on 28-May-2021 (Fri)

If it were possible to measure and obtain results of both serum cortisol and plasma ACTH immediately at the time of patient presentation, the diagnosis and cause of adrenal insufficiency could be established without delay in most cases

Plasma aldosterone and renin levels should also be determined if primary adrenal insufficiency is suspected.

Unfortunately, plasma ACTH results are usually not available immediately and it is important (as with the patient who presents in shock) to determine quickly 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 and a decision regarding ongoing treatment. The ACTH value, generally available later, can be used to establish the level of the defect.

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 [25-27]. As a result, it is best to perform the test in the morning to avoid a falsely abnormal result in a healthy subject [28]

Standard high-dose test (250 mcg) — A normal response to the high-dose (250 mcg as an intravenous [IV] bolus) ACTH stimulation test is a rise in serum cortisol concentration after either 30 or 60 minutes to a peak of ≥18 to 20 mcg/dL (500 to 550 nmol/L) [26,30-32]. A normal response to the high-dose (250 mcg) ACTH stimulation test excludes primary adrenal insufficiency [33] and most patients with secondary adrenal insufficiency.

Low-dose test (1 mcg) — The low-dose (1 mcg as an IV bolus) ACTH stimulation test criteria for a normal cortisol response after 20 or 30 minutes are more variable: 17 to 22.5 mcg/dL (400 to 620 nmol/L) [25,26,30,34-36].

Secondary adrenal insufficiency — The low dose test may have advantages over the standard high dose test in some clinical settings, in particular, for the diagnosis of recent onset ACTH deficiency (secondary adrenal insufficiency) and chronic partial pituitary ACTH deficiency [20].

In patients with recent onset ACTH deficiency (eg, within one to two weeks after pituitary surgery), the adrenal glands have not yet become completely atrophic and are still capable of responding to ACTH stimulation. Only insulin-induced hypoglycemia or the metyrapone test is completely reliable in these patients [38,39]. The practical clinical importance of this limitation is unclear.

However, the high-dose test performs well when it is performed at least four months after surgery, or nine months after radiation therapy. In one report, only 2 of 137 patients with 30-minute cortisol values between 18.2 and 22.7 mcg/dL (510 and 635 nmol/L) subsequently developed adrenal insufficiency [40].

A meta-analysis of 28 studies evaluated the diagnostic utility of the high and low dose ACTH stimulation tests. At 95 percent specificity, the sensitivity of the high-dose test for primary adrenal insufficiency (97.5 percent) was greater than that for either test for secondary adrenal insufficiency (57 to 61 percent). Thus, while an abnormal response to this test is very helpful for establishing the diagnosis of adrenal insufficiency and a normal response excludes the diagnosis of primary adrenal insufficiency, a normal response does not exclude the diagnosis of secondary adrenal insufficiency [41]. However, in another study of 26 patients, 23 had a normal response to the 250 mcg test but an abnormal response to the 1 mcg test. None were treated with glucocorticoids; no one developed clinical symptoms of adrenal insufficiency over the 19- to 24-month follow-up [42].

Some studies indicate that the low-dose test can detect partial adrenal insufficiency (as can occur with the chronic use of inhaled glucocorticoids or early adrenal destruction by infectious or autoimmune disease) that may be missed by the standard high-dose test, which provides a supraphysiologic stimulus that can stimulate a diseased adrenal gland that still has some residual function [20,37]. As a result, some advocate use of the low-dose test in patients with suspected secondary or tertiary adrenal insufficiency [32,34,43]. However, other studies suggest a similar diagnostic performance: in the meta-analysis of 44 patients mentioned above, at 95 percent specificity, the sensitivities of the low-dose (61.4 percent) and high-dose (57 percent) tests were similar and receiver-operating curves were similar [41].

Based upon these observations, we suggest the 1 mcg low-dose ACTH test if new or recent onset ACTH deficiency is suspected (eg, one to two weeks after pituitary surgery). For all other patients, including those who are more than four months post-pituitary surgery, we suggest starting with the high dose ACTH stimulation test.

Adrenal crisis — In an acutely ill patient with possible adrenal crisis, therapy should be started before the diagnosis is established. It is essential that treatment of patients who present with acute adrenal insufficiency/possible adrenal crisis not be delayed while diagnostic tests are performed. Blood for serum cortisol and serum chemistry (electrolytes) should be drawn; some clinicians also draw and hold samples for later measurement of ACTH, renin, and aldosterone if the diagnosis of adrenal insufficiency is likely.

Abdominal CT should be performed since it can detect enlarged adrenal glands or adrenal calcification; these findings eliminate autoimmune disease and suggest an infectious, hemorrhagic, or metastatic cause (algorithm 1) [56-61]. However, the absence of enlarged or calcified adrenal glands does not exclude tuberculosis as the cause. Measurement of antiphospholipid antibodies can be helpful when hemorrhage is present in a patient not receiving anticoagulants [62].

Patients presenting initially with tuberculous adrenal insufficiency almost always have obvious active tuberculosis elsewhere [56,63]. Chest radiograph, urine culture for Mycobacterium tuberculosis, and tuberculin skin testing should be performed if the diagnosis is not clear. Complement fixation titers for Histoplasma capsulatum should be obtained when appropriate.