Single-center experience and long-term outcomes of duct-to-duct biliary reconstruction in infantile living donor liver transplantation.

The indications for duct-to-duct (DD) biliary reconstruction in living donor liver transplantation (LDLT) for small children are still controversial. In this study, the feasibility of DD biliary reconstruction versus Roux-en-Y (RY) biliary reconstruction was investigated in terms of long-term outcomes. Fifty-six children who consecutively underwent LDLT with a weight less than or equal to 10.0 kg were enrolled. Biliary reconstruction was performed in a DD fashion for 20 patients and in an RY fashion for 36 patients. During a minimum follow-up of 2 years, the incidence of biliary strictures was 5.0% in the DD group and 11.1% in the RY group. Cholangitis during the posttransplant period was observed in the RY group only. There were no deaths related to biliary problems. This study shows that DD reconstruction in LDLT for small children (weighing 10.0 kg or less) is a feasible option for biliary reconstruction.

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.

Randomized, multicenter trial comparing tacrolimus plus mycophenolate mofetil to tacrolimus plus steroids in hepatitis C virus-positive recipients of living donor liver transplantation.

The purpose of this prospective, randomized, multicenter trial was to evaluate the effects of a steroid-avoiding immunosuppression protocol on hepatitis C virus (HCV)-positive recipients of living donor liver transplantation (LDLT). Seventy-five HCV-positive LDLT recipients were included in this study, and they were randomized to receive tacrolimus (TAC) plus a corticosteroid (ST; n = 35) or TAC plus mycophenolate mofetil (MMF; n = 40). Biopsy-proven acute rejection (BPAR) was treated with steroid pulse therapy in both groups. Protocol biopsy was performed 3, 6, and 12 months after LDLT and annually thereafter. Histological recurrence of HCV (fibrosis stage ≥ F1 according to the METAVIR score), BPAR resistant to 2 sets of steroid pulse therapy, hepatocellular carcinoma (HCC) recurrence, retransplantation, and patient death were defined as events, and the primary endpoint was event-free survival. The median follow-up was 55 months. The event-free survival rates at 1, 3, and 5 years were 38.2%, 11.8%, and 5.9%, respectively, for the ST group and 25.0%, 17.5%, and 14.6%, respectively, for the MMF group (P = 0.45). The overall 5-year patient survival rates were similar for the ST group (82.7%) and the MMF group (81.0%, P = 0.28). Steroid-resistant BPAR occurred in only 1 patient from the MMF group. HCC recurrence occurred for 1 patient from the ST group and 2 patients from the MMF group. HCV recurrence rates with a fibrosis stage ≥ F1 1 and 3 years after LDLT were 59.4% and 85.9%, respectively, for the ST group and 74.2% and 81.9%, respectively, for the MMF group (P = 0.57). In conclusion, our steroid-avoidance regimen had no apparent impact on LDLT outcomes for HCV-positive recipients.

Re-evaluation of the indications for liver transplantation in Wilson's disease based on the outcomes of patients referred to a transplant center.

The aim of this study was to re-evaluate the indications and timing of LT for WD. From 2000 to 2009, eight patients with WD who had been referred to our institution for LT were enrolled in this study. The mean patient age was 15.9 yr (range, 7-37 yr). Four patients could not receive LT, because there were no available donors. All four patients were treated with chelating agent medication. Three of them (two of two patients with fulminant WD and one of two with cirrhotic WD) who did not undergo LT are still alive and doing well with stable liver functional tests. Only one of the patients with cirrhotic WD who did not undergo LT died of hepatic failure. Even among the four patients who underwent LT, one with fulminant WD recovered from hepatic encephalopathy with apheresis therapy and chelating agent. He later required LT because of severe neutropenia from d-penicillamine. The other three patients who underwent LT recovered and have been doing well. Some of the patients with WD can recover and avoid LT with medical treatment. Even when WD has progressed liver cirrhosis and/or fulminant hepatic failure at the time of diagnosis, medical treatment should be tried before considering LT.

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.

Peritransplant gastrointestinal symptoms in familial amyloidotic polyneuropathy.

