肝臟移植手術患者的預後研究

Study on the prognosis of patients underwent liver transplantation

蕭智陽(Chih-Yang Hsiao)

指導教授 ： 胡瑞恒

共同指導教授 ： 黃凱文(Kai-Wen Huang)

國立臺灣大學/醫學院/臨床醫學研究所/博士(2021年)

https://doi.org/10.6342/NTU202104568

摘要

肝臟移植是末期肝病患者爭取長期存活的唯一治療方式。世界第一例人體肝臟移植執行於1963年，在肝臟移植發展的最初二十年間，手術成果與患者預後相當不好，不僅手術的死亡率高，術後的器官排斥問題也十分嚴重，平均術後一年存活率只有三成，大多數患者無法長期存活，肝臟移植因而在當時被認為是一個相當困難而危險的治療方式。到了1980年初，免疫抑制藥物的臨床應用有了突破性進展，環孢靈素的使用顯著地減少器官排斥的問題，讓肝臟移植患者的存活率大幅提升。1987年美國威斯康辛大學UW器官保存液的發明，改善了器官保存的效果，此時期肝臟移植的手術技術與術後的重症照護也逐漸發展成熟，這讓移植的成果穩定進步，全世界每年的肝移植數量也明顯成長並普及至更多區域。然而在某些國家或地區，屍體器官捐贈的來源數量並不足以供應眾多等候肝移植患者的需求，因此活體部分肝移植技術在九零年代迅速發展，並且在器官捐贈來源不足地區逐漸成為主要的肝移植方式。為了更加擴展活體部分捐肝的器官來源，血型不相容的肝臟移植成為千禧年後的另一個重要發展議題。如今，隨著新型免疫抑制藥物使用，搭配血漿置換等減敏治療技術的成熟，血型不相容的排斥問題已大部分被克服。
台灣慢性肝炎帶原者人數眾多，有許多患者罹患肝硬化與肝癌。每年有一千多名患者因急性肝衰竭或末期肝病，需等候肝臟移植。但國人大體捐贈觀念較西方保守，屍肝移植數量稀少，每年約不到一百例，主要之器官移植來源為活體親屬的部分捐肝，因此發展出以活體部分肝臟移植為主的肝臟移植經驗。數十年來隨著醫療照護水準進步、手術技術發展成熟、與穩定有效的抗排斥藥物研發，肝臟移植患者的器官存活時間與生命得到明顯延長，如今肝臟移植患者的手術後五年平均存活率可達八成。然而，受到許多因素影響，肝臟移植患者手術後短期與長期的照護問題與預後，仍有許多困難的問題尚待解決。手術後早期的血管併發症雖然罕見，但很可能是嚴重且致命的，一旦發生需要立即處理，否則會導致急性肝衰竭甚至死亡。膽道相關的併發症通常雖不會立即致命，但處理起來十分困難，患者經常需多次治療，且在反覆治療過程中經常經歷感染與肝功能惡化，而影響患者生存預後。這些併發症會直接或間接導致移植肝臟功能的衰竭惡化，嚴重可導致患者死亡，因此其發生之相關因子與處理方式值得探討。另外，移植患者需長期服用免疫抑制的抗排斥藥物，過去研究報告其新發生惡性腫瘤的機會比一般人高。惡性腫瘤也是肝移植患者在長期穩定追蹤時，肝臟因素以外所導致死亡的重要原因。這些惡性腫瘤的發生形式，與其對患者造成的影響，需進一步研究探討。此外，長期服用抗排斥藥物會造成免疫力低下與提升感染風險，藥物的腎毒性會傷害腎功能，並引起代謝症候群等許多不良副作用。然而，肝臟移植患者長期抗排斥藥物的血中濃度應維持多少，目前國際上也沒有通用的臨床共識指引給出治療建議。近年來血型不相容活體肝移植技術的進步與發展，開拓了活體親屬捐肝的器官來源，提供器官短缺的地區另一種選擇機會。愈來愈多研究顯示血型不相容的活體肝移植為安全而有效的選項，然而患者術後各方面的預後是否與傳統血型相容肝臟移植相同，仍未有定論。
臺大醫院自1989年完成首例屍體捐贈肝臟移植手術，而後於1997年完成首例活體部份肝臟移植。本文以台大醫院的肝臟移植患者為對象，分別針對以下主題進行肝臟移植患者手術後的預後分析研究，包括：手術後早期肝動脈栓塞的再灌流失敗、小兒肝移植後的膽道併發症、肝移植後發生的惡性腫瘤、成人肝移植後長期血中抗排斥藥物濃度、與ABO血型不相容肝移植。我們的研究發現，部分患者手術後早期發生肝動脈栓塞且再灌流失敗，保守的藥物支持性治療仍可能存活，未必需要二次移植。早期發生的小兒膽道併發症較晚期發生者預後不佳，應積極地手術介入；晚期發生的膽道併發症無論使用影像介入或手術治療，預後皆相對較好；年齡超過兩歲、接受多次肝腸吻合術與肝動脈栓塞，為小兒肝移植後發生膽道併發症的危險因子。再者，肝移植患者發生新的惡性腫瘤的危險性為一般人的三倍，形式以移植後淋巴球增生疾病與膀胱癌最常見，不同於西方最常見的皮膚癌。此外，肝移植患者移植後五年的血中的抗排斥藥物濃度與長期的生存預後相關，若維持在4.6−10.2 ng/mL的範圍內，可擁有較低的死亡風險。在血型不相容移植的部分，我們的經驗顯示手術與存活預後與傳統的血型相容移植相比無明顯差別。
肝臟移植發展至今半個世紀，手術技術發展已然相對純熟，醫療照護的進步與有效的抗排斥藥物的發展大幅改善患者預後。吾人最終目標是要讓肝臟移植成為一個更普及而安全的治療方式，盼望在可見的未來，患者能擁有與一般人相同的平均餘命，從移植手術中得到完全的治癒。

