Method-Specific Cortisol and Dexamethasone Thresholds Increase Clinical Specificity of the Dexamethasone Suppression Test for Cushing Syndrome

Abstract

Background The dexamethasone suppression test (DST) is the recommended first-tier test for suspected Cushing syndrome (CS). Missed dexamethasone intake or insufficient dexamethasone serum exposure may yield false positive results. Quantification of serum dexamethasone in DST samples may therefore improve test performance. Methods Simultaneous quantification of dexamethasone and cortisol by liquid chromatography-tandem mass spectrometry in 400 DST serum samples (100 overt CS, 200 excluded CS, 100 adrenal incidentalomas with (possible) autonomous cortisol secretion, AI-ACS) randomly selected within the indication groups. The 2.5th percentile of dexamethasone in patients with excluded CS was considered the lower limit of normal (LLN). Results Serum dexamethasone varied from undetectable to 20.2 ng/mL with a median of 4.8 ng/mL (95% CI 4.5-5.1 ng/mL). Dexamethasone was undetectable in only 16 patients (4%), suggesting non-compliance. The dexamethasone LLN was 1.8 ng/mL (4.6 nmol/L). Decreased glomerular filtration rate and diabetes mellitus were associated with higher serum dexamethasone concentration, while body mass index, sex, age, nicotine, and oral contraceptives had no significant effect. By excluding the 27 samples with dexamethasone <LLN and applying the method-specific cortisol cutoff of 2.4 µg/dL (66 nmol/L) to samples with suspected CS, the clinical specificity for CS increased from 67.5% to 92.4% while preserving 100% clinical sensitivity. Among 100 AI-ACS samples (defined by immunoassay), 4 samples had dexamethasone <1.8 ng/mL and 14 samples had cortisol <2.4 µg/dL, which excluded autonomous cortisol secretion. Conclusions Quantification of dexamethasone and method-specific cortisol cutoffs in DST samples may reduce the false positive rate and lower the proportion of patients requiring further workup.

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study

“…However, the 247 ACS exceeded the total number of patients included in all previous studies on this topic (n=154). [9][10][11][12] Third, we relied on a single 1 mg DST only, with variability in the performance of the cortisol assays used between centres over time, and without availability of dexamethasone serum concentrations 29 . However, the biochemical tests used to assess if there is cortisol autonomy have not been changed over the last 25 years.Fourth, it is possible that the inclusion criteria '1 mg DST result' by itself leads to some bias, because some patients with adrenal incidentaloma may not have undergone testing.…”

Metyrapone Versus Osilodrostat in the Short-Term Therapy of Endogenous Cushing’s Syndrome: Results From a Single Center Cohort Study

“…As previously performed ( 20 , 21 ), commercially available analytical procedures were used for measurement of serum and salivary cortisol (the Immulite 2000 Xpi from Siemens), and for the analysis of UFC (a manual radioimmunoassay from Immuntech).…”

Diagnosis and management of hypertension in patients with Cushing's syndrome: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension

“…However, further hormonal assessment may be considered in patients with a high pretest probability of Cushing's syndrome (see previous paragraph), or who, in the 6 months following initial testing, show progression of symptoms that could potentially be driven by hypercortisolism. Additionally, if 1 mg DST results are not in line with the clinical suspicion, it might be worthwhile to measure also dexamethasone levels, as suggested by recent studies [145,146]. In the case of an abnormal initial result, positivity of at least one of the remaining screening tests is required to establish the diagnosis of Cushing's syndrome, especially given that cyclicity/variability in Cushing's syndrome is not an infrequent phenomenon, with a prevalence in Cushing's disease above 15% [147].…”