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        肝切除術(shù)前肝功能的評(píng)估方法

        2017-08-18 22:29:18林凱臨孫惠川
        上海醫(yī)藥 2017年15期

        林凱臨+孫惠川

        摘 要 肝切除是肝癌患者獲得長期生存的最主要治療手段。多數(shù)肝癌患者存在不同程度的肝功能受損現(xiàn)象,準(zhǔn)確評(píng)估肝癌患者肝切除術(shù)前的肝功能有助于降低手術(shù)死亡率。本文回顧現(xiàn)有的肝切除術(shù)前肝功能評(píng)估方法,概要介紹余肝體積評(píng)估及干預(yù)手段的研究進(jìn)展,以期進(jìn)一步指導(dǎo)臨床實(shí)踐。

        關(guān)鍵詞 肝切除術(shù) 肝功能評(píng)估 余肝

        中圖分類號(hào):R735.7; R730.56 文獻(xiàn)標(biāo)識(shí)碼:A 文章編號(hào):1006-1533(2017)15-0020-08

        Preoperative assessment of liver function*

        LIN Kailin**, SUN Huichuan***

        (Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China)

        ABSTRACT Surgical resection remains the major curative treatment option for patients with liver cancer. However, most patients with primary liver cancer have an impaired liver function. Preoperative assessment of liver function is therefore important in reducing postoperative morbidity and mortality. Here we review the current advances in preoperative assessment of liver function and the update in evaluating and augmenting future remnant liver volume in order to further guide clinical practice.

        KEY WORDS hepatectomy; liver function assessment; remnant liver

        原發(fā)性肝癌(90%以上是肝細(xì)胞癌,簡稱肝癌)是我國男性發(fā)病率位居第4、死亡率位居第3的惡性腫瘤類型[1]。目前,肝切除是肝癌患者獲得長期生存的最主要治療手段。但是,在接受肝切除術(shù)的肝癌患者中,由于80%患者的肝癌與乙型肝炎病毒感染相關(guān),72.1% ~ 82.3%的肝癌患者合并肝硬化[2],致使他們的肝臟再生能力和儲(chǔ)備功能受損。根據(jù)2011年國際肝臟外科學(xué)組制定的術(shù)后肝功能衰竭(post-operative liver failure, PLF)標(biāo)準(zhǔn),肝癌肝切除的PLF發(fā)生率為9% ~ 18.6%[3-4]。因此,準(zhǔn)確評(píng)估肝癌患者肝切除術(shù)前的肝臟儲(chǔ)備功能不僅有助于降低手術(shù)死亡率,而且有助于減少術(shù)后中長期出現(xiàn)肝功能不全,避免無腫瘤復(fù)發(fā)的死亡。

        1 常用的肝功能評(píng)估方法

        常用的肝功能評(píng)估方法包括Child-Pugh評(píng)分[5]、吲哚菁綠15 min清除率[6]、肝靜脈壓力梯度(hepatic venous pressure gradient, HVPG)[7-8]和肝硬化血清學(xué)標(biāo)志物[9]等。為評(píng)估肝切除范圍的安全性,人們還開發(fā)出了利用CT測定肝臟體積的技術(shù),以用以評(píng)估肝切除范圍對(duì)PLF的影響[10]。

        1.1 Child-Pugh評(píng)分

        Child-Pugh評(píng)分是一種基于5項(xiàng)易于測得的參數(shù)評(píng)估肝功能的方法[5]。該方法臨床應(yīng)用廣泛,但亦存在問題。例如,Child-Pugh分級(jí)比較寬泛,且涉及到的“腹水”、“肝性腦病”等因素的界定較為主觀,有時(shí)結(jié)果會(huì)偏離臨床實(shí)際[11-12],故即使Child-Pugh分級(jí)為A級(jí),患者在術(shù)后出現(xiàn)肝功能失代償?shù)目赡苄匀圆恍13]。因此,尚需使用其他方法來評(píng)估此類患者的肝功能儲(chǔ)備。

