Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum.
Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum.
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DOI：
10.1002/hep.28265
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发表时间：
2016-04
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影响因子：
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通讯作者：
Williamson C
中科院分区：
文献类型：
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作者：
Abu-Hayyeh S;Ovadia C;Lieu T;Jensen DD;Chambers J;Dixon PH;Lövgren-Sandblom A;Bolier R;Tolenaars D;Kremer AE;Syngelaki A;Noori M;Williams D;Marin JJ;Monte MJ;Nicolaides KH;Beuers U;Oude-Elferink R;Seed PT;Chappell L;Marschall HU;Bunnett NW;Williamson C
产科面临的一个挑战是将病理性症状与与妊娠正常变化相关的症状区分开来，其典型特征是需要区分妊娠期皮肤瘙痒是妊娠肝内胆汁淤积症（ICP）的早期症状还是由于良性妊娠瘙痒。ICP的特点是血清胆汁酸升高，并发自发性早产和死产。ICP的生物标志物对于早期诊断和治疗以及使其与其他孕产妇疾病区分开来将是非常宝贵的。新合成的三种硫酸黄体酮化合物，其浓度以前没有研究过，并在三组ICP患者的血清中进行了检测，发现在妊娠9 - 15周和症状出现之前（第1组病例/样本：ICP n = 35/80，无并发症妊娠= 29/100），这表明所有三种硫酸黄体酮都是ICP的预后因素。孕酮硫酸盐浓度与瘙痒严重程度相关，并与自体归一素联合使用，可区分瘙痒的孕妇，这些孕妇随后会发展为ICP和妊娠瘙痒（组2:ICP n = 41，妊娠瘙痒n = 14）。在第三组妊娠前三个月的样本中，随后发生ICP （ICP/无并发症妊娠n = 54/51）的低风险无症状妇女血清中所有孕酮硫酸盐均显著升高。最后，我们从机制上表明，孕酮硫酸盐通过在小鼠中唤起Tgr5依赖性抓痕反应来介导瘙痒。结论：我们发现硫酸孕酮代谢物是ICP的预后指标，将有助于预测ICP的发病，并将其与良性妊娠瘙痒症区分开来，从而为高危人群提供针对性的产科护理。黄体酮硫酸盐- TGR5瘙痒轴的描述确定了ICP中瘙痒管理的治疗靶点。(肝脏病学63:1287 2016;1298)
A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9‐15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first‐trimester samples all progesterone sulfates were significantly elevated in serum from low‐risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5‐dependent scratch response in mice. Conclusion: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high‐risk population. Delineation of a progesterone sulfate‐TGR5 pruritus axis identifies a therapeutic target for itch management in ICP. (Hepatology 2016;63:1287–1298)