Auxiliary Liver Transplantation Research Articles

Auxiliary liver transplantation with flow-regulated portal vein arterialization offers a successful therapeutic option in acute hepatic failure - investigations in heterotopic auxiliary rat liver transplantation

Heterotopic auxiliary liver transplantation (HALT) with portal vein arterialization (PVA) was proposed in acute hepatic failure (AHF). However, clinical results of PVA are controversial because of lacking standardized flow-regulation. In rats, we examined HALT with flow-regulated PVA in AHF. Group A: HALT with flow-regulated PVA and 85% resection of the native liver to induce AHF [acute experiments (n = 8), killing after 7 days (n = 8) and after 6 weeks (n = 11)]. Group B: 85% liver-resection (n = 10). The average blood-flow in the arterialized portal vein in HALT achieved normal values (1.7 +/- 0.4 ml/min/g liver-weight). After reperfusion, the diameters of the sinusoids (6.4 +/- 0.6 microm), the postsinusoidal venules (31.1 +/- 3.3 microm) and the intersinusoidal distance (17.9+/-0.7 microm) also achieved normal values. The functional sinusoidal density amounted to 335 +/- 48/cm. The 6-week survival was nine of 11 with excellent liver function (Quick's value: 110% +/- 7.8%). The hepatobiliary radioisotope scanning with (99mTc) ethyl hepatic iminodiacetic acid (EHIDA) showed no significant differences between the native livers and grafts. The hepatocellular morphology was regular, apart from low-grade necroses in two grafts. The grafts' sinusoidal endothelial cells did not show any morphological changes. In group B, however, all rats died from AHF within 6 days. HALT with flow-regulated PVA achieved good results regarding microcirculation, morphology and function and can reliably bridge AHF.

Doppler Ultrasonographic and Scintigraphic Assessment of an Auxiliary Heterotopic Liver Transplantation With Portal Vein Arterialization in Pigs

Objective Our aim was to evaluate liver graft integrity and function using scintigraphy and ultrasonography in a porcine model of auxiliary heterotopic liver transplantation with portal vein arterialization (AHLT-PVA). Materials and Methods Using Doppler ultrasonography we evaluated eight AHLT-PVA by parenchymal echogenicity, portal and arterial anatomy, and portal and biliary system flow. Two types of scintigraphy were performed: microaggregated human albumin colloid scintigraphy and diisopropyl iminodiacetic acid (DISIDA) scintigraphy, both labeled with 99mTc. Results The animals were distributed into two groups. The first group consisted of three animals with clinical suspicion of graft dysfunction, in which the ultrasonographic study revealed areas of parenchymal destructuring. In the scintigraphic study, heterogenous uptake was observed; there was no uptake in one animal. Necropsy of these three animals revealed areas of graft necrosis. The second group consisted of five animals with good clinical evolutions, in which the ultrasonographic study showed portal dilation, portal flow with arterial spiculations, and homogenous echogenicity of the hepatic parenchyma. The scintigraphic study revealed homogenous uptake by the graft and an elimination speed of the hepatobiliary agent similar to that of the native liver. Conclusions An heterogenous echostructure of the graft provided a sign of poor prognosis indicating necrosis in the same way as heterogenous uptake or nonuptake of radioisotope upon scintigraphy. Scintigraphy is a good method to evaluate biliary function and bile elimination. In an AHLT-PVA, the main ultrasound findings derived from arterialization were dilation of the portal system and portal flow with arterial spiculations.

Portal Hyperperfusion Causes Disturbance of Microcirculation and Increased Rate of Hepatocellular Apoptosis: Investigations in Heterotopic Rat Liver Transplantation With Portal Vein Arterialization