        1.2 終末期肝病模型(model for end-stage liver disease, MELD)評(píng)分

        MELD評(píng)分主要用以評(píng)估終末期肝病患者的生存時(shí)間[14],亦有研究顯示可用以預(yù)測肝部分切除患者的手術(shù)風(fēng)險(xiǎn)。MELD評(píng)分≤10被認(rèn)為可安全施行肝切除術(shù)[13]。該方法目前主要用以篩選準(zhǔn)備接受肝移植的患者[14-15]。

        1.3 吲哚菁綠15 min清除率

        吲哚菁綠清除試驗(yàn)是一種定量分析肝功能的方法,可用以預(yù)測肝切除術(shù)后患者的死亡率[6]。對(duì)患者經(jīng)靜脈一次性注射吲哚菁綠0.5 mg/kg后,測出15 min時(shí)的吲哚菁綠滯留率(retention rate of indocyanine green at 15 minutes, ICG-R15)。ICG-R15在藥理學(xué)上大抵等于吲哚菁綠15 min清除率。需注意的是,吲哚菁綠和膽紅素在肝細(xì)胞轉(zhuǎn)運(yùn)過程中結(jié)合于相同載體并表現(xiàn)為相互競爭性抑制作用。因此,對(duì)高膽紅素水平的梗阻性黃疸患者,吲哚菁綠清除試驗(yàn)不再有效,此時(shí)可用99mTc-二乙烯三胺五乙酸半乳糖基人血清白蛋白顯像技術(shù)作為肝功能儲(chǔ)備評(píng)估的替代方法[16]。

        擴(kuò)大的肝切除術(shù)因遺留較小的肝剩余體積而常伴有較高的并發(fā)癥發(fā)病率和死亡率[17]。對(duì)不伴有慢性肝炎或肝硬化的患者,不發(fā)生PLF的最小安全肝剩余體積為肝總體積的20% ~ 33%[18]。當(dāng)患者的肝功能異常時(shí),應(yīng)避免對(duì)其施行肝大部切除術(shù)(通常定義為切除≥3段Couinaud肝段)。ICG-R15對(duì)評(píng)估肝切除術(shù)的安全性具有重要意義。安全的肝大部切除術(shù)所對(duì)應(yīng)的ICG-R15為10% ~ 14%[6,19-20]。Makuuchi等[6]提出,對(duì)ICG-R15為10% ~ 20%的患者,最小的安全肝剩余體積為肝總體積的2/3。對(duì)ICG-R15<30%的患者,施行單肝段切除術(shù)是安全的。對(duì)ICG-R15更高的患者,施行肝楔形切除術(shù)或腫瘤摘除術(shù)亦是可行的。但若患者存在腹水或血清總膽紅素水平異常(>34.3 mol/L)時(shí),應(yīng)避免施行肝切除術(shù)[6,21]。近期,Kokudo等[22]還提出了一種新的肝功能分級(jí)方法白蛋白-吲哚菁綠評(píng)估法,其預(yù)測值=0.663×log10 ICG-R15(%)-0.071 8×白蛋白值(g/L)(界限在-2.20 ~ -1.39間),旨在更好地進(jìn)行術(shù)前肝功能評(píng)估,并在前期研究中取得了與Child-Pugh評(píng)分類似的效果,然要實(shí)際臨床應(yīng)用尚有待更深入的研究和實(shí)踐的檢驗(yàn)。

