An impaired pituitary-adrenal signalling axis in stable cirrhosis is linked to worse prognosis

Abstract

Background & aims: Inadequate adrenal function has been described in patients with cirrhosis. We investigated (i) the pituitary-adrenal axis at different clinical stages and (ii) the clinical impact of decreased serum cortisol levels in stable patients with advanced chronic liver disease (ACLD).

Methods: We included 137 outpatients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement in the prospective VICIS study (NCT03267615). Patients were stratified into six clinical stages: S0: subclinical portal hypertension (PH) (HVPG 6-9 mmHg), S1: clinically significant PH (HVPG ≥10 mmHg) without varices, S2: presence of varices, S3: previous variceal bleeding, S4: previous non-bleeding decompensation, and S5: further decompensation.

Results: Fifty-one patients had compensated ACLD (S0: n = 13; S1: n = 12; S2: n = 26), whereas 86 patients had decompensated ACLD (S3: n = 7; S4: n = 46; S5: n = 33). Serum total cortisol (t-Cort) showed a strong correlation with estimated serum free cortisol (f-Cort; Spearman's ρ: 0.889). With progressive clinical stage, median ACTH levels (from S0: 44.0 pg/ml to S5: 20.0 pg/ml; p = 0.006), t-Cort (from S0: 13.9 μg/dl to S5: 9.2 μg/dl; p = 0.091), and cortisol binding globulin (from S0: 49.3 μg/ml to S5: 38.9 μg/ml; p <0.001) decreased, whereas f-Cort (p = 0.474) remained unchanged. Lower t-Cort levels independently predicted bacterial infections (asHR: 1.11; 95% CI: 1.04-1.19; p = 0.002), further decompensation (asHR: 1.08; 95% CI: 1.02-1.12; p = 0.008), acute-on-chronic liver failure (ACLF; asHR: 1.11; 95% CI: 1.04-1.19; p = 0.002), and liver-related death (asHR: 1.09; 95% CI: 1.01-1.18; p = 0.045).

Conclusions: The pituitary-ACTH-adrenal-cortisol axis is progressively suppressed with increasing severity of cirrhosis. Lower t-Cort is an independent risk factor for bacterial infections, further decompensation of ACLF, and liver-related mortality-even in stable outpatients with cirrhosis.

Clinical trial number: Vienna Cirrhosis Study (VICIS; NCT: NCT03267615).

Impact and implications: In a cohort of stable outpatients, we observed progressive suppression of the pituitary-adrenal axis with increasing clinical stage of advanced chronic liver disease (ACLD). Increased levels of bile acids and systemic inflammation (assessed by interleukin-6 levels) could be involved in this suppression. Serum total cortisol (t-Cort) was strongly correlated with serum free cortisol (f-Cort) and lower t-Cort levels were independently associated with a higher risk of adverse clinical outcomes, including bacterial infections, further decompensation, acute-on-chronic liver failure, and liver-related death.

Keywords: ACTH; Advanced chronic liver disease; Bile acids; Cirrhosis; Cortisol; Inflammation; Non-invasive testing; Portal hypertension.

Graphical abstract

Fig. 1

Patient flow-chart. ACLD, advanced chronic liver disease; f-Cort, serum free cortisol; HCC, hepatocellular carcinoma; HVPG, hepatic venous pressure gradient; LT, liver transplantation; t-Cort, serum total cortisol.

Fig. 2

Plasma levels of serum total and free cortisol and cortisol binding globulin. Plasma levels of (A) serum total cortisol, (B) cortisol binding globulin, (C) serum free cortisol and (D) serum total cortisol/serum free cortisol ratio in patients with different stages of ACLD. Patients stratified by EASL stages. Levels of significance of group comparisons determined by the Kruskal–Wallis test: (A) p = 0.091, (B) p <0.001, (C) p = 0.474, and (D) p = 0.002. The median and interquartile range for every group is shown.

Fig. 3

Plasma levels of components of the pituitary-adrenal axis, systemic inflammation and bile acids. Plasma levels of (A) adrenocorticotropic releasing hormone (ACTH), (B) interleukin-6, (C) bile acids, (D) total cholesterol, (E) HDL cholesterol, (F) aldosterone and (G) corticosterone in patients with different stages of ACLD. Patients stratified by EASL stages. Levels of significance of group comparisons by Kruskal-Wallis test: (A) p = 0.006, (B) p <0.001, (C) p <0.001, (D) p = 0.818, (E) p = 0.392, (F) p <0.001, and (G) p = 0.826. The median and interquartile range for every group is provided.

Fig. 4

Correlations between serum free cortisol and other parameters of the pituitary-adrenal axis. Correlations of serum free cortisol and (A) serum total cortisol, (B) adrenocorticotropic releasing hormone (ACTH), (C) cortisol binding globulin and (D) albumin. Correlation coefficients as assessed by Spearman’s ρ with 95% confidence intervals (95% CI) and levels of significance: (A) ρ = 0.889 (95% CI: 0.846–0.921), p <0.001; (B) ρ=0.436 (95% CI: 0.282–0.567), p <0.001; (C) ρ = -0.039 (95% CI: -0.212 to 0.137), p = 0.659; (D) ρ = -0.060 (95% CI: -0.233 to 0.116), p = 0.489.

Fig. 5

Clinical outcomes. Cumulative incidence of (A) bacterial infections, (B) first/further hepatic decompensation, (C) acute-on-chronic liver failure (ACLF) and (D) liver-related death within five years of follow-up stratified by serum total cortisol (t-Cort) levels. (A, C) Liver transplantation and death and (B, D) liver transplantation and non-liver related death were considered competing risks, respectively. Levels of significance of cumulative incidences compared via Gray’s test: (A) p = 0.023; (B) p = 0.026; (C) p = 0.005; (D) p = 0.067.