摘要: 門靜脈栓塞術(PVE)可引起栓塞肝葉的萎縮和非栓塞肝葉的代償性再生。但是由于PVE術后殘余肝臟(FLR)再生不充分,因此部分患者在PVE術后仍不適合行肝切除術。近年來,行PVE同時行肝靜脈栓塞術(HVE)的肝靜脈剝奪術(LVD)顯示出誘導FLR進一步再生的效果。相比聯合肝臟離斷和門靜脈結扎二步肝切除術,LVD觸發了更快、更強的FLR再生,且術后并發癥發生率和病死率更低。本文總結了LVD的相關文獻,介紹LVD的有效性并分析各種技術路徑的差異和安全性,認為LVD是一種安全且有效的術前預處理方法。
關鍵詞: 肝靜脈剝奪術; 門靜脈栓塞; 肝靜脈栓塞基金項目: 國家自然科學基金(82027807, 81930119)
Research advances in liver venous deprivation
HE Bensong 1,2 , XIAO Ming 3,4 , ZHANG Qijia 4 , XIANG Canhong 4 , WANG Yanxiong 1,2 , LI Yingbo 1,2 , WANG Zhishuo 1,21. Graduate School, Qinghai University, Xining 810001, China; 2. Department of Hepatobiliary Surgery, The Affiliated Hospital ofQinghai University, Xining 810001, China; 3. Department of Hepatobiliary Surgery, The Second Hospital of Shandong University,Jinan 250033, China; 4. Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine,Tsinghua University, Beijing 102218, China
Corresponding author: XIANG Canhong, roy.xx@163.com (ORCID: 0000-0002-2316-5778)
Abstract: Portal vein embolization (PVE) can induce atrophy of the embolized lobe and compensatory regeneration of the non-embolized lobe. However, due to inadequate regeneration of future liver remnant (FLR) after PVE, some patients remainunsuitable for hepatectomy after PVE. In recent years, liver venous deprivation (LVD), which combines PVE with hepatic veinembolization (HVE), has induced enhanced FLR regeneration. Compared with associating liver partition and portal vein ligationfor staged hepatectomy (ALPPS), LVD triggers faster and more robust FLR regeneration, with lower incidence rate ofpostoperative complications and mortality rate. By reviewing related articles on LVD, this article introduces the effectiveness ofLVD and analyzes the differences and safety of various technical paths, and it is believed that LVD is a safe and effectivepreoperative pretreatment method.
Key words: Liver Venous Deprivation; Portal Vein Embolization; Hepatic Vein Embolization
