Interpretation of the short Synacthen test in the presence of low cortisol-binding globulin: two case reports

Abstract

AddressesContext Ten percent of serum total cortisol (TC) is unbound; the remainder is bound to cortisol-binding globulin (CBG) and, to a lesser extent, albumin. CBG concentrations can drop significantly, particularly in critical illness, resulting in a low TC although the free, active, cortisol may be normal or increased. In the context of a low CBG, the diagnosis of pituitary-adrenal insufficiency with measurements of TC is difficult.Objective To remind clinicians of the difficulty in interpreting TC when the CBG is low, the circumstances when CBG concentrations may decrease and that measurement of CBG and calculation of the free cortisol index can help in the assessment of pituitary-adrenal reserve.Case We present two patients at risk of primary and secondary adrenal insufficiency with a poor response to 250 mg Synacthen. In both cases we confirmed low CBG concentrations but a normal free cortisol index (FCI), confirming normal pituitary-adrenal reserve.Intervention In case one, we have been able to avoid long-term steroid replacement therapy. We continue to reduce the steroid dose in case 2 but have been limited by the need for high-dose steroid treatment for exacerbations of the patient's airways disease. ConclusionThe use of TC in the assessment of the hypothalamic-pituitaryadrenal (HPA) axis may give rise to misleading results if the CBG concentration is low. The FCI may be a better marker of pituitary-adrenal reserve in these subjects. Clinicians should be cautious when interpreting abnormal cortisol results and we emphasize the importance of good clinical assessment.

Glucocorticoid Measurements in Health and Disease - Metabolic Implications and the Potential of 24-h Urine Analyses

“…Measurement of serum free cortisol concentration appear to be most appropriate approach for assessing adrenal function in critically ill patients, who often have reduced CBG and albumin levels and consequently reduced total serum cortisol concentrations, even after ACTH stimulation [26,59]. The decreased total binding of cortisol to CBG in critically ill patients results in larger albumin-bound and free proportions [26], of which overall cortisol concentrations are reduced due to simultaneously lowered albumin and theper se -high metabolic clearance of the unbound fraction.…”

Individual variations in behavior and free cortisol responses to acute stress in tiger pufferfishTakifugu rubripes

“…Steroid hormone availability to the target tissue is controlled by steroid binding proteins 17 and it has been suggested that the biological activity of cortisol is proportional to the levels of free cortisol, which is the biologically active fraction 18 . As free cortisol is biologically active, small changes in the level could have marked effects on animal physiology, and the free fraction seems more closely associated with the HPA activity than total plasma cortisol 19–22 . Therefore, there has been considerable interest in studying the dynamics of free and bound cortisol in mediating the stress response and behavior in mammals and birds 23–25 .…”

“…18 As free cortisol is biologically active, small changes in the level could have marked effects on animal physiology, and the free fraction seems more closely associated with the HPA activity than total plasma cortisol. [19][20][21][22] Therefore, there has been considerable interest in studying the dynamics of free and bound cortisol in mediating the stress response and behavior in mammals and birds. [23][24][25] Although CBG is not yet identified in teleosts, a similar binding protein of high affinity and low capacity has been characterized in at least 20 species of fish.…”

Acute Hepatic Failure

“…The use of salivary cortisol has been shown to correlate well with FC, although in ventilated patients this may be dif fi cult to obtain. Alternatively, the free cortisol index (see equation below) can be calculated by measuring both CBG and TC levels, which has also been shown to correlate well with FC levels [ 31 ] . These alternative measures of FC may prove to be better methods of assessing RAI rather than relying on TC levels alone.…”