At a Glance

Addison’s disease (AD), also known as primary adrenal insufficiency or hypoadrenalism, is a rare disorder of the adrenal glands. It affects the production of cortisol and aldosterone. It may occur at any age and affects both sexes equally. Because of common therapeutic use of steroids, secondary adrenal insufficiency is relatively common.

Autoimmune adrenalitis is responsible for 70-90% of AD, with the rest caused by other infectious diseases, replacement by metastatic cancer or lymphoma, adrenal hemorrhage or infarction, or drugs. Autoimmune adrenalitis involves destruction of the cortex by both humoral and cell-mediated immune mechanisms. Anatomic destruction of adrenal glands include surgical removal, infections, hemorrhage, and metastatic invasion. Other causes, such as metabolic failure in hormone production, include congenital adrenal hyperplasia, enzyme inhibitors (metyrapone, ketoconazole, aminoglutethimide), and cytotoxic agents (mitotane).

Infectious causes of adrenal insufficiency include tuberculosis, fungal infections, cytomegalovirus and Mycobacterium avium-intracellulare (usually in reference to HIV infection), syphilis, and African trypanosomiasis.

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Bilateral adrenal hemorrhage can inhibit adrenal function. This usually occurs in specific settings, such as within disseminated infection (Meningococcus, Pseudomonas aeruginosae, Streptococcus, pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Haemophilus influenzae, and Staphylococcus aureus) and clotting abnormalities (anticoagulant drug or heparin therapy or coagulopathy, thromboembolic disease, hypercoagulable states, such as antiphospholipid syndrome). Other associations include physical trauma, the postoperative state, sepsis, and severe stress.

Metastatic disease with replacement of the cortex of both adrenal glands can cause adrenal insufficiency. This is most commonly associated with lung, breast, stomach, or colon cancer; melanoma; and lymphoma.

Drugs are important causes of primary adrenal insufficiency, including drugs that inhibit cortisol biosynthesis, such as etomidate, ketoconazole, metyrapone, and suramin. Other drugs accelerate the metabolism of cortisol and most synthetic glucocorticoids by inducing hepatic mixed-function oxygenase enzymes (e.g., phenytoin, barbiturates, and rifampin).

The clinical presentation of adrenal insufficiency is variable, depending whether the onset is acute, leading to adrenal crisis, or chronic, with symptoms more insidious and vague. Therefore, the diagnosis of adrenal insufficiency depends on a critical level of clinical suspicion.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Confirmation of the clinical diagnosis of adrenal insufficiency should include:

Demonstrating inappropriately low cortisol secretion

Determining whether the cortisol deficiency is dependent on or independent of adrenocorticotropic hormone (ACTH) deficiency and evaluating mineralocorticoid secretion in patients without ACTH deficiency

Seeking a treatable cause of the primary disorder (e.g., histoplasmosis involving the adrenal glands or a pituitary adenoma compromising normal pituitary function)

Serum cortisol and plasma ACTH should be measured immediately at patient presentation, so the diagnosis and cause of adrenal insufficiency can be established without delay in most cases.

Test Results indicative of the Disorder

If serum cortisol is inappropriately low and a simultaneous plasma ACTH concentration is very high, the patient has primary adrenal insufficiency.

If both the serum cortisol and plasma ACTH concentrations are inappropriately low, the patient has secondary (i.e., pituitary disease) or tertiary (hypothalamic disease) adrenal insufficiency.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Unfortunately, plasma ACTH results are usually not available immediately, and it is important to quickly determine whether primary adrenal insufficiency is the cause. This can be done indirectly by stimulating the adrenal gland with exogenous ACTH. It is useful to measure plasma ACTH and serum cortisol before injecting the ACTH; however, in the acute setting, the cortisol response will be used to make the diagnosis of adrenal insufficiency, as well as a decision regarding ongoing treatment. The ACTH value, generally available later, can be used to establish the level of the defect. In evaluating patients with adrenal insufficiency, measurements should be made in the morning, if possible, when plasma ACTH and serum cortisol concentrations are usually at their highest value. However, in urgent or emergent evaluation of patients with potential adrenal insufficiency, blood samples should be drawn at any time before administration of glucocorticoid therapy.

What Lab Results Are Absolutely Confirmatory?

ACTH Stimulation (Cosyntropin) Test

  • Cosyntropin is synthetic ACTH (1-24), which has the full biologic potency of native ACTH (1-39).

  • It is a rapid stimulator of cortisol and aldosterone secretion.

  • This is an initial test to distinguish primary from secondary adrenal insufficiency.

  • There are several protocols used to assess the response to exogenous ACTH administration.

Low-dose ACTH stimulation test

  • This test involves physiological plasma concentrations of ACTH and provides a more sensitive index of adrenocortical responsiveness. The low-dose ACTH test is performed by measuring serum cortisol immediately before and 30 minutes after intravenous (IV) injection of Cosyntropin in a dose of either 1 mcg or 0.5 mcg per 1.73 m2.

