Living Donor Liver Transplantation for Congenital Portosystemic Shunt Presenting With Hyperinsulinemic Hypoglycemia.

BACKGROUND: A congenital portosystemic shunt (CPSS) is defined as abnormal vascular communications between the portal vein and the systemic vein. Encephalopathy, hepatopulmonary syndrome, and portopulmonary hypertension are manifestations in patients with CPSS. Hyperinsulinemic hypoglycemia is also one of the manifestations of CPSS. Hyperinsulinemic hypoglycemia secondary to CPSS is caused by a lack of hepatic first-pass elimination of insulin, which is secreted from pancreatic beta cells. CASE PRESENTATION: A 7-month-old boy had hypergalactosemia detected by newborn mass screening. Enhanced abdominal computed tomography showed the absence of the portal vein trunk and extrahepatic portosystemic communication between the superior mesenteric vein and the inferior vena cava. He had suffered from uncontrollable hyperinsulinemic hypoglycemia under protein and lactose restriction. We performed living donor liver transplantation (LDLT) using a left lateral segment graft from his father. The postoperative course was uneventful and the hypoglycemic attacks disappeared. CONCLUSION: We believe that uncontrolled hyperinsulinemic hypoglycemia secondary to CPSS is an indication of LDLT.

Adverse effects of graft congestion and ameliorative effects of hepatocyte growth factor after liver transplantation in rats.

Living donor liver transplantation (LT) and deceased donor split-LT often result in congestion within liver grafts. The regenerative process and function of congested areas, especially graft congestion associated with LT, are not well understood. Therefore, we created new rat models with congested areas in partially resected livers and orthotopically transplanted these livers into syngeneic rats to observe liver regeneration and function in congested areas. This study aimed to compare liver regeneration and the function of congested areas after liver resection and LT, and to explore a new approach to ameliorate the adverse effects of graft congestion. Although the congested areas after liver resection regenerated normally on postoperative day 7, the congested areas after LT had poor regeneration with abscess development on postoperative day 7. Necrotic areas in congested areas were larger after LT than after liver resection on postoperative days 1, 3, and 7 ( p < 0.05, p < 0.05, and p < 0.01, respectively). Although congested areas after liver resection did not affect survival, in the LT model, the survival of rats with congested areas was significantly poorer even with larger grafts than that of rats with smaller noncongested grafts ( p = 0.04). Hepatocyte growth factor administration improved the survival rate of rats with congested grafts from 41.7% to 100%, improved the regeneration of congested areas, and significantly reduced the size of necrotic areas ( p < 0.05). Thus, congested areas in liver grafts may negatively impact recipients. Short-term administration of hepatocyte growth factor may improve postoperative outcomes of recipients with graft congestion and contribute to more effective use of liver grafts (approval number: MedKyo-23137, Institutional Ethics Committee/Kyoto University).

Efficacy of steroid therapy for improving native liver survival after pediatric acute liver failure with immune activation.

AIM: Recent evidence suggests that acute liver failure (ALF) in some patients may reflect a dysregulated immune response, and that corticosteroids improve survival of the native liver in ALF patients with high serum alanine aminotransferase levels, which are an indication of liver inflammation. However, it is unclear whether steroids are effective for pediatric acute liver failure (PALF). The aim of this retrospective case-control study is to examine whether steroid therapy for PALF accompanied by immune activation improves the survival of native liver and to identify factors that predict responses to steroid treatment. METHODS: Of 38 patients with PALF treated at Kyoto University Hospital from February 2006 to August 2022, 19 receiving steroids who met the specific criteria for identifying the pathophysiology of immune activity in the liver (the "Steroid group"), and seven steroid-free patients who also met the criteria ("Nonsteroid group") were enrolled. Patients in the "Steroid group" were categorized as "responders" or "nonresponders" according to treatment outcome. Clinical and histological data were analyzed. RESULTS: Survival of the native liver in the Steroid group was significantly higher than that in the Nonsteroid group (68% vs. 0%, respectively; p = 0.0052). Nonresponders were significantly younger, with higher Model for End-stage Liver Disease and pediatric end-stage liver disease scores, higher prothrombin time - international normalized ratio, and higher serum ferritin levels than responders. Massive hepatic necrosis was more common in nonresponders. CONCLUSION: Steroid therapy is effective for PALF patients with liver inflammation; however, liver transplantation should be prioritized for young children with ALF accompanied by severe coagulopathy or massive hepatic necrosis.

