Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism
Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism
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DOI：
10.1172/jci.insight.93136
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发表时间：
2017-04-20
期刊：
影响因子：
8
通讯作者：
Reincke, Martin
中科院分区：
文献类型：
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作者：
Arlt, Wiebke;Lang, Katharina;Reincke, Martin
背景肾上腺醛固酮过多是继发性高血压最常见的原因，并与心血管疾病发病率增加有关。然而，原发性醛固酮增多症的不良代谢风险超出了高血压，胰岛素抵抗、2型糖尿病和骨质疏松症的发生率增加，这不能简单地用醛固酮过量来解释。我们对174例新诊断的原发性醛固酮增多症患者（103例单侧腺瘤，71例双侧肾上腺增生）的24小时尿类固醇代谢组进行了基于质谱的分析，并与162例健康对照，56例内分泌不活跃的肾上腺腺瘤患者，104例轻度亚临床患者和47例临床上明显的肾上腺皮质醇过量患者进行了比较。我们还分析了57例醛固酮腺瘤患者的腺瘤组织中皮质醇产生的CYP11B1和醛固酮产生的CYP11B2酶的表达，采用免疫组织化学和数字图像分析。原发性醛固酮增多症患者皮质醇和糖皮质激素代谢产物总量显著增加（P均< 0.001），只有临床上明显的肾上腺皮质库欣综合征患者的糖皮质激素分泌量超过皮质醇和糖皮质激素代谢产物总量。代谢风险的几个替代参数与糖皮质激素显著相关，但与盐皮质激素输出无关。肿瘤内CYP11B1表达与相应的体内糖皮质激素排泄显著相关。单侧肾上腺切除术解决了盐皮质激素和糖皮质激素过量。在45例连续检测的患者中，有13例（29%）发现术后肾上腺功能不全的证据。我们的数据表明，糖皮质激素共分泌是常见的原发性醛固酮增多症，并有助于相关的代谢风险。单独使用盐皮质激素受体拮抗剂治疗可能不足以抵消接受药物治疗的原发性醛固酮增多症患者的不良代谢风险。
BACKGROUND. Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess.METHODS. We performed mass spectrometry-based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis.RESULTS. Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients.CONCLUSION. Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism.