Yukihiro Inomata

Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy

Objective: Familial amyloid polyneuropathy (FAP), which is a fatal disorder inherited in an autosomal dominant fashion, is characterized by systemic accumulation of polymerized transthyretin (TTR) in the peripheral nerves and systemic organs. Liver transplantation has become an accepted treatment of this disorder because it stops the major production of amyloidogenic TTR. However, improved survival of transplant patients compared with that of nontransplant patients has not been sufficiently demonstrated. This study investigated whether transplantation improved the long-term outcome of patients by comparing the survival of patients who had transplantations with that of patients who had not had transplantations. Methods: Eighty consecutive patients with FAP Val30Met who visited Kumamoto University Hospital between January 1990 and December 2010 were studied. The transplant group consisted of 37 patients who had a partial hepatic graft via living donor transplantation in Japan or who underwent liver transplantation in Sweden, Australia, or the United States. The nontransplant group consisted of 43 patients with FAP. Survival was evaluated by using Kaplan-Meier analysis, and the difference in survival was examined via the log-rank test. Results: The transplant group had prolonged survival (p < 0.001) compared with the nontransplant group. The estimated probability of survival at 10 years was 56.1% for the nontransplant group vs 100% for the transplant group. Conclusion: Liver transplantation should be considered as an effective treatment in clinical management of patients with FAP Val30Met. Classification of evidence: This study provides Class III evidence that liver transplantation prolongs survival in patients with FAP Val30Met.

Long-term outcomes of pediatric living donor liver transplantation in Japan: An analysis of more than 2200 cases listed in the registry of the japanese liver transplantation society

The Japanese Liver Transplantation Society (JLTS) was established in 1980 in order to characterize and follow trends in patient characteristics and graft survival among all liver transplant patients in Japan. This study analyzed the comprehensive factors that may influence the outcomes of pediatric patients who undergo living donor liver transplantation (LDLT) by evaluating the largest cohort in the world. Between November 1989 and December 2010, 2224 pediatric patients underwent LDLT in Japan. There were 998 male (44.9%) and 1226 female donors (55.1%) without donor mortalities related to transplant surgery. There were 946 male (42.5%) and 1278 female (57.5%) recipients with a median age of 4.0 years (range: 13 days to 17.9 years). Cholestatic liver disease was the leading indication for LDLT (n = 1649; 76.2%), followed by metabolic disorders (n = 194; 8.7%), acute liver failure (n = 192; 8.6%) and neoplastic liver disease (n = 66; 3.0%). The 1‐, 5‐, 10‐ and 20‐year patient survival rates were 88.3%, 85.4%, 82.8% and 79.6%, respectively. Blood‐type incompatibility, recipient age, etiology of liver disease and transplant era were found to be significant predictors of overall survival. We are able to achieve satisfactory long‐term pediatric patient survival outcomes in the JLTS series without compromising the living donors.

Living-related liver transplantation for alagille syndrome

Alagille syndrome (AGS) is an autosomal dominant genetic disorder characterized by chronic cholestasis, congenital heart disease, peculiar facies, butterfly-like vertebrae, and posterior embryotoxon. Liver dysfunction is the common presentation of AGS, and liver transplantation may be indicated. This study examines the outcome of living-related liver transplantation (LRLT) for AGS. Twenty patients with AGS (median age 5.0 years, range 0.6–12.9) underwent LRLT at Kyoto University Hospital between June 1990 and February 2002. Five potential donors were excluded because of paucity of intrahepatic bile ducts diagnosed by preoperative liver biopsy and one because of a hepatic vascular anomaly. The overall 5-year patient survival was 80.4%. Three patients died as the result of the following: complications related to surgery, heart failure caused by progressive pulmonary artery stenosis, and a graft with unsuspected bile duct paucity. Liver dysfunction was improved in all successful cases, and catch-up growth occurred in 90% of patients. LRLT is an efficacious treatment modality for AGS if donors are selected by cautious evaluation to rule out unsuspected bile duct paucity.

Liver transplantation in Japan -Registry by the Japanese Liver Transplantation Society-†

As of December 31, 2013, a total of 7474 liver transplants have been carried out at 66 institutions in Japan. This total included 7255 living‐donor transplants and 219 deceased‐donor transplants (216 from heart‐beating donors and 3 from non‐heart‐beating donors). The annual total of liver transplants in 2013 decreased to 408, from 422 in 2012. The number of liver transplants from living donors decreased to 369, from 381, whereas the number of liver transplants from heart‐beating deceased donors did not change significantly. The most frequent indication was cholestatic disease, followed by neoplastic disease. In terms of graft liver in living‐donor cases, right‐lobe graft was the most popular (36%). Patient survival following transplantations from heart‐beating donors (1 year, 85.9%; 3 years, 82.6%; 5 years, 81.3%; 10 years, 73.8%) was similar to those from living donors (1 year, 83.8%; 3 years, 79.6%; 5 years, 77.1%; 10 years, 71.9%; 15 years, 67.8%; 20 years, 66.1%). Graft survival was very much the same as patient survival. As for ABO‐incompatible transplantation, transplant period affected the outcome significantly, probably due to local infusion therapy and rituximab prophylaxis, which were introduced in many transplant centers after 2000 and 2004, respectively.

