Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, University Hospital Graz, Graz, Austria.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, University Hospital Graz, Graz, Austria.
BMC Gastroenterol. 2021 Dec 7;21(1):460. doi: 10.1186/s12876-021-02045-4.
Cholestasis might lead to an impairment of adrenal function as suggested by in vitro and in vivo data as well as by clinical findings. Bile acid and adrenal steroid metabolism not only share the receptors farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (TGR5), but supraphysiological bile acid levels were found to stimulate steroidogenesis independent of FXR and TGR5. Our previous experimental findings revealed that mice fed bile acids or subjected to common bile duct ligation develop hypercortisolemia. We thus aimed to assess adrenal gland function in patients with cholestasis.
Adrenal gland function was assessed in 36 patients with cholestasis and in 32 patients without cholestasis by measuring total serum cortisol, adrenocorticotropic hormone (ACTH), as well as the increase of cortisol 20 and 30 min after administration of 1 µg of ACTH. Bile acid levels and bile acid pool composition were determined by high-resolution mass spectrometry.
Patients with cholestasis per definition had markedly elevated levels of alkaline phosphatase (AP), bilirubin and serum bile acids. Baseline cortisol and maximum cortisol after ACTH stimulation were significantly higher in patients with cholestasis compared to controls. Increase of cortisol after ACTH stimulation and ACTH did not differ. In the cholestasis group, baseline cortisol correlated with bilirubin but not with AP, total serum bile acids and levels of conjugated and unconjugated bile acid species. Patients with duration of cholestasis < 6 months (n = 30) had significantly higher baseline cortisol levels than those with long standing cholestasis (> 6 months), together with higher bilirubin levels.
We find no evidence of adrenal insufficiency in non-cirrhotic patients with cholestasis. In contrast, patients with cholestasis show hypercortisolism associated with disease severity as mirrored by levels of bilirubin. Lack of ACTH increase in cholestasis suggests a direct effect of cholestasis on adrenals and not on the pituitary gland. Further studies are needed to elucidate the mechanism of cortisol elevation in patients with cholestasis and its clinical significance.
体外和体内数据以及临床发现表明，胆汁淤积可能导致肾上腺功能受损。胆汁酸和肾上腺类固醇代谢不仅共享法尼醇 X 受体 (FXR) 和 G 蛋白偶联胆汁酸受体 1 (TGR5)，而且还发现超生理水平的胆汁酸可独立于 FXR 和 TGR5 刺激类固醇生成。我们之前的实验结果表明，给予胆汁酸或进行胆总管结扎的小鼠会出现皮质醇增多症。因此，我们旨在评估胆汁淤积患者的肾上腺功能。
通过测量总血清皮质醇、促肾上腺皮质激素 (ACTH) 以及在给予 1µg ACTH 后 20 和 30 分钟皮质醇的增加量，评估 36 例胆汁淤积患者和 32 例无胆汁淤积患者的肾上腺功能。通过高分辨率质谱法测定胆汁酸水平和胆汁酸池组成。
根据定义，胆汁淤积患者的碱性磷酸酶 (AP)、胆红素和血清胆汁酸水平明显升高。与对照组相比，胆汁淤积患者的基础皮质醇和 ACTH 刺激后的最大皮质醇水平明显更高。ACTH 刺激后皮质醇的增加和 ACTH 没有差异。在胆汁淤积组中，基础皮质醇与胆红素相关，但与 AP、总血清胆汁酸以及结合和未结合胆汁酸种类的水平无关。病程<6 个月的胆汁淤积患者 (n=30) 的基础皮质醇水平明显高于病程较长的患者 (>6 个月)，同时胆红素水平也较高。
我们在非肝硬化胆汁淤积患者中没有发现肾上腺功能不全的证据。相反，胆汁淤积患者表现出皮质醇增多症，与胆红素水平反映的疾病严重程度相关。在胆汁淤积中缺乏 ACTH 的增加表明胆汁淤积对肾上腺的直接影响，而不是对垂体的影响。需要进一步研究来阐明胆汁淤积患者皮质醇升高的机制及其临床意义。
