Higher hydrocortisone dose increases bilirubin in hypopituitary patients‐ results from an RCT

BACKGROUND: Bilirubin has anti‐oxidative and anti‐inflammatory properties, which may explain its proposed protective effects on the development of cardiometabolic disorders. Glucocorticoids affect heme oxygenase regulation in vitro, which plays a key role in bilirubin production. Effects of variations in glucocorticoid exposure on circulating bilirubin levels in humans are unknown. Here we tested whether a higher hydrocortisone replacement dose affects circulating bilirubin in hypopituitary patients. MATERIALS AND METHODS: A randomized double‐blind cross‐over study (ClinicalTrials.gov, number NCT01546992) was performed in 47 patients with secondary adrenal failure [10‐week exposure to a higher hydrocortisone dose (0·4–0·6 mg/kg body weight) vs. 10 weeks of a lower hydrocortisone dose (0·2–0·3 mg/kg body weight)]. RESULTS: Plasma total bilirubin was increased by 10% from 7 to 8 μM in response to the higher hydrocortisone dose (P = 0·033). This effect was inversely related to age (P = 0·042), but was unaffected by sex, obesity and (replacement for) other hormonal insufficiencies. The higher hydrocortisone dose also resulted in lower alkaline phosphatase (P = 0·006) and aspartate aminotransferase activities (P = 0·001). CONCLUSION: Bilirubin is modestly increased in response to higher glucocorticoid exposure in humans, in conjunction with lower alkaline phosphatase and aspartate aminotransferase activities, which are supposed to represent biomarkers of a pro‐inflammatory state and enhanced liver fat accumulation.