原位辅助性部分肝移植研究进展

原位辅助性部分肝移植作为多模式肝移植的一种分支,以其对患者创伤较小、符合生理、无无肝期等优势日益受到关注,但目前临床尚未较大规模地开展和应用,且原肝和供肝肝细胞再生和门静脉血流之间的功能竞争等问题仍然令人迷惑,尚需更多的临床实践和动物实验来不断地丰富该领域的理论和实践。     

Native hepatectomy after auxiliary partial orthotopic liver transplantation

In countries where a living donor is the only source of the graft, the limited size of the graft is of serious concern when considering extending the procedure to adult recipients. In order to overcome this problem, auxiliary partial orthotopic liver transplantation (APOLT) was applied to the concept that the residual native liver would support the graft function until the graft expanded enough to work by itself. We herein report on a 20-year-old woman with primary sclerosing cholangitis (PSC), who received a small-size liver graft by APOLT. Computed tomography and scintigraphy showed that the graft had regenerated sufficiently 1 month after the operation. The diseased residual native liver is potentially carcinogenetic. Therefore, second-stage native hepatectomy was done 35 days after the first operation. Histopathologic examination of the resected native liver revealed biliary cirrhosis with PSC but no evidence of cholangiocarcinoma. Second-stage native hepatectomy after APOLT seems to be a curative treatment for chronic end-stage liver disease with graft size mismatch that may be as good as orthotopic liver transplantation. Received: 22 October 1998 Received after revision: 15 January 1999 Accepted: 26 February 1999     

活体肝部分移植的进展

活体肝部分移植的进展管文贤李开宗３２年前，Ｓｔａｒｚｌ成功地开展临床首例肝移植以来，目前肝移植术已成为晚期肝病患者有效的治疗手段。近年在北美、欧州上百个移植中心，以每年约５０００例的业绩，使肝移植术得到不断发展和完善，现总例数已突破３００００例〔１～...     

Porcine model of auxiliary partial orthotopic liver transplantation for acute liver failure

BACKGROUND: Auxiliary partial orthotopic liver transplantation (APOLT) has been an effective alternative in acute liver failure (ALF), but clinically several problems remain to be resolved. Thus, we attempt to establish an APOLT model for ALF using a large animal and demonstrate the validity of our model. METHODS: In experiment 1, we created an animal model of ALF using pig. ALF was induced by resection of 70% of the whole liver under total hepatic vascular exclusion (THVE). The duration of ischemia was 90 minutes. In experiment 2, we tried to make an APOLT model by using this ALF model as a recipient. That is, during 90 minutes of THVE, 70% hepatectomy and subsequent partial orthotopic transplantation was completed. RESULTS: In experiment 1, six of seven pigs died within three days with jaundice and massive ascites. Based on microcirculatory disturbance of the remnant liver and hepatocellular necrosis, 70% hepatectomy with 90 minutes of THVE was considered a proper model of ALF. In experiment 2, six out of seven APOLT model animals survived more than four days. T. Bil levels in the APOLT model remained consistently within the normal range throughout the observation period. In immunohistochemistry, several labeled nuclei stained with Ki67 were identified in native liver of the APOLT model. CONCLUSIONS: This APOLT procedure provided temporary liver function support and enabled the recipient to survive until the failing native liver had regenerated. Our APOLT model could be suitable and useful for understanding the role of APOLT in ALF.     

