1. 
   

   What are normal and stress production of endogenous corticocosteroids?

   
   
2. 
   

   What are the types of adrenal insufficiency?

   
   
3. 
   

   Which patients are at high risk of adrenal insufficiency or critical illness-related corticosteroid insufficiency and therefore may benefit from physiologic or pharmacologic steroid treatment of their illnesses?

   
   
4. 
   

   For those patients who need corticosteroid supplementation, which agents should be used, and for how long?

Adrenal insufficiency (AI) was described by Thomas Addison in 1855 as a fatal disease caused by tuberculous adrenalitis and adrenal gland failure. In 1949, the synthesis of cortisone resulted in life-saving therapy for Addison disease. However, this was shortly followed by reports of patient deaths from presumed adrenal crisis due to abrupt cortisone withdrawal in the perioperative period. These reports resulted in a new standard of administration of high doses of supplemental corticosteroids during periods of physical stress, although this practice may not be universally warranted.

Primary AI (Addison disease) refers to primary adrenal gland dysfunction. It has a prevalence of 40–110 cases per million people and an incidence of six cases per million people per year. Secondary AI denotes pituitary disease with adrenocorticotropic hormone (ACTH) hormone deficiency. The prevalence of secondary AI is approximately 150–280 per million. Hypothalamic dysfunction is responsible for tertiary AI. It usually arises after abrupt withdrawal or reduction in corticocosteroid dose, in the setting of chronic exogenous corticosteroids, and is reasonably common in the hospital setting, although the exact prevalence is unknown (Table 151-1).

The adrenal gland consists of a cortex that produces steroid hormones and a medulla that produces catecholamines. The adrenal cortex is divided into three layers. The outermost layer, the zona glomerulosa, produces mineralocorticoids, primarily aldosterone. The middle layer, the zona fasciculata, produces glucocorticoids, primarily cortisol and to a lesser extent, cortisone. The zona reticularis, the innermost layer, produces adrenal androgens.

The release of glucocorticoids is controlled by the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus secretes corticotropin-releasing hormone (CRH), which acts on the pituitary to produce adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal glands to produce cortisol, which inhibits further production of CRH. Cortisol secretion is diurnal, with the highest levels in the morning and lowest around midnight. Daily endogenous secretion of glucocorticoid is equivalent to 5–7 mg/day of oral prednisone or 20–30 mg/day of hydrocortisone (Table 151-5). During stress, cortisol synthesis can increase tenfold.

All cells in the human body have glucocorticoid receptors, reflecting the integral role of glucocorticoids in physiologic homeostasis. Glucocorticoids regulate carbohydrate, lipid and amino acid metabolism, facilitate catecholamine production and action, and maintain cardiovascular integrity, with additional effects on wound healing, the immune system and the nervous system.

Primary Adrenal Insufficiency

Primary AI arises when greater than 90% of adrenal tissue is destroyed, resulting in loss of glucocorticoid and mineralocorticoid function. Absence of glucocorticoids result in an increase in ACTH and melanocyte-stimulating hormone levels, while the absence of aldosterone results in increased renin levels.

Autoimmune Adrenalitis

In developed nations, 80% of primary AI is due to autoimmune disease, which may occur in isolation or as a manifestation of a polyglandular autoimmune syndrome. Autoimmune polyendocrine syndrome type I (APS-I) underlies up to 15% of autoimmune adrenalitis. It usually presents with hypoparathyroidism or chronic mucocutaneous candidiasis during childhood, with adrenal insufficiency developing by 10 to 15 years of age. It is also frequently associated with primary hypogonadism, childhood alopecia, and malabsorption. It is caused by mutations in the autoimmune regulator (AIRE) gene, inherited in an autosomal recessive fashion. Mutations in AIRE interfere with the normal culling of autoreactive T cells, leading to the eventual autoimmune destruction of endocrine glands.

Autoimmune polyglandular syndrome type II (APS-II) is more prevalent than APS-I, and has autosomal dominant transmission with incomplete penetrance. In half the cases, AI is the first manifestation, often associated with the later development of autoimmune thyroid disease and type 1 diabetes mellitus. The clinical spectrum may also include hypogonadism, vitiligo (seen in up to 15% of primary AI), myasthenia gravis, rheumatoid arthritis, antiphosholipid antibody syndrome, and celiac disease.

