修回日期: 2016-05-20
接受日期: 2016-05-31
在线出版日期: 2016-09-18
妊娠肝内胆汁淤积症(intrahepatic cholestasis of pregnancy, ICP)是妊娠特有疾病, 常发生于妊娠中晚期, 临床上以皮肤瘙痒、生化上以肝内胆汁淤积的血液学指标异常、病程上以临床表现及生化异常在产后迅速消失或恢复正常为特征. 其诊断仍然是基于用其他原因不能解释的妊娠期皮肤瘙痒症状及以血清转氨酶和/或胆汁酸水平升高为突出表现的肝功能受损的排除性诊断, 同时将孕期任何时间胆汁酸水平≥40 μmol/L定义为重度ICP. ICP发病机制尚不清楚, 其主要危害是增加早产、羊水胎粪污染及围生儿死亡率, 难以预测的胎儿缺氧可能导致死胎、产时胎儿窘迫, 甚至死产, 因担心死胎发生而使医源性早产率和剖宫产率升高. ICP胎儿缺氧死亡的原因和机制尚未阐明. 可能与子宫-胎盘-胎儿单位代偿储备基础结构受损及应激代偿功能下降、胎儿血及羊水高水平胆汁酸对胎盘绒毛表面血管及脐血管浓度依赖性收缩作用有关. 监护评价病情、宫缩及胎儿情况, 积极预防控制宫缩, 使用熊去氧胆酸500-1500 mg/d, 或联合应用二线药物S-腺苷蛋氨酸800-1000 mg/d或利福平300-1200 mg/d促进胆汁酸排泄, 促进胎儿生长及肺发育, 产前维生素K1预防母儿出血, 以及适时终止妊娠, 是ICP规范治疗的基本措施. 孕周、胎儿状况及病情程度等是决定ICP适时终止妊娠的关键, 把握选择性早期分娩原则仍是避免延长孕周过程中发生死胎风险的有效措施.
核心提要: 妊娠肝内胆汁淤积症(intrahepatic cholestasis of pregnancy, ICP)诊断基于其他原因不能解释的妊娠期皮肤瘙痒症状及以血清转氨酶和/或胆汁酸水平升高的排除性诊断, 同时将孕期任何时间胆汁酸水平≥40 μmol/L定义为重度ICP.
引文著录: 黄桂琼, 王晓东. 妊娠肝内胆汁淤积症研究进展. 世界华人消化杂志 2016; 24(26): 3749-3756
Revised: May 20, 2016
Accepted: May 31, 2016
Published online: September 18, 2016
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disease, characterized by maternal pruritus and abnormal serum biochemistries in the late second and third trimester of pregnancy. The symptoms and abnormal biochemistries resolve rapidly after fetal delivery. As a diagnosis of exclusion, the diagnosis of ICP is based on unexplained pruritus with other causes and impaired liver function presenting with elevated serum liver transaminases and/or bile acids. It is considered as severe ICP when bile acid ≥ 40 μmol/L during pregnancy. The pathogenesis of ICP is still unclear. Adverse perinatal outcomes associated with ICP are focused on increased risk of preterm, meconium-stained amniotic fluid, and perinatal mortality. Unpredictable fetal hypoxia may result in intrauterine fetal death, fetal distress during birth and even stillbirth, and lead to an increase of iatrogenic preterm and cesarean section. The etiology and pathogenesis of fetal stress in ICP are not yet clarified, which may be associated with impaired infrastructure and decreased stress-compensatory in human utero-placental-fetal unit, and related with vascular constriction of chorionic veins and umbilical cord due to elevated bile acids in fetal serum and amniotic fluid. The essential measures of standard treatment of ICP include: (1) monitoring and evaluation of disease, uterine contraction and fetus; (2) prevention and treatment of uterine contraction; (3) treatment with ursodeoxycholic acid (500-1500 mg/d) alone or in combination with S-adenosylmehionine (800-1000 mg/d) or rifampicin (300-1200 mg/d) to promote drainage of bile acids; (4) promotion of fetal growth and lung development; (5) treatment with vitamin K1 before delivery to prevent maternal and fetal hemorrhage; (6) and timely termination of pregnancy. Gestational weeks, fetal condition and severity of disease need to be taken into account when obstetricians decide the time of termination. Elective early delivery is still an effective measure to avoid stillbirth during prolongation of gestational weeks.
