同型半胱氨酸尿癥一例漏診分析及文獻(xiàn)復(fù)習(xí)

靳大川，姬廣森，武淑芳，楊亞琦，袁曉燕

同型半胱氨酸尿癥一例漏診分析及文獻(xiàn)復(fù)習(xí)

靳大川，姬廣森，武淑芳，楊亞琦，袁曉燕

目的 探討同型半胱氨酸尿癥的發(fā)病機(jī)制、臨床特點(diǎn)及診斷要點(diǎn)，減少漏誤診。方法 回顧分析1例同型半胱氨酸尿癥漏診病例資料，并復(fù)習(xí)相關(guān)文獻(xiàn)。結(jié)果 患者為55歲男性，主要表現(xiàn)為下肢深靜脈血栓形成(deep venous thrombosis， DVT)和肺血栓栓塞癥(pulmonary thromboembolism， PTE)及長(zhǎng)期的骨質(zhì)疏松，外院診斷為DVT、PTE，給予溶栓抗凝等治療，癥狀稍改善出院。患者來我院復(fù)查時(shí)發(fā)現(xiàn)血液同型半胱氨酸(Hcy)異常升高(51.8 μmol/L)，進(jìn)一步行基因檢測(cè)證實(shí)胱硫醚合成酶基因c.572C>T和c.919G>A雜合性突變(錯(cuò)義突變型)。確診為同型半胱氨酸尿癥，予維生素B6、葉酸、維生素B12口服治療3個(gè)月，患者癥狀完全改善，血液Hcy降至正常。結(jié)論 同型半胱氨酸尿癥臨床表現(xiàn)復(fù)雜而缺乏特異性，易漏診。臨床對(duì)頑固性DVT、PTE和骨質(zhì)疏松且血液Hcy水平異常者，應(yīng)警惕同型半胱氨酸尿癥，行相關(guān)基因檢測(cè)有助于確診。

同型半胱氨酸尿癥；胱硫醚合成酶；靜脈血栓形成；基因突變；漏診

同型半胱氨酸尿癥是一種罕見的常染色體隱性遺傳性含硫氨基酸代謝障礙，全球發(fā)生率約為1︰344 000[1-2]。然而該病不同地區(qū)發(fā)病率差異較大，卡塔爾為全球發(fā)病率最高的國(guó)家，新生兒發(fā)病率高達(dá)1︰1800[3]。世界上首例患者由Carson和Neill[4]于1962年報(bào)道?；蛲蛔儗?dǎo)致胱硫醚-β-合成酶(CBS)活性缺陷是同型半胱氨酸尿癥最常見的發(fā)病原因[5]，該病引起的主要生物化學(xué)改變?yōu)槿斫M織中積聚大量的同型半胱氨酸(Hcy)，血尿Hcy水平升高，進(jìn)而引起多系統(tǒng)復(fù)雜的并發(fā)癥，包括玻璃體移位、骨質(zhì)疏松、長(zhǎng)骨變細(xì)和延長(zhǎng)、面部顴骨區(qū)域皮膚片狀發(fā)紅、智力發(fā)育延遲及全身各部位血栓栓塞等[1,6]。我國(guó)同型半胱氨酸尿癥少有報(bào)道，流行病學(xué)研究則是空白[7]。我院近期收治1例長(zhǎng)期漏診的同型半胱氨酸尿癥，現(xiàn)分析漏診原因如下。