OBJECTIVES: Gastrointestinal dysfunction is a common complication in familial amyloidotic polyneuropathy, and gastrointestinal symptoms are associated with a patient's nutritional status. The object of this study was to evaluate changes in peritransplant gastrointestinal symptoms and the nutritional status of familial amyloidotic polyneuropathy patients using the modified body mass index following a living-donor liver transplant. MATERIALS AND METHODS: In a retrospective analysis, we compared 17 Japanese familial amyloidotic polyneuropathy patients who underwent living-donor liver transplant in Kumamoto University Hospital between 2000 and 2009 with a control group of 28 patients with chronic liver disease. We analyzed the peritransplant gastrointestinal symptoms, nutritional status, duration of central venous catheterization, and postoperative hospital stay. The Mann-Whitney U test and Fisher exact test were used to analyze relations between the familial amyloidotic polyneuropathy group and control group, and the Wilcoxon signed-rank test, to analyze the relation of perioperative modified body mass index, with a value for P < .05 considered statistically significant. RESULTS: The duration of central venous catheterization and postoperative hospital stay were significantly longer in the familial amyloidotic polyneuropathy group than they were in the control group. There was no significant difference between modified body mass index preoperatively and 1 year after living-donor liver transplant. Although gastrointestinal symptoms were typically mild before living-donor liver transplant, the familial amyloidotic polyneuropathy group experienced a temporary deterioration in gastrointestinal symptoms after receiving the living-donor liver transplant but recovered after approximately 2 months. CONCLUSIONS: Although familial amyloidotic polyneuropathy patients experienced temporary exacerbations of gastrointestinal symptoms, their nutritional status was not affected during the peritransplant period, and they generally recovered within 2 months.

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.

Genomic polymorphisms in 3ß-hydroxysterol Δ24-reductase promoter sequences.

It was recently reported by the present team that 3ß-hydroxysterol Δ24-reductase (DHCR24) is induced by hepatitis C virus (HCV) infection. In addition, upregulation of DHCR24 impairs p53 activity. In human hepatoma HuH-7 cells, the degree of DHCR24 expression is higher than in normal hepatic cell lines (WRL68) at the transcriptional level. The genomic promoter sequence of DHCR24 was characterized and nucleotide substitutions were observed in HuH-7 cells at nucleotide numbers -1453 (G to A), -1420 (G to T), -488 (A to C) and -200 (G to C). The mutations of these sequences from HuH-7 cell types to WRL68 cell types suppressed DHCR24 gene promoter activity. The sequences were further characterized in hepatocytes from patient tissues. Four tissues from HCV-positive patients with cirrhosis or hepatocellular carcinoma (#1, 2, 3, 5) possessed HuH-7 cell type sequences. Interestingly, one patient with liver cirrhosis (#4) possessed WRL68 cell-type sequences; this patient had been infected with HCV and was HCV negative for 17 years after interferon therapy. Next, the effect of HCV infection on these polymorphisms was examined in humanized chimeric mouse liver and HuH-7 cells. The human hepatocytes possess WRL68 cell type and did not show the nucleotide substitution after HCV infection. The HCV-replicon was removed by interferon treatment and established the cured K4 cells. These cells possess HuH-7 cell type sequences. Thus, this study showed the genomic polymorphism in DHCR24 promoter is not directly influenced by HCV infection.

Intrahepatic artery pseudoaneurysm associated with a metallic biliary stent after living donor liver transplantation: report of a case.

An intrahepatic artery pseudoaneurysm (IHAA) is a very rare but potentially lethal complication occurring after liver transplantation. This report presents a case of an IHAA associated with a metallic biliary stent after liver transplantation. A 40-year-old male underwent living donor liver transplantation (LDLT) using a left lobe graft. The bile duct reconstruction was performed with Roux-en-Y hepaticojejunostomy. He developed obstructive jaundice 5 years after LDLT, and had biliary stricture of the anastomosis area, therefore, the two metallic biliary stents were finally positioned at the stricture of the biliary tract. He suddenly developed hematemesis 8 years after LDLT, and computerized tomography scan showed an IHAA. Although seven interlocking detachable coils were placed at the neck of the aneurysm, hematemesis recurred 3 days after the initial embolization. Therefore, retransplantation was successfully performed 25 days after the embolization of IHAA using a right lobe graft from his son. In conclusion, metal stent insertion can lead to the fatal complication of HAA. The placement of a metallic stent could have been avoided in this case. Percutaneous metallic stent insertion for biliary stenosis after liver transplantation should therefore only be performed in carefully selected patients.

Sclerosing encapsulating peritonitis after living donor liver transplantation: a case successfully treated with tamoxifen: report of a case.

