Role and Research Progress of Hyperhomocysteinemia in the Pathogenesis of Recurrent Spontaneous Abortion
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摘要: 复发性自然流产（recurrent spontaneous abortion，RSA）是影响2%～5%育龄女性的常见生殖系统疾病。近年来研究表明，同型半胱氨酸（homocysteine，Hcy）代谢异常，尤其是高同型半胱氨酸血症（hyperhomocysteinemia，HHcy），可能在RSA的发生发展中发挥重要作用。通过系统梳理国内外相关研究，综述了Hcy的代谢调控特点及其在妊娠期的动态变化，重点总结HHcy通过血管内皮损伤、氧化应激、免疫—凝血异常、滋养细胞功能障碍以及表观遗传等多途径参与RSA发病机制的研究进展。同时，分析了Hcy代谢相关基因多态性（如MTHFR、MTRR、CBS）以及营养和生活方式因素在HHcy形成中的作用，并讨论叶酸及维生素B12补充在降低Hcy水平和改善妊娠结局中的潜在意义。综上，HHcy可能是RSA的重要但常被忽视的代谢危险因素，针对高风险人群开展早期筛查和个体化营养干预有望改善妊娠结局。Abstract: Recurrent spontaneous abortion （RSA） is a common reproductive disorder affecting approximately 2%～5% of women of childbearing age. Recent studies have indicated that abnormalities in homocysteine （Hcy） metabolism, particularly hyperhomocysteinemia （HHcy）, may play an important role in the onset and progression of RSA. By systematically reviewing relevant studies from both domestic and international sources, this article summarizes the metabolic regulation of Hcy and its dynamic changes during pregnancy, with a focus on recent advances in understanding the involvement of HHcy in the pathogenesis of RSA through multiple pathways, including vascular endothelial dysfunction, oxidative stress, immunothrombotic dysregulation, trophoblast dysfunction, and epigenetic modifications. In addition, the roles of Hcy metabolism-related genetic polymorphisms （such as MTHFR, MTRR, and CBS）, as well as nutritional and lifestyle factors, in the development of HHcy are analyzed. The potential significance of folic acid and vitamin B12 supplementation in lowering Hcy levels and improving pregnancy outcomes is also discussed. In conclusion, HHcy may represent an important but often overlooked metabolic risk factor for RSA. In summary, early screening and individualized nutritional interventions in high-risk populations may help improve pregnancy outcomes.
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Key words:
- Recurrent spontaneous abortion /
- Hyperhomocysteinemia /
- Homocysteine /
- Folic acid /
- Vitamin B12
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图 2 高同型半胱氨酸血症诱导免疫-凝血异常的机制
Figure 2. Mechanisms of immunothrombotic abnormalities induced by hyperhomocysteinemia
图 4 高同型半胱氨酸致复发性自然流产的多通路整合机制图
Figure 4. Integrated multi-pathway mechanistic diagram of recurrent spontaneous abortion induced by hyperhomocysteinemia
表 1 复发性自然流产（RSA）与同型半胱氨酸（Hcy）相关性的病例对照研究
Table 1. Case-control studies on the correlation between RSA and Hcy
作者 实验组 对照组 结果 结论 Nelen，et al[48] 123例RSA患者 104名正常女性 空腹Hcy （≥18.3 μmol/L） 和后负荷Hcy （≥61.5 μmol/L）与RSA相关 升高的Hcy是RSA的危险因素 Raziel，et al[6] 36例非妊娠RSA患者 40名经产妇 31% RSA患者发现HHcy RSA患者更可能出现HHcy Zammiti，et al[46] 350例RSA患者 200名正常女性 两组Hcy水平相似 RSA风险与Hcy水平无关 Creus，et al[47] 60例RSA患者 30名正常女性 两组Hcy水平无显著差异 RSA与HHcy无关 Chakraborty，et al[49] 126例合并PCOS的RSA患者 117名无PCOS的正常女性 实验组Hcy表达显著升高 （70.63% vs. 57.26%; P<0.05） HHcy可能增加RSA风险 Zarfeshan Fard，
et al[50]50例RSA患者 50名至少两次正常妊娠女性 实验组Hcy表达更高 （P=0.002），T等位基因更常见 677CT基因型可能为流产风险标志 Lin，et al[33] 403例RSA患者 342名正常女性 实验组Hcy表达高于对照组 MTHFR 677CT和MTRR 66AG基因突变增加Hcy表达 注：RSA = 复发性流产；Hcy = 同型半胱氨酸；HHcy = 高同型半胱氨酸血症。 
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