1 臨床資料

男，55歲，美籍白人。因下肢深靜脈血栓形成(deep venous thrombosis， DVT)、肺血栓栓塞癥(pulmonary thromboembolism， PTE)在外院治療后1個(gè)月，來我院國(guó)際醫(yī)療部例行復(fù)查?；颊?.5個(gè)月前無明顯誘因出現(xiàn)左小腿及足踝部持續(xù)腫脹2周，于當(dāng)?shù)蒯t(yī)院就診，門診查體見左下肢膝關(guān)節(jié)以下腫脹，皮溫可，無皮膚色素沉著、潰瘍、膿性分泌物及明顯壓痛，活動(dòng)后加重，休息后減輕，以左下肢DVT？收入院治療。無高血壓病、冠心病、糖尿病病史，無肝炎、結(jié)核等傳染病病史，無藥物、食物過敏史；30年前因股部切割傷于美國(guó)某醫(yī)院行股動(dòng)脈斷裂血管吻合術(shù)，術(shù)中輸血量不詳，輸血過程順利，未出現(xiàn)輸血反應(yīng)；10余年前健康體檢發(fā)現(xiàn)骨質(zhì)疏松，未行任何治療?；颊呱诿绹?guó)，長(zhǎng)期居住中國(guó)，無放射性物質(zhì)及有害物質(zhì)長(zhǎng)期接觸史，無煙酒嗜好；患者父母早年去世，死因不詳。系統(tǒng)查體未見異常體征。?？撇轶w：雙下肢無畸形，各關(guān)節(jié)活動(dòng)自如；左下肢膝關(guān)節(jié)以下及足踝部腫脹，皮溫可，無皮膚色素沉著、潰瘍、膿性分泌物及明顯壓痛；股動(dòng)脈搏動(dòng)可，足背動(dòng)脈搏動(dòng)弱，右側(cè)肢體未見明顯異常。右股部見一約7 cm縱形切口，色淺灰，質(zhì)韌，無明顯壓痛及皮下波動(dòng)感。行雙下肢靜脈彩色多普勒超聲(彩超)檢查證實(shí)左下肢DVT。胸部CT檢查示：左肺動(dòng)脈主干及部分分支、右下肺動(dòng)脈主干內(nèi)見斑片狀充盈缺損影，提示PTE。查血常規(guī)正常；凝血酶原時(shí)間11.6 s(正常參考值11～14 s)，凝血酶原活動(dòng)度137%(正常參考值85%～150%)，國(guó)際標(biāo)準(zhǔn)化比值0.85(正常參考值0.82～1.12)，纖維蛋白原2.54 g/L(正常參考值2～4 g/L)，活化部分凝血活酶時(shí)間32.1 s(正常參考值30～46 s)，凝血酶時(shí)間19.0 s(正常參考值14～21 s)，纖維蛋白降解產(chǎn)物3.39 mg/L(正常參考值<5 mg/L)，D-二聚體1.27 mg/L(正常參考值<0.5 mg/L)；肝功能、腎功能、血糖檢查均無明顯異常。確診為：左下肢DVT、PTE。給予纖溶酶200 U/d、血塞通注射液400 mg/d靜脈滴注，達(dá)肝素鈉5000 U/12 h皮下注射溶栓抗凝治療，并輔以活血化淤中成藥治療。2周后患者患肢腫脹減輕，股動(dòng)脈搏動(dòng)可，足背動(dòng)脈搏動(dòng)弱，患者自動(dòng)出院。

2 結(jié)果

患者出院后1個(gè)月，來我院國(guó)際醫(yī)療部例行復(fù)查。行常規(guī)檢查發(fā)現(xiàn)血液Hcy水平51.8 μmol/L(正常參考值<15 μmol/L)。詳細(xì)詢問患者家族史，得知其姐姐亦有異常血栓病變。經(jīng)患者同意，采集血標(biāo)本進(jìn)行遺傳代謝相關(guān)基因檢測(cè)，檢測(cè)結(jié)果提示：胱硫醚合成酶基因c.572C>T和c.919G>A雜合性突變(錯(cuò)義突變型)。綜合以上檢查資料，全面分析病情，確診為同型半胱氨酸尿癥，患者長(zhǎng)期存在的骨質(zhì)疏松、DVT和PTE均為同型半胱氨酸尿癥所致。給予維生素B6、葉酸、維生素B12口服，并且限制高蛋氨酸食物攝入。3個(gè)月后復(fù)查血Hcy濃度下降至正常水平；胸部CT檢查示雙肺動(dòng)脈主干及部分分支內(nèi)仍可見線樣低密度影；雙下肢靜脈彩超檢查示：血管腔內(nèi)徑正常，其內(nèi)未見異?；芈??；颊甙Y狀完全緩解。

