Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, O&N1 Box 503, 3000, Leuven, Belgium.
Crit Care. 2024 Sep 5;28(1):295. doi: 10.1186/s13054-024-05079-8.
Hypocholesterolemia hallmarks critical illness though the underlying pathophysiology is incompletely understood. As low circulating cholesterol levels could partly be due to an increased conversion to cortisol/corticosterone, we hypothesized that glucocorticoid treatment, via reduced de novo adrenal cortisol/corticosterone synthesis, might improve cholesterol availability and as such affect adrenal gland and skeletal muscle function.
In a matched set of prolonged critically ill patients (n = 324) included in the EPaNIC RCT, a secondary analysis was performed to assess the association between glucocorticoid treatment and plasma cholesterol from ICU admission to day five. Next, in a mouse model of cecal ligation and puncture-induced sepsis, septic mice were randomized to receive either hydrocortisone (1.2 mg/day) (n = 17) or placebo (n = 15) for 5 days, as compared with healthy mice (n = 18). Plasma corticosterone, cholesterol, and adrenocortical and myofiber cholesterol were quantified. Adrenal structure and steroidogenic capacity were evaluated. Muscle force and markers of atrophy, fibrosis and regeneration were quantified. In a consecutive mouse study with identical design (n = 24), whole body composition was assessed by EchoMRI to investigate impact on lean mass, fat mass, total and free water.
In human patients, glucocorticoid treatment was associated with higher plasma HDL- and LDL-cholesterol from respectively ICU day two and day three, up to day five (P < 0.05). Plasma corticosterone was no longer elevated in hydrocortisone-treated septic mice compared to placebo, whereas the sepsis-induced reduction in plasma HDL- and LDL-cholesterol and in adrenocortical cholesterol was attenuated (P < 0.05), but without improving the adrenocortical ACTH-induced CORT response and with increased adrenocortical inflammation and apoptosis (P < 0.05). Total body mass was further decreased in hydrocortisone-treated septic mice (P < 0.01) compared to placebo, with no additional effect on muscle mass, force or myofiber size. The sepsis-induced rise in markers of muscle atrophy and fibrosis was unaffected by hydrocortisone treatment, whereas markers of muscle regeneration were suppressed compared to placebo (P < 0.05). An increased loss of lean body mass and total and free water was observed in hydrocortisone-treated septic mice compared to placebo (P < 0.05).
Glucocorticoid treatment partially attenuated critical illness-induced hypocholesterolemia, but at a cost of impaired adrenal function, suppressed muscle regeneration and exacerbated loss of body mass.
尽管低胆固醇血症是危重病的标志，但潜在的病理生理学仍不完全清楚。由于循环中胆固醇水平降低可能部分是由于向皮质醇/皮质酮的转化率增加所致，我们假设糖皮质激素治疗通过减少新合成的肾上腺皮质醇/皮质酮，可能会改善胆固醇的可用性，并因此影响肾上腺和骨骼肌功能。
在 EPaNIC RCT 中纳入的一组持续时间较长的危重病患者（n=324）的匹配集内进行了二次分析，以评估从 ICU 入院到第 5 天期间糖皮质激素治疗与血浆胆固醇之间的关联。接下来，在盲肠结扎和穿刺诱导的脓毒症小鼠模型中，将脓毒症小鼠随机分为接受氢化可的松（1.2mg/天）（n=17）或安慰剂（n=15）治疗 5 天，与健康小鼠（n=18）进行比较。定量检测血浆皮质酮、胆固醇以及肾上腺皮质和肌纤维胆固醇。评估肾上腺结构和类固醇生成能力。定量检测肌肉力量以及萎缩、纤维化和再生的标志物。在具有相同设计的连续小鼠研究中（n=24），通过 EchoMRI 评估全身成分，以研究其对瘦体重、脂肪量、总水量和游离水量的影响。
在人类患者中，从 ICU 第 2 天到第 3 天，糖皮质激素治疗与更高的血浆 HDL-和 LDL-胆固醇相关，直到第 5 天（P<0.05）。与安慰剂相比，氢化可的松治疗的脓毒症小鼠的血浆皮质酮不再升高，而脓毒症诱导的血浆 HDL-和 LDL-胆固醇以及肾上腺皮质胆固醇降低得到缓解（P<0.05），但并未改善肾上腺皮质对 ACTH 诱导的 CORT 反应，且伴有肾上腺皮质炎症和细胞凋亡增加（P<0.05）。与安慰剂相比，氢化可的松治疗的脓毒症小鼠的总体体重进一步下降（P<0.01），对肌肉质量、力量或肌纤维大小没有额外作用。氢化可的松治疗并未影响脓毒症诱导的肌肉萎缩和纤维化标志物的增加，而与安慰剂相比，肌肉再生标志物受到抑制（P<0.05）。与安慰剂相比，氢化可的松治疗的脓毒症小鼠中观察到瘦体重、总水量和游离水量的丢失增加（P<0.05）。
糖皮质激素治疗部分缓解了危重病引起的低胆固醇血症，但代价是肾上腺功能受损、肌肉再生受抑制以及体重进一步减轻。
