尿素循环障碍及高氨血症的诊断与处理

尿素循环障碍是临床上较为常见的一类遗传代谢病,是由于尿素循环相关6种主要酶的基因突变导致氨基酸分解代谢产生的氨不能通过尿素循环形成尿素排出体外,导致患儿出现血氨增高,引起一系列以脑功能障碍（拒乳、呕吐、嗜睡、昏迷、惊厥、共济失调、攻击性行为）为突出临床表现的一类疾病,是儿童高氨血症最常见的遗传学病因,总发病率约为1/30000.该病临床症状的严重程度与酶缺陷的程度呈正相关,酶的缺陷越重,患儿就发病越早,病情越重,部分轻度酶缺陷患儿可以出现间歇性发病或晚发病.由于高氨血症对神经系统损伤严重,因此早期诊断和治疗是改善预后,挽救患儿生命的关键.     

新生儿高氨血症30例

目的 探讨新生儿高氨血症的病因分布、临床特点、治疗措施及预后,提高对新生儿高氨血症的早期诊断率及预后判断.方法 对广州市妇女儿童医疗中心新生儿科2005年1月-2010年8月收治的30例高氨血症新生儿的临床表现、实验室检查、治疗效果等进行回顾性分析.结果 本组新生儿高氨血症病因为遗传性尿素循环障碍、丙酸血症、甲基丙二酸血/尿症、异戊酸血症、戊二酸血症.一过性高氨血症及获得性高氨血症,其首发症状主要为反应差、呼吸急促,其他有吸吮无力、喂养困难、发绀、呻吟、呕吐等;主要体征有意识障碍、四肢肌张力改变、肝脏大;主要实验室检查改变有血常规异常、高乳酸血症、代谢性酸中毒、头颅B超异常、电解质紊乱、凝血功能障碍及血/尿氨基酸异常.住院期间高氨血症病死率为46.67%,死亡病例血氨水平为(1 284.86±746.09) μmol·L-1,明显高于自动出院患儿血氨水平(335.11±172.57) μmol·L-1(t=4.621,P＜0.001)及治愈患儿的血氨水平(219.65±22.32) μmol·L-1(t=5.334,P＜0.001).结论 临床上出现不明原因的反应差、呼吸急促、喂养困难、呕吐等症状需注意高氨血症,应及早行血氨、血/尿代谢检查明确诊断.一旦诊断为高氨血症,应早期干预,降低病死率及减少后遗症的发生,并定期复查血氨水平来判断患儿的预后.     

尿素循环障碍所致急慢性肝病的识别与治疗

不同基因缺陷导致不同类型的尿素循环障碍（urea cycle disorders,UCDs）,导致不同的生化改变与不同程度的肝脏损伤,其中部分UCDs患者首发表现为肝脏疾病。临床医师对于UCDs均要有充分认知,对于不明原因肝损伤合并神经系统表现者要考虑到UCDs可能性。对于UCDs合并肝损伤的治疗,要根据病因及肝损伤的程度给予相应治疗,肝移植可作为UCDs的对因治疗方法,改善UCDs患儿肝功能。针对UCDs的细胞移植与基因治疗研究,在动物实验阶段展示了良好的疗效与安全性,还需临床试验进一步验证。     

尿素循环障碍所致新生儿高氨血症基因筛查和早期干预

目的 探讨广东地区新生儿尿素循环障碍（UCD）的发病率,以实现UCD相关新生儿高氨血症（NHA）早期识别与干预。方法 收集2019年至2022年广东地区多中心38 159个新生儿基因筛查数据,统计UCD新生儿基因阳性率,分析基因筛查中确诊的9例与UCD相关NHA患儿临床干预和疗效。结果 UCD基因阳性率0.472%,Citrin缺陷病最常见（基因阳性率0.314%）。其中3例Citrin缺陷病均为SLC25A13基因c.852＿855delTATG纯合致病性变异,不同的确诊和临床干预时期,预后不同。另外6例UCD相关NHA患儿起病早,病情进展快,经积极早期对症治疗后,2例瓜氨酸血症I型患儿好转,4例患儿死亡和1例失访。结论 NHA的病因复杂多样,以UCD最为常见,临床表现缺乏特异性,容易漏诊、误诊,早期血、尿代谢筛查联合UCD相关基因筛查可实现UCD相关NHA的早期识别和诊疗,可指导遗传咨询和再次妊娠的产前诊断。     

尿素循环障碍导致的危重症识别及对策

尿素循环障碍是一组罕见的严重疾病,急性期主要表现为高氨血症,引起急性脑病,可发生在任何年龄,尤其是新生儿,认识不足和延迟诊断很普遍.文章将从临床表现、血氨浓度、血气分析、血氨基酸及酰基肉碱分析、头颅磁共振成像和治疗等方面进行概述.早期识别、早期诊断和早期治疗可改善神经系统不良预后.     

