Decreased maximal cortisol secretion rate in patients with cirrhosis: Relation to disease severity

Christina M Lovato; Thierry Thévenot; Sophie Borot; Vincent Di Martino; Clifford R Qualls; Frank K Urban 3rd; Richard I Dorin

doi:10.1016/j.jhepr.2021.100277

Decreased maximal cortisol secretion rate in patients with cirrhosis: Relation to disease severity

JHEP Rep. 2021 Mar 19;3(3):100277. doi: 10.1016/j.jhepr.2021.100277. eCollection 2021 Jun.

Authors

Christina M Lovato¹, Thierry Thévenot², Sophie Borot³, Vincent Di Martino², Clifford R Qualls^{4

5}, Frank K Urban 3rd⁶, Richard I Dorin^{1

5}

Affiliations

¹ Department of Internal Medicine/Endocrinology, Diabetes and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
² Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Universitaire Jean Minjoz, Besançon, France.
³ Service d'Endocrinologie-Métabolisme et Diabétologie-Nutrition, Hôpital Jean Minjoz, Besançon, France.
⁴ Department of Mathematics and Statistics, University of New Mexico, Albuquerque, NM, USA.
⁵ New Mexico Veterans Affairs Healthcare System, Albuquerque, NM, USA.
⁶ Department of Electrical and Computer Engineering, Florida International University, Miami, FL, USA.

Abstract

Background & aims: Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins.

Methods: Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61).

Results: Maximal cortisol secretion rate (CSR_max) was significantly decreased (p = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24-0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33-0.46), and CSR_max was negatively correlated with CP score (r = -0.19, p = 0.01). Free cortisol elimination rate was significantly (p = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min^-1) compared with that in the CP ≤8 group (0.21 ± 0.21 min^-1), and free cortisol elimination rates were negatively correlated with CP score (r = -0.23, p = 0.01). A significant correlation between CSR_max and free cortisol elimination rate (r = 0.88, p <0.001) was observed.

Conclusions: CSR_max and free cortisol elimination rates were significantly reduced according to severity of cirrhosis. In contrast to stimulated total cortisol concentrations, CSR_max estimates were independent of cortisol-binding protein concentrations. Results provide additional evidence of subnormal adrenocortical function in patients with cirrhosis.

Lay summary: We applied numerical analytic methods to characterise adrenocortical function in patients with varying stages of chronic liver disease. We found that patients with more severe cirrhosis have decreased rate of free cortisol elimination and decreased maximal cortisol secretion rate, which is a measure of adrenocortical function. In contrast to conventional measures of adrenocortical function, those obtained using numerical methods were not affected by variation in corticosteroid binding globulin and albumin concentrations. We conclude that patients with cirrhosis demonstrate measurable abnormalities of adrenocortical function, evidence of which supports aspects of the hepatoadrenal syndrome hypothesis.

Keywords: ACLF, acute-on-chronic liver failure; ACTH, adrenocorticotrophin; AI, adrenal insufficiency; Adrenal insufficiency; CBG, corticosteroid-binding globulin; CIRCI, critical illness-related corticosteroid insufficiency; CP, Child-Pugh; CPR, cortisol production rate; CRP, C-reactive protein; CRT, corticosteroid replacement therapy; CSR, cortisol secretion rate; CSRbase, basal CSR (before ACTH stimulation); CSRmax, maximal CSR; Computer-assisted numerical analysis; HPA, hypothalamic–pituitary–adrenal; HSD, hydroxysteroid dehydrogenase; Hydrocortisone; INR, international normalised ratio; Liver disease; MCR, metabolic clearance rate; MELD, model for end-stage liver disease; Metabolic clearance rate; PAI, primary adrenal insufficiency; RAI, relative adrenal insufficiency; RCT, randomised clinical trial; SAI, secondary adrenal insufficiency; SCOTCH, Supplemental Corticosteroids in Cirrhotic Hypotensive Patients With Suspicion of Sepsis; STB, standardised beta.