Clinical results of portal vein arterialization (PVA) in liver transplantation are controversial. One reason for this is the lack of a standardized flow regulation. Our experiments in rats compared PVA with blood-flow regulation to PVA with hyperperfusion in heterotopic auxiliary liver transplantation (HALT). In group I (n = 19), the graft’s portal vein was completely arterialized via the right renal artery in-stent technique, using a 0.3-mm stent, leading to a physiological average portal blood flow. In group II (n = 19), a 0.5-mm stent was used. In group II, the average portal blood flow after reperfusion was significantly elevated (group II: 6.4 ± 1.5; group I: 1.7 ± 0.4 mL/min/g of liver weight; P < .001). The sinusoidal diameter after reperfusion was significantly greater in group II (9.8 ± 0.5 μm) than in group I (5.5 ± 0.2 μm; P < .001). Red blood cell velocity in the dilated sinusoids was significantly lower in group II (171 ± 18 μm/s) than in group I (252 ± 13 μm/s). Stasis of erythrocytes occurred; consequently, the functional sinusoidal density was significantly reduced in group II (38 ± 7%) compared with group I (50 ± 3%; P < .01). Two hours after reperfusion of the portal vein, the number of apoptotic hepatocytes was significantly higher in group II than in group I (I: 0 ± 0 vs II: 7 ± 9 M30-positive hepatocytes/10 high-power fields). The 6-week survival rate was 9 of 11 in both groups. In group II, 6 of 9 grafts showed massive hepatocellular necroses after 6 weeks, whereas in group I, only 1 of 9 presented a slight hepatocellular necrosis. Finally, our results demonstrate negative effects of portal hyperperfusion in transplanted livers, which are correctable by adequate flow regulation.

Improved technique of heterotopic auxiliary rat liver transplantation with portal vein arterialization

In acute, potentially reversible hepatic failure, auxiliary liver transplantation is a promising alternative approach. Using the auxiliary partial orthotopic liver transplantation (APOLT) method--the orthotopic implantation of auxiliary segments--most of the technical problems (lack of space for the additional liver mass, the portal vein reconstruction, and the venous outflow) are avoided, but extensive resections of the native liver and the graft are necessary. Erhard described the heterotopic auxiliary liver transplantation (HALT) with portal vein arterialization (PVA). Initial clinical results demonstrated that an adequate liver function can be achieved using this technique. We developed and improved a technique of HALT with flow-regulated PVA in the rat to perform further investigations. The aim of this paper is to explain in detail this improved experimental surgical technique. Liver transplantations were performed in 122 male Lewis rats: After a right nephrectomy, the liver graft, which was reduced to about 30% of the original size, was implanted into the right upper quadrant of the recipient's abdomen. The infrahepatic caval vein was anastomosed end-to-side. The donor's portal vein was completely arterialized to the recipient's right renal artery in stent technique. Using a stent with an internal diameter of 0.3 mm, the flow in the arterialized portal vein was regulated to achieve physiologic parameters. The celiac trunk of the graft was anastomosed to the recipient's aorta, end-to-side. The bile duct was implanted into the duodenum. After improvements of the surgical technique, we achieved a perioperative survival of 90% and a 6-week survival of 80% in the last 112 transplantations. We developed a standardized and improved technique, which can be used for experiments of regeneration and inter-liver competition in auxiliary liver transplantation. Furthermore, this technique is suitable for the investigation of the influence of portal vein arterialization and portal hyperperfusion on liver microcirculation, function, and morphology.

Auxiliary partial orthotopic living donor liver transplantation in a patient with alcoholic liver cirrhosis to overcome donor steatosis

The efficacy of auxiliary partial orthotopic liver transplantation (APOLT) to overcome the problems associated with a markedly steatotic graft in a living donor has not been fully explored. We have recently performed APOLT in a patient with alcoholic liver disease, where the only potential candidate donor was affected by 50% macrovesicular steatosis and 30% microvesicular steatosis. The recipient's left liver was resected and the donor's left liver, corresponding to a 0.46% graft-to-recipient weight ratio, was orthotopically transplanted. The postoperative course of this patient was uneventful, except for a transient large amount of ascites. Native liver volume in the recipient serially decreased, and the volume of the graft serially increased after transplantation. Four months after transplantation, the donor and recipient are doing well with a normal liver function. In conclusion, APOLT may be a feasible solution for a markedly steatotic living donor graft in patients with alcoholic liver disease.

Which is better to overcome the portal steal phenomenon in auxiliary partial orthotopic liver transplantation: Inflow or outflow occlusion?

Which is better to overcome the portal steal phenomenon in auxiliary partial orthotopic liver transplantation: Inflow or outflow occlusion?

Auxiliary partial orthotopic living donor liver transplantation for a child with congenital absence of the portal vein

Congenital absence of the portal vein (CAPV) is a rare malformation of the mesenteric vasculature in which visceral venous blood bypasses the liver, completely draining into the systemic circulation through a congenital porto-systemic shunt. Liver transplantation has rarely been indicated for patients with this disease. We present a child with CAPV who was managed successfully by living donor auxiliary partial orthotopic liver transplantation (APOLT), while preserving the right lobe of the native liver. In conclusion, APOLT for patients with CAPV is a feasible and ideal procedure because portal vein (PV) diversion is not necessary.

