Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, Leuven, Belgium.
Department of Medicine III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany; Diabetes and Nutritional Sciences, Rayne Institute, Denmark Hill Campus, King's College London, London, UK.
Lancet Diabetes Endocrinol. 2015 Oct;3(10):805-15. doi: 10.1016/S2213-8587(15)00224-7. Epub 2015 Jun 10.
Critical illness represents a life-threatening disorder necessitating recruitment of defence mechanisms for survival. Herein, the hypothalamic-pituitary-adrenal axis is essential. However, the relevance of a relative insufficiency of the hypothalamic-pituitary-adrenal axis in critical illness, which is diagnosed by a suppressed cortisol response to exogenous adrenocorticotropic hormone (ACTH) irrespective of the plasma cortisol concentration, is controversial. Findings from several studies have provided insights that clarify at least part of this controversy. Rather than an activated hypothalamic-pituitary-adrenal axis, ACTH-independent regulators have been reported to contribute to increased cortisol availability during critical illness. One of these regulators is reduced cortisol breakdown, mediated by suppressed expression and activity of cortisol metabolising enzymes in the liver and kidneys. This downstream mechanism increases concentrations of plasma cortisol, but the ensuing feedback-inhibited ACTH release, when sustained for more than 1 week, has been shown to negatively affect adrenocortical integrity and function. Reduced adrenocortical ACTH signalling could explain reduced cortisol responses to exogenous ACTH. Whether such reduced cortisol responses in the presence of raised plasma (free) cortisol identifies adrenal failure needing treatment is unlikely. Additionally, reduced cortisol breakdown affects the optimum dose of hydrocortisone treatment during critical illness. Identification of patients with an insufficient hypothalamic-pituitary-adrenal axis response and the optimum treatment for this disorder clearly need more well designed preclinical and clinical studies.
危重病代表一种危及生命的疾病，需要动员防御机制以维持生存。在此过程中，下丘脑-垂体-肾上腺轴至关重要。然而，危重病患者下丘脑-垂体-肾上腺轴相对不足的相关性仍存在争议，这种不足是通过外源性促肾上腺皮质激素（ACTH）激发试验检测到皮质醇反应受抑制来诊断的，而与血浆皮质醇浓度无关。多项研究的结果提供了一些见解，至少部分澄清了这一争议。在危重病期间，增加皮质醇的可用性并非由激活的下丘脑-垂体-肾上腺轴引起，而是由 ACTH 独立的调节因子所介导，这些调节因子包括减少皮质醇的分解代谢，这是通过肝脏和肾脏中皮质醇代谢酶的表达和活性受抑制来实现的。这种下游机制增加了血浆皮质醇的浓度，但随之而来的 ACTH 释放受到反馈抑制，如果持续超过 1 周，则已被证明会对肾上腺皮质的完整性和功能产生负面影响。ACTH 信号转导减少可解释外源性 ACTH 激发试验时皮质醇反应降低的原因。在存在升高的血浆（游离）皮质醇的情况下，皮质醇反应降低是否能确定需要治疗的肾上腺功能衰竭，这是不太可能的。此外，皮质醇分解代谢减少会影响危重病期间氢化可的松治疗的最佳剂量。明确存在下丘脑-垂体-肾上腺轴反应不足的患者，并确定该疾病的最佳治疗方法，显然需要更多设计良好的临床前和临床研究。