        1.4 HVPG

        門脈壓力的正常值為5 ~ 10 mmHg。由于大多數(shù)情況下無法直接測量門脈壓力,故臨床上多采用通過頸靜脈穿刺、置管來測量HVPG,估算門靜脈與下腔靜脈間的壓力梯度,借此反映門脈壓力情況。因此,門脈壓力可用HVPG指代(正常值為1 ~ 5 mmHg)?,F(xiàn)一般認(rèn)為,胃底食管靜脈曲張患者的HVPG>10 mmHg,存在腹水患者的HVPG>8 mmHg[7]。巴塞羅那臨床肝癌分期小組將有臨床意義的門脈高壓定義為HVPG>10 mmHg[23],而其發(fā)表的肝癌治療指南則將門脈高壓列為肝切除術(shù)的禁忌證之一[24-25]。門脈高壓亦可用其他臨床表現(xiàn)指代,包括食管靜脈曲張、脾大(最大直徑>12 cm)和血小板計(jì)數(shù)<1×105/ml[3,26]。門脈高壓患者通常伴有較嚴(yán)重的肝纖維化,肝切除術(shù)后的并發(fā)癥和肝功能不全發(fā)生率、死亡率均較高[27]。不過,也有研究認(rèn)為,這些門脈高壓征象不應(yīng)視為代償期肝硬化患者肝切除術(shù)的絕對(duì)禁忌證[28]。盡管術(shù)后食管靜脈曲張破裂出血可致高達(dá)30%的死亡率[29],但經(jīng)采取諸如術(shù)前內(nèi)鏡套扎、使用質(zhì)子泵抑制劑或H2受體阻滯劑等預(yù)防措施以及進(jìn)行謹(jǐn)慎的術(shù)前肝功能評(píng)估等措施,仍可保證部分門脈高壓患者的術(shù)后結(jié)局和長期生存不受門脈高壓因素的影響[30-31]。

        1.5 血清學(xué)標(biāo)志物

        肝硬化的血清學(xué)標(biāo)志物包括透明質(zhì)酸、層粘連蛋白、Ⅳ型膠原和Ⅲ型前膠原氨基端肽水平等,既往主要被用來評(píng)估慢性肝病的進(jìn)展、炎癥活動(dòng)和肝纖維化程度以及治療效果[32-34]。一項(xiàng)回顧性研究顯示,肝切除術(shù)前的乙型肝炎病毒DNA、血清前白蛋白、透明質(zhì)酸和層粘連蛋白水平均與術(shù)后肝功能不全相關(guān)[9]。Okuda等[35]的研究發(fā)現(xiàn),Mac-2結(jié)合蛋白的糖基化異構(gòu)體(glycosylated isoforms of Mac-2 binding protein, M2BPGi)水平可用來預(yù)測肝切除者的PLF,且見在肝纖維化程度相同時(shí),丙型肝炎病毒感染患者的M2BPGi水平顯著高于非丙型肝炎病毒感染患者,提示丙型肝炎病毒感染患者的M2BPGi水平的預(yù)測性可能更強(qiáng)。

        2 肝臟體積的評(píng)估

        多種影像學(xué)技術(shù)均可用來評(píng)估余肝體積,包括閃爍掃描術(shù)[36-37]、超聲顯像術(shù)[38]、CT[39-43]和MRI[44],其中利用CT測定余肝體積已成為肝切除和移植術(shù)前的最常用方法[45-47]。1992年Soyer等[48]利用CT信息構(gòu)建肝臟的三維圖像,經(jīng)外科醫(yī)師標(biāo)記肝切除范圍后,由放射科醫(yī)師計(jì)算出余肝體積。他們的研究發(fā)現(xiàn),余肝體積≥35%的患者均未出現(xiàn)PLF,因此推測35%的余肝體積是肝切除術(shù)的安全界值。需指出的是,上述余肝體積均是相對(duì)于包括腫瘤體積在內(nèi)的全肝體積而言的。顯然,肝臟體積在不同患者間存在差異,腫瘤體積也會(huì)影響全肝體積的計(jì)算。因此,必須建立健康者標(biāo)準(zhǔn)肝臟體積的數(shù)學(xué)模型,后者還可用于在活體部分供肝移植時(shí)計(jì)算受體所需的肝組織量和供體需保留的肝組織量的最低值。1995年Urata等[47]提出了通過體表面積或體重預(yù)測健康成人和小兒肝臟體積的數(shù)學(xué)公式。盡管它們均可較為準(zhǔn)確地計(jì)算出健康者的肝臟體積,但采用體表面積的公式似更易使用。其后Kubota等[10]提出,可以CT測定的需切除的非腫瘤肝組織體積與通過Urata公式計(jì)算得到的標(biāo)準(zhǔn)化肝臟體積的比值來預(yù)測肝切除術(shù)的安全性。后來,大多數(shù)外科醫(yī)師便采用余肝體積來評(píng)估肝切除術(shù)后出現(xiàn)肝功能不全的風(fēng)險(xiǎn)[43]。

