Introduction
Adrenal dysfunction is known to occur in patients with liver cirrhosis during infection or acute decompensation and is associated with adverse outcomes, especially acute-on-chronic liver failure (ACLF) in these patients (1). However, little is known about pituitary-adrenal signaling in stable patients with ACLD.
Aims & Methods
We aimed to evaluate (i) the pituitary-adrenal axis and (ii) the prognostic value of total serum cortisol (t-Cort) in a cohort of outpatients with advanced chronic liver disease (ACLD).
Consecutive outpatients with ACLD and hepatic venous pressure gradient (HVPG) ≥6 mmHg within the prospective VICIS (NCT03267615) study were included. Exclusion criteria were intake of corticosteroids, a history of liver transplantation (LT), hepatocellular carcinoma, vascular liver disease, occlusive portal vein thrombosis and evidence of infection. According to d’Amico et al. (2) patients were stratified into 6 subgroups for their clinical stage of ACLD (S0: subclinical portal hypertension [PH], S1: clinically significant PH (CSPH) without varices, S2: CSPH with varices; S3: history of variceal bleeding, S4: non-bleeding decompensation S5: ACLD with further decompensation). Competing risk regression was conducted considering LT and death - or non-liver-related death, as appropriate - as competing.
Results
In total, 137 patients (compensated: S0: n=13, S1: n=12, S2: n=26; decompensated: S3: n=7, S4: n=46, S5: n=33) with male predominance (67.9%; median age: 58.1 years) were included. Median ACTH (from S0: 44.0pg/mL to S5: 20.0pg/mL; p=0.006), cortisol binding globulin (from S0: 49.3µg/mL to S5: 38.9µg/mL; p<0.001) and serum total cortisol (t-Cort; from S0: 13.9µg/dL to S5: 9.2µg/dL; p=0.091) levels decreased throughout the substages of ACLD, while serum free cortisol (f-Cort; from S0: 6.5ng/mL to S5: 5.7ng/mL; p=0.474) stayed unchanged.
Importantly, t-Cort showed a strong correlation with f-Cort and (Spearman’s ρ: 0.889). Lower levels of t-Cort were independently predictive of bacterial infections (adjusted subdistribution hazard ratio [asHR] per µg/dL: 1.11, 95% confidence interval [95%CI]: 1.04-1.19; p=0.002), (further) decompensation (asHR: 1.08; 95%CI: 1.02-1.12; p=0.008), ACLF (asHR: 1.11; 95%CI: 1.04-1.19; p=0.002), as well as liver-related death (asHR: 1.09; 95%CI: 1.01-1.18; p=0.045).
Youden’s index determined t-Cort level <12 µg/dL as ideal cutoff for the prediction of ACLF. Overall, n=87/137 (63.5%) patients exhibited t-Cort <12 µg/dL. The cumulative incidence of ACLF was more than 3 times higher in patients with t-Cort <12 µg/dL at 1 year (15.6% vs. 4.4%), 2 years (28.4% vs. 6.9%) and 3 years (34.4% vs. 11.0%) of follow-up (p=0.005).
Conclusion
Pituitary-adrenal signaling is impaired in cirrhosis. Lower levels of both t-Cort are independently linked to bacterial infections, (further) decompensation, ACLF and liver-related death, possibly due to impaired stress response. Moreover, t-Cort <12 µg/dL identifies stable patients with ACLD with a particularly high risk of ACLF.
References
1. Piano S, Favaretto E, Tonon M, Antonelli G, Brocca A, Sticca A, Mareso S, et al. Including Relative Adrenal Insufficiency in Definition and Classification of Acute-on-Chronic Liver Failure. Clin Gastroenterol Hepatol 2020;18:1188-1196.e1183.
2. D'Amico G, Morabito A, D'Amico M, Pasta L, Malizia G, Rebora P, Valsecchi MG. Clinical states of cirrhosis and competing risks. J Hepatol 2018;68:563-576.