辅助性原位尸肝部分移植治疗Wilson病的疗效初探

目的:总结我院2002年7月19日施行的辅助性原位尸体肝部分移植治疗Wilson病(肝豆状核变性)病例,探讨该移植技术的可行性和初步临床疗效。方法:通过双灌注快速取肝法获取血型为A型的供肝;在整型台上用CUSA沿肝脏镰状韧带的左侧劈离肝脏,取第Ⅱ、Ⅲ段为重230g的部分移植供肝,仔细结扎断面的管道系统,历时185min。受体女性,22岁,血型A型,因锥体外系症状逐渐加重而具肝移植指征,切除受体病肝左外侧叶(Ⅱ、Ⅲ段),将供肝(Ⅱ、Ⅲ段)原位植入。用5鄄0Prolene缝线分别对供体鄄受体的肝左静脉和门静脉左支行端端连续吻合,均预留“增宽因子”,于受体胃十二指肠动脉水平与供肝的左肝动脉以8鄄0Prolene缝线间断吻合。胆道对合取左肝管鄄空肠Roux鄄en鄄Y式吻合。术中予甲基泼尼松龙静脉注射1000mg,术后采用激素、FK506和骁悉联合免疫抑制治疗。结果:热缺血时间为6min,冷缺血时间15.5h,手术时间6.5h,术中输血1400ml。术后第3天开始进食和离床活动,至今病人已生存16个月,完全恢复正常生活,血清铜和铜蓝蛋白水平恢复正常,移植肝脏体积无明显萎缩,手足震颤明显减轻。结论:辅助性原位尸体部分肝移植是治疗Wilson病的良好方法,同时可避免活体部分肝移植给供体带来的风险。     

Bridging hyperacute liver failure by ABO-incompatible auxiliary partial orthotopic liver transplantation

Uncontrollable intracranial pressure elevation in hyperacute liver failure often proves fatal if no suitable liver for transplantation is found in due time. Both ABO-compatible and auxiliary partial orthotopic liver transplantation have been described to control such scenario. However, each method is associated with downsides in terms of immunobiology, organ availability and effects on the overall waiting list.     

Functional portal flow competition after auxiliary partial orthotopic living donor liver transplantation in noncirrhotic metabolic liver disease

Auxilliary partial orthotopic liver transplantation (APOLT) was introduced initially as a tentative or permanent support for patients with potentially reversible fulminant hepatic failure and has extended its indication to congenital metabolic disorder of the liver that has otherwise normal functional integrity. Postoperative management of APOLT is complicated because of functional portal flow competition between the native and graft liver. The native portal vein diversion to the graft is sometimes indicated to prevent functional competition; however, it is still an open question whether this technique can be theoretically indicated for APOLT patients. The authors report a on patient with ornithine transcarbamylase deficiency who received APOLT from a living donor without native portal vein diversion. Because of functional portal vein competition between the native and graft liver, the patient had to have portal vein diversion, portal vein embolization, and finally native hepatectomy to induce the graft regeneration after APOLT. After the experience of the current case, primary portal vein diversion for APOLT with noncirrhotic metabolic liver disease patients to prevent functional portal flow competition is recommended.     

A novel auxiliary partial orthotopic liver transplantation model in rats

BACKGROUND: Although auxiliary partial orthotopic liver transplantation (APOLT) has become a well-accepted procedure recently, a practical experiment model in APOLT using small animals has yet to be developed. METHODS: Male Lewis rats were used for both donors and recipients. An auxiliary partial graft was obtained by ex vivo resection of the donor right and caudate lobes, and was transplanted orthotopically into the recipient after resection of the recipient medial and left hepatic lobes. Portal vein and hepatic duct reconstructions were by the cuff technique, and supra- and intrahepatic vena cava were sutured continuously. Operative outcomes, serum chemistry, liver tissue blood flow, angiographic and histopathological findings were then examined. Conventional orthotopic liver transplantation (OLT) procedures were also undertaken as a control. RESULTS: One-day, 1-week and 1-month survival rate of APOLT group was 100, 85 and 85%, respectively. AST in the APOLT group on the 1st postoperative day was significantly higher than in the OLT group. No significant differences were recognized in serum albumin and total bilirubin levels between the two groups. Although the portogram of an APOLT rat showed slight narrowing at the cuff anastomosis site, both the graft and the native liver were opacified similarly. The liver tissue blood flow on the 5th postoperative day in the native liver and the graft returned to as high as 95 and 74% of the values on laparotomy, respectively. Histological examinations of the auxiliary graft 1 month after transplantation showed mild ductular proliferation and mononuclear cell infiltration around the portal triads. CONCLUSION: This novel APOLT model in rats allows practical and reproducible results, and may be of value in the basic study of APOLT procedures.     

