Adrenal insufficiency (Addison disease) and treatment
Primary adrenal insufficiency (Addison disease) most often involves the destruction of all regions of the adrenal cortex. There are deficiencies of cortisol, aldosterone, and the various androgens, and levels of CRH and ACTH increase in a compensatory manner. Autoimmune dysfunction is responsible for 80% to 90% of cases in developed countries, whereas tuberculosis is the predominant cause in developing countries. Medications that inhibit cortisol synthesis (eg, ketoconazole) or accelerate cortisol metabolism (eg, phenytoin, rifampin, phenobarbital) can also cause primary adrenal insufficiency.
Secondary adrenal insufficiency most commonly results from exogenous corticosteroid use, leading to suppression of the hypothalamic-pituitary-adrenal axis and decreased ACTH release, resulting in impaired androgen and cortisol production. Mirtazapine and progestins (eg, medroxyprogesterone acetate, megestrol acetate) have also been reported to induce secondary adrenal insufficiency. Secondary disease typically presents with normal mineralocorticoid concentrations.
Weight loss, dehydration, hyponatremia, hyperkalemia, and elevated blood urea nitrogen are common in Addison disease. Hyperpigmentation is common in Addison disease and may involve exposed and non-exposed parts of the body. Hyperpigmentation is usually not seen in secondary adrenal insufficiency because of low amounts of melanocyte-stimulating hormone
The short cosyntropin stimulation test can be used to assess patients with suspected hypocortisolism. An increase to a cortisol level of 18 mcg/dL or more (500 nmol/L) rules out adrenal insufficiency.
Patients with Addison disease have an abnormal response to the short cosyntropin stimulation test. Plasma ACTH levels are usually 400 to 2000 pg/mL (88 to 440 pmol/L) in primary insufficiency versus normal to low (5–50 pg/mL [1.1–11 pmol/L]) in secondary insufficiency. A normal cosyntropin-stimulation test does not rule out secondary adrenal insufficiency.
Other tests include the insulin hypoglycemia test, the metyrapone test, and the CRH stimulation test.
Goals of the treatment are to limit morbidity and mortality, return the patient to a normal functional state, and prevent episodes of acute adrenal insufficiency.
Hydrocortisone, cortisone, and prednisone are the glucocorticoids of choice, administered twice daily at the lowest effective dose while mimicking the normal diurnal adrenal rhythm of cortisol production.
Recommended starting total daily doses are hydrocortisone 15 to 25 mg daily, which is approximately equivalent to cortisone acetate 25 to 37.5 mg, or prednisone 2.5 mg. Two thirds of the dose is given in the morning, and one third is given 6 to 8 hours later. The patient’s symptoms can be monitored every 6 to 8 weeks to assess proper glucocorticoid replacement.
0.05 to 0.2 mg orally once daily can be used to replace mineralocorticoid loss. If parenteral therapy is needed, 2 to 5 mg of deoxycorticosterone trimethylacetate in oil can be administered intramuscularly every 3 to 4 weeks. The major reason for adding the mineralocorticoid is to minimize development of Hyperkalemia.
Because most adrenal crises occur because of glucocorticoid dose reductions or lack of stress-related dose adjustments, patients receiving corticosteroid replacement therapy should add 5 to 10 mg hydrocortisone (or equivalent) to their normal daily regimen shortly before strenuous activities, such as exercise.
During times of severe physical stress (eg, febrile illnesses and after accidents), patients should be instructed to double their daily dose until recovery. Treatment of secondary adrenal insufficiency is identical to primary disease treatment, with the exception that mineralocorticoid replacement is usually not necessary.
Pharmacotherapy of Acute Adrenal Insufficiency
Acute adrenal insufficiency (also known as adrenal crisis or addisonian crisis) represents a true endocrine emergency. Stressful situations, surgery, infection, and trauma are potential events that increase adrenal requirements, especially in patients with some underlying adrenal or pituitary insufficiency. The most common cause of adrenal crisis is abrupt withdrawal of exogenous glucocorticoids in patients receiving chronic treatment that resulted in hypothalamicpituitary- adrenal-axis suppression.
Hydrocortisone given parenterally is the corticosteroid of choice because of its combined glucocorticoid and mineralocorticoid activity. The starting dose is 100 mg IV by rapid infusion, followed by a continuous infusion (usually 10 mg/h) or intermittent bolus of 100 to 200 mg every 24 hours. IV administration is continued for 24 to 48 hours. If the patient is stable at that time, oral hydrocortisone can be started at a dose of 50 mg every 6 to 8 hours, followed by tapering to the individual’s chronic replacement needs.
Fluid replacement often is required and can be accomplished with IV dextrose 5% in normal saline solution at a rate to support blood pressure. If hyperkalemia is present after the hydrocortisone maintenance phase, additional mineralocorticoid supplementation can be achieved with fludrocortisone acetate 0.1 mg daily.
Patients with adrenal insufficiency should carry a card or wear a bracelet or necklace that contains information about their condition. They should also have easy access to injectable hydrocortisone or glucocorticoid suppositories in case of an emergency or during times of physical stress, such as febrile illness or injury.