劉方舟， 錢(qián)亦淳， 趙炎斌， 王玥， 閆衛(wèi)， 樊玉文， 虞同華， 胡婷婷， 張園

論 著

甲狀腺術(shù)后甲狀旁腺功能減退和低鈣血癥影響因素分析

劉方舟， 錢(qián)亦淳， 趙炎斌， 王玥， 閆衛(wèi)， 樊玉文， 虞同華， 胡婷婷， 張園

目的探討甲狀腺術(shù)后低鈣血癥和甲狀旁腺功能減退的影響因素以及資料分析。方法回顧江蘇省腫瘤醫(yī)院頭頸外科2016年1月至2017年1月收治的183例經(jīng)手術(shù)治療的甲狀腺疾病患者手術(shù)后低鈣血癥和甲狀旁腺功能減退情況。分析年齡、性別、病理診斷、中央?yún)^(qū)淋巴結(jié)清掃、頸側(cè)區(qū)淋巴結(jié)清掃、手術(shù)范圍、手術(shù)時(shí)間、術(shù)前血鈣水平、術(shù)前甲狀旁腺激素水平與術(shù)后甲狀旁腺功能減退及低鈣血癥的關(guān)系。結(jié)果183例術(shù)后病理診斷為甲狀腺癌163例(89.07%)，甲狀腺其他疾病20例(10.93%)。術(shù)后141例甲狀旁腺功能正常的患者中7例(4.96%)發(fā)生低鈣血癥，42例甲狀旁腺功能減退的患者中26例(61.91%)發(fā)生低鈣血癥。單因素分析顯示，性別、中央?yún)^(qū)淋巴結(jié)清掃、頸側(cè)區(qū)淋巴結(jié)清掃、手術(shù)范圍、手術(shù)時(shí)間、術(shù)前甲狀旁腺激素水平與術(shù)后甲狀旁腺功能減退相關(guān)。年齡、性別、中央?yún)^(qū)淋巴結(jié)清掃、頸側(cè)區(qū)淋巴結(jié)清掃、手術(shù)范圍、手術(shù)時(shí)間與術(shù)后低鈣血癥相關(guān)。結(jié)論手術(shù)范圍大、女性、行中央?yún)^(qū)淋巴結(jié)清掃、行頸側(cè)區(qū)淋巴結(jié)清掃、手術(shù)時(shí)間長(zhǎng)、術(shù)前甲狀旁腺激素水平低的患者術(shù)后甲狀旁腺功能減退的發(fā)生率高。手術(shù)范圍大、年齡較大、女性、行中央?yún)^(qū)淋巴結(jié)清掃、行頸側(cè)區(qū)淋巴結(jié)清掃以及手術(shù)時(shí)間長(zhǎng)的患者術(shù)后低鈣血癥的發(fā)生率高。

甲狀腺切除術(shù)； 甲狀旁腺； 甲狀旁腺功能減退癥； 低鈣血癥; 影響因素分析

甲狀腺手術(shù)是治療甲狀腺疾病尤其甲狀腺癌的主要方法。低鈣血癥是甲狀腺術(shù)后最常見(jiàn)的并發(fā)癥之一，而甲狀旁腺功能減退(hypoparathyroidism，HPT)是其主要原因。一般術(shù)后6個(gè)月內(nèi)血鈣恢復(fù)正常稱(chēng)為暫時(shí)性低鈣血癥，發(fā)生率0.3%～49%；>6個(gè)月甚至終身不能恢復(fù)正常稱(chēng)為永久性低鈣血癥，發(fā)生率0～13%[1-8]。多種因素與術(shù)后低鈣血癥及甲狀旁腺功能減退的發(fā)生有關(guān)，包括性別、年齡、手術(shù)范圍、手術(shù)時(shí)間、頸部淋巴結(jié)清掃和術(shù)前血鈣水平等[2,9]。然而，這些因素與甲狀旁腺功能減退及低鈣血癥的關(guān)系尚不明確。我們探討甲狀腺術(shù)后甲狀旁腺功能減退和低鈣血癥相關(guān)的影響因素以及術(shù)后低鈣血癥的資料分析。

1 資料和方法

1.1 研究對(duì)象 收集2016年1月至2017年1月江蘇省腫瘤醫(yī)院頭頸外科收治并經(jīng)手術(shù)治療的甲狀腺疾病患者作為研究對(duì)象。納入標(biāo)準(zhǔn)：均有甲狀腺手術(shù)指征，手術(shù)范圍達(dá)到一側(cè)腺葉以上，排除有頸部手術(shù)史、有甲狀旁腺疾病史和術(shù)前有甲狀旁腺功能或血鈣水平異常者。

