上呼吸道感染患儿口服尼美舒利后发生瑞氏综合征及猝死样症状
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摘要
患儿,男,6岁3个月, 2个月前因上呼吸道感染、发热,父母参照说明书予以尼美舒利口服,半小时后抽搐,呼吸心跳骤停,急诊检查发现低酮性低血糖,代谢性酸中毒,血清转氨酶及肌酶显著升高,肾功能受损。经积极复苏治疗后患儿意识及生命体征恢复,但是智力、运动严重倒退。患儿血液游离肉碱降低,中长链酯酰肉碱增高,尿液戊二酸、3-羟基戊二酸、异戊酰甘氨酸、乙基丙二酸等增高,提示多种酯酰辅酶A脱氢酶缺乏症。经维生素B2、左卡尼汀、苯扎贝特等治疗后患儿病情逐渐好转,3个月后复查生化指标恢复正常。患儿ETFDH基因存在复合杂合突变,c.341G>A(p.R114H)为已知突变(来自母亲),c.1484C>G(p.P495R)为未报道的新突变(来自父亲)。患儿最终确诊为多种酰基辅酶A脱氢酶缺乏症,因发热服用尼美舒利诱发急性代谢危象,导致瑞氏综合征、猝死样发作。遗传代谢病是导致瑞氏综合征、猝死的一组主要病因,生化及基因分析是识别潜在疾病的关键。
A boy aged 6 years and 3 months developed upper respiratory tract infection and pyrexia 2 months ago and was given oral administration of nimesulide by his parents according to directions. Half an hour later, the boy experienced convulsions and cardiopulmonary arrest, and emergency examination found hypoketotic hypoglycemia, metabolic acidosis, significant increases in serum aminotransferases and creatine kinase, and renal damage. Recovery of consciousness and vital signs was achieved after cardiopulmonary resuscitation, but severe mental and movement regression was observed. The boy had a significant reduction in free carnitine in blood and significant increases in medium-and long-chain fatty acyl carnitine, urinary glutaric acid, 3-hydroxy glutaric acid, isovalerylglycine, and ethylmalonic acid, suggesting the possibility of multiple acyl-CoA dehydrogenase deficiency. After the treatment with vitamin B2, L-carnitine, and bezafibrate, the boy gradually improved, and reexamination after 3 months showed normal biochemical parameters. The boy had compound heterozygous mutations in the ETFDH gene, i.e., a known mutation, c.341 G>A(p.R114 H), from his mother and a novel mutation, c.1484 C>G(p.P495 R), from his father. Finally, he was diagnosed with multiple acyl-CoA dehydrogenase deficiency. Reye syndrome and sudden death symptoms were caused by nimesulide-induced acute metabolic crisis. It is concluded that inherited metabolic diseases may be main causes of Reye syndrome and sudden death, and biochemical and genetic analyses are the key to identifying underlying diseases.
A boy aged 6 years and 3 months developed upper respiratory tract infection and pyrexia 2 months ago and was given oral administration of nimesulide by his parents according to directions. Half an hour later, the boy experienced convulsions and cardiopulmonary arrest, and emergency examination found hypoketotic hypoglycemia, metabolic acidosis, significant increases in serum aminotransferases and creatine kinase, and renal damage. Recovery of consciousness and vital signs was achieved after cardiopulmonary resuscitation, but severe mental and movement regression was observed. The boy had a significant reduction in free carnitine in blood and significant increases in medium-and long-chain fatty acyl carnitine, urinary glutaric acid, 3-hydroxy glutaric acid, isovalerylglycine, and ethylmalonic acid, suggesting the possibility of multiple acyl-CoA dehydrogenase deficiency. After the treatment with vitamin B2, L-carnitine, and bezafibrate, the boy gradually improved, and reexamination after 3 months showed normal biochemical parameters. The boy had compound heterozygous mutations in the ETFDH gene, i.e., a known mutation, c.341 G>A(p.R114 H), from his mother and a novel mutation, c.1484 C>G(p.P495 R), from his father. Finally, he was diagnosed with multiple acyl-CoA dehydrogenase deficiency. Reye syndrome and sudden death symptoms were caused by nimesulide-induced acute metabolic crisis. It is concluded that inherited metabolic diseases may be main causes of Reye syndrome and sudden death, and biochemical and genetic analyses are the key to identifying underlying diseases.
引文
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[22]Ong MM, Wang AS, Leow KY, et al. Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2(+/-)mice[J].Free Radic Biol Med, 2006, 40(3):420-429.
[23]陈俊操,陈平洋.新生儿多种酰基辅酶A脱氢酶缺乏症1例[J].中国当代儿科杂志, 2013, 15(12):1098-1099.
[24]程衍杨,唐越,刘奥杰,等.两例晚发型戊二酸尿症Ⅱ型患者的临床及其ETFDH基因研究[J].中国当代儿科杂志,2017, 19(9):975-978.
[25]方润桃,刘洁玉,杨艳玲,等.小儿脂质沉积性肌病的临床、病理及分子遗传学分析[J].中华实用儿科临床杂志, 2014,29(14):1095-1099.