新生儿尿素循环障碍5例临床分析

目的 总结新生儿尿素循环障碍（UCDs）的临床特征、诊治过程、转归及预后,以提高对该病的认识。方法回顾性分析2017年7月至2022年7月收治的经基因测序证实为阳性变异的5例新生儿UCDs的临床特点、治疗及预后等资料。结果 5例新生儿中男4例、女1例,胎龄（39.0±1.2）周,出生体重（3 642.0±511.6）g,中位发病日龄2(1～5)d,初始血氨水平（1 386.8±398.4）μmol/L。起病特征分别为纳差3例、低体温2例、气促2例、呕吐1例,均有肌张力减退、意识障碍及惊厥。原发病为鸟氨酸氨甲酰转移酶缺乏症(OTCD)3例,氨甲酰磷酸合成酶1缺乏症（CPS1D）2例。OTCD患儿瓜氨酸降低,尿乳清酸增高,存在3种基因致病变异,其中c. 177 delA和c. 387-1 G>T为新发变异。CPS 1 D患儿瓜氨酸降低,尿乳清酸浓度正常或降低,基因测序存在4个变异位点,其中c. 548 T>C和c. 3 G>C为新发变异。5例UCDs新生儿均在饮食控制及药物治疗的基础上叠加透析疗法以快速清除血氨,其中3例患儿血氨水平降至（164.0±47.1）μmol/L...     

尿素循环障碍所致精神异常的识别与治疗

尿素循环障碍(urea cycle disorders,UCDs)是一类以血氨升高为主要特征的遗传代谢病,临床表现除神经系统症状及肝功能损害外,还可表现为智能损害、精神错乱、孤独症谱系障碍、抑郁、焦虑或躁狂等精神行为异常.降低血氨是改善UCDs精神异常的关键步骤.本章就UCDs导致精神异常的发生机制、临床识别及治疗措施...     

尿素循环障碍的药物治疗

先天性尿素循环障碍是一类严重的遗传代谢病,由于尿素循环中的酶缺陷所致,发病率低,致残率及致死率高。由于病因及个体生活状态不同,患者临床表现各异,半数患者发生高氨血症,造成急性或慢性脑损伤及肝损害,需要个体化饮食、药物治疗及肝移植治疗。尿素循环障碍的主要治疗原则是减少体内氨生成,促进氨排泄,降低血氨,尽可能防治高氨血症。氮清除剂作为尿素循环障碍治疗的核心药物,通过与甘氨酸或谷氨酰胺结合,消耗体内多余的氨。文章对氮清除剂等降氨药物的药理作用、药代动力学特征及临床应用等方面进行阐述,以期为临床合理用药提供参考。     

高鸟氨酸血症-高氨血症-同型瓜氨酸尿症综合征的诊断与治疗

高鸟氨酸血症-高氨血症-同型瓜氨酸尿症(HHH)综合征是尿素循环障碍中一种少见类型,患者临床表现缺乏特异性,个体差异显著,临床识别困难,须通过生化代谢及基因分析才能确诊.文章从发病机制、临床表现、代谢特点、诊断和治疗的进展对HHH综合征进行归纳,以提高对本病的理解,为临床诊断和治疗提供参考.     

重视新生儿高氨血症

新生儿高氨血症病因复杂、进展迅速,如漏诊或血氨控制不及时,会导致患儿生命危险或预后不良。但由于新生儿高氨血症临床表现缺乏特异性,加之临床医师认识不足,常导致误诊或漏诊。现对新生儿高氨血症诊治中的临床问题进行总结和讨论,以引起临床医师的重视,提高诊疗水平,降低致残率及病死率。     

Diagnostic value of orotic acid excretion in heritable disorders of the urea cycle and in hyperammonemia due to organic acidurias