        關(guān)于健康成人的標(biāo)準(zhǔn)化肝臟體積(cm3),一般通過體表面積計(jì)算得到,最常用的就是Urata公式,即706.2×體表面積(m2)+2.4。2008年Yoshizumi等[49]發(fā)現(xiàn),如體表面積<2 m2,使用Urata公式算得的肝臟體積偏低,故提出了自己的修正公式,即772×體表面積(m2)。中國研究者也經(jīng)研究提出了通過體重計(jì)算中國成人標(biāo)準(zhǔn)化肝臟體積的計(jì)算公式(華西公式),即11.5×體重(kg)+334,并發(fā)現(xiàn)該公式算得的肝臟體積較Urata公式更準(zhǔn)確[50]。有研究比較了余肝體積/體重和余肝體積/標(biāo)準(zhǔn)化肝臟體積對(duì)PLF的預(yù)測能力,結(jié)果發(fā)現(xiàn)前者的預(yù)測結(jié)果更準(zhǔn)確[42,51]。Vauthey等[52]提出的西方成人肝臟體積計(jì)算公式為1 267.28×體表面積(m2)-794.41(Vauthey公式),并已在多項(xiàng)研究中得到驗(yàn)證[53-55]。

        對(duì)肝臟健康和損傷患者,采用余肝體積預(yù)測PLF的界值是不同的。大多數(shù)研究者認(rèn)為,對(duì)無肝臟損傷患者,余肝體積>30%的肝切除術(shù)是安全的;對(duì)肝硬化患者,余肝體積>40%或50%的肝切除術(shù)是安全的[10,18,41,56]。不足的余肝體積與不良的術(shù)后結(jié)局相關(guān),主要并發(fā)癥發(fā)生率也會(huì)提高,包括PLF發(fā)生率提高和住院時(shí)間延長等[39,41,57]。根據(jù)Ribero等[58]的研究,安全肝切除的閾值用標(biāo)準(zhǔn)化肝臟體積(用Vauthey公式算得)指示時(shí)應(yīng)為:對(duì)肝臟健康患者,20%;對(duì)有化療相關(guān)肝臟損傷患者,30%;對(duì)慢性肝病患者,40%。

        利用CT測算余肝體積的最主要優(yōu)點(diǎn)是無創(chuàng)性,且CT常用于臨床隨訪,故亦易獲得用以計(jì)算余肝體積的CT圖像。筆者也曾研究過中國肝癌患者余肝體積的安全界值[59],發(fā)現(xiàn)對(duì)Child-Pugh分級(jí)為A級(jí)的肝癌患者(未區(qū)分是否伴有肝硬化),半肝切除術(shù)的安全余肝體積界值是35%或250 cm3。