Sclerosing encapsulating peritonitis (SEP) is a rare cause of bowel obstruction. It is difficult to diagnose and the prognosis is poor. This report describes a case of SEP after living donor liver transplantation that was successfully treated with tamoxifen. A 56-year-old male, that had received a liver transplant for hepatitis C virus-related hepatocellular carcinoma 5 years earlier, was admitted with continuous abdominal pain and nausea. He had increased C-reactive protein levels and white blood cell count, and underwent laparotomy 5 days after hospitalization. The surgical findings showed ascites and SEP of the small bowel. An attempt to peel off the adhesions was stopped because there was a strong risk of intestinal tract damage. Tamoxifen treatment was initiated for SEP after surgery. The patient's symptoms gradually improved and he was able to resume feeding. He had been symptom-free for over 3 years at the last follow-up.

Liver transplant from an ABO-incompatible and hepatitis C antibody-positive but an HCV-RNA negative living donor in a familial amyloid polyneuropathy patient.

Familial amyloid polyneuropathy is a rare, progressively disabling, and ultimately fatal inherited disease. Liver transplant is currently the only available treatment proven to halt the progression of familial amyloid polyneuropathy. We report a 31-year-old woman with familial amyloid polyneuropathy who received a living-donor liver transplant from her husband who was hepatitis C virus antibody-positive but HCV-RNA negative and ABO incompatible. Six years after the transplant, both donor and recipient have normal liver biochemistry results; no hepatitis C viral load has been detectable in the recipient. This is the first report of a living ABO-incompatible liver transplant from an anti-hepatitis C virus antibody-positive but an HCV-RNA negative donor. This experience suggests that the use of an anti-hepatitis C virus antibody-positive hepatic graft is possible in select circumstances.

Pathological changes long after liver transplantation in a familial amyloidotic polyneuropathy patient.

Liver transplantation (LT) reportedly prolongs the survival of patients with familial amyloidotic polyneuropathy (FAP), a fatal hereditary systemic amyloidosis caused by mutant transthyretin (TTR). However, what happens in systemic tissue sites long after LT is poorly understood. In the present study, we report pathological and biochemical findings for an FAP patient who underwent LT and died from refractory ventricular fibrillation more than 16 years after FAP onset. Our autopsy study revealed that the distributions of amyloid deposits after LT were quite different from those in FAP amyloidogenic TTR V30M patients not having had LT and seemed to be similar to those observed in senile systemic amyloidosis (SSA), a sporadic systemic amyloidosis derived from wild-type (WT) TTR. Our biochemical examination also revealed that this patient's cardiac and tongue amyloid deposits derived mostly from WT TTR. We propose that FAP patients after LT may suffer from SSA-like WT TTR amyloidosis in systemic organs.

Current state of domino transplantation in Japan in terms of surgical procedures and de novo amyloid neuropathy.

The status of domino liver transplantation (DLT) in Japan was evaluated. DLT and familial amyloidotic polyneuropathy (FAP) recipients who underwent living donor liver transplantation (LDLT) at Kumamoto University were reviewed with attention to surgical procedures. Thirty-nine DLTs were performed in Japan until 2010, and survival rates at 1 and 3 years were 82% and 63.6%, respectively. Six of 21 DLT recipients who survived for more than 3 years developed amyloid depositions within organs, and de novo amyloid neuropathy was reported in three patients. DLT from FAP recipients in Kumamoto was safely performed with preservation of the retrohepatic inferior vena cava in FAP recipients. All 20 FAP recipients who were DLT donors are alive with the exception of one who died of the original FAP 9 years after LDLT. The outcomes of DLT and FAP recipients in Kumamoto were satisfactory.

A thoracoabdominal approach in revision of the hepatic hilum after left lobe living donor liver transplantation.

We present an approach to safely expose the hepatic hilum for revision procedures after left lobe living donor liver transplantation. A 14-year-old adolescent girl who had undergone left lobe living donor liver transplantation experienced repeated episodes of cholangitis. Because treatment with interventional techniques failed, surgical revision was indicated. The right thoracoabdominal approach was selected to minimize dissection. Intraoperative findings showed adhesive kinking of the Roux-Y limb just distal to the bilioenteric anastomosis, and a side-to-side jejunojejunostomy was performed. The thoracoabdominal approach leads to easy and excellent reoperative exposure of the hilar site of a left lobe liver graft.

Manifestations of transthyretin-related familial amyloidotic polyneuropathy: long-term follow-up of Japanese patients after liver transplantation.