Deceased donor non-composite split liver and intestinal transplantation for children.

Children with intestinal failure suffer liver damage associated with parenteral nutrition: a condition known as intestinal failure-associated liver disease (IFALD), which requires transplantation of both liver and intestine. In many countries, simultaneous transplantation of these two organs is performed using grafts from a deceased donor, but there have been no such cases in Japan, and the details of the procedure are not clear. Recently, we performed simultaneous split liver and intestinal transplantation in two premature infants with IFALD, using organs from identical deceased donors and achieved good results. These are the first two cases of this procedure being performed in Japan. We report these cases and discuss the important aspects of the surgical and perioperative management.

Chronological alterations in de novo malignancies after living-donor liver transplantation: A cohort study of 1781 recipients using annual comparisons of standardized incidence ratios.

BACKGROUND: De novo malignancies (DNMs) are a major adverse event after solid organ transplantation; however, their characteristics and recent trends after living-donor liver transplantation (LDLT) remain unclear. METHODS: We retrospectively reviewed 1781 primary LDLT recipients (1990-2020) and annually calculated standardized incidence ratios (SIRs) of DNMs compared to the age-adjusted Japanese general population. RESULTS: After 21 845 person-years follow-up, 153 DNM lesions (8.6%) were identified in 131 patients (7.4%). The incidence was 0.007 person-years. DNMs included 81 post-transplant lymphoproliferative disorders (PTLDs), 14 colorectal, 12 lung, and 12 gastric cancers, and so on. Comorbid DNMs significantly worsened recipient survival than those without (p < .001). The 5- and 10-year recipient survival after DNM diagnosis were 65% and 58%, respectively. Notably, SIR1993-1995: 8.12 (95% CI: 3.71-15.4, p < .001) and SIR1996-1998: 3.11 (1.34-6.12, p = .01) were significantly high, but had decreased time-dependently to SIR2005-2007: 1.31 (0.68-2.29, p = .42) and SIR2008-2010: 1.34 (0.75-2.20, p = .33), indicating no longer significant difference in DNMs development. Currently, however, SIR2014-2016: 2.27 (1.54-3.22, p < .001) and SIR2017-2019: 2.07 (1.40-2.96, p < .001) have become significantly higher again, reflecting recent aging of recipients (>50 years) and resultant increases in non-PTLD DNMs. Furthermore, characteristically in LDLT, the fewer the donor-recipient HLA-mismatches, the less the post-transplant DNMs development. CONCLUSION: DNM development after LDLT was significantly higher than in the general population due to higher PTLD incidence (1993-1998), but once became equivalent (2005-2013), then significantly increased again (2014-2019) due to recent recipient aging and resultant increase in solid cancers.

Living donor liver transplantation for myocerebrohepatopathy spectrum due to POLG mutations.

BACKGROUND: POLG is one of several nuclear genes associated with mitochondrial DNA maintenance defects and is a group of diseases caused by mitochondrial DNA deficiency that results in impaired adenosine triphosphate production and organ dysfunction. Myocerebrohepatopathy spectrum (MCHS) is the most severe and earliest presentation of POLG mutations, and liver transplantation (LT) for MCHS has never been reported. CASE PRESENTATION: The patient was a 3-month-old boy with acute liver failure and no neurological manifestations (e.g., seizures). We performed a living donor LT using a left lateral segment graft from his father. The postoperative course was uneventful. Subsequently, a homozygous POLG mutation (c.2890C>T, p. R964C) was identified by multigene analysis of neonatal/infantile intrahepatic cholestasis. Moreover, respiratory chain complex I, II, and III enzyme activities and the ratio of mtDNA to nuclear DNA in the liver were reduced. Therefore, we considered that these clinical manifestations and examination findings met the definition for MCHS. During meticulous follow-up, the patient had shown satisfactory physical growth and mental development until the time of writing this report. CONCLUSION: We presumed that the absence of remarkable neurologic manifestations prior to LT in patients with MCHS is a good indication for LT and contributes to a better prognosis in the present case.