Long‐Term Outcome of Adult‐to‐Adult Living Donor Liver Transplantation for Post‐Kasai Biliary Atresia

Our objective was to analyze problems in the perioperative management and long‐term outcome of living donor liver transplantation (LDLT) for biliary atresia (BA). Many reports have described the effectiveness of liver transplantation (LT) for BA, particularly in pediatric cases, but little information is available regarding LT in adults (≥16 years old). Between June 1990 and December 2004, 464 patients with BA underwent LDLT at Kyoto University Hospital, of whom 47 (10.1%) were older than 16 years. In this study, we compared the outcomes between adult (≥16 years old) and pediatric (<16 years old) patients. The incidence of post‐transplant intestinal perforation, intra‐abdominal bleeding necessitating repeat laparotomy and biliary leakage was significantly higher (p < 0.0001, <0.001 and <0.001, respectively) in adults. Overall cumulative 1‐, 5‐ and 10‐year survival rates in pediatric patients were significantly higher (p < 0.005) than in adults. Two independent prognostic determinants of survival were identified: a MELD score over 20 and post‐transplant complications requiring repeat laparotomy. Outcome of LDLT in adult BA patients was poorer than in pediatric patients. It seems likely that LT will be the radical treatment of choice for BA and that LDLT should be considered proactively at the earliest possible stage.

Manifestations of Transthyretin-Related Familial Amyloidotic Polyneuropathy: Long-Term Follow-Up of Japanese Patients After Liver Transplantation

PurposeTo observe which symptoms of transthyretinrelated familial amyloidotic polyneuropathy (FAP) progressed in the long term after liver transplantation (LT), focusing on cardiac, kidney, and ocular symptoms.MethodsWe reviewed the medical records of 34 Japanese patients with FAP, who underwent LT between 1994 and 2006. The mean follow-up period (±SD) after LT was 9.6 ± 3.4 years. Of the 34 patients, 30 had FAP amyloidogenic transthyretin (ATTR) Val30Met, 1 had FAP ATTR Ser50Ile, and 3 had FAP ATTR Tyr114Cys.ResultsThe 10-year survival rates from the onset of FAP and from the time of LT were 100% and 91.4%, respectively. Progression of ocular amyloidosis was seen in 17 (50%) patients, 13 of whom had de novo amyloid deposits in the vitreous body; progression of cardiac amyloidosis was seen in 10 (29%) patients, 4 of whom had newly granular sparkling echo on echocardiography, and 9 of whom had newly implanted pacemakers or implantable cardioverter-defibrillators. Although the mean serum creatinine levels did not increase significantly after LT in any of the patients, the estimated glomerular filtration rate had decreased significantly by 7 years after LT.ConclusionAlthough LT is life-saving for patients with FAP, we observed progression of the ocular and cardiac symptoms of FAP in a significant number of these patients over the long term after LT.

Changes in pathological and biochemical findings of systemic tissue sites in familial amyloid polyneuropathy more than 10 years after liver transplantation

Objective To elucidate the long-term effects of liver transplantation (LT) on familial amyloid polyneuropathy (FAP). Methods We investigated clinicopathological and biochemical characteristics of systemic tissues in four autopsied cases of FAP patients surviving more than 10 years after LT and seven autopsied cases without LT. For analysing the truncated form of transthyretin (TTR) in amyloid, we also employed specimens from additional 18 FAP patients. Results Several tissue sites such as the heart, tongue and spinal cord had moderate-to-severe amyloid deposits but other tissues showed no or mild amyloid deposition. Those findings seemed similar to those observed in senile systemic amyloidosis (SSA), a sporadic amyloidosis caused by wild-type (WT) TTR. Also, amyloid deposits in systemic tissue sites except for the spinal cord in patients after LT derived mostly from WT TTR secreted from the normal liver grafts. In addition, in non-transplantation patients, proportions of WT TTR seemed to be relatively high in those tissue sites in which patients after LT had severe amyloid deposition, which suggests that WT TTR tends to form amyloid in those tissue sites. Finally, although the truncation of TTR in amyloid deposits did not depend on undergoing LT, we elucidated the truncation of TTR occurred predominantly in patients from non-endemic areas of Japan, where FAP amyloidogenic TTR V30M patients are late onset and low penetrance, compared with patients from an endemic area of Japan. Conclusions FAP may shift to systemic WT TTR amyloid formation after LT, which seems to be similar to the process in SSA. The truncation of TTR in amyloid deposits may depend on some genetic or environmental factors other than undergoing LT.