1.2 手術(shù)方式 有2種方式：甲狀腺單側(cè)腺葉切除術(shù)(包括單側(cè)腺葉+峽部切除術(shù))；甲狀腺全切術(shù)。手術(shù)均由本科室經(jīng)驗(yàn)豐富的醫(yī)生實(shí)施。

1.3 觀察項(xiàng)目與方法 入院后常規(guī)檢查患者甲狀旁腺激素(parathyroid hormone，PTH)及血鈣。術(shù)后第l天清晨復(fù)測(cè)PTH及血鈣并詳細(xì)詢(xún)問(wèn)有無(wú)低鈣臨床癥狀。血鈣<2.08 mmol/L視為低鈣血癥(參考值2.08～2.60 mmol/L)。PTH<1.6 pmol/L視為甲狀旁腺功能減退(1.6～6.9 pmol/L)。評(píng)估以下因素與甲狀旁腺功能減退及低鈣血癥發(fā)生的關(guān)系：患者年齡和性別、術(shù)前血鈣水平、術(shù)前PTH水平、手術(shù)范圍、中央?yún)^(qū)淋巴結(jié)清掃、頸側(cè)區(qū)淋巴結(jié)清掃、手術(shù)時(shí)間、病理診斷。

1.4 統(tǒng)計(jì)學(xué)方法 應(yīng)用SPSS19.0統(tǒng)計(jì)軟件進(jìn)行數(shù)據(jù)統(tǒng)計(jì)分析，計(jì)數(shù)資料應(yīng)用χ2檢驗(yàn)，計(jì)量資料采用F檢驗(yàn)，血鈣和PTH的比較采用Pearson相關(guān)分析，P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 一般資料 共183例入組，其中男51例(27.87%)，女132例(72.13%)，年齡(43±16)歲。術(shù)后病理診斷為甲狀腺癌163例(89.07%)；甲狀腺其他疾病20例(10.93%)，包括結(jié)節(jié)性甲狀腺腫、橋本甲狀腺炎、甲狀腺腺瘤、亞急性甲狀腺炎。行甲狀腺單側(cè)腺葉切除術(shù)84例(45.90%)，甲狀腺全切術(shù)99例(55.10%)。手術(shù)后42例(22.95%)發(fā)生甲狀旁腺功能減退，33例(18.03%)發(fā)生低鈣血癥。

2.2 甲狀腺術(shù)后低鈣血癥與甲狀旁腺功能減退的關(guān)系 甲狀旁腺功能減退與低鈣血癥的發(fā)生相關(guān)(P=0.000)。但是甲狀旁腺功能正常的患者也會(huì)發(fā)生低鈣血癥，而部分甲狀旁腺功能減退的患者血鈣卻在正常范圍。術(shù)后141例甲狀旁腺功能正常者中7例(4.96%)發(fā)生低鈣血癥，42例甲狀旁腺功能減退者中26例(61.91%)發(fā)生低鈣血癥，16例(38.09%)未發(fā)生低鈣血癥(表1)。低鈣癥狀多為持續(xù)性，經(jīng)補(bǔ)鈣治療后，癥狀在3～7 d緩解，血鈣能維持在正常或接近正常水平。

表1 甲狀腺術(shù)后低鈣血癥與甲狀旁腺功能減退的關(guān)系[例(%)]

2.3 甲狀腺術(shù)后甲狀旁腺功能減退的相關(guān)單因素分析 單因素分析顯示：性別(P=0.017)、中央?yún)^(qū)淋巴結(jié)清掃(P=0.000)、頸側(cè)區(qū)淋巴結(jié)清掃(P=0.045)、手術(shù)范圍(P=0.001)、術(shù)前PTH濃度(P=0.032)、手術(shù)時(shí)間(P=0.001)可能與術(shù)后甲狀旁腺功能減退有關(guān)，而年齡(P=0.531)、病理診斷(P=0.254)、術(shù)前血鈣濃度(P=0.589)與甲狀腺術(shù)后甲狀旁腺功能減退無(wú)關(guān)，見(jiàn)表2。

表2 甲狀腺術(shù)后甲狀旁腺功能減退的相關(guān)單因素分析[例(%)]