The protective association of HLA-C*12:02 and HLA-DQB1*06:01 with severe acute hepatitis of unknown origin in the Japanese population.

Global surveillance has been conducted to elucidate the pathogenesis of acute hepatitis of unknown origin (AHUO), However, the factors associated with the aggravation of this serious disease are unclear. Therefore, we conducted a HLA association study to identify HLA alleles or haplotypes predisposing or protective against Japanese AHUO. The HLA 5 locus (HLA-A, HLA-B, C, DRB1, and DQB1) 4-digit genotyping results of 72 AHUO patients who underwent liver transplantation at our institution between 2000 and 2021 were compared to those of 873 healthy Japanese controls. Protective associations of HLA-B*52:01 (p-corrected (pc) = 3.15 × 10-3 ), HLA-C*12:02 (pc = 1.66 ×10-3 ), HLA-DQB1*06:01 (pc = 1.42 × 10-2 ), and HLA-DRB1*15:02 (pc = 1.36 × 10-2 ) with severe AHUO in Japanese patients were observed. The amino acid residues of tryptophan at position 156, which are located in the antigen-binding grooves of the HLA-C protein, showed a protective association with AHUO, showing a significant difference from other amino acid variations (pc = 9.0 × 10-4 ). Furthermore, 5 amino acid residues of the HLA-DQB1 protein were also protectively associated with AHUO with a significant difference from other amino acid variations (pc = 1.42 × 10-2 to 2.89 × 10-2 ). These alleles have a protective association with the aggravation of AHUO in the Japanese population.

Effects of Adding Congested Segment IV to the Left Lateral Graft on Short-term Outcomes in Pediatric Living-donor Liver-transplant Recipients.

Background: In some pediatric patients undergoing living-donor liver transplantation, segment IV without the middle hepatic vein can be added to a left lateral segment graft to obtain larger graft volume. Because no clear consensus on this technique exists, this study investigated the effects of congested areas on postoperative outcomes in pediatric patients with biliary atresia undergoing living-donor liver transplantation. Methods: We retrospectively reviewed data of recipients with biliary atresia aged ≤15 y who had undergone living-donor liver transplantation at Kyoto University Hospital between 2006 and 2021 and with graft-to-recipient weight ratios (GRWR) of ≤2%. Based on the percentage of congested area in the graft, patients were classified into the noncongestion (n = 40; ≤10%) and congestion (n = 13; >10%) groups. To compare the differences between groups with similar nooncongestive GRWRs and investigate the effect of adding congested areas, patients in the noncongestion group with GRWRs of ≤1.5% were categorized into the small noncongestion group (n = 24). Results: GRWRs and backgrounds were similar between the noncongestion and congestion groups; however, patients in the congestion group demonstrated significantly longer prothrombin times, higher ascites volumes, and longer hospitalization. Further, compared with the small noncongestion group, the congestion group had significantly greater GRWR and similar noncongestive GRWR; however, the congestion group had significantly longer prothrombin time recovery (P = 0.020, postoperative d 14), higher volume of ascites (P < 0.05, consistently), and longer hospitalization (P = 0.045), requiring significantly higher albumin and gamma-globulin transfusion volumes than the small noncongestion group (P = 0.027 and P = 0.0083, respectively). Reoperation for wound dehiscence was significantly more frequent in the congestion group (P = 0.048). Conclusions: In pediatric liver-transplant recipients, adding a congested segment IV to the left lateral segment to obtain larger graft volume may negatively impact short-term postoperative outcomes.

Present state of intestinal transplantation in Japan.