- Citation: Huang GQ, Wang XD. New insights into diagnosis and treatment of intrahepatic cholestasis of pregnancy. Shijie Huaren Xiaohua Zazhi 2016; 24(26): 3749-3756
- URL: https://www.wjgnet.com/1009-3079/full/v24/i26/3749.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i26.3749
妊娠肝内胆汁淤积症(intrahepatic cholestasis of pregnancy, ICP)也称产科胆汁淤积症(obstetric cholestasis, OC), 是妊娠特有疾病, 常发生于妊娠中晚期, 临床上以皮肤瘙痒、生化上以肝内胆汁淤积的血液学指标异常、病程上以临床表现及生化异常在产后迅速消失或恢复正常为特征[1,2]. 其发病率为0.1%-15.6%[3], 有明显的地域性和种族差异, 发病机制尚不清楚, 可能涉及多因素, 包括激素、遗传及环境因素等. 其不良胎儿结局(adverse fetal outcomes, AFOs)包括早产、新生儿入住ICU、胎死宫内等[4], 时常困扰临床医生和孕妇, 尤其是急性胎儿低氧缺氧可能导致围生儿突然死亡, 机制不清, 防不胜防, 曾被称为产科"百慕大之谜". ICP对母体而言是"良性疾病", 但其发病时间和临床表现与其他妊娠期重型肝病具有相似之处, 可能延误甚至掩盖对妊娠期重型肝病的识别[5]. 因此, 如何在延长孕周过程中避免围生儿死亡和排除妊娠期重型肝病, 一直是ICP临床诊治关注的焦点[6].
与子痫前期一样, ICP研究也具有悠久的历史和较为丰富的文献资料, 但其病因和发病机制迄今仍不清楚, 临床诊疗也不尽规范.
自1883年Ahlfeld首次详细描述"妊娠复发性黄疸"后, 该病即逐步进入广大医学工作者的研究视野. 1966年, Haemmerli根据该病的病例特征, 首先以妊娠肝内胆汁淤积症命名该病, 部分欧洲(英国)文献称该病为产科胆汁淤积症(obstetric cholestasis, OC). 1976年, Reid全面报道56例OC不良妊娠结局, 此后, 诸多学者从基础到临床对ICP进行了深入研究和探索; 各国临床指南相继发布, 临床诊疗逐步规范.
自2011年以来, 国内外关于ICP的基础与临床研究都取得了重要进展, 我国指南也经过了几年临床实践, 2015年中华医学会对《妊娠期肝内胆汁淤积症诊疗指南(第1版)》进行了修订, 发布了《妊娠期肝内胆汁淤积症诊疗指南(2015)》[7]. 2015年版指南能更好指导临床, 但关于将早发型ICP归入重度、没有提及重度ICP防治早产及促进胎肺成熟治疗、促进胆汁酸排泄药物推荐等问题, 还值得进一步探讨. 本文仅就临床关注问题所取得的主要研究进展进行综述, 以提振围产医学工作者对该病诊治的信心.
ICP发病有明显的地域性和种族差异. 南美智利、亚马孙河流域玻利维亚是全球ICP发病率最高的地区, 达9.2%-15.6%, 南美印第安混血儿的ICP发病率最高[8]. 欧洲发病率为0.5%-1.5%, 北欧波罗的海尼亚湾以瑞典为代表的斯堪的纳维亚为欧洲高发区[9]. 中国长江流域ICP为2.3%-6.0%[10], 其中成都为5.2%, 为亚洲高发区. 同时, ICP复发率约30%-70%[11,12], 而且, ICP冬季发病率高, 占30%[12]; 双胎妊娠ICP发病率高, ICP患者中, 多胎达35%[5], 芬兰有项研究发现双胎妊娠ICP的发病率为14%, 而三胎妊娠时为43%[13]; 有口服避孕药诱导的肝内胆汁淤积病史者, 发生ICP的风险更高[2]; 也有研究发现微量元素硒缺乏[14,15]、维生素D缺乏[16]与ICP的发生有关. 有不明原因死胎及新生儿死亡史, 在产前保健过程中也应引起足够重视[17].