3 討論

3.1 發(fā)病機(jī)制及分型 同型半胱氨酸尿癥患者血液Hcy水平升高的原因是基因突變或遺傳導(dǎo)致的Hcy代謝障礙。在體內(nèi)，很多器官均可產(chǎn)生Hcy，會(huì)對(duì)機(jī)體骨骼系統(tǒng)、眼、中樞神經(jīng)系統(tǒng)、血管產(chǎn)生細(xì)胞毒性，正常情況下機(jī)體主要通過肝臟和腎臟將產(chǎn)生的Hcy排出體外或通過代謝消除其毒性[8]。血液中過高的Hcy引起骨質(zhì)疏松的作用機(jī)制尚不清楚，但有研究發(fā)現(xiàn)Hcy會(huì)抑制膠原和原纖維的交聯(lián)，使體內(nèi)正常的微原纖維構(gòu)型被破壞[9-12]。

還有研究顯示，血液中高Hcy水平與血栓前狀態(tài)和血管內(nèi)皮損傷有關(guān)，易出現(xiàn)廣泛的血管內(nèi)血栓形成[13]。這可能是因?yàn)镠cy氧化產(chǎn)生過氧化氫和活性氧，并且Hcy能滅活內(nèi)皮來源的一氧化氮和血栓調(diào)節(jié)蛋白，導(dǎo)致血小板聚集、血管收縮和抗凝系統(tǒng)受損[14]。證據(jù)表明，血液Hcy水平每升高5 μmol/L，發(fā)生血栓形成的危險(xiǎn)性升高41%～84%，并且血液Hcy水平升高是高血壓病、吸煙等傳統(tǒng)危險(xiǎn)因素之外的獨(dú)立危險(xiǎn)因素[15]。

按發(fā)病機(jī)制，同型半胱氨酸尿癥主要分為3型：①CBS活性缺失或下降型，為最常見、最經(jīng)典類型，血液和尿液Hcy水平升高，進(jìn)而使更多的Hcy再次轉(zhuǎn)化為蛋氨酸，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和維生素B6親和力下降型；③甲基轉(zhuǎn)移酶缺陷型，導(dǎo)致Hcy無法通過再生轉(zhuǎn)化為蛋氨酸[16]。目前發(fā)現(xiàn)有160多種與同型半胱氨酸尿癥有關(guān)的CBS基因突變(http://cbs.lf1.cuni.cz/mutations.php)，其中主要為錯(cuò)義突變(>67%)[7,18]。本例為雜合性CBS基因突變(錯(cuò)義突變型)，屬于最常見的CBS活性缺失型。

3.2 臨床特點(diǎn) 同型半胱氨酸尿癥可表現(xiàn)為發(fā)育延遲，智力障礙，癲癇，眼部異常(嚴(yán)重的近視和晶狀體異位)，骨骼畸形(骨質(zhì)疏松、脊柱側(cè)彎、馬方綜合征樣體型、腿外翻、弓形足、干骺端異常增寬、胸骨畸形、蜘蛛腳樣指趾)，異常升高的骨折風(fēng)險(xiǎn)，動(dòng)靜脈血栓形成等[1,19-25]。該病還可引起譫妄、雙極性情感障礙、Capgras綜合征等精神障礙，這類在智力障礙和神經(jīng)疾病基礎(chǔ)上出現(xiàn)的妄想也稱為妄想性錯(cuò)認(rèn)綜合征[15,26-27]。同型半胱氨酸尿癥患者的智商變異很大，從10至130不等，一般智商較高者多為維生素B6治療有效的病情較輕患者[25]。表現(xiàn)為嚴(yán)重進(jìn)行性智力障礙患者一般伴有精神疾患，多見于血液Hcy水平重度升高時(shí)(>100 μmol/L)[25,27]。

血管系統(tǒng)異常是同型半胱氨酸尿癥最重要、最突出和最致命的臨床表現(xiàn)，可見于任何年齡段患者人群，而50%的患者在30歲前出現(xiàn)血管內(nèi)血栓形成[28-31]。血栓栓塞性病變可影響患者所有的動(dòng)脈和靜脈血管，最常報(bào)道的有腦血管意外、PTE、頸動(dòng)脈閉塞、腎動(dòng)脈閉塞。靜脈血栓栓塞性疾病也是同型半胱氨酸尿癥患者的主要死因[29]。早年出現(xiàn)的晶狀體半脫位、明顯和進(jìn)行性加重的近視也是同型半胱氨酸尿癥最常見的臨床表現(xiàn)[2]。大部分患者在3歲后因晶狀體半脫位引起嚴(yán)重的近視和虹膜震顫，才得以臨床診斷[25]。本例無視網(wǎng)膜病變，有明確的骨質(zhì)疏松和靜脈血栓栓塞性疾病，但較輕微，雖然影像學(xué)檢查發(fā)現(xiàn)有PTE，但是患者未出現(xiàn)急性PTE癥狀，可能與其為雜合性基因突變、突變位點(diǎn)較少有關(guān)。

