Efficacy of auxiliary partial orthotopic liver transplantation for cure of hemophilia in a canine hemophilia A model

Metabolic liver disease can be cured by orthotopic liver transplantation. Some successful cases of whole or partial liver transplantation have been reported. Because liver function in these recipients is normal save for the production of the responsive metabolic factor, auxiliary partial orthotopic liver transplantation (APOLT) may produce a benefit. However, no experimental model of APOLT for metabolic liver diseases has been reported. We established a canine APOLT model to evaluate the clinical feasibility and efficacy of APOLT to cure hemophilia. The donor normal beagle dog was used to establish an APOLT model. A left lobe partial liver graft taken from the donor was orthotopically transplanted to the recipient after resection of the native left lobe preserving the native right lobe. Recipients showed no atrophy and comparable blood flow in both the graft and the native liver at the time of exploration after APOLT. Thus, APOLT was performed from a normal donor to a recipient with hemophilia A. In this recipient, blood factor VIII activity markedly increased after APOLT and was maintained for 7 weeks. No episode of bleeding was seen during the observation. In conclusion, a canine APOLT model was successfully established as evidenced by sustained production of factor VIII in a hemophilia recipient. These findings suggest the clinical feasibility and efficacy of APOLT for metabolic liver diseases.     

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     

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。     

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。     

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     

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.     

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.     

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.     

Portal blood flow and liver regeneration in auxiliary partial orthotopic liver transplantation in a canine model

Functional competition has been shown to lead to a detrimental outcome in auxiliary liver transplantation. We evaluated the interaction in auxiliary partial orthotopic liver transplantation between the native liver and the graft in terms of portal flow and regeneration. The need for diversion of the portal flow to the graft was also assessed. Reduced-size liver grafts were transplanted orthotopically after partial hepatectomy in beagles. There were two groups: the preserved group, where portal inflow to the native liver was preserved, and the ligated group, where it was interrupted. Portal flow was measured serially and liver regeneration was evaluated on postoperative day 5. Functional competition was not observed in the preserved group. On the other hand, ligation of the native liver portal vein had no obviously detrimental effects on the remnant native liver. This leads to the conclusion that the portal vein to the native liver can be safely ligated to prevent functional competition.     

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。     

Portal flow diversion is essential for graft survival in canine auxiliary partial orthotopic liver transplantation

After auxiliary partial orthotopic liver transplantation for inborn errors of metabolism, finding a balance in portal blood flow distribution between native liver and graft is complicated. We investigated the correction of hypoallantoinuria in the Dalmatian dog with a reduced-size Beagle orthotopic auxiliary liver graft, depending on intra-operative intervention in the portal flow. There were three groups: a ligation group, where the host portal vein was tied off, a free-flow group with random flow to both livers and a banding group, where the host portal vein was banded with an adjustable strapband. Metabolic correction was initially seen in all groups, but ligation led to portal hypertension and early mortality. In the free-flow group, correction was lost after 7 days, while banding preserved correction until 6 weeks. We conclude that acute ligation can lead to portal hypertension and free-flow leads to hypoperfusion and early loss of metabolic correction. Banding divided the portal blood flow between host liver and graft and prolonged metabolic correction.     

Feasibility of auxiliary partial orthotopic liver transplantation from living donors for patients with adult-onset type II citrullinemia.

More than 20 patients with adult-onset type II citrullinemia have undergone liver transplantation, showing dramatic therapeutic effects. In Japan, living donor liver transplantation is the standard technique of liver transplantation because of the rare availability of cadaveric donors. The feasibility of auxiliary partial orthotopic liver transplantation (APOLT) for adult-onset type II citrullinemia to overcome the problem of a small-for-size graft in living donor liver transplantation has not been defined. We recently performed APOLT for patients with type II citrullinemia. Here, we present 2 patients: patient 1 was a 32-year-old man and patient 2 was a 43-year-old woman. Both patients suffered from hepatic encephalopathy, and laboratory data showed highly elevated plasma levels of ammonia and citrulline. In patient 1, the liver graft was obtained from a patient with familial amyloid polyneuropathy as a domino liver transplant. In patient 2, APOLT was performed after graft donation from her husband. The postoperative clinical courses of both patients were uneventful, and the neurological symptoms were completely resolved. The plasma concentrations of ammonia and citrulline normalized rapidly in both patients. APOLT can provide an adequate hepatocyte mass to correct the underlying enzyme deficiency in adult patients with type II citrullinemia. In addition, APOLT can be carried out safely to overcome the limitation of graft volume in living donor liver transplantation.     

Resolution of hepatopulmonary syndrome after auxiliary partial orthotopic liver transplantation in Abernethy malformation. A case report.

Congenital absence of portal vein and extrahepatic portocaval shunt, also referred to as an Abernethy type 1, is a rare malformation of the mesenteric vasculature. A 9-year-old girl presented with dyspnea on exertion and orthodeoxia. A diagnosis of an Abernethy malformation type 1b and hepatopulmonary syndrome (HPS) was made, and she underwent auxiliary partial orthotopic liver transplantation (APOLT). Symptoms and signs of HPS resolved 2 months after the operation. HPS in Abernethy syndrome is a manifestation of normal portal blood flow bypassing the liver and can be ameliorated by redirecting blood flow to a segment of liver with normal portal anatomy. APOLT is a feasible and successful surgical procedure for patients with Abernethy malformation and HPS.     

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.     

Severe late acute allograft rejection in a child after living-related auxiliary partial orthotopic liver transplantation for ornithine transcarbamylase deficiency

Auxiliary liver transplantation (ALT) is known to correct liver-based metabolic disorders. However, it remains unclear whether the presence of a native liver influences the long-term prognosis of ALT for metabolic diseases. We reported on a 4-yr-old girl who had undergone living-related auxiliary partial orthotopic liver transplantation (APOLT) for ornithine transcarbamylase deficiency and experienced severe late acute rejection 18 months after liver transplantation, during weaning of immunosuppressive agents. Results of histological analysis of the graft indicated very severe acute rejection (rejection activity index, 9/9), and computed tomography revealed graft liver atrophy. These observations suggest the possibility that severe rejection might occur in APOLT, especially during weaning of immunosuppression.