ICP发生可能是多因素共同作用的结果, 涉及遗传、激素和环境等多种因素, 遗传因素决定ICP的易感性, 环境因素诱发ICP的发生并决定其严重程度[18].
ICP发病呈现一定的复发性和家族聚集性. Savander等[13]发现ICP患者16%有家族史, 同胞姐妹发病率高达12%, 并呈现X-连锁显性遗传/常染色体显性遗传. 大量遗传学研究发现, ICP与ATP8B1、ABCB11、ABCB4[19,20]、ABCC2[21]、NR1H4[22]等很多基因关系密切, 这些基因主要是通过调节胆汁酸转运而影响肝内胆汁淤积. 另有学者[23]通过探讨ICP患者中人类白细胞抗原HLA-DRB1基因多态性与ICP的关系, 发现HLA-DR6等位基因可能是ICP发病的易感基因之一; 雌激素受体2[24]和雌激素受体β[25]、染色体2p3不平衡连锁区附近微卫星标志[26]、CYP1A1[27]和CYP1B1[28]基因多态性与ICP的发生均有一定的关系. 不同的个体可能发现一个或几个致病基因, 且不同的人群中基因突变呈现的形式也不一致, 可能与种族和地域差异引起基因突变热点不同相关, 无特定的遗传方式, 具有一定的遗传异质性.
ICP是妊娠期雌激素相关性肝病. 动物研究[29,30]发现雌激素主要通过影响胆汁酸盐载体表达和定位而引起胆汁淤积. 可降调肝细胞毛细胆管膜载体有机阴离子载体多药耐药相关蛋白2和胆汁酸载体; 降低肝细胞窦膜上Na+-K+-ATP酶活性, 抑制窦膜载体Na+依赖性牛磺酸共转运蛋白活性, 降调Na+-牛磺胆酸共转运多肽和有机阴离子转运多肽. 雌激素代谢产物D-环葡萄糖醛酸雌激素与胆汁酸结构相似, 可能在在载体竞争, 胆汁酸载体数量和活性下降, 导致胆汁排泄障碍. 孕激素似乎也起着同样重要的作用, 有研究[31]发现ICP患者体内孕酮硫酸代谢产物3α/3β增高, 可能耦合胆汁酸信号通路, 影响胆固醇表型; 竞争抑制牛磺胆酸输入泵和胆盐输出泵影响胆汁酸摄取和排泄[32,33]; 某些特定代谢产物为FXR拮抗因子, 影响胆汁酸代谢[34]. 更有学者认为有些孕酮硫酸盐早于血清胆汁酸的升高, 可以作为ICP发病预测因子[35].
ICP是妊娠期雌激素相关性肝病, 目前仍认为是良性自限性疾病, 但ICP产妇患肝胆系统疾病[39]、免疫相关性疾病[40]的风险增加. 随访研究ICP孕妇子代至16岁, 发现其体质指数及血脂异常风险增高[41].
ICP的主要危害是其导致的不良胎儿结局, 包括早产、新生儿入住ICU、胎死宫内等[4]. ICP先兆早产率近20%, 近90%发生于32 wk后[42]; ICP围生儿缺氧死亡率增高, 常突然发生, 难以预测, 主要发生于妊娠35 wk后[42]、未足月正式临产前, 95%死胎死产突然发生于先兆早产、偶然宫缩或临产初期[42]. 先兆早产、不规律宫缩或临产初期、羊水胎粪污染是其主要诱因[42,43]. 尤其是重度ICP, 妊娠35 wk及以后, 重度ICP胎儿进入死亡高危期, 不规律或规律性子宫收缩、羊水粪染可能是ICP胎儿缺氧的重要诱因.
ICP胎儿缺氧死亡的原因和机制尚未阐明. 可能与子宫-胎盘-胎儿单位(utero-placental-fetal unit, UPF)代偿储备基础结构受损及应激代偿功能下降、胎儿血及羊水高水平胆汁酸对胎盘绒毛表面血管及脐血管浓度依赖性收缩作用有关. 高浓度胆汁酸的细胞毒作用也曾受到重视[44].
