulate the failing adrenal gland, a feature notably absent in secondary adrenal insufficiency given the low, rather than elevated, ACTH in that setting.

Addisonian crisis, an acute, severe presentation of adrenal insufficiency, is a medical emergency and presents with profound hypotension progressing to shock, severe abdominal pain sometimes mimicking an acute abdomen, vomiting, confusion, and, biochemically, hyponatremia and hyperkalemia (the latter reflecting the loss of mineralocorticoid activity), sometimes with hypoglycemia.

It may be the presenting feature of previously undiagnosed adrenal insufficiency, or may be precipitated by intercurrent illness, surgery, or trauma in a patient with known, previously stable, adrenal insufficiency who has not had their glucocorticoid replacement appropriately increased to cover the physiological stress.

• Morning serum cortisol, drawn between 8 and 9 am to align with the normal diurnal peak, is a useful initial screening test: a low level is suggestive, while a sufficiently high level can reasonably exclude the diagnosis, though intermediate levels require further, more definitive testing.

• The shortSynacthen(ACTH stimulation) test is the definitive diagnostic test, measuring serum cortisol before and after administration of synthetic ACTH: an inadequate rise in cortisol confirms adrenal insufficiency, since the adrenal gland fails to respond appropriately to exogenous stimulation.

• Plasma ACTH distinguishes primary from secondary adrenal insufficiency, being elevated in primary disease (reflecting the pituitary's appropriate, compensatory response to the low cortisol) and low or inappropriately normal in secondary disease (reflecting the underlying pituitary or hypothalamic problem).

• Electrolytes typically show hyponatremia and hyperkalemia in primary adrenal insufficiency, reflecting the mineralocorticoid deficiency, a pattern not generally seen in secondary adrenal insufficiency given the preserved aldosterone production in that setting.

Further investigation is directed at identifying the underlying cause once the diagnosis is confirmed: 21-hydroxylase antibodies support an autoimmune cause, adrenal imaging (CT) assesses for hemorrhage, infiltration, or metastatic disease, and tuberculosis specific investigation is pursued where relevant given the epidemiological context.

Differentials for chronic, non-specific symptoms such as fatigue and weight loss are broad and include many other endocrine and systemic conditions, though the combination with postural hypotension, hyperpigmentation, and the characteristic electrolyte pattern should specifically raise suspicion for adrenal insufficiency. The differential for an acute presentation resembling Addisonian crisis includes sepsis and other causes of shock, which can coexist with or precipitate an Addisonian crisis in a susceptible patient.

• Chronic replacement therapy requires both glucocorticoid and mineralocorticoid replacement in primary adrenal insufficiency, reflecting the deficiency of both hormone classes. Glucocorticoid replacement is typically with hydrocortisone, given in divided doses through the day to mimic, as closely as practical, the normal diurnal cortisol rhythm, with the highest dose given on waking. Mineralocorticoid replacement is with fludrocortisone, titrated according to blood pressure, electrolytes, and plasma renin activity.

• Sick day rules are an essential component of patient education: glucocorticoid replacement doses must be increased, typically doubled or tripled depending on the severity of the intercurrent illness, during any significant physiological stress, including fever, infection, vomiting, or surgery, given the inability of the affected adrenal gland to mount its own appropriate stress response. Patients should be provided with a steroid emergency card or equivalent medical alert identification, and, in many settings, are provided with an emergency injectable hydrocortisone kit for use if unable to tolerate oral medication or in the event of impending crisis.

• Addisonian crisis is a medical emergency requiring immediate treatment, which should not be delayed pending confirmatory biochemical testing if the diagnosis is clinically suspected: intravenous hydrocortisone (typically 100 mg immediately, followed by ongoing dosing), aggressive intravenous fluid resuscitation with 0.9% saline to correct the associated hypovolemia and hyponatremia, and correction of hypoglycemia with intravenous dextrose if present.

Once the acute crisis has been treated, the underlying precipitant should be identified and treated (for example, sepsis or another intercurrent illness), and the patient transitioned back to their maintenance oral glucocorticoid and mineralocorticoid replacement once stable, with education reinforced regarding sick day rule adherence to reduce the risk of future crises.

Patients on long term exogenous corticosteroid therapy for another condition, who are suspected of having hypothalamic pituitary adrenal axis suppression as a consequence, should have their steroid tapered gradually rather than stopped abruptly wherever clinically feasible, and should similarly be counseled regarding the need for stress dose steroid coverage during acute illness or surgery, following broadly the same sick day rule principles as primary adrenal insufficiency, given their similarly impaired ability to mount an endogenous stress response.

Referral: endocrinology for all confirmed or suspected adrenal insufficiency, for diagnosis confirmation, cause investigation, and establishment of an appropriate long term replacement and sick day management plan.