Establishment of model of immunological tolerance induced by auxiliary liver transplantation in rats

目的 利用PVG(TR-1c)和DA(RT-1a)大鼠分别为供受体,联合进行辅助性肝移植和异位心脏移植,建立大鼠辅助性肝移植诱导免疫耐受模型.方法辅助性肝移植采用重建门静脉法,异位心脏移植采用腹腔吻合法.结果同品系对照组和实验组动物及其移植心脏存活超过100d,而异品系对照组移植心脏只存活7 d.结论在受体肝脏存在的情况下,辅助性供肝依然发挥其诱导耐受的效应.经长期观察,供肝无萎缩,耐受诱导效应持续存在,指示心脏搏动良好.因此,该模型在肝移植基础研究中具有实用价值。

Pathology Findings in a Model of Auxiliary Liver Transplantation With Portal Vein Arterialization in Pigs

Objective To determine the histological findings and temporal evolution that occur in auxiliary liver grafts as a consequence of arterialization of the portal vein (PVA). Materials and methods We evaluated 10 auxiliary heterotopic liver transplants with arterialization of the PVA. The histological study was performed using an optical microscope to process liver samples with staining using hematoxylin and eosin. A biopsy of native liver tissue was used as a control. Results Two animals were excluded from the study, one due to ischemic necrosis of the graft and one that died 4 hours after transplant. All of the remaining eight animals underwent a histological study at 1 day, 7 days, and 14 days. The most significant histological findings were: (1) dilation of portal areas and sinusoids, which were detected at 24 hours and persisted; (2) thickening of the interlobular septum, which was observed after day 7 and progressively increased to day 14; (3) bile duct hyperplasia detected at the seventh day. Conclusions The consistent, early findings in a pig liver with PVA included vascular dilation of the portal area and the sinusoids, with bile duct hyperplasia extending progressively and the thickening of interlobular connective tissue septa with a generalized perilobular connective tissue reaction, which did not seem to alter the internal structure of the lobule, which showed histologically normal hepatocytes. The fibrous reaction may be the first stage in chronic hepatopathy. Further long-term studies are required in this model.

Current role of liver transplantation for the treatment of urea cycle disorders: A review of the worldwide English literature and 13 cases at Kyoto University

To address the current role of liver transplantation (LT) for urea cycle disorders (UCDs), we reviewed the worldwide English literature on the outcomes of LT for UCD as well as 13 of our own cases of living donor liver transplantation (LDLT) for UCD. The total number of cases was 51, including our 13 cases. The overall cumulative patient survival rate is presumed to be more than 90% at 5 years. Most of the surviving patients under consideration are currently doing well with satisfactory quality of life. One advantage of LDLT over deceased donor liver transplantation (DDLT) is the opportunity to schedule surgery, which beneficially affects neurological consequences. Auxiliary partial orthotopic liver transplantation (APOLT) is no longer considered significant for the establishment of gene therapies or hepatocyte transplantation but plays a significant role in improving living liver donor safety; this is achieved by reducing the extent of the hepatectomy, which avoids right liver donation. Employing heterozygous carriers of the UCDs as donors in LDLT was generally acceptable. However, male hemizygotes with ornithine transcarbamylase deficiency (OTCD) must be excluded from donor candidacy because of the potential risk of sudden-onset fatal hyperammonemia. Given this possibility as well as the necessity of identifying heterozygotes for other disorders, enzymatic and/or genetic assays of the liver tissues in cases of UCDs are essential to elucidate the impact of using heterozygous carrier donors on the risk or safety of LDLT donor-recipient pairs. In conclusion, LT should be considered to be the definitive treatment for UCDs at this stage, although some issues remain unresolved.

Cadaveric Orthotopic Auxiliary Split Liver Transplantation and Kidney Transplantation: An Alternative for Type 1 Primary Hyperoxaluria

Liver transplantation (LTX) corrects the enzymatic defect responsible for type 1 primary hyperoxaluria (PH1). It has been advocated in combination with kidney transplantation (KTX) in patients with renal failure from PH1 because KTX alone can result in early graft loss. A 58-year-old male patient with PH1 on hemodialysis underwent resection of the left lateral segment of the liver followed by orthotopic auxiliary left lateral segment liver transplantation and kidney transplantation from a deceased donor. The serum oxalate dropped from 34.8 micromol/L before transplant to 3.6-8.3 in the first months posttransplant to <1 micromol/L (normal range 0.4-3.0). One year after posttransplant, the patient has an iothalamate glomerular filtration rate of 58 ml/min. Orthotopic auxiliary LTX is an alternative to whole LTX in PH1. By using a split deceased donor liver, it does not deprive the donor pool and protects the recipient from liver failure in case of graft loss.

