Successful living donor liver transplantation for liver failure due to maternal T cell engraftment following cord blood transplantation in X-linked severe combined immunodeficiency disease: Case report.

Maternal T cells from perinatal transplacental passage have been identified in up to 40% of patients with severe combined immunodeficiency (SCID). Although engrafted maternal T cells sometimes injure newborn tissue, liver failure due to maternal T cells has not been reported. We rescued a boy with X-linked SCID who developed liver failure due to engrafted maternal T cell invasion following living donor liver transplantation (LDLT) following unrelated umbilical cord blood transplantation (UCBT). After developing respiratory failure 3 weeks postpartum, he was diagnosed with X-linked SCID. Pathological findings showed maternal T cells engrafted in his liver and hepatic fibrosis gradually progressed. He underwent UCBT at 6 months, but hepatic function did not recover and liver failure progressed. Therefore, he underwent LDLT using an S2 monosegment graft at age 1.3 years. The patient had a leak at the Roux-en-Y anastomosis, which was repaired. Despite occasional episodes of pneumonia and otitis media, he is generally doing well 6 years after LDLT with continued immunosuppression agents. In conclusion, the combination of hematopoietic stem cell transplantation (HSCT) and liver transplantation may be efficacious, and HSCT should precede liver transplantation for children with X-linked SCID and liver failure.

The Causes and Outcomes of Early Relaparotomy Following Pediatric Living Donor Liver Transplantation.

Early relaparotomy of adult recipients after living donor liver transplantation (LDLT) is significantly associated with poor prognosis. However, there are few reports focusing on pediatric recipients after LDLT. The aim of this study is to clarify the causes and outcomes of early relaparotomy after pediatric LDLT. A total of 265 pediatric recipients (272 LDLTs) transplanted from May 2001 to October 2015 were retrospectively analyzed. Early relaparotomy was defined as surgical intervention performed within 3 months after LDLT. Early relaparotomy was performed 49 times for 33 recipients (12.5%). The recipient and graft survival rates in the early relaparotomy group were significantly lower than those in the nonearly relaparotomy group, respectively (75.0% and 63.6% versus 96.6% and 95.8%; both P < 0.001). Left lateral segment grafts were used significantly more frequently in the nonrelaparotomy group (P = 0.01). According to the multivariate analysis, the preoperative Pediatric End-Stage Liver Disease (PELD)/Model for End-Stage Liver Disease (MELD) score of the early relaparotomy group was significantly higher than that of the nonearly relaparotomy group (13.7 versus 6.3; P = 0.04). According to the receiver operating characteristic curve, the preoperative PELD/MELD score cutoff point was 17.2. Early relaparotomy due to infectious causes led to significantly poorer graft survival than that due to noninfectious causes (P = 0.04). In conclusion, the recipient and graft survival rates of the early relaparotomy group were significantly lower than those of the nonearly relaparotomy group. A high preoperative PELD/MELD score was a risk factor for early relaparotomy. In particular, early relaparotomy due to infection showed a poor prognosis.

Serum Mac-2 binding protein glycosylation isomer predicts the activation of hepatic stellate cells after liver transplantation.

BACKGROUND AND AIM: Serum Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel fibrosis marker for various chronic liver diseases. We investigated the ability of M2BPGi to predict liver fibrosis in liver transplant (LT) recipients. METHODS: A total of 116 liver biopsies were performed in 113 LT recipients. The serum level of M2BPGi was also measured on the same day. The median age at LT and liver biopsy was 1.1 and 11.8 years, respectively. Serum M2BPGi levels and liver fibrosis status using METAVIR fibrosis score were compared. Immunohistological evaluation by anti-α-smooth-muscle actin (αSMA) was performed, and the relationship between αSMA positive rate and serum M2BPGi levels was investigated. RESULTS: The median M2BPGi level was 0.78 (range, 0.22-9.50), and 65, 29, 16, 5, and 1 patient(s) had METAVIR fibrosis scores of F0, F1, F2, F3, and F4, respectively. In patients with F0 fibrosis, median M2BPGi level was 0.69 and was significantly lower than in patients with F1 (median 0.99, P < 0.01), F2 (median 1.00, P = 0.01), and F3 fibrosis (median 1.53, P < 0.01). Area-under-the-curve analysis of the ability of M2BPGi level to predict liver fibrosis grade were > F1: 0.716, > F2: 0.720, and > F3: 0.900. Three patients with acute cellular rejection showed high levels of M2BPGi, which decreased after the treatment. A positive correlation existed between M2BPGi levels and αSMA positive rate (r2  = 0.715, P < 0.01). CONCLUSION: Mac-2 binding protein glycosylation isomer is a novel liver fibrosis marker in LT recipients and is also increased in patients with acute liver injuries, especially acute cellular rejection, even when fibrosis is absent.