Intravital imaging of neutrophil recruitment in hepatic ischemia-reperfusion injury in mice.

Background Neutrophils are considered responsible for the pathophysiologic changes during hepatic ischemia-reperfusion (I/R) injury; however, few studies have examined real-time intravital neutrophil recruitment. Here, we show a method for imaging the neutrophil recruitment in hepatic I/R injury using two-photon laser scanning microscopy (TPLSM). Methods LysM-eGFP mice were subjected to 45 min of partial warm hepatic ischemia followed by reperfusion. Mice received an intravenous injection of tetramethylrhodamine isothiocyanate–labeled albumin to visualize the microvasculature. Using time-lapse TPLSM technique, we directly observed the behavior of neutrophils in I/R injury. Results At low magnification, four to six hepatic lobules could be visualized. The number of adherent neutrophils continued to increase for 4 hr after reperfusion, whereas their crawling velocity reached a maximum of 2 hr after reperfusion and then decreased gradually. High-magnification images revealed the presence or absence of blood circulation in sinusoids. Six hours after control operation or reperfusion, circulation was maintained in all sinusoids in the control group, whereas spotty nonperfused areas accompanied by neutrophil infiltration could be observed in the I/R group. Adherent neutrophils in perfused areas in the I/R group had more elongated shapes and moved more quickly than those in nonperfused areas and in the control group. Some hepatocytes affected by I/R injury showed the changes in their size and fluorescent intensity, which could attract neutrophils. Conclusions TPLSM was successfully used for intravital imaging of hepatic I/R injury in mice and has potential for a wide range of applications to investigate the mechanism of I/R injury.

Incidence and risk factors for new-onset diabetes in living-donor liver transplant recipients.

With the increased number of long‐term survivors after liver transplantation, new‐onset diabetes after transplantation (NODAT) is becoming more significant in patient follow‐up. However, the incidence of new‐onset diabetes after living‐donor liver transplantation (LDLT) has not been well elucidated. The aim of this study was to evaluate the incidence and risk factors for NODAT in adult LDLT recipients at a single center in Japan. A retrospective study was performed on 161 adult patients without diabetes who had been followed up for ≥three months after LDLT. NODAT was defined according to the 2003 American Diabetes Association/World Health Organization guidelines. The recipient‐, donor‐, operation‐, and immunosuppression‐associated risk factors for NODAT were assessed. Overall, the incidence of NODAT was 13.7% (22/161) with a mean follow‐up of 49.8 months. In a multivariate analysis, the identified risk factors for NODAT were donor liver‐to‐spleen (L‐S) ratio (hazard ratio [HR] = 0.022, 95% confidence interval [CI] = 0.001–0.500, p = 0.017), and steroid pulse therapy for acute rejection (HR = 3.320, 95% CI = 1.365–8.075, p = 0.008). In conclusion, donor L‐S ratio and steroid pulse therapy for acute rejection were independent predictors for NODAT in LDLT recipients. These findings can help in screening for NODAT and applying early interventions.

Management of undifferentiated sarcoma of the liver including living donor liver transplantation as a backup procedure

We present the cases of 3 children with huge undifferentiated sarcoma of the liver who were treated with surgical excision including liver transplantation as an option and adjuvant chemotherapy. All 3 patients were males aged 10, 13, and 15 years old. The size of the tumor was 10, 15, and 20 cm in diameter, respectively. The youngest patient is disease free and doing well 43 months after resection. The 13-year-old patient presented with tumor rupture and underwent operation. The primary tumor and the ruptured tissue fragments were removed and he was given postoperative chemotherapy. The patient is disease free and doing well 52 months after surgery. The oldest patient had an unresectable tumor in the hilar region. Preoperative chemotherapy was given but later discontinued owing to severe side effects. He underwent living donor liver transplantation followed by postoperative chemotherapy. The patient had recurrent tumor 24 months after transplantation that was excised at reoperation. He is doing well and is disease free 18 months after the second procedure. Complete removal of the tumor including total hepatectomy and transplantation when indicated and suitable pre- and/or postoperative chemotherapy is an effective treatment for children with undifferentiated sarcoma of the liver.