Auxiliary Partial Orthotopic Liver Transplantation with De Novo Autoimmune Hepatitis in the Allograft and Leftover Primary Biliary Cirrhosis in the Native Liver

Auxiliary Partial Orthotopic Liver Transplantation with De Novo Autoimmune Hepatitis in the Allograft and Leftover Primary Biliary Cirrhosis in the Native Liver

Hepatocyte transplantation for metabolic liver disease: UK experience

For end-stage liver disease and liver-based metabolic conditions the accepted treatment is liver transplantation. With developments in surgical techniques and immunosuppressive drug therapy the survival of patients and grafts is now good. In the conventional procedure the patient's whole liver is replaced with a liver obtained from a braindead or living donor. When the donor liver is too big it can be reduced to a compatible size; and, recently, split-liver procedures have been performed whereby the right lobe is transplanted into an adult and the smaller left lobe into a child,1 thus increasing the effective donor pool. Another important advance in surgical technique is the use of auxiliary liver transplantation for patients with acute liver failure and certain liver-based metabolic defects such as Crigler–Najjar syndrome type I, urea cycle defects, and familial hypercholesterolaemia. In this procedure, part of the patient's liver, often the left lobe, is replaced with part of a donor liver. In a patient with acute liver failure this leaves open the possibility of regeneration of the native liver, in which case immunosuppression can be stopped and the graft allowed to atrophy; and in a patient with a metabolic disorder the native liver will be available for future gene therapy. The results of auxiliary liver transplantation in man2 have supported observations in animals that small amounts of liver tissue can provide sufficient function to correct an underlying metabolic defect. This finding was a spur to work on hepatocyte transplantation for such disorders. The aim is to repopulate the liver with donor hepatocytes, injected either directly into the liver or into the spleen, from which they migrate to the liver. If the technique proves successful, hepatocyte transplantation offers several potential advantages. In terms of supply, there is the possibility of using cells from livers that are unsuitable for conventional transplantation because of steatosis or trauma. The patient does not have to undergo major surgery; moreover, in metabolic conditions the native liver provides a safety net in case of failure. One of the most important advantages is the availability of the liver as a target organ for gene therapy when this becomes a clinical reality. Experience of hepatocyte transplantation has been gained in patients with acute liver failure3,4 and metabolic liver diseases such as Crigler–Najjar syndrome type I,5 glycogen storage disease type 1a,6 and urea cycle defects.7 The background to this work has been described elsewhere.8–11 The current paper discusses the sources of hepatocytes, the isolation process, preclinical studies and clinical experience in the UK, especially in the treatment of liver-based inborn errors of metabolism.

Immunosuppression Withdrawal After Auxiliary Liver Transplantation for Acute Liver Failure

Background The potential for immunosuppression withdrawal is the rationale for auxiliary liver transplantation (AUX) in patients with acute liver failure (ALF). Patients and methods Forty-four AUX were performed in 28 adults and 16 children with ALF secondary to seronegative hepatitis ( n = 20; 45%), paracetamol hepatotoxicity ( n = 14; 32%), acute viral hepatitis (hepatitis B virus [HBV] n = 3, Epstein-Barr virus n = 1; 9%), drug-induced hepatitis ( n = 3; 7%), autoimmune hepatitis ( n = 2; 5%), and mushroom poisoning ( n = 1; 2%). All patients fulfilled the King’s College Hospital transplant criteria for ALF. After partial hepatectomy, 38 patients received a segmental auxiliary graft and six, a whole auxiliary graft. Immunosuppression was based on calcineurin inhibitors and steroids. Results Thirty-four patients (77%) are alive after a median follow-up of 30 months (range 4 to 124). Eight adults and two children died of sepsis ( n = 6; 14%) at a median interval of 30 days (range 2 to 66), intraoperative cardiac failure ( n = 1), brain edema on postoperative day 8 ( n = 1), sudden death on day 35 ( n = 1), and multiple organ failure associated with HBV recurrence 4 years after transplantation ( n = 1). Three patients underwent retransplantation for small-for-size graft syndrome with sepsis on postoperative day 15 ( n = 1) and for ductopenic rejection 4 and 15 months after AUX ( n = 2). In 10/31 (32%) survivors (6/18 adults and 4/13 children) immunosuppression was completely withdrawn after a median of 19 months. Conclusion Complete immunosuppression withdrawal can be achieved in a significant proportion of patients after AUX for ALF.