2.4 甲狀腺術(shù)后低鈣血癥的相關(guān)單因素分析 在對(duì)甲狀腺術(shù)后低鈣血癥的影響因素分析后發(fā)現(xiàn)，年齡(P=0.031)、性別(P=0.015)、中央?yún)^(qū)淋巴結(jié)清掃(P=0.000)、頸側(cè)區(qū)淋巴結(jié)清掃(P=0.045)、手術(shù)范圍(P=0.000)、手術(shù)時(shí)間(P=0.013)等因素可能與甲狀腺術(shù)后低鈣血癥有關(guān)；病理診斷(P=0.231)、術(shù)前血鈣(P=0.150)及PTH濃度(P=0.079)與甲狀腺術(shù)后低鈣血癥無(wú)關(guān)，見(jiàn)表3。

2.5 低鈣處理 對(duì)有明確低鈣癥狀的患者給予口服鈣爾奇D每天3次，每次1片，并根據(jù)臨床表現(xiàn)和實(shí)驗(yàn)室結(jié)果調(diào)整用量。對(duì)于病情嚴(yán)重或預(yù)計(jì)低鈣時(shí)間較長(zhǎng)的患者，給予10%葡萄糖酸鈣溶液靜脈注射，10 ml/次，必要時(shí)可重復(fù)，直到臨床癥狀消失。同時(shí)給予骨化三醇0.25 mg，每天1次。經(jīng)治90%以上患者低鈣癥狀在3～7 d內(nèi)緩解。同時(shí)，我們應(yīng)用中成藥丹參川芎制劑10 ml/d靜脈滴注用以改善術(shù)后甲狀旁腺的微循環(huán)，此研究尚在進(jìn)行中。另外，術(shù)中保護(hù)術(shù)區(qū)甲狀旁腺血供，盡量減少其供血血管痙攣十分重要。

表3 甲狀腺術(shù)后低鈣血癥的相關(guān)單因素分析

3 討論

急性低鈣血癥患者可表現(xiàn)為輕度的神經(jīng)系統(tǒng)癥狀，如末端肢體麻木、口周感覺(jué)異常、手足痙攣，面神經(jīng)征和陶瑟征[10]，嚴(yán)重者可發(fā)生喉痙攣和氣管痙攣，導(dǎo)致呼吸窘迫而危及生命。長(zhǎng)期低鈣可出現(xiàn)轉(zhuǎn)移性鈣化如低鈣性眼病和損害腎臟。本研究中，術(shù)后甲狀旁腺功能正常者低鈣較輕，臨床癥狀不明顯或僅表現(xiàn)為手足麻木，甲狀旁腺功能減退者低鈣癥狀較重，少數(shù)嚴(yán)重者發(fā)生“雞爪樣”抽搐。我們對(duì)患者術(shù)后血鈣和PTH進(jìn)行相關(guān)分析發(fā)現(xiàn)，PTH正常的患者也會(huì)出現(xiàn)術(shù)后低鈣血癥，部分有手足麻木癥狀，但此類(lèi)患者癥狀多為自限性的，與文獻(xiàn)報(bào)道一致[11-13]。此外，我們發(fā)現(xiàn)一些患者甲狀旁腺功能低下而血鈣水平卻正常，可能是由于患者血鈣代償能力較強(qiáng)或PTH下降的幅度不大所致。

通常認(rèn)為甲狀旁腺功能降低是手術(shù)引起，主要原因有：①甲狀旁腺血運(yùn)受損；②甲狀旁腺挫傷；③誤切甲狀旁腺。甲狀旁腺通常附在甲狀腺背面外膜上，但也有發(fā)現(xiàn)位于甲狀腺包膜內(nèi)或甲狀腺實(shí)質(zhì)內(nèi)[15-18]，甲狀腺手術(shù)時(shí)很容易誤切除，造成甲狀旁腺功能減退。根據(jù)Demeester-Mirkine等[19]研究，低鈣血癥是一個(gè)復(fù)雜的，受多種因素影響的癥狀。甲狀旁腺功能減退可能是其主要原因[20]，但除甲狀旁腺功能減退以外，低鈣血癥的原因可能還有以下幾點(diǎn)：①血鈣稀釋?zhuān)蜮}排出增加；②降鈣素釋放入血；③腎功能不全；④骨饑餓現(xiàn)象。甲狀腺術(shù)后激素水平恢復(fù)正常，骨骼恢復(fù)正常代謝導(dǎo)致血鈣下降[21]。