關鍵字

肝臟移植 ； 預後 ； 併發症 ； 惡性腫瘤 ； 抗排斥藥 ； 藥物濃度

並列摘要

Liver transplantation provides the only chance of long-term survival for patients with end-stage liver disease. The first ever liver transplantation was performed in 1963. In the first 2 decades thereafter, liver transplantation outcomes and prognosis were quite poor. The surgical mortality rate was high, and there was the serious complication of organ rejection. The 1-year survival rate was only 30. Liver transplantation was considered a difficult and dangerous procedure until the early 1980s, when there was a breakthrough in immunosuppressant therapy innovation. The use of cyclosporine significantly reduced organ rejection rates and greatly improved survival rates associated with liver transplantation. Another important advancement, in 1987, was the improvement of graft preservation techniques by hypothermic perfusion utilizing University of Wisconsin (UW) solution. Around this time, surgical techniques and postoperative intensive care after liver transplantation also gradually developed and matured. Outcomes have steadily improved, and liver transplantation provision has increased in terms of frequency and geographical coverage worldwide. However, organ shortages are common. The availability of cadaveric organ donation is often insufficient to cover the numbers of patients on waiting lists. Living donor liver transplantation, therefore, developed in the 1990s and gradually became mainstream in areas with organ shortages. To further expand the living donor pool, ABO-incompatible liver transplantation rose to prominence in the 2000s. Currently, with the use of rituximab and desensitization interventions, such as total plasma exchange, the problem of organ rejection after ABO-incompatible liver transplantation has almost been overcome.
In Taiwan, there are many chronic hepatitis virus carriers; there is a substantial associated burden of cirrhosis and liver cancer. Each year, more than 1000 patients with acute liver failure or end-stage liver disease await liver transplantation in Taiwan. However, organ donation in Taiwan is not as popular as in Western countries. Fewer than 100 deceased donor liver transplantations are performed annually in Taiwan. The main organ source is partial liver donation from living relatives. Therefore, transplant surgeons in Taiwan tend to perform a higher proportion of living donor liver transplantations compared with surgeons in Western countries.
Over the decades, with advancements in medical care standards, surgical techniques, and antirejection medications, the graft and patient survival associated with liver transplantation has significantly improved. Today, the 5-year postoperative survival rate among liver transplant recipients is around 80%. However, there are still many difficulties that need to be addressed in the short- and long-term care of liver transplant recipients. Although early postoperative vascular complications are rare, they can be serious and fatal. Once such complications occur, they need to be treated immediately to prevent acute liver failure or even death. Biliary tract–related complications are usually not immediately fatal, but they are difficult to manage. Patients often need multiple treatments and often experience infection or liver function deterioration during repeated treatments, which impacts survival and prognosis. These complications directly or indirectly lead to the deterioration of graft function, and they occasionally led to death. Therefore, the associated risk factors and treatment strategies are worth further investigation. Furthermore, transplant recipients need to take lifelong immunosuppressive drugs. Studies have reported a higher risk of malignancy among transplant patients compared with the general population. Malignancy is an important cause of death during the long-term follow-up of liver transplant recipients. The incidence and risk factors of these malignancies and their impact on patients require further investigation. Additionally, long-term immunosuppression is associated with an increased risk of infection. Also, most immunosuppressants are nephrotoxic and cause many adverse effects, such as metabolic syndrome. However, there