PURPOSE: To observe which symptoms of transthyretin-related familial amyloidotic polyneuropathy (FAP) progressed in the long term after liver transplantation (LT), focusing on cardiac, kidney, and ocular symptoms. METHODS: We 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. RESULTS: The 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. CONCLUSION: Although 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.

Factors predicting persistent thrombocytopenia after living donor liver transplantation in pediatric patients.

Thrombocytopenia is common after LT for pediatric end-stage liver diseases. Seventy-six pediatric patients (≤15 yr old) who underwent LDLT were evaluated for the incidence and predictive factors of post-transplant thrombocytopenia (PLT <100, 000/mm(3) ). The prevalence of thrombocytopenia at two wk and at 12 months post-transplant was 22/76 (28.9%) and 11/62 (17.7%), respectively. Thrombocytopenia at two wk after LDLT was significantly associated with age at transplant, preoperative PLT, GRWR, acute rejection, and CMV infection in univariate analysis. Moreover, preoperative PLT, GRWR, and acute rejection had a strong correlation in multivariate analysis. Thrombocytopenia at 12 months after LDLT was associated only with preoperative PLT. We also demonstrated that vascular complications caused thrombocytopenia and that successful treatment recovered the PLT. These results showed that, in addition to considering the preoperative PLT, post-operative monitoring of platelets is very helpful for the early detection of adverse events related to the graft liver in pediatric liver transplant patients.

Development of hepatic angiomyolipoma accompanied with focal nodular hyperplasia long after treatment of pelvic rhabdomyosarcoma.

Survivors of childhood cancer have a higher risk of developing a secondary neoplasm in their lifetime. The increased risk of a second malignant neoplasm is related to treatment of the primary tumor and genetic predisposition. We describe a 19-year-old man with 2 hepatic masses, one of which was diagnosed as a hepatic angiomyolipoma and the other as focal nodular hyperplasia 14 years after the treatment of stage IV pelvic rhabdomyosarcoma. The combination of these tumors has not previously been reported in the literature.

Coefficient factor for graft weight estimation from preoperative computed tomography volumetry in living donor liver transplantation.

In the clinical setting of living donor liver transplantation (LDLT), it is common to find a discrepancy between the graft volume estimated by preoperative computed tomography volumetry and the actual graft weight (AGW) measured on the back-table. In this study, we attempt to find the coefficient factor that correlates the estimated graft volume to the AGW. Whole livers explanted in 25 LDLT recipients (17 cirrhotic and 8 morphologically normal with familial amyloid polyneuropathy) were evaluated to compare cirrhotic livers and noncirrhotic normal livers. In addition, right lobe grafts (n = 39) and left lobe grafts (n = 35) used in LDLTs were also evaluated to further determine the correlation between estimated graft volume and AGW. The correlation coefficient between estimated liver volume and actual liver weight was 1.01 in whole cirrhotic livers, whereas it was 0.85 in whole livers with familial amyloid polyneuropathy. In the partial liver grafts, it was 0.84 in right lobe grafts and 0.85 in left lobe grafts. In conclusion, we suggest that a correlation coefficient of 0.85 should be applied for the accurate calculation of the graft weight from the volume estimated by preoperative computed tomography in LDLT.

Difficulty in sustaining hepatic outflow in left lobe but not right lobe living donor liver transplantation.

BACKGROUND: Hepatic outflow block is one of the major complications leading to severe graft dysfunction after left lobe living donor liver transplantation (LDLT). METHODS: Medical records of 46 recipients of a left lobe LDLT were reviewed. The method of outflow reconstruction and post-transplant morphological changes of hepatic veins were investigated. The subjects were followed up until September 2008, with a median follow-up period of 2.0 yr (range: 0.5-5.9 yr). RESULTS: There were no multiple outflow tracts to be reconstructed, and the median caliber of the single orifices with or without venoplasty was 32.0 mm. The difference between the angle of hepatic veins to the sagittal plane measured on computed tomography was calculated for pre-operative donors and post-operative recipients a month after LDLT. Both left and middle hepatic veins showed a significantly greater change in angle than the right hepatic vein. Both left and middle hepatic veins more frequently showed a nearly flat wave form on Doppler study one month after LDLT. In the 46 recipients of left lobe grafts, three developed outflow block (6.5%). CONCLUSIONS: The middle and left hepatic veins tend to distort and stretch during graft regeneration. These characteristics seem to be associated with outflow disturbances.