ICP胎盘绒毛间腔狭窄30%[45]、胎盘小叶胎儿血管系统容积缩窄29%[46], 绒毛交换表面积[47]及其对氧的通透功能[48]正常, 绒毛间腔及绒毛血管容积缩窄导致UPF单位代偿储备基础结构受损, 但并未导致非应激情况下胎儿血氧供应不足, ICP胎儿没有慢性缺氧[48]和FGR[42,49]表现, ICP胎儿缺氧仍表现为急性缺氧[43].
UPF血管床血流调节依赖于局部产生和循环的血管舒张因子. 促肾上腺皮质激素释放激素(corticotropin-releasing hormone, CRH)肽类家族是应激级联效应的初始调节神经肽, 包括CRH和尿皮素(urocortin, UCN), 通过自身受体激活效应的超短阳性反馈回路[50], 在应激代偿调节中处于中心作用. 来源于母体及胎儿的应激因素刺激合成释放CRH/UCN, 对UPF血管产生最强效浓度依赖性舒张作用, 充分扩张UPF血管床, 增加血氧储备, 满足胎儿一过性低氧或缺氧应激需求; ICP患者UPF单位CRH/UCN表达受限[51,52], 可能导致UPF单位不能代偿低氧缺氧应激而发生胎儿急性缺氧甚至死亡.
因此, 提出ICP胎儿缺氧死亡的假说: 雌激素释放及代谢障碍, 导致肝内胆汁淤积和先兆早产, 母胎血及羊水胆汁酸水平升高, 绒毛间腔及绒毛血管容积缩窄; 同时胎盘绒毛表面血管及脐血管对胆汁酸水平反应性收缩甚至痉挛, UPF单位具有强效血管扩张功能的CRH/UCN应激神经肽应激表达受限, 导致UPF单位对低氧缺氧应激代偿功能受限, 导致胎儿缺氧甚至死亡.
1992年, Reyes比较全面总结ICP诊断要点: 以妊娠期皮肤瘙痒为主要症状; 血清胆汁酸升高(≥10 μmol/L)或合并转氨酶轻至中度升高; 可伴轻度黄疸; 脂溶性消化不良, 如食欲不振、便溏和脂肪泄等, 但无明显的恶心、呕吐、厌油和乏力等消化道症状, 也无明显肝病体征; 妊娠是皮肤瘙痒及生化异常的唯一原因, 症状、体征及其生化异常在产后迅速消失或恢复正常. 该诊断标准逐渐被广泛采用.
妊娠期出现皮肤瘙痒, 每周监测血清胆汁酸、转氨酶水平, 排除皮肤及其他肝脏疾病即应疑诊为ICP. ICP仍然是基于用其他原因不能解释的妊娠期皮肤瘙痒症状及以血清转氨酶和/或胆汁酸水平升高为突出表现的肝功能受损的排除性诊断[6]. 需要排除妊娠期皮肤病, 排除肝胆系统其他疾病及重症肝病; 需要产后随访进行回顾性修正诊断. ICP症状及其生化异常在产后迅速消失或恢复正常, 产后10 d后复查肝脏功能及胆汁酸水平. 若生化异常产后6 wk仍持续存在, 则需要排除潜在肝胆疾病可能.
虽然大量研究致力于发现ICP不良妊娠结局的预测因子, 以更好的规范其诊断和治疗, 但目前循证医学证据表明没有一项指标与ICP不良围生儿结局之间有稳定的确切关系, 并能独立预测不良围生儿结局. 但比较一致的观点认为, 总胆汁酸水平与ICP病情程度、围生结局之间最具相关性.
很多研究[53]发现胆汁酸增加子宫肌壁上缩宫素受体的敏感性和表达, 引起子宫收缩而发生自发性早产. Glantz等[54]报道瑞典大样本回顾性研究(690例ICP患者)发现总胆汁酸≥40 μmol/L, 自发性早产、新生儿窒息及羊水粪染的发病率均增加. Geenes等[4]的研究也显示胆汁酸升高明显增加患者自发性早产、新生儿入住ICU及围产儿死亡的风险, 与正常妊娠相比, OR值分别为5.39、2.68及2.58, 同时发现早产率、羊水粪染率及围产儿死亡的发生率随着胆汁酸的升高而增加.