  • There is no commercially available preparation of “low dose” Cosyntropin. One prepares the low-dose solution of Cosyntropin locally; the vials of Cosyntropin currently available contain 250 mcg and come with sterile normal saline solution used as diluent.

  • Using radioimmunoassay to measure serum cortisol, a value of 18 mcg/dL or more, before or after ACTH injection, is indicative of normal adrenal function.

High-dose ACTH stimulation test

  • This test consists of measuring serum cortisol immediately before and at 30 and 60 minutes after IV injection of 250 mcg of Cosyntropin. This dose of Cosyntropin results in pharmacological plasma ACTH concentrations for the 60-minute duration of the test.

  • The advantage of the high-dose test is that the Cosyntropin can be injected intramuscularly (IM), because pharmacologic plasma ACTH concentrations are still achieved.

  • A serum cortisol value of 20 mcg/dL or more at any time during the test, including before injection, is indicative of normal adrenal function.

  • Salivary cortisol can also be measured during this test. Salivary cortisol increases to 19±0.8 ng/mL (range: 8.7-36 ng/mL) 1 hour after injection.

Eight-hour ACTH stimulation test

  • The 8-hour test, which is now rarely performed, consists of infusing 250 mcg of Cosyntropin continuously over 8 hours in 500 mL of isotonic saline. A 24-hour urine specimen is collected the day before and the day of infusion for cortisol or 17-hydroxycorticoid (OHCS) and creatinine determination, and serum cortisol is determined at the end of the infusion. Plasma ACTH concentrations are supraphysiologic throughout the infusion.

  • The 24-hour urinary excretion of 17-OHCS should increase 3- to 5-fold over baseline on the day of ACTH infusion. Serum cortisol should reach 20 mcg/dL within 30-60 minutes after infusion begins and exceed 25 mcg/mL after 6-8 hours.

Two-day ACTH infusion test

  • The 2-day ACTH infusion test is similar to the 8-hour infusion test, except the same dose of ACTH is infused for 8 hours on 2 consecutive days.

  • This test may be helpful in distinguishing secondary from tertiary adrenal insufficiency. The 1-day, 8-hour test is too short for this purpose, whereas longer tests add little further useful information.

  • Urinary excretion of 17-OHCS should exceed 27 mg during the first 24 hours of infusion and 47 mg during the second 48 hours. Serum cortisol should reach 20 mcg/mL witihin 30-60 minutes after ACTH infusion begins and exceed 25 mcg/mL after 6-8 hours. Both serum and urinary steroid values increase progressively thereafter, but the ranges of normal are not well-defined.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

ACTH Stimulation (Cosyntropin) Test Limitations

  • In healthy individuals, cortisol responses are greatest in the morning, but, in patients with adrenal insufficiency, the response to Cosyntropin is the same in the morning and afternoon. Thus, these tests should be done in the morning to minimize the risk of misdiagnosis in a normal individual.

  • The criteria for a minimal normal cortisol response of 18-20 mcg/dL are derived from the responses of healthy volunteers. However, in some studies, higher cutoff points for the diagnosis of adrenal insufficiency are based on the ACTH test responses of patients known to have an abnormal response to insulin.

  • Variability in cortisol assays creates an additional problem with setting criteria for a normal response to ACTH that applies to all centers. Studies comparing cortisol results obtained with different assays showed a positive bias of radioimmunoassay (RIA) and enzyme immunoassay (EIA) assays of 10-50% compared to a reference value obtained using isotope dilution GC-MS.

  • In women, the response to ACTH is affected by the use of oral contraceptives, which increase cortisol binding globulin (CBG) levels.

  • The response to ACTH varies with the underlying disorder. If the patient has hypopituitarism with deficient ACTH secretion and secondary adrenal insufficiency, then the intrinsically normal adrenal gland should respond to maximally stimulating concentrations of exogenous ACTH if given for a long enough time. The response may be less in normal subjects, and patients may initially be sluggish due to adrenal atrophy resulting from chronically low stimulation by endogenous ACTH. Conversely, if the patient has primary adrenal insufficiency, endogenous ACTH secretion is already elevated and there should be little or no adrenal response to exogenous ACTH.

  • A clearly subnormal response to the low-dose or high-dose ACTH stimulation test is diagnostic of primary or secondary adrenal insufficiency, whereas a normal response excludes both disorders.

  • Cortisol values between 18 and 25.4 mcg/dL represent a range of uncertainty in which patients may have discordant responses to ACTH, insulin, and/or metyrapone. Higher concentrations represent a normal response in the non-intensive care (ICU) setting.

  • The low-dose test is not valid if there has been recent pituitary injury and supports the conclusion that a 30-minute serum cortisol concentration less than 18 mcg/dL indicates impaired adrenocortical reserve.

  • The low-dose test does not reliably indicate HPA axis suppression in preterm infants whose mothers received dexamethasone for less than 2 weeks before delivery to hasten fetal lung development. The corticotropin releasing hormone (CRH) test should be used in this situation.

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