is no consensus or standard guideline regarding serum tacrolimus levels for liver transplant recipients. In recent years, the advancement of ABO blood type–incompatible living donor liver transplantation has expanded the organ donor pool from living relatives, providing another option, particularly for regions with organ shortages. There is accumulating evidence in support of ABO-incompatible living donor liver transplantation as a safe and effective option. However, debate remains regarding whether the prognosis associated with ABO-incompatible living donor transplantation is equivalent to that associated with traditional blood type–compatible liver transplantation.
The National Taiwan University Hospital conducted the first deceased donor liver transplantation in 1989 and then conducted the first living donor liver transplantation in 1997. This dissertation reports on an analysis of prognosis among liver transplant recipients who underwent their procedures at National Taiwan University Hospital. Prognosis was analyzed in terms of early hepatic arterial thrombosis with failed revascularization, biliary complications after pediatric liver transplantation, malignancies after liver transplantation, long-term tacrolimus blood trough levels associated with adult liver transplantation, and ABO-incompatible living donor liver transplantation. This research yielded findings and raised several issues that warrant further investigation. Patients who had early hepatic artery thrombosis with failed revascularization after liver transplantation may survive with conservative treatment, and re-transplantation may not be necessary. Children with biliary complications in the early stage had relatively unfavorable outcomes compared with those who had late-stage biliary complications, and aggressive surgical intervention might be justified. In contrast, children with late biliary complications treated by either radiological or surgical methods had better long-term prognoses. Recipient age older than 2 years, post Kasai portoenterostomy revision, and the presence of hepatic artery thrombosis were the most important risk factors for biliary complications. Furthermore, there was a 3-fold increased risk of de novo malignancy among liver transplant recipients compared with the general population. The most common de novo malignancies after liver transplantation were lymphoproliferative disease and bladder cancer, which differed from the observations from Western countries. Additionally, patients with mean tacrolimus blood trough levels in the range of 4.6 to 10.2 ng/mL 5 years after liver transplantation had better long-term survival than patients with higher or lower trough levels. As for ABO-incompatible living donor liver transplantation, outcomes were acceptable and comparable to traditional liver transplantation.
Liver transplantation has been available for more than half a century, and advancements in surgical techniques, medical care, and antirejection medications have greatly improved transplant recipient prognosis. The ultimate goal is to optimize the safety and accessibility of liver transplantation. In the near future, hopefully, patients will have the same life expectancy as general population and liver transplantation will be considered a truly curative treatment for acute liver failure and end-stage liver disease.

並列關鍵字

liver transplantation ； prognosis ； complication ； malignancy ； immunosuppressant ； tacrolimus

參考文獻

1. Starzl, T. E., Marchioro, T. L., Vonkaulla, K. N. et al. Homotransplantation of the Liver in Humans. Surg Gynecol Obstet 117, 659-676, (1963).

2. Starzl, T. E., Groth, C. G., Brettschneider, L. et al. Orthotopic homotransplantation of the human liver. Ann Surg 168, 392-415, (1968).

3. Busuttil, R. W. International Liver Transplantation Society 2009 presidential address: The internationalization of liver transplantation. Liver Transplantation 16, 558-566, (2010).

4. Starzl, T. E., Klintmalm, G. B., Porter, K. A. et al. Liver transplantation with use of cyclosporin a and prednisone. N Engl J Med 305, 266-269, (1981).

5. Starzl, T. E., Todo, S., Fung, J. et al. FK 506 for liver, kidney, and pancreas transplantation. Lancet 2, 1000-1004, (1989).