        利用CT測算的余肝體積來評(píng)估肝切除術(shù)前的肝功能有一定局限性,有時(shí)評(píng)估結(jié)果與實(shí)際肝功能及預(yù)測的術(shù)后結(jié)局不符[60],即此時(shí)余肝體積并不能對(duì)等地反映余肝功能,后者還會(huì)受到肝臟基礎(chǔ)疾病如肝纖維化、肝硬化和脂肪變性等的影響。因此,尚需確定患者肝臟是否存在基礎(chǔ)疾病方能更正確地應(yīng)用余肝體積的概念[61],這對(duì)在誘導(dǎo)或新輔助化療治療之后再接受肝切除術(shù)的患者尤為重要,因?yàn)楦闻K實(shí)質(zhì)可能在化療治療后發(fā)生脂肪變性或靜脈閉塞[62]。在缺乏術(shù)前活組織檢查的情況下,肝臟實(shí)質(zhì)損害或病變通常難以在術(shù)前得到確認(rèn)。目前,基于余肝體積數(shù)據(jù)而定的肝切除術(shù)篩選標(biāo)準(zhǔn)并無定論,文獻(xiàn)中提及的最小安全余肝體積在10% ~ 40%間,與不同的肝病分級(jí)及不同的測算方法有關(guān)[63]。實(shí)際上,PLF還受到患者年齡、肝臟受損程度、手術(shù)技術(shù)和余肝的定義等諸多因素的影響[18]。因此,尋找最小的安全余肝體積很困難,且可能也不符合患者的利益。此外,盡管CT可用于監(jiān)測門靜脈栓塞(portal vein embolization, PVE)后余肝體積的變化,但余肝體積并不總是能對(duì)等地反映余肝功能。有研究報(bào)告,PVE后肝臟功能的改變與其體積的改變間存在偏差,余肝功能的改變甚于余肝體積的增加[61]。當(dāng)膽道或血管梗阻時(shí),無功能肝臟的存在會(huì)影響余肝功能[43]。PVE后一側(cè)肝萎縮也會(huì)影響余肝功能[64]。

        為克服上述缺陷,有研究試圖將肝功能檢測和功能性肝臟成像技術(shù)結(jié)合起來用以評(píng)估肝功能儲(chǔ)備[65]。3D分析技術(shù)的發(fā)展已使精確計(jì)算余肝體積成為可能。利用基于增強(qiáng)型CT的3D圖像重建技術(shù)可在精確評(píng)估功能性余肝體積時(shí)排除缺血和充血狀態(tài)的影響。

        3 術(shù)前改善肝臟功能以提高肝切除術(shù)的安全性

        約90%的肝癌患者存在不同程度的肝功能損害,其中大多數(shù)為慢性肝損害且不伴有癥狀[66]。因此,在決定施行肝切除術(shù)時(shí),對(duì)患者的肝功能進(jìn)行評(píng)估與制定合理的手術(shù)方案同樣重要。避免因余肝體積不足及功能低下所引起的術(shù)后肝功能失代償是提高肝切除術(shù)安全性的主要目標(biāo),采取的措施以增加余肝體積為重。肝部分切除術(shù)的死亡率在20世紀(jì)70年代時(shí)高達(dá)20%[67],但隨著人們對(duì)肝臟解剖結(jié)構(gòu)的認(rèn)識(shí)加深、手術(shù)技術(shù)的完善,加之仔細(xì)篩選患者,目前肝切除術(shù)的安全性很高,手術(shù)死亡率已<5%[68]?,F(xiàn)有若干種術(shù)前促余肝增生的方法來提高肝癌的可切除率。

        對(duì)肝功能儲(chǔ)備異常(ICG-R15在10% ~ 20%間)的準(zhǔn)備接受肝大部切除術(shù)患者(余肝體積<60%)或肝功能正常的準(zhǔn)備接受擴(kuò)大的肝切除術(shù)患者(余肝體積<40%),施行PVE可確保肝切除術(shù)的安全性[10]。PVE可通過栓塞腫瘤所在肝葉的同側(cè)門脈而誘導(dǎo)余肝增生,以降低擴(kuò)大的肝切除術(shù)后的肝衰竭和死亡發(fā)生率[10,69],同時(shí)亦可用來排除余肝增生不良患者于手術(shù)治療外[70]。一些研究比較了在擴(kuò)大的肝切除術(shù)前是否施行PVE的結(jié)果,發(fā)現(xiàn)PVE組患者的長期結(jié)局與非PVE組患者相當(dāng)、甚至更佳[71-74],且PVE組患者還均是在過去通常被認(rèn)為因余肝體積過小而難以安全地接受手術(shù)治療的患者。

