van Guldener Coen, Stam Frank, Stehouwer Coen D A
Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands.
Clin Chem Lab Med. 2005;43(10):1026-31. doi: 10.1515/CCLM.2005.180.
Hyperhomocysteinaemia almost invariably occurs in patients with end-stage renal disease (ESRD), but there is debate whether, within the group of ESRD patients, higher or lower plasma homocysteine concentrations are related to an increased risk of vascular disease. Homocysteine is thought to be vasculotoxic in high concentrations, but it may also lead to elevated levels of its precursor, S-adenosylhomocysteine (AdoHcy), which is a potent inhibitor of the transmethylation pathway, in which S-adenosylmethionine (AdoMet) donates its methyl group to a variety of acceptors. Impairment of this transmethylation pathway in ESRD patients has been suggested by high AdoHcy levels, decreased AdoMet/AdoHcy ratios, decreased protein repair requiring methyltransferases, and by DNA hypomethylation. Stable isotope techniques using labelled methionine have indeed demonstrated a decreased whole body transmethylation flux in ESRD patients. These studies have also shown that folic acid treatment is capable of restoring transmethylation rates to normal values. The remaining hyperhomocysteinaemia after folic acid treatment in ESRD is probably due to a persistent impairment of homocysteine clearance through transsulphuration. DNA hypomethylation with its concurrent alterations in gene expression is largely improved by folate treatment. The adverse effects of hyperhomocysteinaemia in ESRD may thus be related to impaired transmethylation. Normalisation of plasma homocysteine does not seem to be required to restore transmethylation to normal levels in ESRD patients.
终末期肾病（ESRD）患者几乎都会出现高同型半胱氨酸血症，但在ESRD患者群体中，血浆同型半胱氨酸浓度较高或较低是否与血管疾病风险增加相关仍存在争议。高浓度的同型半胱氨酸被认为具有血管毒性，但它也可能导致其前体S-腺苷同型半胱氨酸（AdoHcy）水平升高，而AdoHcy是转甲基途径的有效抑制剂，在该途径中，S-腺苷甲硫氨酸（AdoMet）将其甲基基团捐赠给各种受体。ESRD患者中高AdoHcy水平、降低的AdoMet/AdoHcy比值、需要甲基转移酶的蛋白质修复减少以及DNA低甲基化提示了该转甲基途径的受损。使用标记蛋氨酸的稳定同位素技术确实证明了ESRD患者全身转甲基通量降低。这些研究还表明，叶酸治疗能够将转甲基率恢复到正常水平。ESRD患者叶酸治疗后仍存在的高同型半胱氨酸血症可能是由于通过转硫化作用清除同型半胱氨酸的持续受损。叶酸治疗在很大程度上改善了DNA低甲基化及其伴随的基因表达改变。因此，ESRD中高同型半胱氨酸血症的不良影响可能与转甲基受损有关。在ESRD患者中，似乎不需要将血浆同型半胱氨酸恢复正常来使转甲基恢复到正常水平。
