A Comprehensive Evaluation of Steroid Metabolism in Women with Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder, mostly occurring in the third trimester. ICP is defined as an elevation of serum bile acids, typically accompanied by pruritus and elevated activities of liver aminotransferases. ICP is caused by impaired biliary lipid secretion, in which endogenous steroids may play a key role. Although ICP is benign for the pregnant woman, it may be harmful for the fetus. We evaluated the differences between maternal circulating steroids measured by RIA (17-hydroxypregnenolone and its sulfate, 17-hydroxyprogesterone, and cortisol) and GC-MS (additional steroids), hepatic aminotransferases and bilirubin in women with ICP (n = 15, total bile acids (TBA) >8 μM) and corresponding controls (n = 17). An age-adjusted linear model, receiver-operating characteristics (ROC), and multivariate regression (a method of orthogonal projections to latent structure, OPLS) were used for data evaluation. While aminotransferases, conjugates of pregnanediols, 17-hydroxypregnenolone and 5β-androstane-3α,17β-diol were higher in ICP patients, 20α-dihydropregnenolone, 16α-hydroxy-steroids, sulfated 17-oxo-C19-steroids, and 5β-reduced steroids were lower. The OPLS model including steroids measured by GC-MS and RIA showed 93.3% sensitivity and 100% specificity, while the model including steroids measured by GC-MS in a single sample aliquot showed 93.3% sensitivity and 94.1% specificity. A composite index including ratios of sulfated 3α/β-hydroxy-5α/β-androstane-17-ones to conjugated 5α/β-pregnane-3α/β, 20α-diols discriminated with 93.3% specificity and 81.3% sensitivity (ROC analysis). These new data demonstrating altered steroidogenesis in ICP patients offer more detailed pathophysiological insights into the role of steroids in the development of ICP.

妊娠肝内胆汁淤积症（Intrahepatic cholestasis of pregnancy, ICP）是一种常见的肝脏疾病，多发生于妊娠晚期。ICP的定义为血清胆汁酸水平升高，通常伴随瘙痒及肝转氨酶活性升高。ICP的发病与胆汁脂质分泌受损有关，其中内源性类固醇可能发挥关键作用。尽管ICP对孕妇本身为良性病变，但可能对胎儿造成危害。本研究通过放射免疫分析法（Radioimmunoassay, RIA）检测了15例总胆汁酸（total bile acids, TBA）＞8μM的ICP患者及17例匹配对照受试者的母体循环类固醇激素，包括17-羟孕烯醇酮（17-hydroxypregnenolone）及其硫酸酯、17-羟孕酮（17-hydroxyprogesterone）与皮质醇（cortisol），并通过气相色谱-质谱联用（Gas Chromatography-Mass Spectrometry, GC-MS）检测了其余类固醇激素，同时检测了两组的肝转氨酶及胆红素水平。本研究采用年龄校正线性模型、受试者工作特征曲线（Receiver Operating Characteristic, ROC）及多元回归分析（正交投影潜结构法，Orthogonal Projections to Latent Structure, OPLS）对实验数据进行评估。结果显示，ICP患者的转氨酶、孕二醇结合物、17-羟孕烯醇酮（17-hydroxypregnenolone）及5β-雄烷-3α,17β-二醇（5β-androstane-3α,17β-diol）水平均升高，而20α-二氢孕烯醇酮（20α-dihydropregnenolone）、16α-羟基类固醇（16α-hydroxy-steroids）、硫酸化17-氧代C19类固醇（sulfated 17-oxo-C19-steroids）及5β-还原类固醇（5β-reduced steroids）水平则显著降低。同时纳入气相色谱-质谱联用与放射免疫分析法检测的类固醇激素构建的OPLS模型，其诊断灵敏度达93.3%、特异度为100%；而仅采用单份样本气相色谱-质谱联用检测的类固醇激素构建的OPLS模型，灵敏度为93.3%、特异度为94.1%。通过构建复合指数，即硫酸化3α/β-羟基-5α/β-雄烷-17-酮类（sulfated 3α/β-hydroxy-5α/β-androstane-17-ones）与结合型5α/β-孕烷-3α/β,20α-二醇类（conjugated 5α/β-pregnane-3α/β, 20α-diols）的比值，经受试者工作特征曲线分析显示，该指数的诊断特异度为93.3%、灵敏度为81.3%。本研究揭示了ICP患者体内类固醇生成的异常改变，为阐明类固醇激素在ICP发病机制中的作用提供了更为细致的病理生理学见解。