[26]代东伶,文飞球,周少明,等.合并重度脂肪肝的迟发型多种酰基辅酶A脱氢酶缺乏症的临床表现及基因分析[J].中华医学遗传学杂志, 2016, 33(2):191-194.
[27]章瑞南,邱文娟,叶军,等.多种酰基辅酶A脱氢酶缺乏症儿童与成人患者临床特点比较[J].临床儿科杂志, 2012,30(5):446-449.
[28]刘兆娥,韩波,孙正芸,等.伴代谢危象的有机酸血症患儿53例临床分析[J].中国小儿急救医学, 2015, 22(12):857-860.
[29]Ersoy EO, Rama D,ünal?, et al. Glutaric aciduria type 2presenting with acute respiratory failure in an adult[J]. Respir Med Case Rep, 2015, 15:92-94.
[30]罗小平,王慕逖,魏虹,等.尿滤纸片法气相色谱-质谱分析技术在遗传性代谢病高危筛查诊断中的应用[J].中华儿科杂志, 2003, 41(4):245-248.
[31]宋金青,杨艳玲,孙芳,等.气相色谱-质谱联用分析在有机酸尿症筛查与诊断中的应用[J].中国医刊, 2006, 41(2):38-40.
[32]王志强,王柠,吴志英.中国南方晚发型多种酰基辅酶A脱氢酶缺陷的电子转移黄素蛋白脱氢酶基因存在高频热点突变c.250G>A[J].中华神经科杂志, 2011, 44(5):368.
[33]Csiky B, Bene J, Wittmann I, et al. Effect of hemodialysis session on the dynamics of carnitine ester profile changes in L-carnitine pretreated end-stage renal disease patients[J]. Int Urol Nephrol, 2013, 45(3):847-855.
[34]Yahyaoui R, Rueda I, Dayaldasani A, et al. C5-carnitine false positive results in newborn screening:what is the cause?[J].Med Clin(Barc), 2015, 144(4):181-182.
[35]YamadaK,KobayashiH,BoR,etal.Elevationof pivaloylcarnitine by sivelestat sodium in two children[J]. Mol Genet Metab, 2015, 116(3):192-194.
[36]Yamaguchi S, Li H, Purevsuren J, et al. Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders:evaluation by in vitro probe acylcarnitine assay[J].Mol Genet Metab, 2012, 107(1-2):87-91.
[37]Zhu M, Zhu X, Qi X, et al. Riboflavin-responsive multiple AcylCoA dehydrogenation deficiency in 13 cases, and a literature review in mainland Chinese patients[J]. J Hum Genet, 2014,59(5):256-261.
[38]HenriquesBJ,RodriguesJV,OlsenRK,etal.Roleof flavinylationinamildvariantofmultipleacyl-CoA dehydrogenation deficiency:a molecular rationale for the effects of riboflavin supplementation[J]. J Biol Chem, 2009, 284(7):4222-4229.
[2]Newton L, Hall SM. Reye's syndrome in the British Isles:report for 1990/91 and the first decade of surveillance[J]. Commun Dis Rep CDR Rev, 1993, 3(1):R11-R16.
[3]Hardie RM, Newton LH, Bruce JC, et al. The changing clinical pattern of Reye's syndrome 1982-1990[J]. Arch Dis Child, 1996,74(5):400-405.
[4]Donati M, Conforti A, Lenti MC, et al. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs:data from drug-induced liver injury case-control study in Italy[J]. Br J Clin Pharmacol, 2016, 82(1):238-248.
[5]Yotsumoto Y, Hasegawa Y, Fukuda S, et al. Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2[J]. Mol Genet Metab, 2008, 94(1):61-67.
[6]Grunert SC. Clinical and genetical heterogeneity of lateonset multiple acyl-coenzyme A dehydrogenase deficiency[J].Orphanet J Rare Dis, 2014, 9:117.
[7]Belay ED, Bresee JS, Holman RC, et al. Reye's syndrome in the United States from 1981 through 1997[J]. N Engl J Med, 1999,340(18):1377-1382.
[8]Yoshida I, Yamashita F. The changing age distribution of Reye's syndrome in the United States and a critique of the CDC criteria[J]. Acta Paediatr Jpn,1990, 32(4):378-380.
[9]Orlowski JP. Whatever happened to Reye's syndrome? Did it ever really exist?[J]. Crit Care Med, 1999, 27(8):1582-1587.
[10]Green A, Hall SM. Investigation of metabolic disorders resembling Reye's syndrome[J]. Arch Dis Child, 1992, 67(10):1313-1317.
[11]HernándezN,BessoneF,SánchezA,etal.Profileof idiosyncratic drug induced liver injury in Latin America:an analysis of published reports[J]. Ann Hepatol, 2014, 13(2):231-239.
[12]Kshirsagar NA, Bachhav SS. Nimesulide controversy:a comparison of EU and Indian scenario[J]. Int J Risk Saf Med,2013, 25(4):239-246.
[13]韩松瑛,刘树森,玄延花,等.尼美舒利引起严重肝损伤致死尸检1例[J].临床与实验病理学杂志, 2008, 24(4):508-509.
