Optimising prednisolone or prednisone replacement in adrenal insufficiency

CONTEXT: Patients with adrenal insufficiency (AI) have higher mortality than the general population, possibly because of excess glucocorticoid exposure at inappropriate times. The cortisol circadian rhythm is difficult to mimic with twice or thrice-daily hydrocortisone. Prednisolone is a once-daily alternative which may improve patient compliance and convenience. OBJECTIVES: Prednisolone day curves can be used to accurately down-titrate patients to the minimum effective dose. We aimed to review prednisolone day curves and determine therapeutic ranges at different timepoints after administration. METHODS: Between August 2013 and May 2021, 108 prednisolone day curves from 76 individuals receiving prednisolone replacement were analysed. Prednisolone concentrations were determined by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Spearman's correlation coefficient was used to determine the relationship between 2-, 4- and 6-hour prednisolone levels compared to the validated standard 8-hour prednisolone level (15-25 μg/L). RESULTS: The median dose was 4mg prednisolone once daily. There was strong correlation between the 4-hour and 8-hour (R=0.8829, p ≤0.0001), and 6-hour and 8-hour prednisolone levels (R=0.9530, p ≤ 0.0001). Target ranges for prednisolone were 37-62 μg/L at 4-hours, 24-39 μg/L at 6-hours and 15-25 μg/L at 8-hours. Prednisolone doses were successfully reduced in 21 individuals and of these, three were reduced to 2mg once daily. All patients were well upon follow-up. CONCLUSION: This is the largest evaluation of oral prednisolone pharmacokinetics in humans. Low dose prednisolone of 2-4mg is safe and effective in most patients with AI. Doses can be titrated with either 4-hour, 6-hour, or 8-hour single timepoint drug levels

Late night salivary cortisol and cortisone should be the initial screening test for Cushing’s syndrome

Endogenous Cushing’s syndrome (CS) poses considerable diagnostic challenges. Although late night salivary cortisol (LNSC) is recommended as a first line screening investigation, it remains the least widely used test in many countries. The combined measurement of LNSC and late-night salivary cortisone (LNS cortisone) has shown to further improve diagnostic accuracy1. We present a retrospective study in a tertiary referral centre comparing LNSC, LNS cortisone, overnight dexamethasone suppression test, low dose dexamethasone suppression test and 24-hour urinary free cortisol results of patients investigated for CS. Patients were categorised into those who had CS (21 patients) and those who did not (33 patients).LNSC had a sensitivity of 95% and a specificity of 91%. LNS cortisone had a specificity of 100% and a sensitivity of 86%. With an optimal cut-off for LNS cortisone of >14.5 nmol/l the sensitivity was 95.2%, and the specificity was 100% with an area under the curve of 0.997, for diagnosing CS. Saliva collection is non-invasive and can be carried out at home.We therefore advocate simultaneous measurement of LNSC and LNS cortisone as the first-line screening test to evaluate patients with suspected CS