INTRODUCTION: Intestinal transplantation (ITx) is the ultimate treatment for intestinal failure (IF). In Japan, most cases of IF are a result of pediatric disease, including secondary or congenital intestinal disease or allied disorders of Hirschsprung's disease. Here, we report the results of the Japanese ITx registry. METHODS: A web-based survey form was completed. We investigated the number, age, sex, indication, surgical procedure, immunosuppressants, postoperative course, and the effects of transplantation in patients who underwent cadaveric or living-donor ITx. RESULTS: By the end of 2022, 42 cases of ITx have been performed in 38 patients in Japan. The donor sources included cadavers (29 cases) and living donors (13 cases). The surgical method was isolated ITx (N = 40) and combined liver and ITx (n = 2). Survival rates were 92%, 73%, and 59% at 1 year, 5 years, and 10 years, respectively. Ninety percent of patients completely discontinued parenteral nutrition. Approximately 80% of the patients had a performance status of 1 or less, indicating that the QOL of patients after ITx was extremely good. CONCLUSION: The results of ITx are acceptable to treat IF patients and the QOL after transplantation is also good.

Ketogenic diet in action: Metabolic profiling of pyruvate dehydrogenase deficiency.

The pyruvate dehydrogenase complex serves as the main connection between cytosolic glycolysis and the tricarboxylic acid cycle within mitochondria. An infant with pyruvate dehydrogenase complex deficiency was treated with vitamin B1 supplementation and a ketogenic diet. These dietary modifications resolved the renal tubular reabsorption, central apnea, and transfusion-dependent anemia. A concurrent metabolome analysis demonstrated the resolution of the amino aciduria and an increased total amount of substrates in the tricarboxylic acid cycle, reflecting the improved mitochondrial energetics. Glutamate was first detected in the cerebrospinal fluid, accompanied by a clinical improvement, after the ketogenic ratio was increased to 3:1; thus, glutamate levels in cerebrospinal fluid may represent a biomarker for neuronal recovery. Metabolomic analyses of body fluids are useful for monitoring therapeutic effects in infants with inborn errors of carbohydrate metabolism.

Hemodynamic and Clinical Response to Liver Transplantation in Children and Young Adults POPH Patients.

Portopulmonary hypertension is an intractable form of pulmonary hypertension. Although liver transplantation is recommended for patients who respond poorly to treatments, the mechanisms by which liver transplantation improves pulmonary hypertension remain unclear. The present study investigated these mechanisms by retrospectively evaluating patients' data. This study retrospectively evaluated echocardiography and catheterization data before and after liver transplantation in 12 patients who underwent liver transplantation from 2001 to 2019. The 12 patients included one male and 11 females, of median age at liver transplantation of 10 years, 2 months. Nine patients underwent liver transplantation for congenital biliary atresia and three for portal vein aplasia or hypoplasia. Mean pulmonary arterial pressure was 44.1 ± 8.1 mmHg at the first cardiac catheter examination, 35.3 ± 7.8 mmHg before liver transplantation, and 29.5 ± 9.3 mmHg 6 months after liver transplantation. Pulmonary artery pressure was reduced by treatments of pulmonary hypertension and by liver transplantation. Pulmonary vascular resistance did not differ before and after liver transplantation, whereas the cardiac index decreased significantly, indicating that the significant reduction in mean pulmonary artery pressure was due to a decrease in cardiac index. Decreased cardiac index was thought to result from improvements in hyperdynamic conditions due to increased (normalized) systemic vascular resistance. Liver transplantation likely suppresses shear stress on pulmonary arteries, preventing further damage by hyper-circulation. A longer-term evaluation is required to determine the effect of improving pulmonary artery remodeling.

Chronological changes in the gut microbiota and intestinal environment in recipients and donors of living donor liver transplantation.