手術(shù)范圍是直接關(guān)系到低鈣血癥的發(fā)生率和嚴(yán)重程度的重要因素[22-23]。手術(shù)范圍越大，對(duì)甲狀旁腺功能的影響越大。文獻(xiàn)報(bào)道，2個(gè)以上的甲狀旁腺誤切才會(huì)表現(xiàn)為甲狀旁腺功能減退[24]；雙側(cè)甲狀腺切除患者往往具有較高的術(shù)后低鈣血癥發(fā)生率[25]。Rosato等[2]在14 934例患者中發(fā)現(xiàn)，0.4%的患者單側(cè)腺葉切除術(shù)后發(fā)生低鈣血癥，0.1%的患者明確為甲狀旁腺功能減退，在除甲狀腺以外的其他手術(shù)中也會(huì)觀察到。然而也有學(xué)者認(rèn)為，即使在單側(cè)甲狀腺切除術(shù)過(guò)程中，單側(cè)的甲狀旁腺損傷也會(huì)導(dǎo)致甲狀旁腺功能減退[26-27]。

本文數(shù)據(jù)顯示，全甲狀腺切除術(shù)引起的低鈣血癥主要是甲狀旁腺功能減退所致，而單側(cè)腺葉切除術(shù)所致的低鈣血癥可能主要是甲狀旁腺以外的因素引起。提示行全甲狀腺切除術(shù)時(shí)需格外注意保護(hù)甲狀旁腺，術(shù)后常規(guī)監(jiān)測(cè)血鈣和PTH。Prim和Yamashita等[28-29]研究顯示，女性術(shù)后低鈣血癥的發(fā)生率顯著高于男性。本組中女性低鈣血癥的發(fā)生率比男性高，同時(shí)女性甲狀旁腺功能減退的發(fā)生率也明顯升高。有研究顯示，女性患者的甲狀旁腺位于甲狀腺包膜內(nèi)的比例較高，這可能是術(shù)后低鈣血癥的發(fā)生率高的原因[25,30]。另外，女性患者的維生素D水平較低也可能與術(shù)后低鈣血癥發(fā)生有關(guān)[29]。眾所周知，老年人尤其是絕經(jīng)期婦女骨質(zhì)疏松的發(fā)生率較高。老年人腎功能下降和(或)PTH缺乏，對(duì)腎臟產(chǎn)生的1，25羥維生素D的調(diào)解能力明顯下降，因此腸道鈣吸收下降，從而導(dǎo)致骨質(zhì)疏松[29]。骨質(zhì)疏松的老年人沒(méi)有足夠可用于交換的鈣儲(chǔ)備來(lái)補(bǔ)充術(shù)后血鈣的下降。

行中央?yún)^(qū)淋巴結(jié)清掃與術(shù)后甲狀旁腺功能減退所致的低鈣血癥發(fā)生率的增加相關(guān)[4,20,31]。在本研究中，我們發(fā)現(xiàn)術(shù)后甲狀旁腺功能減退和低鈣血癥的發(fā)生與行中央?yún)^(qū)淋巴結(jié)清掃均相關(guān)，行雙側(cè)中央?yún)^(qū)淋巴結(jié)清掃的患者甲狀旁腺功能減退和低鈣血癥的發(fā)生率明顯增高。甲狀旁腺的位置常位于中央?yún)^(qū)淋巴結(jié)清掃范圍內(nèi)，清掃時(shí)容易造成甲狀旁腺誤切和供血血管損傷從而造成甲狀旁腺功能減退。由于對(duì)側(cè)的甲狀旁腺功能可以代償，單側(cè)清掃對(duì)甲狀旁腺功能影響較小，而雙側(cè)清掃影響較大。

納米碳懸液注射最近被應(yīng)用到前哨淋巴結(jié)活檢中對(duì)淋巴結(jié)的識(shí)別[32-34]。我們的前期研究顯示，納米碳懸液注射可以幫助識(shí)別甲狀旁腺?gòu)亩诩谞钕偈中g(shù)中保護(hù)旁腺[35]。注射納米碳懸液后，甲狀腺以及周?chē)牧馨徒Y(jié)被黑染而甲狀旁腺負(fù)染色，術(shù)者可以更容易識(shí)別甲狀旁腺。注射納米碳后，淋巴結(jié)的顯影將導(dǎo)致更徹底的淋巴結(jié)清掃，但可能加重了對(duì)甲狀旁腺血供的破壞，從而抵消了納米碳對(duì)旁腺的識(shí)別保護(hù)作用。另外，甲狀腺與甲狀旁腺關(guān)系臨床上人為分為A、B、C三型，在我們的研究中，因?yàn)榭紤]到單側(cè)腺葉切除及全甲狀腺切除這個(gè)因素，不同側(cè)的A、B、C類(lèi)型可能不同，所以，我們對(duì)于該三型不作為臨床因素的納入標(biāo)準(zhǔn)。

