Naoya Yamada

Protocol liver biopsy is the only examination that can detect mid-term graft fibrosis after pediatric liver transplantation

AIM To assessed the clinical significance of protocol liver biopsy (PLB) in pediatric liver transplantation (LT). METHODS Between July 2008 and August 2012, 89 and 55 PLBs were performed in pediatric patients at two and five years after LT, respectively. We assessed the histopathological findings using the Metavir scoring system, including activity (A) and fibrosis (F), and we identified factors associated with scores of ≥ A1 and ≥ F1. Our results clarified the timing and effectiveness of PLB. RESULTS The incidences of scores of ≥ A1 and ≥ F1 were 24.7% and 24.7%, respectively, at two years after LT and 42.3% and 34.5%, respectively, at five years. Independent risk factors in a multivariate analysis of a score of ≥ A1 at two years included ≥ 2 h of cold ischemic time, no acute cellular rejection and an alanine amino transaminase (ALT) level of ≥ 20 IU/L (P = 0.028, P = 0.033 and P = 0.012, respectively); however, no risk factors were identified for a score of ≥ F1. Furthermore, no independent risk factors associated with scores of ≥ A1 and ≥ F1 at five years were identified using multivariate analysis. A ROC curve analysis of ALT at two years for a score of ≥ A1 demonstrated the recommended cutoff value for diagnosing ≥ A1 histology to be 20 IU/L. The incidence of scores of ≥ A2 or ≥ F2 at two years after LT was 3.4% (three cases), and all patients had an absolute score of ≥ A2. In contrast to that observed for PLBs at five years after LT, the incidence of scores of ≥ A2 or ≥ F2 was 20.0% (11 cases), and all patients had an absolute score of ≥ F2. In all cases, the dose of immunosuppressants was increased after the PLB, and all ten patients who underwent a follow-up liver biopsy improved to scores of ≤ A1 or F1. CONCLUSION PLB at two years after LT is an unnecessary examination, because the serum ALT level reflects portal inflammation. In addition, immunosuppressive therapy should be modulated to maintain the ALT concentration at a level less than 20 IU/L. PLB at five years is an excellent examination for the detection of early reversible graft fibrosis because no serum markers reflect this finding.

Living donor liver transplantation from an asymptomatic mother who was a carrier for ornithine transcarbamylase deficiency

Wakiya T, Sanada Y, Urahashi T, Ihara Y, Yamada N, Okada N, Egami S, Sakamoto K, Murayama K, Hakamada K, Yasuda Y, Mizuta K. Living donor liver transplantation from an asymptomatic mother who was a carrier for ornithine transcarbamylase deficiency.

The role of operative intervention in management of congenital extrahepatic portosystemic shunt

BACKGROUND AND AIMS Congenital extrahepatic portosystemic shunt (CEPS) is a rare venous malformation in which mesenteric venous blood drains directly into the systemic circulation. It is still a matter of debate whether conservative or operative strategies should be used to treat symptomatic CEPS. The aim of this study was to evaluate the role of operative intervention in the management of CEPS. METHODS Between June 2004 and August 2010, 6 consecutive patients with symptomatic CEPS were treated in our department. There were 3 male and 3 female patients, with a median age of 3.5 years (range, 1-8). Their demographic, clinical, and laboratory data were analyzed. All patients were scheduled to undergo shunt ligation or liver transplantation (LT). RESULTS Living donor LT was carried out in 4 patients, and shunt ligation in 2. After a median follow-up of 25 months, all the patients are alive currently with marked relief of symptoms. CONCLUSION Shunt ligation or LT for symptomatic CEPS is potentially curative.

Maternal grafts protect daughter recipients from acute cellular rejection after pediatric living donor liver transplantation for biliary atresia

Some studies have found that gender mismatch between donors and recipients are related to poor graft prognosis after liver transplantation. However, few studies have investigated the impact of gender mismatch on acute cellular rejection (ACR) in pediatric living donor liver transplantation (LDLT). This retrospective study investigated the clinical significance of these factors in ACR after pediatric LDLT. Between November 2001 and February 2012, 114 LDLTs were performed for recipients with biliary atresia (BA) using parental grafts. We performed univariate and multivariate analyses to identify the factors associated with ACR. The donor–recipient classifications included mother donor to daughter recipient (MD; n = 43), mother to son (n = 18), father to daughter (FD; n = 33), and father to son (n = 20) groups. The overall incidence rate of ACR in the recipients was 36.8%. Multivariate analysis showed that gender mismatch alone was an independent risk factor for ACR (P = 0.012). The FD group had a higher incidence of ACR than the MD group (P = 0.002). In LDLT, paternal grafts with gender mismatch were associated with a higher increased incidence of ACR than maternal grafts with gender match. Our findings support the possibility that maternal antigens may have an important clinical impact on graft tolerance in LDLT for patients with BA.

