Addison Disease

Addison disease is primary adrenal insufficiency. Destruction or dysfunction of the adrenal cortex itself causes deficiency of both glucocorticoid (cortisol) and mineralocorticoid (aldosterone).

It differs from secondary adrenal insufficiency, which arises from inadequate pituitary ACTH stimulation. The regulatory pathway is different, so secondary insufficiency generally spares mineralocorticoid production.

• Autoimmune adrenalitis is the most common cause in high income settings. It 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, and was historically the leading cause worldwide. Other infectious causes include disseminated fungal infection and, in the context of HIV, cytomegalovirus adrenalitis.

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

A distinct and common cause of adrenal insufficiency in everyday practice is suppression of the hypothalamic pituitary adrenal axis from prolonged exogenous corticosteroid use. Technically this is secondary rather than primary adrenal insufficiency, but it is highly relevant to recognize because it is so common.

It creates a specific risk with abrupt steroid withdrawal or during physiological stress such as intercurrent illness or surgery.

Chronic, insidious presentation is typical. Features are 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. It results from the markedly elevated ACTH that occurs in an attempt to stimulate the failing adrenal gland. The related peptide, melanocyte stimulating hormone, is cleaved from the same precursor molecule.

It is absent in secondary adrenal insufficiency, where ACTH is low rather than elevated.

Addisonian crisis, an acute, severe presentation of adrenal insufficiency, is a medical emergency. It presents with:

• profound hypotension progressing to shock
• severe abdominal pain, sometimes mimicking an acute abdomen
• vomiting and confusion
• 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. It may also be precipitated by intercurrent illness, surgery, or trauma in a patient with known, previously stable, adrenal insufficiency whose glucocorticoid replacement was not 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. A sufficiently high level can reasonably exclude the diagnosis. Intermediate levels need further, more definitive testing.

• The short Synacthen (ACTH stimulation) test is the definitive diagnostic test. It measures 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. It is elevated in primary disease, reflecting the pituitary's appropriate, compensatory response to the low cortisol. It is 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. This pattern is not generally seen in secondary adrenal insufficiency, where aldosterone production is preserved.

Once the diagnosis is confirmed, further investigation looks for the cause. 21-hydroxylase antibodies support an autoimmune cause. Adrenal imaging (CT) assesses for hemorrhage, infiltration, or metastatic disease. Tuberculosis specific investigation is pursued where relevant given the epidemiological context.

The differential for chronic, non-specific symptoms such as fatigue and weight loss is broad and includes many other endocrine and systemic conditions. 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. These can coexist with or precipitate an Addisonian crisis in a susceptible patient.

Chronic replacement therapy in primary adrenal insufficiency requires both glucocorticoid and mineralocorticoid replacement, reflecting the deficiency of both hormone classes.

• Glucocorticoid replacement is typically hydrocortisone, given in divided doses through the day to mimic, as closely as practical, the normal diurnal cortisol rhythm, with the highest dose on waking.
• Mineralocorticoid replacement is fludrocortisone, titrated according to blood pressure, electrolytes, and plasma renin activity.

Sick day rules are an essential component of patient education. Increase glucocorticoid replacement doses, typically doubling or tripling them depending on the severity of the intercurrent illness, during any significant physiological stress, including fever, infection, vomiting, or surgery. The affected adrenal gland cannot mount its own appropriate stress response.

Provide a steroid emergency card or equivalent medical alert identification. In many settings patients also receive an emergency injectable hydrocortisone kit, for use if they cannot 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, 100 mg immediately, followed by 100 mg every 6 hours or a continuous infusion of 200 mg over 24 hours, tapered to maintenance dosing over 2 to 3 days as the precipitating illness resolves
• aggressive intravenous fluid resuscitation with 0.9% saline to correct the associated hypovolemia and hyponatremia
• correction of hypoglycemia with intravenous dextrose if present

Once the acute crisis has been treated, identify and treat the underlying precipitant (for example, sepsis or another intercurrent illness). Transition the patient back to maintenance oral glucocorticoid and mineralocorticoid replacement once stable. Reinforce education on sick day rule adherence to reduce the risk of future crises.

Patients on long term exogenous corticosteroid therapy for another condition may have hypothalamic pituitary adrenal axis suppression. Taper their steroid gradually rather than stopping abruptly wherever clinically feasible.

Counsel them on the need for stress dose steroid coverage during acute illness or surgery. Broadly the same sick day rule principles apply as in primary adrenal insufficiency, because they have a 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.