摘要
目的探讨二氮嗪治疗先天性高胰岛素血症(CHI)患儿的疗效及其安全性。方法计算机检索国内外已发表的二氮嗪治疗CHI患儿疗效及其安全性的相关文献,检索数据库包括:PubMed、Cochrane Library、EMbase等英文数据库,以及中国生物医学文献数据库、万方数据库、维普数据库、中国知网等中文数据库;检索时间设定为各数据库建库至2019年9月;纳入研究的文献语种限制为中文及英文。采用Microsoft Office Excel软件,分析文献基本特征、CHI患儿临床症状及基因突变情况、二氮嗪治疗疗效及不良反应发生情况。结果①文献检索结果:按照检索策略,共计检索符合本研究纳入与排除标准的文献为24篇,纳入CHI患儿为791例。②文献基本特征:发表时间分别为1998—2007年、2008—2014年、2015—2019年的文献各为6篇(25.0%)、5篇(20.8%)与13篇(54.2%);而文献来源分布于亚洲、美国、澳大利亚、欧洲地区各为9篇(37.5%)、4篇(16.7%)、2篇(8.3%)及9篇(37.5%)。③CHI患儿临床症状及基因检测结果:这24篇文献中,18篇(75.0%)报道309例CHI患儿的临床症状,其中147例(47.6%)表现为自主神经兴奋性增高的惊厥发作症状,其余患儿临床表现不典型,包括面色苍白、拒乳、易激惹等。13篇(54.2%)报道627例CHI患儿的基因突变情况,发生ABCC8和(或)KCNJ11等ATP敏感的K+通道(KATP)相关基因突变者为123例(19.6%),GLUD1基因突变者为44例(7.0%),GCK基因突变者为10例(1.6%),HNF4A基因突变者为3例(0.5%),其他基因突变者为10例(1.6%),而未发生基因突变患儿为437例(69.7%)。④二氮嗪治疗结果及CHI患儿预后:24篇文献纳入的791例CHI患儿中,207例(26.2%)治疗有效,548例(69.3%)无效,36例(4.5%)未知(6例放弃治疗,12例未采用二氮嗪治疗,18例因药物不良反应停用二氮嗪治疗)。11篇报道196例患儿经二氮嗪治疗后血糖控制情况,58例(29.6%)血糖恢复正常,其余138例(70.4%)血糖未被控制。10篇报道110例患儿精神运动发育迟缓发生情况,42例(38.2%)发生精神运动发育迟缓,2例(1.8%)患儿死亡(未说明精神运动发育情况),其余66例(60.0%)未发生精神运动发育迟缓症状。⑤二氮嗪治疗导致的不良反应:24篇文献纳入的791例CHI患儿中,162例(20.5%)CHI患儿发生多毛症、118例(14.9%)发生心血管系统相关不良反应、53例(6.7%)发生胃肠道反应,而中性粒细胞减少症、血小板减少症、高钾血症各为48例(6.1%)、16例(2.0%)、3例(0.4%),其他不良反应,如高尿酸血症、酮症性酸中毒伴高渗性昏迷等为22例(2.8%)。结论部分CHI患儿由于基因突变,而对二氮嗪治疗不敏感。二氮嗪治疗CHI患儿疗效各异,导致的不良反应较多,涉及全身多个系统。目前,有关二氮嗪治疗CHI患儿的疗效及其安全性文献,数据尚不完整、报道偏倚较高,尚需要更多高质量、多中心临床研究进一步证实该药的疗效及其安全性。
Objective To explore efficacy and safety of diazoxide in treatment of children with congenital hyperinsulinemia(CHI).Methods Literatures on efficacy and safety of diazoxide in treatment of children with CHI published at home and abroad were searched by computer.PubMed,Cochrane Library,EMbase,China Biology Medicine disc,Wanfang,VIP and China National Knowledge Infrastructure databases were searched manually and automatically by computer from the date of database inception to September 2019,with the language restricted to Chinese and English.Microsoft Office Excel was used to analyze the basic features of literature,clinical symptoms and gene mutations in children with CHI,therapeutic effects of diazoxide and occurrence of adverse reactions.Results①Literatures search results:according to search strategy,24 pieces of literatures in line with the inclusion and exclusion criteria of this study,including 791 cases of children with CHI were enrolled.②Basic characteristics of literatures:the distributions of literature published in 1998-2007,2008-2014,and 2015-2019 were 6 pieces(25.0%),5 pieces(20.8%)and 13 pieces(54.2%),respectively.The children with CHI enrolled in 9 pieces(37.5%)of literatures were distributed in Asia,and children with CHI in 4 pieces(16.7%),2 pieces(8.3%)and 9 pieces(37.5%)of literatures were distributed in United States,Australia and Europe,respectively.