Pediatric liver transplantation for neonatal-onset Niemann-Pick disease type C: Japanese multicenter experience.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive inherited disease characterized by lysosomal accumulation of free cholesterol in macrophages within multiple organs. Infantile-onset NPC often presents with jaundice and hepatosplenomegaly from birth, but these symptoms usually improve during early childhood, and it rarely progresses to liver failure. We report three cases from different hospitals in Japan; the patients developed neonatal-onset NPC, and liver transplantation (LT) was performed as a life-saving procedure. LT was performed at 19 days, 59 days, and 4 months of age, respectively. The last patient was diagnosed with NPC before LT, while the first two patients were diagnosed with neonatal hemochromatosis at LT. In these two patients, the diagnosis of NPC was made more than a year after LT. Even though oral administration of miglustat was started soon after the diagnosis of NPC, all patients showed neurological regression and required artificial respiratory support. All patients survived more than one year after LT; however, one patient died due to tracheal hemorrhage at 4.5 years of age, and another one patient was suspected as recurrence of NPC in liver graft. In conclusion, while LT may be a temporary life-saving measure in patients with neonatal-onset NPC leading to liver failure, the outcome is poor especially due to neurological symptoms. A preoperative diagnosis is thus critical.

Increased tacrolimus blood concentration by Beni-Madonna - a new hybrid citrus cultivar categorized as 'Tangor', in a liver transplant patient: likely furanocoumarin-mediated inhibition of CYP3A4 or P-glycoprotein.

ADVERSE EVENT: A drug interaction leading to greater exposure to tacrolimus. DRUG IMPLICATED: Tacrolimus and Beni-Madonna (a new cultivar citrus categorized as 'Tangor'). THE PATIENT: A 9-month-old girl with biliary atresia (body weight, 7.5 kg) taking tacrolimus after liver transplantation. EVIDENCE THAT LINKS THE DRUG TO THE EVENT: The time course was consistent with the appearance of the interaction, which was confirmed by an increase in the blood concentration of tacrolimus. Dihydroxybergamottin was detected in peel of Beni-Madonna and in peel and fruit pulp of grapefruit. MANAGEMENT: Avoiding Beni-Madonna intake. MECHANISM: Inhibition of activity of CYP3A4, P-glycoprotein, or both, by Beni-Madonna. IMPLICATION FOR THERAPY: Clinicians should be aware of this potential interaction, and patients taking drugs such as tacrolimus (the kinetics of which are affected by grapefruit juice) should avoid Beni-Madonna intake. HYPOTHESIS TO BE TESTED: Further study is required to determine if other Citrus species categorized as Tangor contain furanocoumarins.

Quality of life after living donor liver transplant for biliary atresia in Japan.

BACKGROUND: Health-related quality of life (HRQOL) is an important outcome in solid organ transplantation. This study evaluated and explored the factors of generic and transplant-specific HRQOL in Japanese pediatric and adolescent patients with biliary atresia (BA) after living donor liver transplant (LDLT). METHODS: A cross-sectional survey using anonymous questionnaires was completed between April and July 2015. Patient medical records were accessed. The Japanese version of Pediatric Quality of Life InventoryTM Generic Core Scales and Transplant Modules (child self-report and parent proxy-report) was administered. RESULTS: Participants consisted of 75 patients (mean age at survey, 9.6 years) and 74 parents. Japanese patients reported higher generic and transplant-specific HRQOL (total score) than that reported by US patients with BA after LT (US I; age at survey, 7.2 years) and by US patients after solid organ transplant (US II; age at survey, 11.3 years; LT, 53.8%; effect size, 0.55-0.96). Japanese parents, however, rated their children's generic HRQOL (total score) similar to that rated by the US I and II parents (0.13 and 0.30, respectively) and reported lower transplant-specific HRQOL (total score) than that reported by US II (0.26). Although the number of types of prescribed drugs was a common factor in HRQOL, most demographic and medical factors (e.g. child's age at survey and consultation frequency) varied with reporter (i.e. patients and parents). CONCLUSIONS: The levels and factors of generic and transplant-specific HRQOL of Japanese pediatric and adolescent patients with BA after LDLT varied with reporter (i.e. patients or parents).

Dorsal approach plus branch patch technique is the preferred method for liver transplanting small babies with monosegmental grafts.

