2026, Vol. 35
引用本文 |
苑咸斌, 胡园园, 杨一帆, 刘玉亮, 薛琬麟, 岳金凤, 杜滨锋, 郭海鹏. 成人鸟氨酸氨甲酰转移酶缺乏症1例及文献复习[J]. 中华急诊医学杂志, 2026, 35(6): 836-840.
成人鸟氨酸氨甲酰转移酶缺乏症1例及文献复习
1. 山东大学齐鲁医院重症医学科, 济南 250012;
2. 山东大学齐鲁医院呼吸与危重症医学科, 济南 250012
2. 山东大学齐鲁医院呼吸与危重症医学科, 济南 250012
鸟氨酸氨甲酰转移酶缺乏症（ornithine transcarbamylase deficiency, OTCD）是最常见的尿素循环障碍疾病，为X连锁遗传病，由鸟氨酸氨甲酰转移酶（ornithine transcarbamylase, OTC）基因突变导致酶活性下降或缺乏[1]。少数成年起病的患者因症状缺乏特异度以及该病的罕见性容易漏诊。本文报道一例成年起病OTCD患者，并检索汇总相关病例报道以提高对其发病特征的认识。
1 病例介绍患者男性，19岁。因“呕吐7 d，视物模糊3 d，抽搐并意识丧失2 d”收入本院重症医学科。入院7 d前患者进食大量高蛋白食物后出现恶心呕吐，输液治疗无缓解。3 d前出现视物模糊。2 d前出现嗜睡、言语模糊、定向力差等症状，后出现抽搐、意识丧失，完善颅脑CT未见明显异常，腰穿测脑脊液压力14.7 mmHg（正常值5~15 mmHg）1 mmH2O=9.807 Pa，常规及生化未见异常，不排除颅内感染，给予抗病毒、降颅压等治疗。1 d前突发呼吸困难，双侧瞳孔散大，颅脑CT提示脑沟回肿胀，予以机械通气、双侧侧脑室钻孔引流术+颅内压电极植入术，但患者术后仍持续高颅内压（ICP 100 mmHg左右, 1 mmHg=0.133 kPa），自主呼吸消失，遂转入本院。
体格检查：T：36.7℃ HR：79次/min RR：15次/min BP：133/92 mmHg。昏迷状态，GCS=E1VTM1，双侧瞳孔不等大，左侧直径5 mm，右侧6 mm，对光反射均消失。双肺听诊呼吸音低，未闻及干湿性啰音。四肢肌张力低，巴宾斯基征未引出。
实验室检查：白细胞21.15×109/L，中性粒细胞比率92%，前降钙素0.914 ng/mL，高敏肌钙蛋白Ⅰ 497.28 ng/L，丙氨酸氨基转移酶60 U/L，总胆红素4.5 μmol/L，肌酐112 μmol/L，钠153 mmol/L。
初步诊断：昏迷待查、脑水肿、中枢性呼吸循环衰竭、尿崩症、癫痫。
入院时患者呈昏迷状态，伴重度颅内高压（ICP 80~120 mmHg）、脑水肿、尿崩症，予以机械通气、脱水降颅压、低温脑保护、抑制尿崩、抗癫痫等治疗。入院第2天，患者血钾呈进行性升高趋势（4.8→6.1→6.3 mmol/L），予以钙剂及胰岛素-葡萄糖治疗未能纠正高钾血症，数小时后又急剧升高至7.3 mmol/L，紧急行血液滤过治疗。送检外周血及脑组织行宏基因组测序（mNGS）以排查感染性病因。入院第4天，送检的外周血和脑组织mNGS均检测出人类疱疹病毒（序列数分别为809条、256条），未检出其他病原微生物，鉴于患者临床表现，病毒性脑炎暂无法排除，给予更昔洛韦抗病毒治疗。复查颅脑CT（图 1）：脑组织弥漫性肿胀，继续加强脱水治疗。入院第5天，检测血氨为4490 μmol/L，结合肝功指标，不除外血氨代谢性疾病，予以血液滤过、精氨酸、导泻及停止蛋白质摄入等措施降血氨，并送检基因检测。入院第6天，血氨降至1595 μmol/L，但患者呈深昏迷状态，伴有脑水肿、脑疝，依赖大剂量血管活性药物维持血压，病情难以逆转，于第7天死亡。
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| 图 1 患者入院第4天颅脑CT |
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基因测序结果（图 2）提示患者（Ⅲ-1）OTC基因存在半合子突变：第493号核苷酸鸟嘌呤G突变为胸腺嘧啶T（c.493G > T），据此确诊为OTCD。追踪患者遗传家系（图 2、3）发现致病性变异来源于患者母亲（Ⅱ-2），患者部分亲属（Ⅲ-2、Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-6、Ⅱ-7）该位点存在杂合变异（图 3），Ⅰ代亲属未接受基因检测。
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| 图 2 基因测序结果红色箭头指示突变位点，患者A半合子突变(c.493G > T)，其父B为正常G，其母C杂合突变 |
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| 图 3 家系图 |