[14]程丹颖,王笑梅,欧蔚妮,等.尼美舒利致急性肝肾衰竭1例并文献复习[J].北京医学, 2015, 37(6):555-557.
[15]江周虹,李春梅.尼美舒利致儿童不良反应文献分析[J].儿科药学杂志, 2011, 17(3):47-48.
[16]Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity[J]. Curr Med Chem, 2009, 16(23):3041-3053.
[17]Przyrembel H, Wendel U, Becker K, et al. Glutaric aciduria type II:report on a previously undescribed metabolic disorder[J].Clin Chim Acta,1976, 66(2):227-239.
[18]Goodman SI, Frerman FE. Glutaric acidaemia type II(multiple acyl-CoA dehydrogenation deficiency)[J]. J Inherit Metab Dis,1984, 7 Suppl 1:33-37.
[19]Singh BK, Tripathi M, Pandey PK, et al. Nimesulide aggravates redoximbalanceandcalciumdependentmitochondrial permeability transition leading to dysfunction in vitro[J].Toxicology, 2010, 275(1-3):1-9.
[20]Licata A, Calvaruso V, Cappello M, et al. Clinical course and outcomes of drug-induced liver injury:nimesulide as the first implicated medication[J]. Dig Liver Dis, 2010, 42(2):143-148.
[21]Mingatto FE, dos Santos AC, Rodrigues T, et al. Effects of nimesulide and its reduced metabolite on mitochondria[J]. Br J Pharmacol, 2000, 131(6):1154-1160.
[22]Ong MM, Wang AS, Leow KY, et al. Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2(+/-)mice[J].Free Radic Biol Med, 2006, 40(3):420-429.
[23]陈俊操,陈平洋.新生儿多种酰基辅酶A脱氢酶缺乏症1例[J].中国当代儿科杂志, 2013, 15(12):1098-1099.
[24]程衍杨,唐越,刘奥杰,等.两例晚发型戊二酸尿症Ⅱ型患者的临床及其ETFDH基因研究[J].中国当代儿科杂志,2017, 19(9):975-978.
[25]方润桃,刘洁玉,杨艳玲,等.小儿脂质沉积性肌病的临床、病理及分子遗传学分析[J].中华实用儿科临床杂志, 2014,29(14):1095-1099.
[26]代东伶,文飞球,周少明,等.合并重度脂肪肝的迟发型多种酰基辅酶A脱氢酶缺乏症的临床表现及基因分析[J].中华医学遗传学杂志, 2016, 33(2):191-194.
[27]章瑞南,邱文娟,叶军,等.多种酰基辅酶A脱氢酶缺乏症儿童与成人患者临床特点比较[J].临床儿科杂志, 2012,30(5):446-449.
[28]刘兆娥,韩波,孙正芸,等.伴代谢危象的有机酸血症患儿53例临床分析[J].中国小儿急救医学, 2015, 22(12):857-860.
[29]Ersoy EO, Rama D,ünal?, et al. Glutaric aciduria type 2presenting with acute respiratory failure in an adult[J]. Respir Med Case Rep, 2015, 15:92-94.
[30]罗小平,王慕逖,魏虹,等.尿滤纸片法气相色谱-质谱分析技术在遗传性代谢病高危筛查诊断中的应用[J].中华儿科杂志, 2003, 41(4):245-248.
[31]宋金青,杨艳玲,孙芳,等.气相色谱-质谱联用分析在有机酸尿症筛查与诊断中的应用[J].中国医刊, 2006, 41(2):38-40.
[32]王志强,王柠,吴志英.中国南方晚发型多种酰基辅酶A脱氢酶缺陷的电子转移黄素蛋白脱氢酶基因存在高频热点突变c.250G>A[J].中华神经科杂志, 2011, 44(5):368.
[33]Csiky B, Bene J, Wittmann I, et al. Effect of hemodialysis session on the dynamics of carnitine ester profile changes in L-carnitine pretreated end-stage renal disease patients[J]. Int Urol Nephrol, 2013, 45(3):847-855.
[34]Yahyaoui R, Rueda I, Dayaldasani A, et al. C5-carnitine false positive results in newborn screening:what is the cause?[J].Med Clin(Barc), 2015, 144(4):181-182.
[35]YamadaK,KobayashiH,BoR,etal.Elevationof pivaloylcarnitine by sivelestat sodium in two children[J]. Mol Genet Metab, 2015, 116(3):192-194.
[36]Yamaguchi S, Li H, Purevsuren J, et al. Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders:evaluation by in vitro probe acylcarnitine assay[J].Mol Genet Metab, 2012, 107(1-2):87-91.
[37]Zhu M, Zhu X, Qi X, et al. Riboflavin-responsive multiple AcylCoA dehydrogenation deficiency in 13 cases, and a literature review in mainland Chinese patients[J]. J Hum Genet, 2014,59(5):256-261.
[38]HenriquesBJ,RodriguesJV,OlsenRK,etal.Roleof flavinylationinamildvariantofmultipleacyl-CoA dehydrogenation deficiency:a molecular rationale for the effects of riboflavin supplementation[J]. J Biol Chem, 2009, 284(7):4222-4229.