PURPOSE: When living donor liver transplantation (LDLT) is performed on small infant patients, the incidence of hepatic artery complications (HACs) is high. Here, we present a retrospective analysis that focuses on our surgical procedure for hepatic arterial reconstruction and the outcomes of monosegmental LDLT. METHODS: Of the 275 patients who underwent LDLT between May 2001 and December 2015, 13 patients (4.7 %) underwent monosegmental LDLT. Hepatic artery reconstruction was performed under a microscope. The size discrepancy between the graft and the recipient's abdominal cavity was defined as the graft to recipient distance ratio (GRDR) between the left hepatic vein and the portal vein (PV) bifurcation on a preoperative computed tomography scan. HACs were defined as hepatic arterial hypoperfusion. RESULTS: Recipient hepatic arteries were selected for the branch patch technique in five cases (38.5 %), and the diameter was 2.2 ± 0.6 mm. The anastomotic approaches selected were the dorsal position of the PV in seven cases (53.8 %) and the ventral position in six, and the GRDRs were 2.8 ± 0.4 and 1.9 ± 0.5, respectively (p = 0.012). The incidence rate of HACs caused by external factors, such as compression or inflammation around the anastomotic site, was significantly higher in monosegmental than in non-monosegmental graft recipients (15.4 vs. 1.1 %, p < 0.001). CONCLUSION: Although monosegmental graft recipients experienced HACs caused by external factors around the anastomotic field, hepatic arterial reconstruction could be safely performed. Important components of successful hepatic arterial reconstructions include the employment of the branch patch technique and the selection of the dorsal approach.

Development of the Japanese version of the Pediatric Quality of Life Inventory™ Transplant Module.

BACKGROUND: Health-related quality of life (HRQOL) is an important outcome in pediatric solid organ transplantation. Considering the emerging problems after transplantation, an evaluation of transplant-specific aspects of HRQOL is essential, but no validated HRQOL measure is available in Japan. The aim of this study was therefore to develop the Japanese version of the Pediatric Quality of Life Inventory™ (PedsQL) Transplant Module Child Self-Report and to investigate its feasibility, reliability, and validity. METHODS: Based on the PedsQL linguistic validation process, the Japanese version of the PedsQL Transplant Module was developed through translation and cognitive interviews (patient testing). The scale's reliability and validity were investigated, using statistical analyses of field tests of the target population. RESULTS: Eighty-seven pairs of pediatric liver-transplant recipients and their parents participated in the field test. The pediatric patients completed the measure in 3-7 min, and the rate of missing items was low (0.27%). Excellent internal consistency and test-retest reliability were confirmed. Known-groups validity, concurrent validity, and convergent and discriminant validity also were confirmed. CONCLUSIONS: Excellent feasibility, reliability, and validity of this Japanese self-report version of the PedsQL Transplant Module Child Self-Report were verified. As a measure of transplant-specific aspects of HRQOL in Japanese pediatric patients who have undergone organ transplants, the Japanese version of the PedsQL Transplant Module is appropriate for use in clinical and research settings.

Recanalized umbilico-caval anastomosis as a temporary portosystemic shunt in pediatric living donor liver transplantation: the crossed fingers method.

A temporary portocaval shunt (TPCS) associated with retrohepatic vena cava preservation prevents the edema caused by splanchnic congestion during liver transplantation (LT), especially for non-cirrhotic cases. We herein report a modified TPCS technique using the recanalized umbilical vein and an end-to-side recanalized umbilico-caval anastomosis for use during pediatric living donor liver transplantation (LDLT). This work evaluated a group of pediatric patients who underwent LDLT between 2001 and 2014 with the conventional TPCS (n=16) vs the recanalized umbilico-caval shunt (the crossed fingers method, n=10). The crossed fingers method was performed by suturing an end-to-side anastomosis of the patent or recanalized umbilical vein to the vena cava using a continuous monofilament suture like "crossing the fingers," that is, placing the left portal vein across the portal vein trunk next to it. The preoperative, surgical, and postoperative characteristics were similar in both groups except for the significantly shorter portal vein clamping time for the crossed fingers method. This method can allow the portal circulation to be totally decompressed before and after implanting the graft and while maintaining the hemodynamic stability throughout all stages of pediatric LDLT.

Antenatal immunoglobulin for prevention of neonatal hemochromatosis.