Infectious Adrenalitis

Tuberculosis is the most common cause of primary AI worldwide, and was the cause of adrenal failure in most of Addison’s original patients. Adrenal involvement in tuberculosis is not common except in disseminated disease, in which it is found in up to 50% of cases. Although recovery of adrenal function is possible after appropriate antituberculous treatment, it often does not occur. AIDS is currently the principal infectious cause of AI in the United States. Causes of AI in AIDS patients include cytomegalovirus, Mycobacterium avium-intracellulare, cryptococcosis, and metastatic Kaposi sarcoma. Other factors may contribute to AI in HIV patients, such as peripheral resistance to glucocorticoid action from chronic inflammation, or use of the appetite stimulant megestrol acetate, which has intrinsic glucocorticoid activity and suppresses the hypothalamic-pituitary-adrenal (HPA) axis. The endemic mycoses, such as histoplasmosis, coccidoidomycosis, and blastomycosis, may rarely cause granulomatous disease of the adrenals severe enough to cause AI.

The adrenal glands may be infiltrated by metastatic disease, most commonly from lung, breast, stomach, or colon cancer, melanoma, or lymphoma. However, metastases rarely destroy enough adrenal tissue for AI to manifest.

Hemorrhagic Infarction

The adrenal gland is vascular and somewhat prone to hemorrhage. Bilateral adrenal hemorrhage may cause AI. It may result from meningococcal septic shock with disseminated intravascular coagulation (Waterhouse-Friderichsen syndrome), as well as overwhelming sepsis with other organisms, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. Other risk factors for adrenal hemorrhage include anticoagulants, coagulopathy, trauma, carcinoma, adrenal vein thrombosis, pregnancy, and any acute medical or surgical illness. Patients often present with back pain and hypotension; CT imaging reveals enlarged adrenal glands with high attenuation.

Drugs

Drugs cause AI by various mechanisms. Etomidate, ketoconazole, metyrapone, and suramin inhibit cortisol synthesis. However, AI only becomes evident in patients with limited pituitary or adrenal reserve, and those previously on glucocorticoid therapy. Phenytoin, rifampin, and barbiturates accelerate the metabolism of cortisol, as well as the metabolism of synthetic steroids, such as dexamethasone and fludrocortisone.

Miscellaneous

Rare causes of primary AI include adrenoleukodystrophy, congenital adrenal hypoplasia, glucocorticoid insensitivity, and defective cholesterol metabolism.

Secondary Adrenal Insufficiency

Any process that interferes with pituitary ACTH secretion may lead to secondary AI. Unlike primary AI, mineralocorticoid secretion is preserved because it is under the control of the renin-angiotensin system. Another distinguishing characteristic of secondary AI is decreased or absent plasma ACTH levels, compared to normal or elevated ACTH levels in primary AI. The most frequent cause of secondary AI is panhypopituitarism, and less commonly isolated ACTH deficiency.

Panhypopituitarism

Panhypopituitarism may result from pituitary tumors, traumatic brain injury, intracranial aneurysm, and pituitary surgery or radiotherapy. Up to 30% of patients with head trauma experience pituitary dysfunction months or years after the initial insult. Less often, panhypopituitarism can be caused by infection (tuberculosis, histoplasmosis), infiltrative diseases, and autoimmune lymphocytic hypophysitis. Although pituitary metastases are frequently found in patients with disseminated cancer, these metastases rarely impede hormone secretion. Sheehan syndrome is massive peripartum blood loss precipitating hypovolemic shock and anterior pituitary infarction. Pituitary apoplexy from hemorrhage into an enlarging pituitary adenoma may also lead to panhypopituitarism during or after pregnancy.

Isolated ACTH Deficiency

Isolated ACTH deficiency is a rare cause of secondary AI and may have an autoimmune origin. It is frequently associated with autoantibodies to pituitary cells and with other autoimmune endocrine disorders, most commonly thyroid disease.

Tertiary Adrenal Insufficiency

Tertiary AI occurs due to any process that involves the hypothalamus and interferes with the secretion of CRH and subsequent ACTH release. The most common cause of tertiary AI is abrupt cessation of glucocorticoid therapy.

Chronic Glucocorticoid Therapy