CAJ | 학술논문

目的评价硫嘌呤甲基转移酶(TPMT)基因型和酶活性检测对炎症性肠病(IBD)患者服用硫唑嘌呤(AZA)发生不良反应的预测价值.方法收集2004年4月-2009年12月有使用AZA指征的IBD确诊患者112例,其中溃疡性结肠炎(UC)26例,克罗恩病(CD)86例.患者每天均服用AZA 2 mg/kg.采用PCR技术检测患者TPMT基因型(*2、*3A、*3B*、3C),高效液相色谱法检测TPMT酶活性.分析达到随访终点(服药达半年或以上,或因不良反应停药)患者的TPMT基因多态性及酶活性与不良反应发生之间的关系及其影响因素.结果 112例患者中不良反应率为33.9%(38/112),以骨髓抑制最常见(20.5%).TPMT*3C杂合子突变率为0.9%(1/112).TPMT酶活性呈单峰正态分布,平均活性为(12.9士4.2)U/ml红细胞.1例TPMT*3C杂合子突变者于用药4周内发生骨髓抑制,TPMT基因型预测骨髓抑制发生的敏感度为4.4 0A(1/23),特异度为1/1.ROC曲线计算TPMT酶活性预测服药3个月内发生骨髓抑制的安全阈为≤4.5 U/ml红细胞,该安全阈预测3个月内骨髓抑制发生的敏感度为3/13,特异度为3/3.合用5-氨基水杨酸(5-ASA)制剂者骨髓抑制的发生率显著高于非合用者(44.4%比12.9%,P=0.000),但发生骨髓抑制者合用5-ASA前后TPMT酶活性差异无统计学意义(P>0.05).结论 TPMT基因突变和酶活性低下对预测发生骨髓抑制的特异性较高,但敏感性较差,合用5-ASA可增加AZA发生骨髓抑制的风险,但与TPMT酶活性无关.
목적 평개류표령갑기전이매(TPMT)기인형화매활성검측대염증성장병(IBD)환자복용류서표령(AZA)발생불량반응적예측개치.방법 수집2004년4월-2009년12월유사용AZA지정적IBD학진환자112례,기중궤양성결장염(UC)26례,극라은병(CD)86례.환자매천균복용AZA 2 mg/kg.채용PCR기술검측환자TPMT기인형(*2、*3A、*3B*、3C),고효액상색보법검측TPMT매활성.분석체도수방종점(복약체반년혹이상,혹인불량반응정약)환자적TPMT기인다태성급매활성여불량반응발생지간적관계급기영향인소.결과 112례환자중불량반응솔위33.9%(38/112),이골수억제최상견(20.5%).TPMT*3C잡합자돌변솔위0.9%(1/112).TPMT매활성정단봉정태분포,평균활성위(12.9사4.2)U/ml홍세포.1례TPMT*3C잡합자돌변자우용약4주내발생골수억제,TPMT기인형예측골수억제발생적민감도위4.4 0A(1/23),특이도위1/1.ROC곡선계산TPMT매활성예측복약3개월내발생골수억제적안전역위≤4.5 U/ml홍세포,해안전역예측3개월내골수억제발생적민감도위3/13,특이도위3/3.합용5-안기수양산(5-ASA)제제자골수억제적발생솔현저고우비합용자(44.4%비12.9%,P=0.000),단발생골수억제자합용5-ASA전후TPMT매활성차이무통계학의의(P>0.05).결론 TPMT기인돌변화매활성저하대예측발생골수억제적특이성교고,단민감성교차,합용5-ASA가증가AZA발생골수억제적풍험,단여TPMT매활성무관.
Objective To assess the predictive value of thiopurine methyltransferase genotyping and enzyme activity in relation to side effects in patients with inflammatory bowel disease (IBD) who were treated with azathioprine (AZA). Methods One hundred and eleven IBD patients (26 with ulcerative colitis and 86 with Cronh's disease) with indication of AZA administration between April 2004 and Dec. 2009 were enrolled. All patients received 2 mg/kg of AZA daily. Polymerase chain reaction and high performance liquid chromatography were used to genotype the TPMT * 2, * 3A, * 3B, * 3C and to detect TPMT activity, respectively. The association of TPMT genotype and activity with side effects was analyzed in patients treated with AZA for 24 weeks or more, or in those discontinued AZA because of adverse effects. Results Adverse effects were reported in 38(33. 9%) patients, the most frequent being myelosuppression (20. 5%). The frequency of TPMT * 3C heterozygous mutation was 0. 9% (1/112). The TPMT activity was (12. 9±4. 8) U/ml RBC with unimodal distribution. One patient with TPMT * 3C heterozygous mutation developed myelosuppression at the 4th week after AZA treatment. The TPMP genotype myelosuppression patients. Conclusions TPMT genotype mutation and low enzyme activity can be used to predict myelosuppression with high specifically and low sensitivity. In patients treated with AZA, co-administration of 5-ASA results in a high frequency of myelosuppression with no effect on TPMT activity.