BACKGROUND/PURPOSE: This prospective study aimed to investigate the dynamic changes in the gut microbiota (GM) and associated intestinal environment, which were assessed by measuring fecal organic acid (OA) concentrations, during the early period after liver transplantation (LT). To understand the fundamental characteristics of the human GM, data obtained from living donors were also analyzed. METHODS: Fixed-point observation was performed in 23 recipients and 21 donors for up to 2 weeks after LT. The GM and OA concentrations were investigated using ribosomal RNA-targeted reverse-transcription quantitative polymerase chain reaction and high-performance liquid chromatography, respectively. RESULTS: Before LT, the recipients exhibited remarkable dysbiosis and OA depletion, which were proportional to the model for end-stage liver disease score. Correlations between the abundances of some specific strains and OA concentrations were observed. After LT, while donor lobectomy caused only slight, transient and reversible changes in the GM and OA concentrations, recipients exhibited delayed recovery in these factors. However, no clear evidence of causality was observed between the GM or OA concentrations and LT outcomes. CONCLUSIONS: The GM and intestinal environment in LT recipients exhibited characteristics that were clearly different from those in donors. LT did not normalize but rather disrupted the GM during the early post-LT period, but its negative clinical impact could be minimized with perioperative management.

Two Cases of Possible Exacerbation of Chronic Rejection After Anti-SARS-CoV-2 Messenger RNA Vaccination: A Case Report.

In post-liver transplant recipients, SARS-CoV-2 infection is a health threat, and novel messenger RNA vaccines such as Pfizer BioNTech BNT162b2 and Moderna mRNA-1273 are aggressively recommended. However, there are few reports on their adverse effects, some of which may be potentially fatal. We have experienced 2 post-liver transplant recipients with exacerbated chronic rejection after vaccination, one of whom had to undergo retransplant and the other who is still in the process of liver function without improvement. These alarming cases will be presented as case reports.

Dysbiosis and Depletion of Fecal Organic Acids Correlate With the Severity of Rejection After Rat Liver Transplantation.

The impact of T cell-mediated rejection (TCMR) after liver transplantation (LT) on the alterations in the gut microbiota (GM) and associated intestinal environment represented by fecal organic acids (OAs) require further elucidation. A rat allogeneic LT model was prepared without immunosuppressants or antibiotics, and a syngeneic model was used as a control. Qualitative and quantitative analyses of fecal samples at fixed time points were performed. Correlation analyses were also performed between liver function and GMs and OA levels. In the allogeneic TCMR group, the number of predominant obligate anaerobes decreased as liver function declined. Clostridioides difficile, Enterobacteriaceae, Enterococcus, Streptococcus, and Staphylococcus were significantly increased. Regarding fecal OA concentration, short-chain fatty acid (SCFA) concentrations were depleted as liver function declined. In contrast, in the syngeneic group, GM and OAs exhibited only slight, transient, and reversible disturbances. In addition, alanine aminotransferase and total bilirubin were positively correlated with the number of Enterobacteriaceae and Enterococcus, and negatively correlated with the fecal concentration of SCFAs. The allogeneic TCMR model demonstrated distinct dysbiosis and depletion of fecal OAs as TCMR progressed after LT. The degree of graft injury was closely related to the number of specific bacterial strains and the concentrations of fecal SCFAs.

The New Challenge in Pediatric Liver Transplantation: Chronic Antibody-Mediated Rejection.

