Salivary cortisol in the diagnosis of adrenal insufficiency: cost efficient and patient friendly

Abstract

Saliva as a diagnostic tool is patient friendly and offers analytical advantages. Hormonal analysis of saliva is not influenced by changes in concentrations of binding globulins as the free concentration of the hormones is measured. Analysis of salivary cortisol is common practice in the diagnostic work-up of hypercortisolism. We investigated the potential role of measuring salivary cortisol when adrenal insufficiency (AI) is suspected, to reduce the numbers of ACTH stimulation tests. Over a period of 6 years, patients undergoing an ACTH stimulation test (tetracosactide, 250 µg) in our hospital were included. Plasma cortisol (Elecsys, Cobas, Roche Diagnostics) and salivary cortisol and cortisone (LC-MS/MS) were determined at t = 0, 30 and 60 min after stimulation. Based on peak plasma cortisol levels, AI was ruled out in 113 patients and was established in 16 patients. Patients without AI displayed maximal salivary cortisol concentrations of 12.6-123.4 nmol/L (95th percentile) after stimulation, as opposed to 0.5-15.2 nmol/L in AI patients. At t = 0 min, a minimal salivary cortisol concentration of 1.0 nmol/L was observed in patients without AI, whereas AI patients had a maximum concentration of 5.9 nmol/L. Using these cut-off values, 34% of the initial patient group could be diagnosed without an ACTH stimulation test (28% >5.9 nmol/L, 6% <1.0 nmol/L). A novel diagnostic algorithm, including early morning salivary cortisol analysis can reduce the numbers of ACTH stimulation tests in patients suspected of AI. This patient-friendly method can thereby reduce total health care costs.

Keywords: LC–MS/MS; adrenal insufficiency; cut-off values; salivary cortisol.

Figure 1

Salivary cortisol (A) and cortisone (B) concentrations during ACTH stimulation tests. Results are given for patients in whom AI was ruled out (black dots) or established (blue dots). Concentrations are shown on a logarithmic scale (X-axis), accompanied by fitted normal distributions (black and blue lines) on an arbitrary Y-axis. Cut-off values (black and blue vertical lines, numbers in boldface) and reference values (underlined numbers in black and blue) are shown.

Figure 2

Effect of different diagnostic approaches on numbers of ACTH stimulation tests in patients suspected of adrenal insufficiency. Current protocols are considered the reference (A). An approach with a second plasma cortisol measurement, in addition to the plasma cortisol requested by the referring physician, is shown in panel B. Panel C displays an approach including salivary cortisol measurements. Percentages of patients with AI ruled out or established are given, as well as the percentage of ACTH stimulation tests performed using the different approaches in B and C.

Figure 3

Novel diagnostic flowchart adrenal insufficiency. When a physician suspects AI in a given patient, an early morning plasma cortisol measurement will be performed. Concentrations above an assay-specific cut-off level (e.g. 550 nmol/L for cortisol I and 420 nmol/L for cortisol II) rule out AI. Below this cut-off level, a salivary cortisol measurement could be performed to select patients for an ACTH stimulation test. Early morning salivary cortisol concentrations >5.9 nmol/L can rule out AI. Peak plasma or salivary cortisol concentrations after stimulation make up the diagnosis.