Research funding: National Natural Science Foundation of China (82027807, 81930119)
肝切除術適用于肝占位性病變、炎癥性疾病、創傷性肝破裂等各種肝疾病,且目前肝大部分切除術的適用范圍在不斷擴大。肝切除術后的死亡率為0% ~ 5%,而并發癥發病率為10% ~ 20%[1-2] 。最常見的死亡原因是腹腔感染和術后肝衰竭。由于殘余肝臟體積(futureliver remnant volumetric, FLR-V)不足可引起術后肝衰竭,因此在進行肝切除術前,首先需要確定切除范圍并排除FLR-V不足的情況,對于存在該問題的患者術前需要增加FLR-V。對于肝功能正常的患者,FLR-V須占肝臟總體積的25%以上[3] ,而對于合并慢性肝病的患者,FLR-V應占肝臟總體積的40%以上[4] ,否則手術切除后出現肝衰竭甚至死亡的風險極高。臨床中采用不同技術來增加FLR-V,并降低術后發生肝衰竭的可能性。門靜脈栓塞(portal vein embolization,PVE)常被用于FLR-V不足患者肝切除前的肝臟準備。然而,在等待肝切除術期間仍存在殘余肝臟(FLR)再生不足無法支持預期肝切除術以及腫瘤進展等問題,故促使研究者進一步探索替代技術。2012年提出了一種新型肝再生方法 — —聯合肝臟離斷和門靜脈結扎二步肝切除術(associating liverpartition and portal vein ligation for staged hepatectomy,ALPPS),相比于PVE,ALPPS術后FLR再生增加2 ~ 3倍,并且切除率可達95% ~ 100%。然而由于其死亡率和術后并發癥發生率居高不下,因此 ALPPS 未能成為標準化、低風險、快速再生的方法[5] 。近年來學者們發現PVE聯合肝靜脈栓塞(hepatic vein embolization, HVE)既能夠實現快速再生,又不會增加臨床風險,并被部分學者認定為提高FLR-V的最優選擇之一。
PVE聯合HVE可根據二者之間的時間間隔分為同時門靜脈聯合肝靜脈栓塞術(PHVE)[6-9]和順序門靜脈聯合肝靜脈栓塞術(PVE-HVE)[10-14]。2016年,PHVE被命名為肝靜脈剝奪術(liver venous deprivation, LVD)[6],之后PHVE又因栓塞入路、栓塞分支和栓塞材料的不同被分為雙栓塞(biembolization, BE)[8] 、擴展肝靜脈剝奪術(extended livervenous deprivation, eLVD)[7] 和放射學同時性門-肝靜脈栓塞術(radiological simultaneous portohepatic vein embolization,RASPE)[15],本文將這些技術統稱為LVD或在LVD基礎上額外栓塞肝中靜脈(middle hepatic veins, MHV)的eLVD。自從提出LVD以來,其安全性和有效性一直備受學者關注,并常與PVE、ALPPS等其他預處理手段相比較。
1 LVD的形成與發展
2007年Lee等[16] 在活體供肝移植研究中發現,在一側移植葉自發性門靜脈閉塞狀態下,移植后的肝靜脈狹窄會加速門靜脈閉塞葉的萎縮,最終導致對側移植葉進一步再生,提示PVE術后同側HVE會促進對側肝再生。2009年,Hwang等[10]將這一理論應用于PVE術后FLR-V仍lt;40% 的 12例肝癌患者中,在 PVE術后(13. 5±4. 2)d進行了HVE,并觀察到明顯FLR再生。其通過右頸內靜脈穿刺實施 HVE,在肝靜脈右支(right hepatic veins,RHV)近端放置腔靜脈濾器以防止在肝靜脈右支栓塞(right hepatic veins embolization, RHVE)過程中彈簧圈位移到下腔靜脈,使用直徑為8 ~ 12 mm的彈簧圈栓塞RHV及其主要分支。然而1例(33%)患者術后出現部分腔靜脈濾器位移進入下腔靜脈,因此轉換了HVE的方式:通過右頸內靜脈的另一個穿刺點將 5F 導管伸入RHV,并在其近端放置一個12 ~ 16 mm血管塞以防止彈簧圈遷移,彈簧圈則通過5F導管插入RHV及其主要分支。在所有RHV大分支完全栓塞后,移除7F鞘和5F導管。自此開創了 HVE 促進 FLR-V 再生的先河,之后PVE-HVE的研究仍在繼續[11-17]。2015年Hwang等[12]再次發表 42 例(包括 2009 年已發表的 12 例患者)接受PVE-HVE治療的患者數據,充分證明PVE術后HVE能夠進一步刺激FLR再生,并且與PVE有相似的并發癥。此外,Niekamp等[13] 對PVE術后仍不能達到手術條件的結直腸癌肝轉移患者進行了挽救性HVE,并為原本不能手術的3例(33%)患者成功進行了肝切除術。2023年,在對PVE-HVE術后肝功能變化的研究[14] 中發現,HVE術后功能性FLR-V的增加程度大于FLR-V,且中位增長率高于單純PVE(71. 3% vs 27. 0%),充分證明PVE-HVE在FLR再生方面有較好的作用。