③Clinical symptoms and genetic test results in children with CHI:among the 24 pieces of literatures,18 pieces(75.0%)reported the onset symptoms of 309 cases of children with CHI included in the study,and 147 cases(47.6%)of them showed symptoms of convulsive seizures with increased autonomic nerves excitability,while the rest of the children had atypical clinical manifestations,including pale paleness,breast rejection,easy to provoke,etc..And 13 pieces(54.2%)of literatures reported gene mutations in 627 cases of children with CHI,and 123 cases(19.6%)had ATP-sensitive potassium channel(KATP)related genes mutations,such as ABCC8 and/or KCNJ11 gene,44 cases(7.0%)had GLUD1 gene mutations,10 cases(1.6%)had GCK gene mutations,3 cases(0.5%)had HNF4A gene mutations,and 10 cases(1.6%)had other gene mutations,while the other 437 cases(69.7%)were without genetic mutations.④Treatment results of diazoxide and prognoses of CHI children:among the 791 cases of CHI children enrolled in 24 pieces of literatures,207 cases(26.2%)were effective with treatment of diazoxide,548 cases(69.3%)were ineffective,and the efficacy of diazoxide in other 36 cases was uncertain(6 cases gave up treatment,12 cases did not use diazoxide,and 18 cases stopped treatment with diazoxide due to its adverse reactions).11 pieces of literatures reported the blood glucose control results of 196 cases of CHI children after treatment with diazoxide,and blood glucose returned to normal in 58 cases(7.3%)of children,blood glucose of the remaining 138 cases(70.4%)were still abnormal after treatment with diazoxide.10 pieces of literatures reported the prognostic outcomes of 110 cases of CHI children,of which 42 cases(38.2%)developed mental retardation,2 cases died,and the remaining 66 cases(60.0%)did not develop symptoms of mental retardation.⑤Adverse reactions of diazoxide:162 cases(20.5%)of hypertrichosis,118 cases(14.9%)of cardiovascular-related adverse reactions,53 cases(6.7%)of gastrointestinal adverse reactions,48 cases(6.1%)of neutropenia,16 cases(2.0%)of thrombocytopenia,3 cases(0.4%)of hyperkalemia,and 22 cases(2.8%)of other adverse reactions,such as hyperuricemia,ketone acidosis complicated with hyperosmolar coma,etc..Conclusions Some CHI children are not sensitive to treatment of diazoxide because of genetic mutations.Diazoxide has different therapeutic effects on children with CHI,resulting in many adverse reactions,involving multiple systems.At present,the literatures on efficacy and safety of diazoxide in treatment of CHI children are incomplete and biased,and more multi-center and high-quality clinical studies are needed to further confirm its efficacy and safety.
作者
娄丽丽
伏洪玲
刘瀚旻
Lou Lili;Fu Hongling;Liu Hanmin(Department of Pediatrics,Key Laboratory of Birth Defects and Related Diseases of Women and Children(Sichuan University),Ministry of Education,Vascular Remodeling and Developmental Defects Research Unit of West China Institute of Women and Children′s Health,West China Second University Hospital,Sichuan University,Chengdu 610041,Sichuan Province,China)
出处
《中华妇幼临床医学杂志（电子版）》
CAS
2020年第3期288-298,共11页
Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition)
基金
四川省科技厅重点研发项目(19ZDYF1169)。