2008年Zecca等[55]即提出, ICP围生儿危险度 = 胆汁酸水平×病程(胆汁酸暴露时间)/孕龄. 孕期任何时间胆汁酸水平≥40 μmol/L, 可能伴发显著增高的胎儿并发症发生率[4,54,56]. 因此, 将孕期任何时间胆汁酸水平≥40 μmol/L定义为重度ICP. 但是, 以胆汁酸水平40 μmol/L作为切割点判断胎儿预后, 尚不能很放心地用于指导临床实践, 对胆汁酸水平<40 μmol/L的ICP患者, 仍不能掉以轻心. 总胆汁酸越高, 尤其是当总胆汁酸>100 μmol/L时, 胎死宫内的风险明显升高, 或者若合并有其他并发症, 如子痫前期, 妊娠期糖尿病等, ICP患者发生胎死宫内的风险也随之升高[4,57].
1997年, Palma等称发生于妊娠第33周前的ICP为早发型ICP. 但目前尚无证据表明, 早发型ICP病情更严重或有更坏的围生结局[2].
ICP的病因及发病机制尚不明确, 其主要危害是增加早产、羊水胎粪污染及围生儿死亡率, 难以预测的胎儿缺氧可能导致死胎、产时胎儿窘迫, 甚至死产, 因担心死胎发生而使医源性早产率和剖宫产率升高. 在对ICP患者进行延长孕周的观察处理过程中, 极有可能发生羊水胎粪污染和胎儿突然死亡, 既要警惕死胎发生, 又要权衡早产对新生儿的近、远期影响.
1次/wk监测评价病情, 及时排除或发现重症肝病; 实时监测子宫收缩, 早产宫缩可能是病情控制不良的信号和胎儿缺氧的诱因; 监测胎动, 32-34 wk每周1次NST, 重度ICP患者于34 wk后每周2次NST, 产程初期CST, 对判断胎儿预后, 捕捉胎儿缺氧征兆, 似乎具有临床实践意义.
ICP早产宫缩可能是病情控制不良的信号和胎儿缺氧的诱因; ICP先兆早产率20%, 近90%发生于32 wk后. 妊娠32 wk后积极有效预防、治疗ICP先兆早产, 捕捉胎儿缺氧征兆, 对延长孕周、改善围生儿结局具有重要意义[1,6,42].
推荐一线药物熊去氧胆酸500-1500 mg/d, 如果效果不明显, 可增加剂量或选择联合应用二线药物S-腺苷蛋氨酸(s-ade-nosyl-methionine, SAMe)800-1000 mg/d、或利福平[2,4,58](rifampicin, RFP)300-1200 mg/d; 除用于早产促进胎肺成熟外, 不推荐使用糖皮质激素治疗ICP.
积极治疗FGR; 妊娠35 wk前, 按2014早产指南使用糖皮质激素促进胎肺发育, 地塞米松6 mg, 肌内注射, 1次/12 h, 连续4次.
预防母儿出血: 产前维生素K1 10 mg im qd, 共3 d. 缓解瘙痒症状, 改善睡眠状态: 苯巴比妥影响胆汁酸合成、促进胆汁酸分泌排泄, 并有镇静作用, 可缓解瘙痒、改善睡眠. 常用剂量30 mg, 3次/d或睡前服用, 平均2 wk一疗程.
应该遵循个体化综合评价原则开展临床实践. 孕周、胎儿状况及病情程度等是决定ICP适时终止妊娠的关键, 把握选择性早期分娩原则[2]仍是避免延长孕周过程中发生死胎风险的有效措施.
虽然没有充分循证证据证明妊娠37 wk前终止妊娠能改善ICP不良围生儿结局, 但妊娠满37 wk后主动干预、尽早终止妊娠可避免继续待产可能出现的死胎风险[59]. 在ICP病因及发病机制明了之前, ICP终止妊娠仍然需要把握选择性早期分娩原则, 抓住晚期早产(34-36 wk+6 d)或足月早期(37-38 wk+6 d)积极终止妊娠的时机, 尽可能避免延长孕周过程中发生的死胎风险[6].
