同型半胱氨酸尿症一例漏诊分析及文献复习

靳大川，姬广森，武淑芳，杨亚琦，袁晓燕

同型半胱氨酸尿症一例漏诊分析及文献复习

靳大川，姬广森，武淑芳，杨亚琦，袁晓燕

目的 探讨同型半胱氨酸尿症的发病机制、临床特点及诊断要点，减少漏误诊。方法 回顾分析1例同型半胱氨酸尿症漏诊病例资料，并复习相关文献。结果 患者为55岁男性，主要表现为下肢深静脉血栓形成(deep venous thrombosis， DVT)和肺血栓栓塞症(pulmonary thromboembolism， PTE)及长期的骨质疏松，外院诊断为DVT、PTE，给予溶栓抗凝等治疗，症状稍改善出院。患者来我院复查时发现血液同型半胱氨酸(Hcy)异常升高(51.8 μmol/L)，进一步行基因检测证实胱硫醚合成酶基因c.572C>T和c.919G>A杂合性突变(错义突变型)。确诊为同型半胱氨酸尿症，予维生素B6、叶酸、维生素B12口服治疗3个月，患者症状完全改善，血液Hcy降至正常。结论 同型半胱氨酸尿症临床表现复杂而缺乏特异性，易漏诊。临床对顽固性DVT、PTE和骨质疏松且血液Hcy水平异常者，应警惕同型半胱氨酸尿症，行相关基因检测有助于确诊。

同型半胱氨酸尿症；胱硫醚合成酶；静脉血栓形成；基因突变；漏诊

同型半胱氨酸尿症是一种罕见的常染色体隐性遗传性含硫氨基酸代谢障碍，全球发生率约为1︰344 000[1-2]。然而该病不同地区发病率差异较大，卡塔尔为全球发病率最高的国家，新生儿发病率高达1︰1800[3]。世界上首例患者由Carson和Neill[4]于1962年报道。基因突变导致胱硫醚-β-合成酶(CBS)活性缺陷是同型半胱氨酸尿症最常见的发病原因[5]，该病引起的主要生物化学改变为全身组织中积聚大量的同型半胱氨酸(Hcy)，血尿Hcy水平升高，进而引起多系统复杂的并发症，包括玻璃体移位、骨质疏松、长骨变细和延长、面部颧骨区域皮肤片状发红、智力发育延迟及全身各部位血栓栓塞等[1,6]。我国同型半胱氨酸尿症少有报道，流行病学研究则是空白[7]。我院近期收治1例长期漏诊的同型半胱氨酸尿症，现分析漏诊原因如下。

1 临床资料

男，55岁，美籍白人。因下肢深静脉血栓形成(deep venous thrombosis， DVT)、肺血栓栓塞症(pulmonary thromboembolism， PTE)在外院治疗后1个月，来我院国际医疗部例行复查。患者1.5个月前无明显诱因出现左小腿及足踝部持续肿胀2周，于当地医院就诊，门诊查体见左下肢膝关节以下肿胀，皮温可，无皮肤色素沉着、溃疡、脓性分泌物及明显压痛，活动后加重，休息后减轻，以左下肢DVT？收入院治疗。无高血压病、冠心病、糖尿病病史，无肝炎、结核等传染病病史，无药物、食物过敏史；30年前因股部切割伤于美国某医院行股动脉断裂血管吻合术，术中输血量不详，输血过程顺利，未出现输血反应；10余年前健康体检发现骨质疏松，未行任何治疗。患者生于美国，长期居住中国，无放射性物质及有害物质长期接触史，无烟酒嗜好；患者父母早年去世，死因不详。系统查体未见异常体征。专科查体：双下肢无畸形，各关节活动自如；左下肢膝关节以下及足踝部肿胀，皮温可，无皮肤色素沉着、溃疡、脓性分泌物及明显压痛；股动脉搏动可，足背动脉搏动弱，右侧肢体未见明显异常。右股部见一约7 cm纵形切口，色浅灰，质韧，无明显压痛及皮下波动感。行双下肢静脉彩色多普勒超声(彩超)检查证实左下肢DVT。胸部CT检查示：左肺动脉主干及部分分支、右下肺动脉主干内见斑片状充盈缺损影，提示PTE。查血常规正常；凝血酶原时间11.6 s(正常参考值11～14 s)，凝血酶原活动度137%(正常参考值85%～150%)，国际标准化比值0.85(正常参考值0.82～1.12)，纤维蛋白原2.54 g/L(正常参考值2～4 g/L)，活化部分凝血活酶时间32.1 s(正常参考值30～46 s)，凝血酶时间19.0 s(正常参考值14～21 s)，纤维蛋白降解产物3.39 mg/L(正常参考值<5 mg/L)，D-二聚体1.27 mg/L(正常参考值<0.5 mg/L)；肝功能、肾功能、血糖检查均无明显异常。确诊为：左下肢DVT、PTE。给予纤溶酶200 U/d、血塞通注射液400 mg/d静脉滴注，达肝素钠5000 U/12 h皮下注射溶栓抗凝治疗，并辅以活血化淤中成药治疗。2周后患者患肢肿胀减轻，股动脉搏动可，足背动脉搏动弱，患者自动出院。

