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

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.