Neonatal hemochromatosis (NH) is a rare disease with a poor prognosis, particularly prior to 2008. Antenatal maternal high-dose immunoglobulin (Ig) is effective in preventing NH recurrence, but the adverse effects of this treatment have not been documented as yet. Here, we report on a patient who underwent high-dose Ig treatment to prevent NH recurrence. The patient was a 31-year-old pregnant Japanese woman. Her first child died of NH after receiving living donor liver transplantation. The patient received high-dose Ig treatment to prevent recurrence of NH from gestational weeks 16 to 35. During the treatment, platelet count gradually decreased, and cesarean section was required at 35 gestational weeks. The child did not develop liver failure. High-dose Ig prevented the recurrence of NH. Caution should be exercised due to possible adverse effects of this treatment.

The outcomes of pediatric living donor liver transplantation using small-for-size grafts: experience of a single institute.

PURPOSE: We aimed to evaluate patients who had undergone pediatric LDLT with small-for-size graft (SFSG) and identify risk factors of graft failure to establish a preoperative graft selection strategy. METHODS: The data was collected retrospectively. SFSG was used in 14LDLTs (5.7%) of 245 LDLTs performed between May 2001 and March 2014. The mean patient age and body weight at LDLT were 12.6 ± 2.0 years and 40.5 ± 9.9 kg, respectively. The graft type was left lobe in six patients, left + caudate lobe in seven patients, and posterior segment in one patient. RESULTS: The graft survival rates in SFSG and non-SFSG groups were 78.9 and 93.1%, respectively (p = 0.045). In the univariate analysis, bleeding volume during LDLT were an independent risk factors for graft failure (p = 0.011). Graft failure was caused by sepsis in all three patients and occurred at a median of 70 postoperative days 70 (range 14-88 days). Among them, two cases showed high preoperative PELD/MELD score (PELD; 19.4 and MELD; 22, respectively). CONCLUSIONS: Pediatric LDLT using SFSG had poor outcome and prognosis, especially when it accompanies the surgical infectious complications with preoperative high PELD/MELD scores.

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.

Impact of the serum ferritin concentration in liver transplantation.

The serum ferritin (SF) concentration is a widely available and objective laboratory parameter. SF is also widely recognized as an acute-phase reactant. The purpose of the present study was to identify the chronological changes in the recipient's SF concentration during liver transplantation (LT) and to clarify factors having an effect on the recipient's intraoperative SF level. In addition, the study retrospectively evaluated the usefulness of measuring SF during LT. Ninety-eight pediatric recipients were retrospectively analyzed. The data were analyzed and compared according to the SF level in the recipient. Patients were classified into 2 groups based on the intraoperative peak SF levels of ≤ 1000 ng/mL (low-SF group) or >1000 ng/mL (high-SF group). The SF value increased dramatically after reperfusion and fell to normal levels within the early postoperative period. The warm ischemia time (WIT) was significantly longer in the high-SF group (47.0 versus 58.5 minutes; P = 0.003). In addition, a significant positive correlation was observed between the peak SF value and WIT (r = 0.35; P < 0.001). There were significant positive correlations between the peak SF value and the donors' preoperative laboratory data, including transaminases, cholinesterase, hemoglobin, transferrin saturation, and SF, of which SF showed the strongest positive correlation (r = 0.74; P < 0.001). The multivariate analysis revealed that WIT and donor's SF level were a significant risk factor for high SF level in the recipient (P = 0.007 and 0.02, respectively). In conclusion, the SF measurement can suggest the degree of ischemia/reperfusion injury (IRI). A high SF level in the donor is associated with the risk of further acute reactions, such as IRI, in the recipient.

Successful rescue of disseminated varicella infection with multiple organ failure in a pediatric living donor liver transplant recipient: a case report and literature review.

A 12-year-old female patient with biliary atresia underwent living donor liver transplantation (LDLT). Twelve months after the LDLT, she developed acute hepatitis (alanine aminotransferase 584 IU/L) and was diagnosed with disseminated varicella-zoster virus (VZV) infection with high level of serum VZV-DNA (1.5 × 10(5) copies/mL) and generalized vesicular rash. She had received the VZV vaccination when she was 5-years-old and had not been exposed to chicken pox before the LDLT, and her serum was positive for VZV immunoglobulin G at the time of the LDLT. Although she underwent treatment with intravenous acyclovir, intravenous immunoglobulin, and withdrawal of immunosuppressants, her symptoms worsened and were accompanied by disseminated intravascular coagulation, pneumonia, and encephalitis. These complications required treatment in the intensive care unit for 16 days. Five weeks later, her clinical findings improved, although her VZV-DNA levels remained high (8.5 × 10(3)copies/mL). Oral acyclovir was added for 2 weeks, and she was eventually discharged from our hospital on day 86 after admission; she has not experienced a recurrence. In conclusion, although disseminated VZV infection with multiple organ failure after pediatric LDLT is a life-threatening disease, it can be cured via an early diagnosis and intensive treatment.