The impact of rituximab in ABO‐incompatible pediatric living donor liver transplantation: The experience of a single center

Previous studies have demonstrated the safety of ABO‐incompatible pediatric LDLT using preoperative plasmapheresis and rituximab; however, no reports have described the timing and dosage of rituximab administration for pediatric LDLT. This study aimed to describe a safe and effective dosage and timing of rituximab for patients undergoing pediatric ABO‐incompatible LDLT based on the experience of our single center. A total of 192 LDLTs in 187 patients were examined. These cases included 29 ABO‐incompatible LDLTs in 28 patients. Rituximab was used beginning in January 2004 in recipients older than two yr of age (first period: 375 mg/m2 in two cases; second period: 50 mg/m2 in two cases; and 200 mg/m2 in eight cases). Two patients who received 375 mg/m2 rituximab died of Pneumocystis carinii pneumonia and hemophagocytic syndrome. One patient who received 50 mg/m2 rituximab required retransplantation as a consequence of antibody‐mediated complications. All eight patients administered 200 mg/m2 survived, and the mean CD20+ lymphocyte count was 0.1% at the time of LDLT. In the preoperative management of patients undergoing pediatric ABO‐incompatible LDLT, the administration of 200 mg/m2 rituximab three wk prior to LDLT was safe and effective.

Effect of repeat Kasai hepatic portoenterostomy on pediatric live-donor liver graft for biliary atresia.

OBJECTIVES Treatment for patients with biliary atresia is a Kasai hepatic portoenterostomy; however, the efficacy of repeat Kasai hepatic portoenterostomy is unclear. This study sought to examine the effect of a prior Kasai hepatic portoenterostomy, especially a repeat Kasai hepatic portoenterostomy, on the outcomes of living-donor liver transplant. MATERIALS AND METHODS One hundred twenty-six of 170 children that underwent a living-donor liver transplant between May 2001, and March 2010, received a living-donor liver transplant for biliary atresia. These patients were divided into 2 groups according to the number of previous portoenterostomies: 1 (group A, n=100) or 2 or more Kasai hepatic portoenterostomies (group B, n=26). Portoenterostomy was performed twice in 24 patients in group B, 3 times in 1, and 4 times in 1. Preoperative, operative factors, mortality, morbidity, and survival rates were examined and compared between groups. RESULTS The surgical factors such as operative time, blood loss per weight, cold ischemia time, and weight of the native liver were significantly greater in group B than they were in group A. The patient survival rates were comparable in the 2 groups (94.5% in group A and 93.3% in group B), and the difference was not statistically significant. No statistically significant difference was observed between the groups with regard to vascular complications, biliary complications, and other factors including postoperative variables. Bowel perforation requiring surgical repair was more frequent in group B than it was in group A. CONCLUSIONS Repeat Kasai hepatic portoenterostomy might have a negative effect on patients who undergo living-donor liver transplant for biliary atresia patients with potential lethal complications such as bowel perforation. More biliary atresia patients could have a liver transplant, with improved survival and better life expectancy, if they have inadequate biliary drainage after the initial Kasai hepatic portoenterostomy.

Veno-occlusive disease/sinusoidal obstruction syndrome associated with potential antibody-mediated rejection after pediatric living donor liver transplantation: a case report.