        肝切除術(shù)前決定對(duì)某一患者是否施行PVE時(shí)需考量一些問題。首先,需個(gè)體化評(píng)估患者的肝臟情況、尤其是有無基礎(chǔ)實(shí)質(zhì)病變,以確定每一特定患者的可接受的余肝體積。其他的患者參數(shù)如身高和體表面積亦應(yīng)予以重視。高大者較矮小者有更大的體表面積,在施行相同程度的肝切除術(shù)時(shí)需有更大的余肝體積。其次,應(yīng)注意患者的年齡、營養(yǎng)狀況、伴發(fā)疾病和功能狀態(tài)均會(huì)影響PVE促余肝增生的程度,進(jìn)而影響手術(shù)的施行[70]。

        序貫施行經(jīng)導(dǎo)管肝動(dòng)脈化療栓塞(transcatheter arterial chemoembolization, TACE)和PVE也是可選用的方法。由于存在基礎(chǔ)肝硬化,接受PVE的肝癌患者獲得的肝再生效果有限[75-77]。此外,接受PVE的肝段的動(dòng)脈血流代償性地增加還可能促進(jìn)動(dòng)脈供血的腫瘤增殖加快[78-80]。因此,序貫施行TACE和PVE的方法應(yīng)運(yùn)而生[71]。有關(guān)研究顯示,與僅接受PVE患者相比,接受序貫方法患者的余肝增生率更高、腫瘤進(jìn)展率更低[71,73]。盡管施行序貫方法存在著肝臟實(shí)質(zhì)缺血的風(fēng)險(xiǎn),但綜合患者的腫瘤可切除率、術(shù)后5年生存率和無瘤生存率考慮,此方法仍是安全可行的[71,73,81]。

        對(duì)肝切除術(shù),主要的限制在于余肝體積不足。盡管前述方法均能有效誘導(dǎo)余肝增生,但要達(dá)到滿意的余肝體積需較長時(shí)間[82]。在余肝增生至足以耐受肝切除術(shù)時(shí),腫瘤進(jìn)展亦可能伴隨而來,尤其是當(dāng)腫瘤侵犯同側(cè)門脈時(shí),腫瘤增殖可能加快,且在栓塞靜脈的對(duì)側(cè)沉積并發(fā)生轉(zhuǎn)移[79,83]。聯(lián)合肝臟離斷和門靜脈結(jié)扎的二步肝切除術(shù)(associated liver partition and portal vein ligation for staged hepatectomy, ALPPS)是近年來相關(guān)手術(shù)技術(shù)的重要?jiǎng)?chuàng)新[82],它的出現(xiàn)較好地解決了上述問題,并已用于結(jié)直腸癌肝轉(zhuǎn)移和脂肪變、肝硬化的肝切除術(shù)[83-87]。施行ALPPS可使余肝增生70%[88],在余肝增生的程度上優(yōu)于PVE[89-90]。ALPPS用于肝癌的適用指征為腫瘤負(fù)荷巨大、具備邊緣余肝體積的患者[89-90],可伴或不伴有大血管侵犯[87],能在一定程度上使得原難以施行切除術(shù)的腫瘤轉(zhuǎn)為具有潛在的可切除性。但短期內(nèi)施行兩次手術(shù)常常伴隨著并發(fā)癥和死亡率的升高[88,90-92],因此對(duì)ALPPS的長期臨床結(jié)局還需觀察。

        4 結(jié)語

        肝切除術(shù)前必須重視肝功能評(píng)估。盡管已有許多方法可用于肝功能評(píng)估,但每種方法均存在局限性,因此應(yīng)綜合多種方法以從多個(gè)角度來評(píng)估肝功能。近年還出現(xiàn)了一些新的肝功能評(píng)估方法,其中肝臟彈力測定有可替代有創(chuàng)的評(píng)估方法的潛力。此外,有研究利用CT、MRI以及核醫(yī)學(xué)灌注評(píng)價(jià)肝葉或肝段的功能[93-94],這些新技術(shù)將有助于更為準(zhǔn)確地評(píng)估占位性病變對(duì)鄰近肝功能的影響以及再生的肝組織功能。

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