Serum total cortisol and free cortisol index give different information regarding the hypothalamus–pituitary–adrenal axis reserve in patients with liver impairment

Abstract

Background: The short synacthen test (SST) is used to investigate patients with suspected hypothalamus -pituitary-adrenal (HPA) axis pathology. A rise of serum total cortisol (total cortisol) above 550 nmol/L is accepted as sufficient adrenal reserve. In total, 80% of cortisol is bound to cortisol-binding globulin (CBG) and 10% to albumin. In the acute phase responses CBG concentrations decrease and can influence the interpretation of SST. The free cortisol index (FCI) is a surrogate marker for free cortisol and is defined as total cortisol (nmol/L)/CBG (mg/L) with an FCI . 12 representing sufficient adrenal reserve. The aim of this study was to compare total cortisol and FCI in the interpretation of SST in patients with liver impairment. Method: SST was done on 26 patients with liver impairment. Total cortisol was measured on Advia Centaur; serum CBG by radioimmunoassay and FCI calculated. Results: Eleven (42%) patients had a total cortisol .550 nmol/L (range 555 -2070) and FCI . 12 (12.0 -68.9) suggesting sufficient cortisol reserve. Three patients (13%) had total cortisol ,550 nmol/L (268 -413) and FCI , 12 (3.5-11.6) consistent with cortisol deficiency. Twelve patients (46%) had a total cortisol ,550 nmol/L (144 -529), but an FCI . 12 (12.0 -52.9). None of the patients had a total cortisol .550 nmol/L and FCI , 12. Conclusion: When total cortisol alone is used to interpret SST in patients with liver impairment, 46% may have been classified as having adrenal insufficiency because of low CBG. FCI may be better for the evaluation of HPA axis insufficiency in patients with liver impairment.

Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease

“…In lieu of direct measurements, surrogate markers have been advocated, of which the Coolens equation and the Free Cortisol Index (FCI) are the most frequently described. The Coolens method has been found to provide values that correlated highly with measured PFC [21] and the FCI has been argued to be a better determinant of HPA-axis function than total cortisol [22]. In our study we found no significant correlation between the peak PFC and FCI.…”

“…Evidence to support this hypothesis has come from studies in critically ill patients which have demonstrated a poor correlation between total and free cortisol estimations, and suggested that free cortisol fraction is more closely related to disease severity than is the total concentration [21,20]. A recent study examining 26 patients with liver impairment compared the Free Cortisol Index (FCI) with standard total cortisol diagnostic criteria and demonstrated that in 46% of patients there was a discrepancy between the two methods [22]. However, this method cannot account for the non-linear binding properties of CBG and thus the higher proportional increase in free cortisol following ACTH stimulation [28].…”

“…Additionally in liver disease, both CBG and albumin production are impaired, thus potentially resulting in increased PFC concentrations making total cortisol a potentially unreliable index of PFC [20,21]. A recent study utilising the Free Cortisol Index (FCI), a surrogate marker for plasma free cortisol, suggested that there is a discrepancy between PFC and TC in the diagnosis of adrenal insufficiency in patients with severe liver disease [22]. Other studies have used salivary cortisol as an index of PFC [23].…”

Assessment of adrenocortical reserve in stable patients with cirrhosis

“…FCI was calculated as a ratio between total cortisol (nmol/L) and CBG (mg/L) [31]. cFC was derived using the Coolen' equation:…”

“…Additionally, a separate analysis was performed using a cut-off value less than 16 lg/dl for peak total serum cortisol, recently proposed as a more sensitive cut-off [21], and a delta cortisol less than 9 lg/dl as suggestive of an inadequate adrenal response [9]. As previously described, FCI above 12 represented sufficient adrenal response [31].…”