仍然应该坚持重度ICP积极处理方案, 加强监护评价, 抓住35 wk后晚期早产以剖宫产积极终止妊娠的时机, 对防止意外死胎发生尤为重要[60].
没有证据表明轻度ICP在孕39 wk前足月早期积极终止妊娠可以改善妊娠结局, 不支持轻度ICP在孕39 wk前足月早期分娩, 监护未发现胎儿缺氧表现, 允许延长孕周至39 wk[2,61], 可经阴道试产, 产程早期加强胎儿监护、人工破膜观察羊水情况, 并放宽产时剖宫产结束分娩指征, 尽量避免困难助产.
虽然目前多数临床医生主张重度ICP于妊娠37 wk分娩, 轻度ICP可延长孕周至39 wk, 但ICP最佳分娩孕周仍未确定[2]. ICP在延长孕周过程中应加强监护, 把握35 wk后积极终止妊娠的指征: ICP以胆汁酸为分度标准尚不能很放心地用于指导临床实践. 发病孕龄≤32孕周, 瘙痒严重影响睡眠、生化异常明显(TBA≥40 μmol/L、ALT≥200 U/L), 合并FGR及ICP死胎史、多胎、先兆早产等, 或在延长孕周过程中出现病情进展、宫缩不能抑制、胎动异常、胎心率变异消失或NST无反应、羊水粪染等, 把握妊娠35 wk后以剖宫产积极终止妊娠的时机仍然十分重要.
妊娠肝内胆汁淤积症发病机制不清, 诊断仍然是基于其他原因不能解释的妊娠期皮肤瘙痒症状及以血清转氨酶和/或胆汁酸水平升高的排除性诊断, 孕期任何时间胆汁酸水平≥40 μmol/L定义为重度ICP. 胎儿缺氧死亡可能与子宫-胎盘-胎儿单位代偿储备基础结构受损及应激代偿功能下降、胎儿血及羊水高水平胆汁酸对胎盘绒毛表面血管及脐血管浓度依赖性收缩作用有关. 监护评价病情、宫缩及胎儿情况, 积极预防控制宫缩, 使用熊去氧胆酸500-1500 mg/d、或联合应用SAMe 800-1000 mg/d或RFP 300-1200 mg/d促进胆汁酸排泄, 促进胎儿生长及肺发育, 产前维生素K1预防母儿出血, 以及终止妊娠, 是ICP规范治疗的基本措施. 孕周、胎儿状况及病情程度等是决定ICP适时终止妊娠的关键, 把握选择性早期分娩原则仍是避免延长孕周过程中发生死胎风险的有效措施.
尽管妊娠肝内胆汁淤积症(intrahepatic cholestasis of pregnancy, ICP)研究历史悠久, 但其病因和发病机制仍不明了, 临床诊疗也不尽规范. 但近几年国内外关于ICP的基础与临床研究都取得了重要进展, 对ICP的发病机制有了进一步认识, 为临床医生提供了最新的ICP诊治及产科处理建议, 协助其进行合理的临床决策, 不断规范ICP的临床诊治.
张宗明, 教授, 首都医科大学北京电力医院普外科
ICP的发病机制、不良胎儿结局的预测指标、ICP最佳分娩孕周、终止妊娠的指征及时机是该领域亟待研究的问题.
ICP胎儿缺氧死亡的原因和机制尚未阐明, 可能与子宫-胎盘-胎儿单位代偿储备基础结构受损及应激代偿功能下降、胎儿血及羊水高水平胆汁酸对胎盘绒毛表面血管及脐血管浓度依赖性收缩作用有关. 将孕期任何时间胆汁酸水平≥40 μmol/L定义为重度ICP. 掌握ICP终止妊娠的时机非常关键.
从流行病学、发病机制、不良妊娠结局、诊断及治疗等方面, 系统阐述了妊娠肝内胆汁淤积症的最新研究进展.
本文根据最新的研究报告, 总结国内外研究成果, 对临床有一定的指导作用, 并在一定程度上规范ICP的临床诊治.
本文阐述了ICP诊断、治疗等方面的最新进展, 提供了最新的产科处理建议, 文章的科学性、创新性和可读性均较好.
手稿来源: 邀请约稿
学科分类: 胃肠病学和肝病学
手稿来源地: 四川省
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