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.

Auxiliary Partial Orthotopic Living Donor Liver Transplantation: Kyoto University Experience

Auxiliary partial orthotopic liver transplantation (APOLT) was initially indicated as a potentially reversible fulminant hepatic failure and non-cirrhotic metabolic liver disease to compensate for enzyme deficiency without complete removal of the native liver. We expand our indication of APOLT for small-for-size grafts to support the function of implanted grafts during the early post-operative period, and for ABO-incompatibility to sustain a patient's life if the patient has a graft failure. We retrospectively reviewed 31 patients undergoing APOLT from living donor. The indication of APOLT was fulminant hepatic failure in 6, non-cirrhotic metabolic liver disease in 6, small-for-size grafts in 13 and ABO-incompatible cases in 6. The cumulative survival rate for APOLT at 1 and 5 years was 57.9% and 50.6%, and 78.8% and 73.8% for standard LDLT. None of the patients who underwent transplantation with APOLT for fulminant hepatic failure had long-term patient survival. The incidence of acute cellular rejection was higher in APOLT (58.1%) than standard LDLT (35.0%). Biliary complication was higher and the need for retransplantation was greater in APOLT than standard LDLT (p < 0.01). The results suggest that the indications of APOLT should be reconsidered in view of the risk for complications and retransplantation.

Establishment of a new pig model for auxiliary partial orthotopic liver transplantation

To establish a new pig model for auxiliary partial orthotopic liver transplantation (APOLT). The liver of the donor was removed from its body. The left lobe of the liver was resected in vivo and the right lobe was used as a graft. After the left lateral lobe of the recipient was resected, end-to-side anastomoses of suprahepatic inferior vena cava and portal vein were performed between the donor and recipient livers, respectively. End-to-end anastomoses were made between hepatic artery of graft and splenic artery of the host. Outside drainage was placed in donor common bile duct. Models of APOLT were established in 5 pigs with a success rate of 80%. Color ultrasound examination showed an increase of blood flow of graft on 5(th) d compared to the first day after operation. When animals were killed on the 5(th) d after operation, thrombosis of hepatic vein (HV) and portal vein (PV) were not found. Histopathological examination of liver samples revealed evidence of damage with mild steatosis and sporadic necrotic hepatocytes and focal hepatic lobules structure disorganized in graft. Infiltration of inflammatory cells was mild in portal or central vein area. Hematologic laboratory values and blood chemical findings revealed that compared with group A (before transplantation), mean arterial pressure (MAP), central venous pressure (CVP), buffer base (BB), standard bicarbonate (SB) and K(+) in group B (after portal vein was clamped) decreased (P<0.01). After reperfusion of the graft, MAP, CVP and K(+) restored gradually. Significant decrease of congestion in portal vein and shortened blocking time were obtained because of the application of in vitro veno-venous bypass during complete vascular clamping. This new procedure, with such advantages as simple vessel processing, quality anastomosis, less postoperative hemorrhage and higher success rate, effectively prevents ischemia reperfusion injury of the host liver and deserves to be spread.

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.

Overcoming the portal steal phenomenon in auxiliary partial orthotopic liver transplantation by modulation of the venous outflow of the native liver

The main drawback of auxiliary partial orthotopic liver transplantation (APOLT) is the competition of the portal flow between the graft and the native liver, leading to graft failure. In two patients with Crigler-Najjar syndrome type I, the intrahepatic resistance of the native liver was increased by occluding the recipients middle hepatic vein during parenchymal transection, leading the portal flow towards the graft. This new surgical technique could encourage centers to recommence APOLT.

Transplantation auxiliaire pour cirrhose: Une alternative possible pour l’utilisation de greffons de petit poids ?

If the ratio liver graft weight/recipient body weight ratio is below 0.8%, there is a high risk of primary non function of the graft in almost 50% of cases. We report the first elective Auxiliary Partial Orthotopic Liver Transplantation using a small cadaveric left graft for cirrhosis. The graft weight/recipient body weight rate was 0.6%. This technique avoided the small-for-size syndrome in the early postoperative period. The native right liver was resected two months later. With a follow-up of 5 years, the patient is in good condition. This original technique could be a solution to increase the number of transplantations using small grafts, especially left grafts, provided by splits or living donors.