Orotic acid excretion in urine is increased in ornithine transcarbamylase deficiency, citrullinemia and argininemia; it is barely increased in argininosuccinic aciduria and normal in carbamylphosphate synthetase deficiency and in hyperammonemia due to organic aciduria. The determination of orotic acid excretion is useful in differentiating the causes of hyperammonemia and reduces the need for enzymatic assays on tissue biopsies for decisions on therapy. The data indicate that orotic acid does not merely reflect ammonia concentration in plasma, but depends on carbamylphosphate concentration. Arginine could play a key role in the regulation of ammonia detoxication.Supported by grant No. 3.591-0.75 of the Swiss National Science Foundation     

Liver transplantation for urea cycle disorders in pediatric patients: A single‐center experience

LT has emerged as a surgical treatment for UCDs. We hypothesize that LT can be safely and broadly utilized in the pediatric population to effectively prevent hyperammonemic crises and potentially improve neurocognitive outcomes. To determine the long‐term outcomes of LT for UCDs, charts of children with UCD who underwent LT were retrospectively reviewed at an academic institution between July 2001 and May 2012. A total of 23 patients with UCD underwent LT at a mean age of 3.4 yr. Fifteen (65%) patients received a whole‐liver graft, seven patients (30%) received a reduced‐size graft, and one patient received a living donor graft. Mean five‐yr patient survival was 100%, and allograft survival was 96%. Mean peak blood ammonia (NH₃) at presentation was 772 μmol/L (median 500, range 178–2969, normal <30–50). After transplantation, there were no episodes of hyperammonemia. Eleven patients were diagnosed with some degree of developmental delay before transplantation, which remained stable or improved after transplantation. Patients without developmental delay before transplantation maintained their cognitive abilities at long‐term follow‐up. LT was associated with the eradication of hyperammonemia, removal of dietary restrictions, and potentially improved neurocognitive development. Long‐term follow‐up is underway to evaluate whether LT at an early age (<1 yr) will attain improved neurodevelopmental outcomes.     

Liver transplantation may prevent neurodevelopmental deterioration in high‐risk patients with urea cycle disorders

UCDs are among the most common inherited metabolic diseases in Japan. We investigated the clinical manifestations, treatment, and prognoses of 177 patients with UCDs who were evaluated and treated from January 1999 to March 2009 in Japan, using a questionnaire survey. Among these 177 patients, 42 (seven with carbamoyl phosphate synthetase 1 deficiency, 27 with ornithine transcarbamylase deficiency, seven with argininosuccinate synthetase deficiency, and one with arginase 1 deficiency) underwent living‐donor LT. Although this study was retrospective and included limited neurodevelopmental information before and after LT, we evaluated whether LT could improve neurodevelopmental outcomes in patients with UCDs. The neurodevelopmental outcomes of patients with a MAC of <300 μmol/L at the time of onset were not significantly different between the LT and non‐LT groups (P=.222). LT may have prevented further neurodevelopmental complications in children with MAC ≥300 μmol/L (P=.008) compared with non‐transplant management. Therefore, Liver transplant should be considered in patients with UCD with a MAC of ≥300 μmol/L at the time of disease onset.     

Neurologic outcome of urea cycle disorder liver transplant recipients may be predicted by pretransplant neurological imaging

Liver transplantation treats the hepatic affectation of UCDs; however, irreversible neurologic damage pretransplant is difficult to assess providing transplant teams with ethical dilemmas for liver transplantation. The purpose of our study was to determine whether pretransplant neuroimaging can predict developmental outcomes post‐liver‐transplant in children with UCDs. Methods: Patients undergoing liver transplantation for UCDs at Cincinnati Children's Hospital Medical Center between 2002 and 2012 were identified. Neurologic assessments prior to and after transplantation were categorized into mild, moderate, or severe disability. Neuroimaging data were categorized into mild, moderate, or severe by a single pediatric neuroradiologist. Results: Fifteen patients were identified of whom eight had neuroimaging prior to transplantation. Of the eight patients that had neuroimaging, four were categorized as severe, one moderate, and three no‐to‐mild delay. All four patients whose imaging was severe were found to have moderate‐to‐severe neurologic delay. Of the three patients with no‐to‐mild changes on neuroimaging two of three were found to have no‐to‐mild delay on developmental assessments after transplantation. Conclusion: Neuroimaging may be a helpful tool in determining developmental prognosis and outcomes post‐liver‐transplantation for UCDs. Further studies maybe needed to validate our preliminary findings.     