Living-related liver transplantation for type II citrullinemia using a graft from heterozygote donor

BACKGROUND: Type II citrullinemia (CTLN2) characterized by a liver-specific argininosuccinate synthetase deficiency is an adult onset genetical disorder caused by the mutation of SLC25A13 gene, which results in fulminant hyperammonemia often with poor prognosis. METHODS: A 16-year-old Japanese boy presented fulminant hyperammonemia and encephalopathy and recovered after aggressive medical treatment. The patient was diagnosed as CTLN2 by plasma amino acid pattern and detection of the mutated SLC25A13 gene. We performed living-related liver transplantation (LRLT) using a graft from the genetically proven heterozygote father. RESULTS: Serum amino acid concentration was normalized within a day after transplantation without protein restriction and medication. The patient's postoperative course was natural. The patient is back in school 6 months after surgery. CONCLUSIONS: Living-related liver transplantation using a graft from genetically proven heterozygote donors might be a permissible treatment modality for CTLN2. Long-term observation may be necessary to make a definite conclusion possible.     

辅助性原位活体肝部分移植一例报告

目的：探讨应用辅助性原位活体肝部分移植治疗Willson's病的可行性。方法：受体女性，20岁，O型血，因肝豆状核变性而接受辅助性原位活体肝部分移植。供体男性，21岁，A型血。手术切除受体病肝左外叶260g，取供体左外叶肝脏295g原位移植于受体。因供受体血型不同，术前行血浆置换，术后以FK506，激素，环磷酰胺联合免疫抑制治疗。结果；受体术后15d出现肝动脉血塞形成，予以溶栓治疗后出现腹腔内出血，术后17d开腹止血，清除血肿，术后发生腹水，肺不张，胆瘘等，均治愈。至今患者已生存1年3个月，并恢复正常生活，铜蓝蛋白水平正常。移植肝脏体系明显增大，手足震颤明显减轻。结论：辅助性原位活体肝部分移植是治疗Willson's病可行的方法。     

Preclinical experiment of auxiliary partial orthotopic liver transplantation as a curative treatment for hemophilia.

The cause of hemophilia is deficiency of coagulation factor VIII production in the liver, which can be cured by liver transplantation. Because the hepatic function of hemophilia patients is quite normal except for production of factor VIII, auxiliary partial orthotopic liver transplantation (APOLT) is beneficial in that patient survival is secured by preserving native liver even in the event of graft loss. However, it is not known whether the graft of APOLT would be enough to cure hemophilia. We evaluated the efficacy and feasibility of APOLT for hemophilia in a canine hemophilia A model that we established. Partial left liver graft was taken from the normal donor (blood factor VIII activity > 60%). The graft was transplanted to the hemophilia beagle dog (blood factor VIII activity < 5%) after resection of the left lobe preserving native right lobe. Changes in time of blood factor VIII activity and liver function parameters were observed after APOLT. APOLT and perioperative hemostatic management were successfully performed. The blood factor VIII activity increased to 30% after APOLT, and was sustained at least 6 weeks throughout the observation period without symptoms of bleeding. The result demonstrated sustained production of factor VIII in the hemophilia recipient after APOLT. Transplantation of approximately one third of whole liver resulted in cure of hemophilia. In conclusion, it is suggested that APOLT would be feasible as a curative treatment of hemophilia A to improve quality of life of the patients.     

Partial liver transplantation from living related donors.

Living related liver transplantation was performed in five cases between June 1989 and July 1991 at Shinshu University Hospital. All of the donors were fathers of the patients and blood type was identical in each case. All of them were discharged from the hospital 2 weeks after hepatectomy without any complications. They started to work 2 months after surgery. Four recipients are surviving but one died. Three are enjoying daily life 17 months after LT in case 1, 5 months after LT in case 4, and 4 months after LT in case 5. Case 2 is still in the hospital 14 months after LT. Advantages of LRLT we noted were (1) cases can be performed totally electively and allow full preparation for the family and the transplant team, (2) primary graft nonfunction has not been observed to date, and (3) 38 patients received the chance of liver transplantation in their own country, which under current legislation would not otherwise have been possible. Disadvantages of LRLT were (1) partial hepatectomy was performed in healthy persons, and (2) retransplantation is difficult.     