2 结果

患者出院后1个月，来我院国际医疗部例行复查。行常规检查发现血液Hcy水平51.8 μmol/L(正常参考值<15 μmol/L)。详细询问患者家族史，得知其姐姐亦有异常血栓病变。经患者同意，采集血标本进行遗传代谢相关基因检测，检测结果提示：胱硫醚合成酶基因c.572C>T和c.919G>A杂合性突变(错义突变型)。综合以上检查资料，全面分析病情，确诊为同型半胱氨酸尿症，患者长期存在的骨质疏松、DVT和PTE均为同型半胱氨酸尿症所致。给予维生素B6、叶酸、维生素B12口服，并且限制高蛋氨酸食物摄入。3个月后复查血Hcy浓度下降至正常水平；胸部CT检查示双肺动脉主干及部分分支内仍可见线样低密度影；双下肢静脉彩超检查示：血管腔内径正常，其内未见异常回声。患者症状完全缓解。

3 讨论

3.1 发病机制及分型 同型半胱氨酸尿症患者血液Hcy水平升高的原因是基因突变或遗传导致的Hcy代谢障碍。在体内，很多器官均可产生Hcy，会对机体骨骼系统、眼、中枢神经系统、血管产生细胞毒性，正常情况下机体主要通过肝脏和肾脏将产生的Hcy排出体外或通过代谢消除其毒性[8]。血液中过高的Hcy引起骨质疏松的作用机制尚不清楚，但有研究发现Hcy会抑制胶原和原纤维的交联，使体内正常的微原纤维构型被破坏[9-12]。

还有研究显示，血液中高Hcy水平与血栓前状态和血管内皮损伤有关，易出现广泛的血管内血栓形成[13]。这可能是因为Hcy氧化产生过氧化氢和活性氧，并且Hcy能灭活内皮来源的一氧化氮和血栓调节蛋白，导致血小板聚集、血管收缩和抗凝系统受损[14]。证据表明，血液Hcy水平每升高5 μmol/L，发生血栓形成的危险性升高41%～84%，并且血液Hcy水平升高是高血压病、吸烟等传统危险因素之外的独立危险因素[15]。

按发病机制，同型半胱氨酸尿症主要分为3型：①CBS活性缺失或下降型，为最常见、最经典类型，血液和尿液Hcy水平升高，进而使更多的Hcy再次转化为蛋氨酸，引起蛋氨酸水平升高及血液胱氨酸和胱硫醚水平下降[5,7,16-17]；②CBS和维生素B6亲和力下降型；③甲基转移酶缺陷型，导致Hcy无法通过再生转化为蛋氨酸[16]。目前发现有160多种与同型半胱氨酸尿症有关的CBS基因突变(http://cbs.lf1.cuni.cz/mutations.php)，其中主要为错义突变(>67%)[7,18]。本例为杂合性CBS基因突变(错义突变型)，属于最常见的CBS活性缺失型。

3.2 临床特点 同型半胱氨酸尿症可表现为发育延迟，智力障碍，癫痫，眼部异常(严重的近视和晶状体异位)，骨骼畸形(骨质疏松、脊柱侧弯、马方综合征样体型、腿外翻、弓形足、干骺端异常增宽、胸骨畸形、蜘蛛脚样指趾)，异常升高的骨折风险，动静脉血栓形成等[1,19-25]。该病还可引起谵妄、双极性情感障碍、Capgras综合征等精神障碍，这类在智力障碍和神经疾病基础上出现的妄想也称为妄想性错认综合征[15,26-27]。同型半胱氨酸尿症患者的智商变异很大，从10至130不等，一般智商较高者多为维生素B6治疗有效的病情较轻患者[25]。表现为严重进行性智力障碍患者一般伴有精神疾患，多见于血液Hcy水平重度升高时(>100 μmol/L)[25,27]。

血管系统异常是同型半胱氨酸尿症最重要、最突出和最致命的临床表现，可见于任何年龄段患者人群，而50%的患者在30岁前出现血管内血栓形成[28-31]。血栓栓塞性病变可影响患者所有的动脉和静脉血管，最常报道的有脑血管意外、PTE、颈动脉闭塞、肾动脉闭塞。静脉血栓栓塞性疾病也是同型半胱氨酸尿症患者的主要死因[29]。早年出现的晶状体半脱位、明显和进行性加重的近视也是同型半胱氨酸尿症最常见的临床表现[2]。大部分患者在3岁后因晶状体半脱位引起严重的近视和虹膜震颤，才得以临床诊断[25]。本例无视网膜病变，有明确的骨质疏松和静脉血栓栓塞性疾病，但较轻微，虽然影像学检查发现有PTE，但是患者未出现急性PTE症状，可能与其为杂合性基因突变、突变位点较少有关。