Examinations of ascites from prophylactic drains can predict intra-abdominal infections after living donor liver transplantation.

Studies suggest that prophylactic intra-abdominal drains are unnecessary for cadaveric liver transplantation using whole liver grafts because there is no benefit from drainage. However, no studies have investigated on the necessity of prophylactic drains after LDLT using split-liver grafts or reduced-liver grafts, which may present a high risk of post-transplant intra-abdominal infections. This retrospective study investigated whether the ascitic data on POD 5 after LDLT can predict intra-abdominal infections and on the post-transplant management of prophylactic drains. Between March 2008 and March 2013, 90 LDLTs were performed. We assessed the number of ascitic cells, biochemical examinations, and cultivation tests at POD1 and POD5. The incidence rates of post-transplant intra-abdominal infections were 24.4%. The multivariate analysis showed that left lobe and S2 monosegment grafts were a significant risk factor for intra-abdominal infections (p = 0.006). The patients with intra-abdominal infections had significantly higher acsitic LDH levels and the positive rate of ascitic culture at POD5 in comparison with patients without infections (p < 0.001 and p = 0.014, respectively). LDLT using left lobe and S2 monosegment grafts yields a high risk for post-transplant intra-abdominal infections, and ascitic LDH and cultivation tests at POD5 via prophylactic drains can predict intra-abdominal infections.

Health-related quality of life in parents of pediatric solid organ transplant recipients in Japan.

Few studies have examined HRQOL in pediatric Tx recipients' parents. This study investigated HRQOL in these parents and relationships between HRQOL and perceived burden of nurturing, family functioning, and social support. Self-report anonymous questionnaires and a survey of medical records were completed between September and December 2013. The SF-36v2, which evaluates physical, psychological, and social health, was used to measure HRQOL. While values for physical and psychological health were higher than standard values (Cohen's d = 0.34 and 0.17, respectively), social health scores were lower (d = 0.21). "Parental consultation unrelated to donation" (standardized partial regression coefficient: ß = -0.52) was associated with physical health. "Family functioning" and "Commuting time between home and primary follow-up hospital" (ß = 0.57 and -0.31) were related to psychological health. "Total score for perceived burden of nurturing" (ß = -0.31) was related to social health. Regarding parental HRQOL, while physical and psychological health was favorable, social health was impaired. In clinical practice, interventions targeting parents' physical conditions and facilitation of community and family understanding and support to share recipients' nurturing are important in improving parental HRQOL.

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/m(2) in two cases; second period: 50 mg/m(2) in two cases; and 200 mg/m(2) in eight cases). Two patients who received 375 mg/m(2) rituximab died of Pneumocystis carinii pneumonia and hemophagocytic syndrome. One patient who received 50 mg/m(2) rituximab required retransplantation as a consequence of antibody-mediated complications. All eight patients administered 200 mg/m(2) 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/m(2) rituximab three wk prior to LDLT was safe and effective.

Impact of post-transplant flow cytometric panel-reactive antibodies on late-onset hepatic venous outflow obstruction following pediatric living donor liver transplantation.

The development of late-onset hepatic venous outflow obstruction (LOHVOO) following pediatric living donor liver transplantation (LDLT) can lead to uncontrollable fibrotic damage in liver grafts, even long-term patency of the graft outflow is achieved with appropriate therapeutic modalities. The aim of this study was to verify our hypothesis that some immunological responses, particularly cellular and/or antibody-mediated rejection (AMR), are associated with LOHVOO, which occurs following damage to liver sinusoidal endothelial cells in zone 3 of liver grafts. One hundred and eighty-nine patients underwent LDLT between May 2001 and December 2010 at our institute. Nine patients (4.8%) were identified as having LOHVOO. The preoperative factors, operative factors, and mortality, morbidity, and survival rates were examined and compared between the groups with and without LOHVOO. No statistical differences were observed between the groups with regard to preoperative factors, technical factors, or postoperative complications. However, FlowPRA reactivity was found to be a statistically significant risk factor for LOHVOO (P=0.006). The patients with both class I- and class II-reactive antibodies also had a significant risk of developing LOHVOO (P=0.03) and exhibited significantly higher retransplant rates. In conclusion, although further studies are needed to clarify this phenomenon, the pathophysiological mechanism underlying the development of LOHVOO after LDLT may be explained by immune-mediated responses that facilitate damage in zone 3 of liver grafts.