2016 年,為了縮短一期栓塞到二期切除術間隔時間,Guiu等[6] 將經皮肝PVE和HVE同時進行,并將其命名為LVD。該方法經皮肝入路用血管封堵器(amplatzervascular plug Ⅱ,AVP)栓塞RHV及其主要分支,并使用1∶1的碘油和氰基丙烯酸正丁酯混合物栓塞RHV遠端分支以及交通靜脈,最后對穿刺道進行栓塞。由于右前葉的2/3靜脈由MHV引流[18-20] ,因此可將RHVE擴展為RHVE+MHVE[7] 。額外的 MHVE 可進一步促進 FLR 再生,Guiu等[7]將其命名為eLVD。多數與PVE進行比較的研究[15,21-23] 表明,LVD 后 FLR-V 增幅gt;PVE,且 LVD 是FLR-V和FLR功能(future liver remnant function, FLR-F)變化的獨立影響因子[24]。2020年出現了RASPE[15],其操作過程與LVD相似。
BE 是經皮肝 PVE 同時采用頸內靜脈入路 AVP 栓塞RHV的操作[8] ,其在經右頸內靜脈入路后使用比目標肝靜脈直徑大80% ~ 100%的AVP栓塞目標肝靜脈,但未使用線圈或液體栓塞材料來栓塞肝靜脈末端及小分支,并且也沒有進行穿刺道的栓塞。Haruki等[25] 和Masthoff 等[26] 研究中的操作方式與此相似。2023 年,Della Corte等[27]研究結果顯示BE與LVD術后安全性和有效性無差異,然而由于BE中患者基線FLR-V更?。↙VD∶484 cm 3 ;BE∶394 cm 3 )且等待時間更長(LVD∶21 d;BE∶26 d),基線 FLR-V與增生程度呈負相關,理論上 BE后FLR增生程度應該比LVD更高。兩者增生程度相似可能是因為LVD使用液體栓塞劑栓塞了可能形成肝靜脈-靜脈通路(即栓塞葉與未栓塞葉邊界)的小分支,從而誘導FLR進一步增生。
隨著LVD技術不斷成熟,與其他術前準備相結合的研究逐漸增多。2018年出現了一種針對肝門部膽管癌患者的方法[21] ,在進行LVD手術時或手術前1周進行經皮膽道引流,可以縮短術前等待時間,并降低腫瘤沿膽管擴散的風險。有學者[28]將MHV結扎納入ALPPS的第一階段;通過腹腔鏡下行 LVD(LP-LVD)也顯示出良好的再生效果[29-30] ;或嘗試先行HVE后行PVE,發現HVE術后門靜脈流量降低,繼續進行PVE時栓塞物質進入對側門靜脈的風險增加,因此HVE術后PVE存在較大意外栓塞風險[31] ;LVD 前行經導管動脈化療栓塞術(TACE),并發現合并肝硬化的肝細胞癌患者 TACE 后LVD同樣能誘導顯著FLR再生[32]。
2 LVD術后的FLR再生
2. 1 體積增生的變化 LVD與二期切除術的間隔時間平均為 31 d,動力學增長率(kinetic growth rates, KGR)為 9. 3 cm 3 /d,eLVD 術后 7 d內的 KGR 為 25 cm 3 /d[7] ,與ALPPS相似[5,33] 。eLVD術后21 d的KGR為9. 6 cm 3 /d,高于單純門靜脈結扎和 PVE,與 LVD相似[6,33-34] ,由此表明LVD術后FLR增生主要集中在前期,且并未觀察到LVD和eLVD之間KGR的差異[35] 。Marino等 [36] 研究亦顯示LVD術后FLR增長高峰出現得比單純PVE更早、更高。一項薈萃分析[37] 指出 ALPPS 術后 FLR 再生率與LVD相比無差異,其中ALPPS和LVD早期KGR無顯著差異(9 d vs 7 d∶23 cm 3 /d vs 26 cm 3 /d,P=0. 31),但由于LVD再生后期 FLR增長率下降,后期 ALPPS的 KGR高于 LVD(9 d vs 21 d∶20 cm 3 /d vs 10 cm 3 /d,P=0. 02)[38] 。與PVE的對比研究[39] 顯示,LVD術后22 d內FLR再生率高于 PVE,而 22 d 后下降至與 PVE 無差異。Panaro等[22] 研究顯示 LVD 術后 21 d 的 KGR 為 16 cm 3 /d,高于Guiu等[6]報道的9. 3 cm 3 /d,其原因可能是LVD后期FLR增長率隨時間增長而下降,而Panaro的研究中LVD術后間隔時間短于Guiu的研究(31 d)。由此可見LVD與二期切除術的間隔時間可以縮短為21 d,且能保持安全性和有效性不變。