3.3 诊断及鉴别诊断 有些国家对于新生儿和(或)出生2～3 d的婴儿通过检测血液中Hcy水平或行串联质谱分析常规筛查同型半胱氨酸尿症。而未经早期筛查患者大多在5～10岁时，因晶状体半脱位和血栓栓塞性病变才得以明确诊断[32]。也有部分病情较轻者，直到成人阶段才被发现[1]，本例即如此。成年确诊者，大多发现时已有明显的骨质疏松。据报道，70%有CBS缺陷的同型半胱氨酸尿症患者在20岁前出现骨质疏松[24,33-34]。但如能在更早阶段控制血液Hcy水平，就可有效防止骨质疏松的发生，未及时治疗者有可能出现压缩性骨折并致脊柱侧弯[24]。

同型半胱氨酸尿症引起的血栓形成可累及人体大小血管，可见于任何年龄段患者，临床对于频发血栓形成患者，尤其是年幼或无明显诱因者，需要常规检测血液Hcy水平[25]。通常尿液分析不如血液检测的诊断意义大，因为尿液分析仅能检测Hcy和混合的二硫化物形式。但血尿液中Hcy水平升高并不仅见于同型半胱氨酸尿症。轻中度血液Hcy水平升高(15～70 μmol/L)可见于亚甲基四氢叶酸还原酶基因C677T多态性、服用影响叶酸或维生素B12代谢药物(如甲氨蝶呤等)、维生素摄入不足、先天性维生素B12代谢障碍(如甲基丙二酸血症)和慢性肾衰竭或癌症患者[30,35-36]。但是对血液Hcy水平重度升高(≥100 μmol/L)者，必须考虑进行遗传学检测来评估患有先天性同型半胱氨酸尿症的可能[1,30,35,37]。

3.4 诊断体会 症状典型的同型半胱氨酸尿症患者漏诊可能性较小，但症状较轻微或表现不典型者，漏诊可能性较大。该病部分患者仅表现为血栓栓塞性病变，也有极少数家族性同型半胱氨酸尿症患者，除有晶状体半脱位以外，并无其他系统任何症状[2,38]。本例近期仅以DVT为主要表现，症状比较轻微，也未出现同型半胱氨酸尿症其他典型而严重的多系统症状，是导致初次就诊漏诊的重要原因。我们认为对于无明显诱因出现血栓栓塞性疾病、青年期即发生的骨质疏松及晶状体半脱位患者，即使无其他典型多系统临床表现，也应常规检测血液Hcy水平，有条件时应进一步行基因检测以确诊。

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A Missed Diagnosis Case Report of Homocystinuria and Literature Review

JIN Da-chuan, JI Guang-sen, WU Shu-fang, YANG Ya-qi, YUAN Xiao-yan

(Department of International Medical Treatment, the Sixth People's Hospital of Zhengzhou, Zhengzhou 450015, China)

Objective To investigate pathogenesis, clinical features, key points of diagnosis and treatment for homocystinuria in order to avoid misdiagnosis and missed diagnosis. Methods Clinical data of 1 missed diagnosis patient with homocystinuria was retrospectively analyzed, and related literature was reviewed. Results A 55-years-old male was diagnosed as having deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE) because of manifestations of DVT, PTE and long-term osteoporosis in a US local hospital, and was treated with thrombolytic and anticoagulant medicine. He was discharged after part improvement of symptoms. The patient was detected abnormally elevated plasma homocysteine (Hcy, 51.8 μmol/L) during his rechecking in our hospital. Further gene sequencing test revealed two heterozygous nucleotide missense mutations in the CBS (Cystathionine β-synthase) gene (c.572C>T & c.919G>A). Homocystinuria was confirmed. Symptoms was relieved completely and plasma homocysteine level was reduced to normal after receiving oral administration of Pyridoxine, Folic Acid and Cobalamin for three months.Conclusion Clinical manifestation of homocystinuria is complex and lack of specificity, and therefore it is easily misdiagnosed. Homocystinuria should be highly suspected for patients with refractory DVT, PTE, osteoporosis and abnormal level of blood Hcy, and relevant gene tests are helpful for clinicians to confirm the diagnosis.

Homocystinuria; Cystathionine β-synthase; Venous thrombosis; Gene mutation; Missed diagnosis

450015 郑州，郑州市第六人民医院国际医疗部

R75

A

1002-3429(2017)04-0046-04

10.3969/j.issn.1002-3429.2017.04.016

2016-08-15 修回时间：2017-01-25)