Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (659 page)

   Two-day infusion test: Serum cortisol should reach 20 μg/mL in 30–60 minutes after the ACTH infusion is begun and exceed 25 μg/mL after 6–8 hours. Both serum and urinary steroid values increase progressively thereafter, but the ranges of normal are not well defined.

   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. Therefore, ACTH stimulation 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 μg/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 apply to all centers. Studies comparing cortisol results obtained with different assays showed a positive bias of Radioimmunoassays (RIA) and EIAs 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 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 sufficiently long time. The response may be less than that in normal subjects and initially sluggish due to adrenal atrophy resulting from chronically low stimulation by endogenous ACTH. If, on the other hand, 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 18.0 and 25.4 μg/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-ICU setting.

   The low-dose test is not valid if there has been recent pituitary injury, and it supports the conclusion that a 30-minute serum cortisol concentration <18 μg/dL indicates impaired adrenocortical reserve. In addition, the low-dose test does not reliably indicate hypothalamic–pituitary–adrenal axis suppression in preterm infants whose mothers received dexamethasone for <2 weeks before delivery to hasten fetal lung development. The CRH test should be used in this situation.

ACTIVATED CLOTTING TIME (ACT)
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   Definition