小体积肝移植和辅助性原位小体积肝移植治疗猪急性肝功能衰竭的近期疗效观察

目的观察小体积肝移植和辅助性原位小体积肝移植治疗猪急性肝功能衰竭的近期疗效。方法急性肝功能衰竭猪随机分为3组接受肝移植治疗:A组行全肝移植(n=5);B组行小体积肝移植(n=5);C组行辅助性原位小体积肝移植(n=5)。各组动物开腹后即刻、切脾后即刻和再灌注后30 min分别监测门静脉压力,并观察术后生化指标变化、病理改变和1周生存率。结果A、B和C三组的移植肝重量与受体体重之比分别为(2．44±0．30)％、(0．76±0．02)％和(0．75±0．03)％。再灌注后30 min,B组移植肝门静脉压力显著高于其它两组(A:B:C=13．3:17．5:12．2 cmH2O, P<0．01),C组原肝门静脉压力显著高于移植肝门静脉压力(14．3:12．2 cmH2O,P<0．05)。A组和C组术后第2天起血清天冬氨酸转氨酶、总胆红素、凝血酶原时间、乳酸和血氨水平明显下降,术后第7天基本恢复至正常水平。B组术后上述生化指标一直维持在较高的水平,术后第2～4天明显高于其它两组(P<0．01)。A组、B组和C组1周生存率分别为100％、20％和80％,B组明显低于其它两组(P<0．05)。结论辅助性原位小体积肝移植治疗急性肝功能衰竭近期疗效优于小体积肝移植,术中不必干预原肝门静脉。     

Auxiliary partial orthotopic liver transplantation for Crigler-Najjar syndrome type I

OBJECTIVE: To determine if auxiliary partial orthotopic liver transplantation (APOLT) has the long-term potential to correct the underlying abnormality in Crigler-Najjar syndrome type 1 (CNS1) without the need for total liver replacement. BACKGROUND: Orthotopic liver transplantation has been used successfully to replace the defective enzyme in CNS1. Experimental studies have shown that only 1% to 2% of the normal hepatocyte mass is needed for bilirubin conjugation. If APOLT corrects the underlying metabolic abnormality, it has the advantage of preserving the native liver, which would serve as a "safety net" should the graft fail, and there is the potential for gene therapy in the future with possible withdrawal of immunosuppression. METHODS: Seven APOLT procedures were performed in six recipients with CNS1. Median age at transplantation was 10.5 years. Six transplants were performed as a left auxiliary liver transplant, and one was performed as a right auxiliary liver transplant. Median serum bilirubin level at transplantation was 320 micromol/L. All patients required 12 to 16 hours of phototherapy daily before the transplant to maintain serum bilirubin levels between 250 and 350 micromol/L. RESULTS: Median serum bilirubin level was 50 micromol/L at day 5 after the transplant and 23 micromol/L at a median follow-up of 32 months. In four children, early severe acute rejection developed, requiring conversion to tacrolimus; one underwent a second transplant for chronic rejection and graft atrophy but died from lymphoproliferative disease 6 months after the second transplant. CONCLUSIONS: This report shows that APOLT is technically feasible and provides adequate hepatocyte mass to correct the underlying metabolic abnormality in CNS1.     