在 PVE 或肝切除的患者中,FLR-F 增加并不總與FLR-V增加相關[40-41] 。肝切除或 ALPPS術后 FLR-F再生速度較緩[42] ,ALPPS 第一階段后 1 周 FLR-F 增益是FLR-V增益的50%[43-45] 。相反,PVE之后的FLR-F再生速度更快[40] 。FLR-F在eLVD術后7 d達到高峰,并隨后開始下降(7 d∶65. 7%;14 d∶56. 7%;21 d∶56. 7%)[7] 。
LVD術后FLR-F再生程度在7、14、21 d時均高于FLR-V再生程度(54. 3% vs 37. 8%;56. 1% vs 50%;68. 2% vs52. 6%),且兩者上升趨勢相似。值得注意的是,FLR-F再生程度在第7天的增幅至少是PVE或ALPPS的2倍。
2. 2 基礎肝病對 FLR 再生的影響 大多數 PVE 術后FLR再生受限的患者,在接受順序HVE治療后,相對于基線FLR,其再生量為(27. 6±8. 6)%[10] 。然而,在病毒性肝炎相關肝硬化患者中,HVE對肝體積的影響遠小于非 肝 硬 化 患 者(KGR∶lt;1%/周 vs gt;4%/周 )[10-12] 。Kobayashi 等[39] 指出 LVD 術后正常肝和有基礎肝病的FLR 再生程度(栓塞后 22 d FLR%-基線 FLR%)分別為:正常肝 14. 9%、纖維化 9. 3%、脂肪變性 6. 7%,表明在LVD術后具有正常肝實質的患者通常會有更大的肝再生能力。合并基礎肝病患者由于存在豐富的肝內靜脈交通支,栓塞無法有效阻斷血流,因此這類患者進行HVE 術后 FLR 再生效果不佳[12] 。國內有學者 [46] 已將PVE/HVE技術應用于乙型肝炎肝硬化合并肝癌患者,并顯示出良好的再生效果和安全性。但由于樣本量不足,結果需要進一步確認。
2. 3 腫瘤分類對再生的影響 根據Hwang等[12]的研究結果顯示,由于腫瘤分類不同,PVE-HVE術后FLR的增長速度也會有所差異。肝內膽管癌和肝門部膽管癌的KGR相似(KGRgt;4%/周)。在經歷了PVE-HVE手術2個月后,1例(25%)肝細胞癌患者幾乎無FLR再生(KGRlt;1%/周),而另外2例(50%)肝細胞癌患者則等待間期超過6個月才行切除術。但也有研究[39,47]認為再生程度與評估的惡性腫瘤類型無關。Guiu等[24] 在LVD和PVE對照研究中單因素分析顯示栓塞技術、年齡和基線FLR-V與FLR-V變化相關,但與肝臟總體積、腫瘤類型和手術類型無關。而造成這種差異的原因是否與介入方式有關尚未明確。經統計,所有行LVD的腫瘤類型中結直腸癌肝轉移占大多數(58%),其余類型為肝門部膽管癌(18%)、肝內膽管癌(9%)、肝細胞癌(9%)、膽囊癌(2%)和其他(4%)。
3 LVD的安全性
3.1 栓塞術中并發癥 術中誤栓MHV發生率為0.8%[12,23,48],栓塞材料意外位移發生率為1.7%[23,26,49]。但術后未進行人為干預,且均未產生嚴重后果。盡管Guiu等[6]提出AVP直徑比目標靜脈直徑大50%可有效避免術后封堵物遷移,但并不能完全避免此類事件的發生[23,26,49]。在經頸靜脈入路中使用液體栓塞材料可能導致栓塞材料溢至肺動脈,因此在決定使用液體栓塞時,應盡量采用經皮經肝入路[14]。
3. 2 栓塞術后并發癥 2003年,Nagino等[50] 對存在肝右后下靜脈的肝內膽管癌患者進行術前預處理時,為了避免肝右靜脈重建在PVE的同時進行了RHVE。21 d后該患者順利進行左三區伴RHV切除并出院,首次證明了術前 PVE 聯合 HVE 術后患者無并發癥出現。Guiu等[24] 研究中發現LVD術后有患者嚴重虛弱,給予補充維生素和離子后虛弱癥狀消失。其他并發癥多為疼痛和發熱[35] ,并發癥發生率與 PVE 術后相似(15% vs15. 6%)。LVD術后肝周血腫偶有發生,故穿刺道栓塞需使用膠水等永久性栓塞劑避免出血[51] 。在 Chebaro等[52] 的研究中,有2例(1. 6%)原發性肝癌患者LVD后死于膿毒性膽管炎,這可能與患者病情較重有關。Hwang等[12] 對7例PVE-HVE術后未接受肝切除術的患者進行1年以上的隨訪,未觀察到如肝膿腫、膽管炎或壞死等并發癥。
