Information
- Adrenal Functional Anatomy: Each adrenal gland is made up of a cortex, which produces sex steroids (androgens, estrogens), mineralocorticoids (aldosterone), and glucocorticoids (cortisol), and a medulla, which produces adrenergic hormones (such as epinephrine). The term “adrenal insufficiency” is commonly used to describe deficiency of both cortisol (which may be isolated) and aldosterone (which is almost always associated with cortisol deficiency).
- Regulation of Adrenal Hormone Production (Figure 29.2): Cortisol production by the adrenal glands is dependent on adrenocorticotrophic hormone (ACTH), which is produced by the pituitary gland. ACTH is regulated by corticotropin-releasing hormone (CRH), which is produced in the hypothalamus. Cortisol feeds back to inhibit CRH and ACTH release, closing the control loop. Cortisol deficiency may be caused by injury either to the adrenal cortex (primary adrenal insufficiency with elevated ACTH) or to the pituitary or hypothalamus (secondary or central adrenal insufficiency with low or “inappropriately normal” ACTH). Primary adrenal insufficiency is often associated with aldosterone deficiency, but central forms of adrenal insufficiency are limited to a deficit in cortisol production because aldosterone production is not dependent on ACTH.
- Classification of Adrenal Insufficiency: Adrenal insufficiency can be defined on the basis of the origin of the disease.
- Primary: The adrenal gland is unable to produce steroid hormones despite adequate corticotropin from the pituitary gland (eg, Addison disease, autoimmune diseases).
- Secondary: a lack of ACTH from the pituitary or CRH from the hypothalamus to stimulate the adrenal gland (eg, brain tumors, infarction, granulomatous disease)
- Tertiary: adrenal deficiency due to the withdrawal of exogenous glucocorticoids (eg, chronic steroid use)
- Signs of Adrenal Insufficiency: The adrenal gland is activated in states of stress, activating the release of catecholamines, glucocorticoids, mineralocorticoids, and factors of the renin-angiotensin-aldosterone axis. Cortisol deficiency is acutely dangerous and causes circulatory collapse with refractory hypotension that may be fatal within hours to days without glucocorticoid replacement. Symptoms and signs of glucocorticoid deficiency include nausea, vomiting, anorexia, weight loss and wasting, weakness, hyponatremia, and eosinophilia. Suspicion of glucocorticoid deficiency is sufficient cause to begin treatment immediately; treatment can be discontinued if adequate adrenal function is demonstrated.
- Causes of Adrenal Insufficiency: A “functional” or “relative” deficiency in cortisol secretion may occur in critical illness, but this is controversial and there are no universally accepted criteria for diagnosis of this condition. Adrenal insufficiency may be caused by drugs that inhibit cortisol production, notably ketoconazole and etomidate. Drugs that accelerate the metabolism of cortisol, such as phenytoin, barbiturates, and rifampin, can contribute to the development of adrenal insufficiency in patients with limited physiologic reserve. The most common cause of adrenal insufficiency is exogenous glucocorticoids (or drugs with glucocorticoid activity such as megestrol acetate) that cause feedback inhibition of ACTH production, which in turn causes atrophy of the cortisol-producing cells in the adrenal gland. Iatrogenic adrenal insufficiency should be considered in all patients taking glucocorticoids, including patients chronically on as little as 5 mg of prednisone daily. Complete recovery from iatrogenic adrenal insufficiency may take months or even years. Causes of adrenal insufficiency are listed in Table 29.5.
- Aldosterone Deficiency: Aldosterone production is regulated by the renin-angiotensin system. The most important action of aldosterone is to promote sodium retention by the kidney. Deficiency of aldosterone causes sodium wasting, hypovolemia, and hypotension. Aldosterone deficiency can be managed in the short term with sufficient sodium and fluid intake, but long-term deficiency is managed with medications having aldosterone receptor agonist activity, such as fludrocortisone. The most common cause of aldosterone deficiency is injury to the adrenal gland itself, which is typically also associated with glucocorticoid deficiency. Isolated mineralocorticoid deficiency is rare.