3.3 診斷及鑒別診斷 有些國(guó)家對(duì)于新生兒和(或)出生2～3 d的嬰兒通過檢測(cè)血液中Hcy水平或行串聯(lián)質(zhì)譜分析常規(guī)篩查同型半胱氨酸尿癥。而未經(jīng)早期篩查患者大多在5～10歲時(shí)，因晶狀體半脫位和血栓栓塞性病變才得以明確診斷[32]。也有部分病情較輕者，直到成人階段才被發(fā)現(xiàn)[1]，本例即如此。成年確診者，大多發(fā)現(xiàn)時(shí)已有明顯的骨質(zhì)疏松。據(jù)報(bào)道，70%有CBS缺陷的同型半胱氨酸尿癥患者在20歲前出現(xiàn)骨質(zhì)疏松[24,33-34]。但如能在更早階段控制血液Hcy水平，就可有效防止骨質(zhì)疏松的發(fā)生，未及時(shí)治療者有可能出現(xiàn)壓縮性骨折并致脊柱側(cè)彎[24]。

同型半胱氨酸尿癥引起的血栓形成可累及人體大小血管，可見于任何年齡段患者，臨床對(duì)于頻發(fā)血栓形成患者，尤其是年幼或無明顯誘因者，需要常規(guī)檢測(cè)血液Hcy水平[25]。通常尿液分析不如血液檢測(cè)的診斷意義大，因?yàn)槟蛞悍治鰞H能檢測(cè)Hcy和混合的二硫化物形式。但血尿液中Hcy水平升高并不僅見于同型半胱氨酸尿癥。輕中度血液Hcy水平升高(15～70 μmol/L)可見于亞甲基四氫葉酸還原酶基因C677T多態(tài)性、服用影響葉酸或維生素B12代謝藥物(如甲氨蝶呤等)、維生素?cái)z入不足、先天性維生素B12代謝障礙(如甲基丙二酸血癥)和慢性腎衰竭或癌癥患者[30,35-36]。但是對(duì)血液Hcy水平重度升高(≥100 μmol/L)者，必須考慮進(jìn)行遺傳學(xué)檢測(cè)來評(píng)估患有先天性同型半胱氨酸尿癥的可能[1,30,35,37]。

3.4 診斷體會(huì) 癥狀典型的同型半胱氨酸尿癥患者漏診可能性較小，但癥狀較輕微或表現(xiàn)不典型者，漏診可能性較大。該病部分患者僅表現(xiàn)為血栓栓塞性病變，也有極少數(shù)家族性同型半胱氨酸尿癥患者，除有晶狀體半脫位以外，并無其他系統(tǒng)任何癥狀[2,38]。本例近期僅以DVT為主要表現(xiàn)，癥狀比較輕微，也未出現(xiàn)同型半胱氨酸尿癥其他典型而嚴(yán)重的多系統(tǒng)癥狀，是導(dǎo)致初次就診漏診的重要原因。我們認(rèn)為對(duì)于無明顯誘因出現(xiàn)血栓栓塞性疾病、青年期即發(fā)生的骨質(zhì)疏松及晶狀體半脫位患者，即使無其他典型多系統(tǒng)臨床表現(xiàn)，也應(yīng)常規(guī)檢測(cè)血液Hcy水平，有條件時(shí)應(yīng)進(jìn)一步行基因檢測(cè)以確診。

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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 鄭州，鄭州市第六人民醫(yī)院國(guó)際醫(yī)療部

R75

A

1002-3429(2017)04-0046-04

10.3969/j.issn.1002-3429.2017.04.016

2016-08-15 修回時(shí)間：2017-01-25)