Adrenal insufficiency
1. What is adrenal insufficiency, and how is it categorized?
“Adrenal insufficiency” is the term used to describe inadequate production of glucocorticoids, mineralocorticoids, or both by the adrenal glands. It can occur because of dysfunction or complete destruction of the adrenal cortex (primary adrenal insufficiency), inadequate adrenocorticotropic hormone (ACTH) production by the pituitary (secondary adrenal insufficiency), or inadequate corticotropin-releasing hormone (CRH) production by the hypothalamus (tertiary adrenal insufficiency).
2. What are common causes of adrenal insufficiency?
Autoimmune adrenalitis (Addison’s disease) is the most common cause of primary adrenal insufficiency and is associated with increased levels of 21-hydroxylase antibodies. Addison’s disease can occur in isolation or in combination with other endocrine deficiencies as part of an autoimmune polyglandular syndrome. The most common cause of central (secondary/tertiary) adrenal insufficiency is withdrawal of glucocorticoids after long-term use. Central adrenal insufficiency can also occur as part of panhypopituitarism from large pituitary tumors or their treatment with surgery and/or radiation therapy. See Table 30-1 for other causes of adrenal insufficiency.
TABLE 30-1.
CAUSES OF ADRENAL INSUFFICIENCY
| Primary | Autoimmune |
| Bilateral adrenal hemorrhage or thrombosis: coagulopathy, meningococcal sepsis | |
| Metastases: lymphoma, lung, breast, renal, gastrointestinal | |
| Infectious: tuberculosis, human immunodeficiency virus, cytomegalovirus, fungal (Histoplasma, Coccidioides) | |
| Adrenoleukodystrophy and other congenital disorders | |
| After adrenalectomy | |
| Infiltrative: hemochromatosis, amyloidosis | |
| Congenital adrenal hyperplasia | |
| Adrenal enzyme deficiency | |
| Drugs (see text) | |
| Secondary | Withdrawal of long-term suppressive glucocorticoid therapy |
| Pituitary tumors including craniopharyngioma | |
| Metastases to the pituitary | |
| Pituitary surgery or irradiation | |
| Lymphocytic hypophysitis | |
| Infiltrative diseases: hemochromatosis, sarcoidosis, histiocytosis X | |
| Infection (e.g., tuberculosis, histoplasmosis) | |
| Sheehan syndrome (massive blood loss leading to shock in the peripartum period) | |
| Severe head trauma disrupting the pituitary stalk or otherwise affecting the pituitary | |
| Tertiary | Withdrawal of long-term suppressive glucocorticoid therapy |
| Hypothalamic tumors | |
| Metastases to the hypothalamus | |
| Infiltrative diseases affecting the hypothalamus | |
| Cranial irradiation | |
| Trauma | |
| Infections (e.g., tuberculosis) |
3. What are common symptoms of adrenal insufficiency?
Most patients report nonspecific symptoms such as weakness, fatigue, and anorexia. Many also complain of gastrointestinal symptoms such as nausea, vomiting, vague abdominal pain, and constipation. Psychiatric symptoms and symptoms of orthostatic hypotension, arthralgias, myalgias, and salt craving are also reported.
4. How does adrenal insufficiency usually present?
Weight loss is a common presenting sign. Hyperpigmentation, particularly of the buccal mucosa and gums, is noted in most patients with primary adrenal insufficiency. Patients should be examined for darkening of the palmar creases, nail beds, and scars forming after onset of ACTH excess. Hyperpigmentation occurs because production of proopiomelanocortin (POMC), a prohormone that is cleaved into ACTH, melanocyte-stimulating hormone (MSH), and other hormones is increased and leads to increased melanin production. Orthostasis is common in both primary and central adrenal insufficiency.
5. What laboratory abnormalities can be found in adrenal insufficiency?
The classic laboratory abnormalities are hyponatremia and hyperkalemia. The hyperkalemia is due to mineralocorticoid deficiency, whereas the hyponatremia occurs mainly because of glucocorticoid deficiency. Hyponatremia is the result of elevated vasopressin values with free water retention, shift of extracellular sodium into cells, and decreased delivery of filtrate to the diluting segments of the nephron due to decreased glomerular filtration rate. Azotemia can be seen because of hypovolemia. Patients often demonstrate a normocytic normochromic anemia and may have eosinophilia and lymphocytosis. Mild to moderate hypercalcemia may occur. Fasting blood glucose is usually low-normal, but occasionally patients can have fasting or postprandial hypoglycemia. Patients with coexisting type 1 diabetes mellitus and adrenal insufficiency may experience greater frequency and severity of hypoglycemic episodes.
6. How do the clinical presentations of primary and central forms of adrenal insufficiency differ?
Hyperpigmentation and hyperkalemia are not observed in secondary/tertiary adrenal insufficiency. Otherwise, the clinical presentations are similar.
7. How is adrenal insufficiency usually diagnosed biochemically?
In the outpatient setting, a low morning cortisol value (< 3 μg/dL) is sufficient to diagnose adrenal insufficiency, and a high morning cortisol value (> 20 μg/dL) excludes the diagnosis. In most instances, a dynamic test, the cosyntropin stimulation test, is also performed. This test determines whether the adrenals are able to respond to maximal stimulation by synthetic ACTH. This test can also be used in the diagnosis of central adrenal insufficiency, as long as sufficient time has elapsed for the adrenal cortex to atrophy in response to lack of ACTH stimulation.
The standard cosyntropin test is performed by collecting a specimen for measurement of a baseline serum cortisol level, administration of 250 μg of cosyntropin (brand name Cortrosyn, Synacthen) intravenously (IV) or intramuscularly (IM), and then collecting specimens for serum cortisol measurement 30 and 60 minutes later. An abnormal result is defined as a stimulated cortisol level at either 30 or 60 minutes of less than 18 to 20 μg/dL (< 450-500 nmol/L). This test can be performed at any time during the day. If an individual is receiving glucocorticoid therapy, the dose should be withheld (12 hours for hydrocortisone, 24 hours for prednisone) before the test is performed to avoid detection of synthetic glucocorticoids in the cortisol assay.
Other dynamic testing includes the insulin tolerance test, metyrapone test, glucagon stimulation test, and CRH stimulation test. The insulin tolerance test evaluates the hypothalamic-pituitary-adrenal (HPA) axis in response to insulin-induced hypoglycemia (blood glucose level < 40 mg/dL). This test should be performed in experienced centers only by trained staff, and should not be performed if the individual has significant coronary artery disease or an uncontrolled seizure disorder.
8. What about the low-dose cosyntropin stimulation test?
It has been argued that mild cases of primary adrenal insufficiency may be missed with the standard-dose cosyntropin stimulation test because the dose of ACTH administered in this test is quite supraphysiologic. Data from studies examining the potential role of low-dose cosyntropin stimulation testing, in which 1 μg cosyntropin is administered, do not clearly establish that the low-dose test is better than the standard test. There are several potential problems with performing the test, including false-positive results because of inaccurate or irreproducible dilution of cosyntropin, the need for IV administration, and the need for carefully timed sampling for serum cortisol levels. It is unclear whether abnormal results from this test are clinically relevant. Therefore the standard-dose test should be used in most instances.
9. What testing can be used to distinguish primary from central adrenal insufficiency?