儿童肾移植19例

目的探讨儿童肾移植尤其是低年龄儿童肾移植的手术策略、围手术期处理及肾移植对儿童生长发育的影响。方法回顾性分析及比较我院19例16岁以下儿童肾移植的临床资料。结果术后出现肾功能延迟恢复3例,3个月内急性排斥2例,1年人/肾存活率均为100%。CsA剂量4.2~11.4mg/kg,平均(7.05±2.03)mg/kg,FK506剂量0.14~0.29mg/kg,平均(0.22±0.06)mg/kg。患儿术前生长发育在正常范围的2例,轻度迟缓7例、中度8例、重度2例。术后1年进入正常生长发育范围的6例,仍为生长发育迟缓的13例(轻度8例,中度迟缓的5例)。结论肾移植是治疗儿童终末期肾病的较理想手段,患儿生长发育迟缓均有改善。严格的配型选择、适宜的手术方式和围手术期处理、恰当的免疫抑制策略和良好的依从性是取得良好效果的关键。     

Attempted dietary treatment of a boy with hyperammonemia due to ornithine transferase deficiency

Dietary treatment of a male patient suffering from the delayed-onset type of OCT deficiency was attempted. Control of the hyperammonemia was attempted by restriction of protein intake, guided by monitoring the plasma ammonia and regular checking of the serum amino acid levels. The influence of supplementary citric acid or lactulose therapy on the plasma ammonia level was investigated and found to be negligible. The therapeutic effect of supplying ornithine and arginine (an essential amino acid in urea cycle disorders) is described. Despite intensive dietary treatment over two and a half years, a incorrigible hyperammonemic crisis resulted in the sudden death of our patients.     

Diagnosis and treatment of urea cycle disorder in Japan

Urea cycle disorder (UCD) is an inborn error of the metabolic pathway producing urea from ammonia, which occurs primarily in the liver. Decreased excretion of nitrogen in the urea cycle due to deficiency of carbamoyl phosphate synthase I (CPSI), ornithine transcarbamylase (OTC), argininosuccinate synthase (ASS), argininosuccinate lyase (ASL), and N‐acetyl glutamate synthase (NAGS) causes hyperammonemia. We examined the clinical manifestations, treatment, and prognosis of 177 patients with UCD from January 1999 to March 2009 in Japan. Compared with a previous study conducted in Japan, a larger number of patients survived without mental retardation, even when the peak blood ammonia was >360 μmol/L. In those with peak blood ammonia >360 μmol/L, an indicator of poor prognosis, the frequency of convulsions, mental retardation, brain abnormality on magnetic resonance imaging, hemodialysis, liver transplantation, and intake of non‐protein formulas was significantly higher than in those with peak blood ammonia <360 μmol/L. In this article, we have reported the current state of UCD to evaluate prognosis and its relationship with peak blood ammonia and hemodialysis.     

干细胞肝内移植治疗高氨血症Ⅱ型6例临床疗效观察

为探讨使用CD133+细胞、脐带间充质干细胞肝动脉内移植对高氨血症Ⅱ型患儿的临床治疗效果和可能存在的作用机制,通过采集健康胎儿脐血, 分离得干细胞悬液,或应用重组人粒细胞集落刺激因子动员患儿父亲外周血5?d后采集单个核细胞,从中分离得到CD133+细胞后,再利用导管介入经皮穿刺肝动脉将上述细胞缓慢输入患儿肝脏,观察患儿临床表现及实验室检查指标如血氨、肝功能、精氨酸、瓜氨酸的改善情况。结果显示,6例患儿移植后血氨水平均呈现明显下降,1~2周之后缓慢回升,但始终低于移植前波动的高水平;谷丙转氨酶同血氨水平变化趋势相类似;血瓜氨酸和精氨酸水平移植后明显增加,且瓜氨酸的增幅超过精氨酸。其中1例典型病例经8个月随访,发现患儿体重身高均较术前增长,睡眠改善,夜啼消失;由对逗引淡漠变为主动追视感兴趣物品,产生简单词汇,精细运动由手眼不协调到拇指中指捏取东西等,大运动方式也有很大进步;GESELL法测评该患儿术后各能区进步平均3.82个月。由此可见,高氨血症患儿移植后血氨下降、肝功能稳定改善,血瓜氨酸、精氨酸稳定增高,在运动、语言、环境适应性等方面都呈现进步趋势。推测干细胞肝动脉移植至少部分激活或补充了鸟氨酸氨甲酰转移酶,从而使血瓜氨酸、精氨酸水平增高,尿素循环障碍在一定程度上得到纠正。