Importance of portal flow diversion in experimental auxiliary partial orthotopic liver transplantation

BACKGROUND: Auxiliary partial orthotopic liver transplantation (APOLT) has successfully been performed in patients with noncirrhotic metabolic diseases. It remains, however, unclear if intervention in the portal venous inflow is necessary to ensure adequate portal blood flow to graft and host liver. In this experimental study we evaluate the hepatic flow during APOLT. METHODS: Left lateral/medial segmental grafts were transplanted from beagle to dalmatian dogs. Vascular structures were anastomosed end-to-end. The effect of diversion of the portal flow was studied in three groups: in the ligation group (n=3) the host portal vein was tied off, the free flow group (n=6) had random flow to both livers. In the banding group (n=11) the host portal vein was banded with a adjustable strapband to restore the pretransplantation flow distribution. RESULTS: After reperfusion the blood flow through the common portal vein decreased from 49 to 36 ml/kg/min (P<0.03) in all animals. Flow through the left portal vein decreased from 26 to 5 ml/kg/min (P<0.0001). Banding restored the flow in the left portal vein to 12 ml/kg/min, although the flow in the free-flow group remained 4 ml/kg/min. In the ligation group the total portal flow was forced toward the graft leading to the highest perfusion: 24 ml/kg/min (P<0.005). Adverse effect of this ligation was the development of portal hypertension. CONCLUSIONS: This experimental study confirms that diversion of the portal flow is necessary for adequate graft perfusion in APOLT. Banding can restore the pretransplantation flow distribution, without compromising the flow in the common portal vein.     

大鼠原位辅助性肝移植治疗急性肝功能衰竭

为了评价大鼠原位辅助性部分肝移植（ＡＰＯＬＴ）对急性肝功能衰竭的支持作用。切除７５％的肝脏并阻残余肝脏的血供５０分钟导大鼠急性肝功能衰竭。治疗组受体计切除７５％并将３０％的供肝植于原位，然后阻断残余的右上叶的右下叶之血供５０分钟。结果显示，大鼠急性肝功能衰竭的５天生存率仅３３％，而接受ＡＰＯＬＴ者５天生存率和移植肝存活率分别为８０％和７３％，术后第５天肝功能基本恢复正常。可见，大肝切除和余肝缺血诱     

A new procedure for temporary auxiliary partial liver transplantation using living donor graft for patients with familial amyloid polyneuropathy

To introduce duct-to-duct biliary anastomosis to conventional temporary auxiliary partial orthotopic liver transplantation (APOLT) using living donor graft for patients with familial amyloid polyneuropathy, we modified the conventional APOLT procedure in a manner characterized by the use of the recipient's common hepatic duct for biliary reconstruction and the preservation of the right posterior section alone for the certain placement of a tube into the corresponding biliary tree for external biliary drainage (modified APOLT). This procedure was performed in 3 patients without biliary complications. No complications associated with the external drainage tube occurred. Here we report the techniques and results for this new procedure.     

Routine use of auxiliary partial orthotopic liver transplantation for children with fulminant hepatic failure: Preliminary report

Auxiliary partial orthotopic liver transplantation (APOLT) has been performed for both metabolic disorders and fulminant liver failure (FHF). When the native liver regenerates, the patients with FHF who undergo APOLT have a chance to withdraw immunosuppression. It may be most beneficial for children. This preliminary report describes our start to routinely offer APOLT as an option to standard OLT for children with FHF in 2005. Six children (ages 8 months to 8 years) received APOLT: 1 in 1996 and the others in 2005 and 2006. The donor ages ranged from 4 to 40 years. We used either a left lateral segment or a left lobe graft. The recipient left lobe, which was removed, showed submassive to massive necrosis at the time of transplantation. All children are alive and well. The first patient who received APOLT in 1996 is currently off immunosuppression with a fully recovered native liver; the grafted liver underwent complete atrophy. The 5 remaining subjects are receiving reduced levels of immunosuppression with close monitoring. Their serial liver biopsy specimens show slight to significant recovery. One developed hepatic artery thrombosis, requiring retransplantation. The native liver was retained at the time of retransplantation (redo APOLT). Other postoperative complications included a bile leak (n = 1), invasive mucomycosis of the arm (preexisting condition; n = 1), biliary stricture (n = 1), and acute cellular rejection (n = 3). Posttransplantation length of stay was 6 to 60 days (median, 15 days). In conclusion, APOLT can be safely performed in children with FHF displaying short-term outcomes comparable to standard transplantations.