Hartl Lukas, Simbrunner Benedikt, Jachs Mathias, Wolf Peter, Bauer David Josef Maria, Scheiner Bernhard, Balcar Lorenz, Semmler Georg, Schwarz Michael, Marculescu Rodrig, Trauner Michael, Mandorfer Mattias, Reiberger Thomas
Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
JHEP Rep. 2023 May 11;5(8):100789. doi: 10.1016/j.jhepr.2023.100789. eCollection 2023 Aug.
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).
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.
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; = 0.006), t-Cort (from S0: 13.9 μg/dl to S5: 9.2 μg/dl; = 0.091), and cortisol binding globulin (from S0: 49.3 μg/ml to S5: 38.9 μg/ml; <0.001) decreased, whereas f-Cort ( = 0.474) remained unchanged. Lower t-Cort levels independently predicted bacterial infections (asHR: 1.11; 95% CI: 1.04-1.19; = 0.002), further decompensation (asHR: 1.08; 95% CI: 1.02-1.12; = 0.008), acute-on-chronic liver failure (ACLF; asHR: 1.11; 95% CI: 1.04-1.19; = 0.002), and liver-related death (asHR: 1.09; 95% CI: 1.01-1.18; = 0.045).
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.
Vienna Cirrhosis Study (VICIS; NCT: NCT03267615).
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.
肝硬化患者存在肾上腺功能不足的情况。我们调查了（i）不同临床阶段的垂体 - 肾上腺轴，以及（ii）晚期慢性肝病（ACLD）稳定患者血清皮质醇水平降低的临床影响。
在前瞻性VICIS研究（NCT03267615）中，我们纳入了137例接受肝静脉压力梯度（HVPG）测量的ACLD门诊患者。患者被分为六个临床阶段：S0：亚临床门静脉高压（PH）（HVPG 6 - 9 mmHg），S1：具有临床意义的PH（HVPG≥10 mmHg）且无静脉曲张，S2：存在静脉曲张，S3：既往静脉曲张出血，S4：既往非出血性失代偿，S5：进一步失代偿。
51例患者为代偿期ACLD（S0：n = 13；S1：n = 12；S2：n = 26），而86例患者为失代偿期ACLD（S3：n = 7；S4：n = 46；S5：n = 33）。血清总皮质醇（t - Cort）与估计的血清游离皮质醇（f - Cort；Spearman等级相关系数：0.889）显示出强相关性。随着临床阶段的进展，促肾上腺皮质激素（ACTH）水平中位数（从S0：44.0 pg/ml到S5：20.0 pg/ml；P = 0.006）、t - Cort（从S0：13.9 μg/dl到S5：9.2 μg/dl；P = 0.091）和皮质醇结合球蛋白（从S0：49.3 μg/ml到S5：38.9 μg/ml；P <0.001）降低，而f - Cort（P = 0.474）保持不变。较低的t - Cort水平独立预测细菌感染（校正后风险比：1.11；95%置信区间：1.04 - 1.19；P = 0.002）、进一步失代偿（校正后风险比：1.08；95%置信区间：1.02 - 1.12；P = 0.008）、慢加急性肝衰竭（ACLF；校正后风险比：1.11；95%置信区间：1.04 - 1.19；P = 0.002）和肝脏相关死亡（校正后风险比：1.09；95%置信区间：1.01 - 1.18；P = 0.045）。
随着肝硬化严重程度的增加，垂体 - ACTH - 肾上腺 - 皮质醇轴逐渐受到抑制。较低的t - Cort是细菌感染、ACLF进一步失代偿和肝脏相关死亡率的独立危险因素——即使在肝硬化稳定的门诊患者中也是如此。
维也纳肝硬化研究（VICIS；NCT：NCT03267615）。
在一组稳定的门诊患者中，我们观察到随着晚期慢性肝病（ACLD）临床阶段的增加，垂体肾上腺轴逐渐受到抑制。胆汁酸水平升高和全身炎症（通过白细胞介素 - 6水平评估）可能参与了这种抑制。血清总皮质醇（t - Cort）与血清游离皮质醇（f - Cort）密切相关，较低的t - Cort水平与不良临床结局的较高风险独立相关，包括细菌感染、进一步失代偿、慢加急性肝衰竭和肝脏相关死亡。
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