A 9-month-old girl with biliary atresia underwent successful living donor liver transplantation from her 42-year-old ABO blood-type incompatible mother. The postoperative course was uneventful until postoperative day (POD) 13 when the recipient displayed an increased volume of drained ascites and decreased her platelet count showing low-velocity portal venous inflow without hepatic venous outflow obstruction. We suspected potential veno-occlusive disease/sinusoidal obstruction syndrome (vod/sos) due to an acute cellular rejection (ACR) episode and performed a liver biopsy (LB). We diagnosed severe episode (Rejection Activity Index Score; P3V3B1 = 7) and started steroid pulse therapy. We performed a second LB on POD 27 because the patient showed weight gain and tender hepatomegaly, diagnosing moderate ACR (P1V3B1 = 5). We started a second course of steroid pulse therapy, but the patients clinical findings did not improve. On POD 43, her third LB finding showed P1V1B1 with improved processes from ACR, but still displaying severe congestion and fibrotic obliteration of small hepatic veins. We suspected that her immunologic responses were associated with antibody-mediated rejection (AMR) because her anti-HLA class I and class II antibodies were positive by flow panel-reactive antibody method and donor-specific antigen class II and C4d staining were also positive. We added mycophenolate mofetil and administered high-dose intravenous immunoglobulin to control the AMR, and anticoagulant therapy for the VOD/SOS. Her clinical findings and graft venous abnormalities finally improved; she was eventually discharged without sequelae on POD 72.

Selection of living donor liver grafts for patients weighing 6kg or less

In the field of pediatric living donor liver transplantation (LDLT), physicians sometimes must reduce the volume of left lateral segment (LLS) grafts to prevent large‐for‐size syndrome. There are 2 established methods for decreasing the size of an LLS graft: the use of a segment 2 (S2) monosegment graft and the use of a reduced LLS graft. However, no procedure for selecting the proper graft type has been established. In this study, we conducted a retrospective investigation of LDLT and examined the strategy of graft selection for patients weighing ≤6 kg. LDLT was conducted 225 times between May 2001 and December 2012, and 15 of the procedures were performed in patients weighing ≤6 kg. We selected S2 monosegment grafts and reduced LLS grafts if the preoperative computed tomography (CT)–volumetry value of the LLS graft was >5% and 4% to 5% of the graft/recipient weight ratio, respectively. We used LLS grafts in 7 recipients, S2 monosegment grafts in 4 recipients, reduced S2 monosegment grafts in 3 recipients, and a reduced LLS graft in 1 recipient. The reduction rate of S2 monosegment grafts for use as LLS grafts was 48.3%. The overall recipient and graft survival rates were both 93.3%, and 1 patient died of a brain hemorrhage. Major surgical complications included hepatic artery thrombosis in 2 recipients, bilioenteric anastomotic strictures in 2 recipients, and portal vein thrombosis in 1 recipient. In conclusion, our graft selection strategy based on preoperative CT‐volumetry is highly useful in patients weighing ≤6 kg. S2 monosegment grafts are effective and safe in very small infants particularly neonates. Liver Transpl 21:233‐238, 2015.

Risk factors and treatments for hepatic arterial complications in pediatric living donor liver transplantation

Hepatic artery complications (HAC) are a serious complication in pediatric liver transplant recipients because its incidence is high and it can occasionally lead to graft liver failure. We herein present a retrospective analysis of our 10‐year experience with pediatric living donor liver transplantation (LDLT) focusing on the risk factors and treatments for HAC.

Varicella Zoster Virus Disease After Pediatric Living Donor Liver Transplantation: Is It Serious?

OBJECTIVES The aim of this study was to evaluate patients who developed varicella zoster virus (VZV) disease after pediatric living donor liver transplantation (PLDLT). METHODS Two hundred fifty-five patients who underwent PLDLT between 1995 and 2010 were included in this study. Pretransplantation vaccination of VZV was performed for all recipients except emergency PLDLTs. Posttransplantation VZV vaccination was administered to the patients with a low VZV antibody titer 2 years or more after transplantation. The clinical course and outcomes of VZV disease in cases were reviewed with the transplant database and hospital medical records. RESULTS Sixty-three patients developed VZV disease (chicken pox in 61, herpes zoster in 2) at a median onset of 36 months after PLDLT and at a median age of 4 years old, with a cumulative incidence of 25%. All chicken pox occurred in VZV antibody-negative patients. The onset of herpes zoster in the two patients occurred within 3 months after PLDLT; in addition, these patients were VZV antibody-positive patients. The clinical presentations of most patients were not serious and there were no disseminated infections. Although only 3 patients (5%) were hospitalized, the other 60 patients (95%) all showed a good response to oral antiviral therapy. CONCLUSIONS Although VZV disease is an infectious disease with a high morbidity rate after PLDLT, it can normally be successfully managed on an outpatient basis at home. Pre- and posttransplantation vaccinations are effective for delaying the onset of chicken pox after PLDLT and to prevent it from developing into a serious illness.