報(bào)道顯示，甲狀旁腺在甲狀腺癌中較甲狀腺良性疾病被誤切的風(fēng)險(xiǎn)大[36]。本研究發(fā)現(xiàn)，甲狀腺疾病的良惡性與術(shù)后低鈣血癥的發(fā)生無(wú)關(guān)聯(lián)，這可能是由于高分辨率B超的普及，使甲狀腺癌被早期發(fā)現(xiàn)。本組甲狀腺癌多為微小癌，手術(shù)時(shí)間短，恢復(fù)快，而本組良性甲狀腺疾病手術(shù)范圍均在單側(cè)腺葉以上，因此手術(shù)創(chuàng)傷差別并不明顯。手術(shù)時(shí)間與低鈣血癥的發(fā)生顯著相關(guān)。手術(shù)時(shí)間與手術(shù)范圍直接相關(guān)，通常手術(shù)范圍大，手術(shù)時(shí)間長(zhǎng)，難度較高，容易損傷甲狀旁腺。另外，手術(shù)時(shí)間長(zhǎng)的患者禁食時(shí)間長(zhǎng)，術(shù)前術(shù)中術(shù)后補(bǔ)液量大，手術(shù)應(yīng)激大，也可能會(huì)增加低鈣血癥的發(fā)生。

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Clinicalanalysisofpost-thyroidectomyhypoparathyroidismandhypocalcaemia

LIUFangzhou,QIANYichun,ZHAOYanbin,WANGYue,YANWei,FANYuwen,YUTonghua,HUTingting,ZHANGYuan.

(DepartmentofHeadandNeckSurgery,JiangsuCancerHospital,Nanjing210009,China)

ZHANGYuan,Email:yzhang1963@163.com

ObjectiveThis study aimed to investigate the influencing factors for post-thyroidectomy hypocalcaemia and hypoparathyroidism as well as the prevention and treatment for postoperative hypocalcaemia.MethodsA total of 183 patients undergoing thyroidectomy in Jiangsu Cancer Hospital were preoperatively and postoperatively assessed for hypocalcemia and hypoparathyroidism.Analyses were performed to evaluate potential elinicopathologic factors for hypocalcaemia and hypoparathyroidism according to age, gender, histopathological diagnosis, central neck dissection, lateral neck dissection, extent of operation, operative time, preoperative serum parathyroid hormone (PTH) level, and preoperative serum calcium level.ResultsA total of 163 patients were diagnosed as thyroid cancer in the 183 patients (89.07%), 20 patients were with other thyroid diseases (10.93%). Hypocalcemia was found in 7 patients (4.96%) from the 141 patients with normal parathyroid function, and in 26 patients (61.91%) from the 42 patients with hypoparathyroidism. From the 42 patients with hypoparathyroidism, 16 patients (38.09%) were without the occurrence of hypocalcemia. The drop-out value of preoperative and postoperative PTH was negative correlated to postoperative calcium. Univariate analysis showed that gender, central neck dissection, lateral neck dissection, extent of operation, operative time, and preoperative serum PTH were related to hypoparathyroidism. Age, gender, central neck dissection, lateral neck dissection, extent of operation and operative time were the factors related to hypocalcaemia.ConclusionsThe risk factors of post-thyroidectomy hypoparathyroidism include female, central neck dissection, lateral neck dissection, large extent of operation, long operative time and low preoperative PTH level. The risk factors of post-thyroidectomy hypocalcaemia include order age, female, central neck dissection, lateral neck dissection, large extent of operation and long operative time.

Thyroidectomy; Parathyroid glands; Hypoparathyroidism; Hypocalcemia; Root cause analysis

江蘇省科技廳重點(diǎn)項(xiàng)目資助(No.BE2016796)

210009 江蘇 南京， 南京醫(yī)科大學(xué)附屬腫瘤醫(yī)院(江蘇省腫瘤醫(yī)院) 頭頸外科

張園，Email:yzhang1963@163.com

10.3969/j.issn.1674-4136.2017.04.006

1674-4136(2017)04-0224-05

2017-03-20][本文編輯：李慶]