4 LVD后的二期手術切除率
有研究[35,53-54] 顯示,LVD術后二期手術切除率高于PVE(87% vs 75%),而二者術中出血、肝門阻斷時間、術中輸注紅細胞量及手術時間均無差異,且LVD組肝臟狀態較差(基礎肝?。篖VD 50% vs PVE 45%)[55] 。不可切除的原因包括患者栓塞后FLR-V不足、患者發現腹膜癌以及患者疾病進展[53-54] 。LVD 二期手術切除率低于 ALPPS(72. 6% vs 90. 6%,Plt;0. 001),可能是因為LVD組原發性肝癌患者較多導致[52] 。LVD術后的二期手術切除率因研究類型和納入患者的病情而異,且受每個中心的選擇和治療偏好的影響。
5 二期肝切除術后并發癥
行LVD患者肝切除術后常見并發癥為出血(41%)、膽瘺(5%)、肝衰竭(17%)、腹水(23. 5%)、門靜脈血栓形成及膽管炎等[7-9] 。LVD 術后肝衰竭導致的死亡率與PVE 術后相似(11% vs 24. 8%,P=0. 145)[35] 。相較于PVE,術前接受LVD治療的患者術后出血事件更多[56] ,這可能與該技術誘發的血流動力學變化有關。Panaro等[22] 報道的 LVD 患者肝切除術后并發癥發生率為76. 9%,其中Claven-Dindo≥3級占7. 7%。Chebaro等[52]研究顯示,LVD后100例行預期肝切除術的患者術后并發癥Claven-Dindo≥3級為21. 9%。
6 二期肝切除術后生存率
Heil等[35]研究顯示,LVD和PVE術后90 d死亡率分別為3%和16%,LVD組的90 d死亡率明顯低于PVE和ALPPS;LVD組死亡原因主要為出血性休克,PVE組為膿毒癥伴多器官功能衰竭(65%)、術后出血(29%)和卒中(6%)。Kobayashi等[39] 研究結果顯示,LVD組肝切除術后1年、2年和3年的生存率分別為95%、81%和81%,PVE組分別為96%、84%和77%;LVD組肝切除術后1年、2年和3年的無病生存率分別為66%、44%和33%,PVE組分別為65%、40%和27%。兩組生存率和無病生存率均無差異。一項薈萃分析[57] 結果亦顯示ALPPS和PVE的1年生存率與LVD相似。
7 尚存爭議的問題
(1)潛在交通支的栓塞:栓塞葉和FLR之間的肝靜脈側支形成可能會降低FLR再生程度,但對有FLR優勢引流靜脈的分支栓塞又會增大肝淤血的風險。因此對于是否栓塞肝靜脈小分支,需根據患者情況決定。(2)LVD-肝切除術間隔時間:對于惡性腫瘤患者,特別是晚期肝癌患者,早期行肝臟切除可降低腫瘤進展的風險。Guiu等[6] 認為栓塞與預期肝切除術之間的時間間隔可以縮短至15 d而不影響再生結果。但因其納入的樣本量較低,故將等待時間縮短為15 d,在促進FLR再生的同時是否能降低腫瘤進展需要進一步討論。(3)適用的基線FLR-V:有報道[26] 稱對于中度 sFLR-V(標準殘肝體積gt;26. 3%)患者,選用PVE或LVD術后sFLR-V再生情況無明顯差異,但LVD操作復雜且相比于PVE創傷較大,所以對中度sFLR-V基線患者首選PVE還是直接選擇LVD需要進一步研究。(4)不同技術路徑對術后FLR再生的影響:由于各LVD技術路徑和栓塞材料不同,Korenblik等[58] 計劃進一步研究各技術對FLR再生的影響。(5)適用患者類型:盡管未通過診斷確定LVD的適應證,但在已有的報道中LVD組結直腸癌肝轉移瘤和肝門部膽管癌更為常見。因此,結直腸癌肝轉移瘤和肝門部膽管癌可能是LVD的良好指征。
8 小結
本文總結了已應用于臨床的部分LVD技術路線及其優勢和安全性,認為LVD可廣泛應用于以結直腸癌肝轉移腫瘤、肝門部膽管癌為代表的不同類型肝臟及膽管腫瘤引起的 FLR 不足患者中,在大范圍肝切除前促進FLR再生,相較于單純PVE有著更顯著的再生效果,為臨床治療提供了另一種選擇,能夠針對患者的病情和個體差異選擇不同的操作方式以達到最佳治療效果。
利益沖突聲明: 本文不存在任何利益沖突。
作者貢獻聲明: 賀本松負責文獻檢索,資料分析,撰寫及修改論文;肖鳴、張琪佳負責收集數據,文獻檢索和整理;王言雄、李迎博、王之爍參與修改;項燦宏負責擬定寫作思路,確定框架,指導撰寫文章并最后定稿。
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