Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
N Engl J Med. 2013 Apr 18;368(16):1477-88. doi: 10.1056/NEJMoa1214969. Epub 2013 Mar 19.
Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism.
In a total of 158 patients in the intensive care unit and 64 matched controls, we tested five aspects of cortisol metabolism: daily levels of corticotropin and cortisol; plasma cortisol clearance, metabolism, and production during infusion of deuterium-labeled steroid hormones as tracers; plasma clearance of 100 mg of hydrocortisone; levels of urinary cortisol metabolites; and levels of messenger RNA and protein in liver and adipose tissue, to assess major cortisol-metabolizing enzymes.
Total and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P<0.001 for both comparisons). Cortisol production was 83% higher in the patients (P=0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P≤0.03 for both comparisons). All these factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P<0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples (P≤0.004 for all comparisons).
During critical illness, reduced cortisol breakdown, related to suppressed expression and activity of cortisol-metabolizing enzymes, contributed to hypercortisolemia and hence corticotropin suppression. The diagnostic and therapeutic implications for critically ill patients are unknown. (Funded by the Belgian Fund for Scientific Research and others; ClinicalTrials.gov numbers, NCT00512122 and NCT00115479; and Current Controlled Trials numbers, ISRCTN49433936, ISRCTN49306926, and ISRCTN08083905.).
危重病常伴有皮质醇增多症，这归因于下丘脑-垂体-肾上腺轴应激激活。然而，危重病患者的促肾上腺皮质激素水平也较低，这可能是由于皮质醇代谢减少所致。
在重症监护病房的 158 例患者和 64 例匹配对照者中，我们检测了皮质醇代谢的五个方面：促肾上腺皮质激素和皮质醇的日水平；作为示踪剂输注氘标记甾体激素时的血浆皮质醇清除率、代谢和生成；100mg 氢化可的松的血浆清除率；尿皮质醇代谢产物水平；以及肝脏和脂肪组织中主要皮质醇代谢酶的信使 RNA 和蛋白质水平。
患者的总循环和游离皮质醇水平始终高于对照组，而促肾上腺皮质激素水平较低（两种比较均 P<0.001）。患者的皮质醇生成率高 83%（P=0.02）。在示踪剂输注和 100mg 氢化可的松给药后，患者的皮质醇清除率降低了 50%以上（两种比较均 P≤0.03）。所有这些因素使患者的血浆皮质醇水平增加了 3.5 倍，与对照组相比（P<0.001）。皮质醇清除率受损也与促肾上腺皮质激素刺激时皮质醇反应降低相关。皮质醇代谢减少与肝脏和肾脏中皮质醇失活减少相关，这提示尿甾体比值、示踪动力学和肝活检样本评估（所有比较 P≤0.004）。
在危重病期间，皮质醇分解减少与皮质醇代谢酶的表达和活性受抑制有关，导致皮质醇增多症和促肾上腺皮质激素抑制。这对危重病患者的诊断和治疗意义尚不清楚。（由比利时科学研究基金会等资助；ClinicalTrials.gov 编号：NCT00512122 和 NCT00115479；以及 Current Controlled Trials 编号：ISRCTN49433936、ISRCTN49306926 和 ISRCTN08083905）。