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在PubMed中检索2005年6月至2025年6月期间成年发病且有详细临床资料的OTCD病例，排除综述、未确诊病例。使用SPSS 26.0进行统计分析，分类数据由n(%)表示，非正态数据以[M(Q1, Q3)]描述，组间比较采用卡方检验（分类变量）和Mann-Whitney U检验（非正态分布的连续变量），以P＜0.05为差异有统计学意义。研究共纳入了50例患者[2-44]，男性占62.00%，总病死率为40.00%。基线特征（表 1）显示死亡组中男性比例、血氨峰值更高（P＜0.001）。昏迷为最常见的症状（表 2），其次还有运动行为异常、呕吐、癫痫发作等。成年起病的诱因（表 3）以激素使用最为常见，同时还和蛋白摄入增加、剧烈运动、化疗、感染、妊娠等有关。
表 1 基线特征
| 指标 | 总人群（50例） | 存活组（30例） | 死亡组（20例） | P值 | 效应量(95% CI) |
| 年龄（岁）a | 36(28, 52) | 35(28, 53) | 44(28, 51) | 0.699 | r = -0.05(-0.33, 0.23) |
| 性别（n, %） | 0.001 | φ = 0.47(0.22, 0.66) | |||
| 女 | 19(38.00) | 17(56.67) | 2(10.00) | ||
| 男 | 31(62.00) | 13(43.33) | 18(90.00) | ||
| 氨水平（初始值，μmol/L）a | 188.00(154.00, 365.50) | 185.00(155.50, 295.50) | 294.00(153.00, 674.00) | 0.182 | r = -0.19(-0.45, 0.10) |
| 氨水平（峰值，μmol/L）a | 377.00(271.00, 697.00) | 284.50(184.25, 366.00) | 700.00(455.50, 1572.50) | 0.001 | r = -0.66(-0.81, -0.44) |
| 接受血液净化治疗（n, %） | 26(52.00) | 17(56.67) | 9(45.00) | 0.419 | φ = 0.1 |
| 注：a为M(Q1, Q3) | |||||
OTC活性缺乏导致尿素循环障碍及高氨血症，血氨升高后消耗α-酮戊二酸、干扰三羧酸循环，引起脑能量代谢障碍，谷氨酰胺蓄积导致渗透性脑水肿[45]。患者脑损伤的程度和血氨水平密切相关，轻中度高氨血症（100~250 μmol/L）常有呕吐、厌食、精神行为改变等症状；严重高氨血症（＞250 μmol/L）常表现为脑水肿、脑疝、昏迷；血氨持续＞400 μmol/L者易出现脑死亡[46-47]。因严重高氨血症易诱发脑水肿及脑疝，若血氨水平超过200 μmol/L，可首选血液净化治疗[48]，以清除血氨等小分子毒素[49-50]。本例患者出现严重高氨血症后，即予以血液滤过等降氨治疗，血氨水平由4490 μmol/L降至1595 μmol/L。
本例患者存在既往未诊断的尿素循环障碍，此次在摄入大量蛋白质并剧烈运动后急性发作，表现为脑水肿、高颅内压与高氨血症。患者因颅高压危象接受脑室外引流，脑组织mNGS检出人类疱疹病毒序列，该病毒少数情况下可引起脑炎、病毒血症等严重并发症[51]，故予以抗病毒治疗，后经基因检测确诊为OTCD，考虑该病毒序列可能源于检测假阳性或潜伏状态[52]，与本次颅高压危象无直接因果关系。患者严重脑水肿，尽管给予了脑室外引流、脱水降颅压及血液滤过等积极干预，病情仍难以逆转。由于基因检测耗时较长，高度怀疑尿素循环障碍时应及早降氨治疗，以减轻脑损伤、降低病死率[1, 53]。
OTCD患者主要在儿童期发病并确诊，病死率25%~40%（男性：40%~50%，女性：10%~30%）[54-56]。因症状缺乏特异度以及本病的罕见性，成年起病患者难以早期识别[10]，统计表明其总死亡率为40.00%，其中成年男性患者的死亡率为58.06%，远高于成年女性患者（10.53%），也高于文献中儿童男性患者的死亡率（40%~50%）[55-56]，这与其X连锁遗传的严重酶缺陷及成年起病带来的诊断延迟密切相关。受发表偏倚影响，本研究估计的死亡率可能偏高，有待前瞻性研究进一步评估疾病预后。成年起病患者的症状与儿童患者类似[55]，可表现为昏迷、运动行为异常、呕吐、癫痫发作等（表 2），但发病诱因存在差异：前者主要为激素使用和蛋白摄入增加（表 3），后者以感染及饮食多样化为主[56]。本例患者近期大量蛋白质摄入及剧烈运动，是OTCD急性发作的明确诱因。
综上所述，存在激素使用或高蛋白饮食等诱因，并出现呕吐、精神行为异常或昏迷等表现的成年患者，应进行血氨筛查以识别代谢危象，缩短成人罕见代谢病的诊断延迟。若血氨＞200 μmol/L或已进展为重症，尽早启动血液净化是减轻脑水肿、改善预后的关键。OTCD患者稳定期需低蛋白饮食及抗高血氨药物治疗，其亲属应接受基因检测与遗传咨询，以明确家系致病基因携带情况并指导优生优育。
作者贡献声明 苑咸斌：论文撰写，胡园园、杨一帆：数据分析，刘玉亮、薛琬麟、岳金凤、杜滨锋：资料收集及整理，郭海鹏、苑咸斌：研究设计、论文修改
知情同意 本研究已获得患者家属的书面知情同意
利益冲突 所有作者均声明不存在利益冲突
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