Antibody-mediated rejection (AMR) of liver allograft transplantation was considered as anecdotal for many decades. However recently, AMR has gained clinical awareness as a potential cause of chronic liver injury, leading to liver allograft fibrosis and eventual graft failure. (1) Methods: Literature on chronic AMR (cAMR) in pediatric post-liver transplant patients was reviewed for epidemiologic data, physiopathology, diagnosis, and treatment approaches. (2) Results: Accurate incidence of cAMR in pediatric liver transplantation remains unknown. Diagnostic criteria of cAMR were suggested by the Banff Working Group in 2016 and are based on standardized histopathological findings, C4d staining pattern, associated with the presence of donor-specific antibodies (DSA). Physio-pathological mechanisms are not clear for the technically difficult-to-obtain animal models reproducing cAMR. Treatment protocols are not established, being limited to case reports and case series, based on experience in ABO incompatible transplantation and kidney transplantation. Immunosuppression compliance with adequate dose adjustment may prevent cAMR. Conversion of Cyclosporine to Tacrolimus may improve pathological findings if treated in early phase. The association of steroids, Mycophenolate Mofetil (MMF) and mTOR inhibitors have shown some synergistic effects. Second-line treatments such as intravenous immunoglobulin (IVIG) and plasma exchange may decrease antibody titers based on ABO incompatible transplant protocols. The use of anti-CD20 (Rituximab) and proteasome inhibitors (Bortezomib) is controversial due to the lack of qualified studies. Therefore, multicenter randomized trials are needed to establish the best therapeutic strategy. In refractory cases, re-transplantation is the only treatment for allograft failure. (3) Conclusions: This literature review collects recent clinical, histopathological, and therapeutical advances of cAMR in liver allograft transplantation of pediatric patients. There are many physio-pathological aspects of cAMR to be clarified. Further efforts with multicenter prospective protocols to manage patients with cAMR are needed to improve its outcome.

The impact of human leukocyte antigen mismatch on recipient outcomes in living-donor liver transplantation.

Donor-recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living-donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990-2020). The primary and secondary endpoints were recipient survival and the incidence of T cell-mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ. Subgroup analyses were also performed in between-siblings that characteristically have widely distributed 0-10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (<18 years). In adult-to-adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p = 0.03, 0.01, 0.03, 0.001, and <0.001 for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ, respectively). This trend was more pronounced when multiple loci were combined (all p < 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA-B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21-5.87; p = 0.02) and recipient survival (HR 2.44, 95% CI 1.11-5.35; p = 0.03) in between-siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor-recipient relationships are parent-to-child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children.

Progress in living donor liver transplantation for biliary atresia and challenges faced: A thirty-year single institutional experience.

BACKGROUND: Biliary atresia (BA) is the most common indication for liver transplantation in the pediatric population, and living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) have been established as a radical treatment for BA .The aim of this study was to clarify the long term outcomes and risk factors affecting the LDLT outcomes, as well as the challenges faced. METHODS: Between 1990 and 2019, 666 BA patients underwent LDLT in our institution and were enrolled in this study. Data regarding the recipient's age, anatomic findings of the biliary tree at Kasai's portoenterostomy, basic characteristics at transplantation, transplant profiles, donor characteristics, and outcomes of LDLT were analyzed. RESULTS: The 1-, 5-, 10-, 15-, 20-, and 25-year graft survival rates of BA patients who underwent LDLT were 88.1%, 85.4%, 81.5%, 78.9%, 76.6%, and 75.5%, respectively. The transplant era, age at transplantation, ABO incompatible transplant, and presence of pulmonary vascular complications were identified as significant risk factors for overall graft survival. When the study period was divided into the first (1990-1999) and second (2000-2019) phases and re analyzed, the outcomes of ABO-incompatible transplants and LDLT for adult BA patients remained inferior to others in the second phase. The 20-year graft survival rate in patients who underwent re transplantation in the second phase was 54.2%. CONCLUSIONS: The outcomes of LDLT in children are generally good, but the immunosuppression procedures need to be further improved for ABO-incompatible cases in the future. Further improvements in LDLT results for adult patients and re transplantation remain challenges to be addressed in this field, and future attempts, including revision to the organ allocation system of deceased donors, are necessary. LEVEL OF EVIDENCE: Level III (case control study).

Management of Epstein-Barr Virus Infection and Post-Transplant Lymphoproliferative Disorder in Pediatric Liver Transplantation.

With the advancement of immunosuppressive strategies, the outcome of liver transplantation during childhood has dramatically improved. On the other hand, Epstein-Barr virus (EBV) infection and associated post-transplant lymphoproliferative diseases (PTLD), such as malignant lymphoma, are serious complications that contribute to morbidity and mortality, and are still an important issue today. Recently, an early diagnosis by quantitative PCR and PET-CT testing, and treatment with rituximab (an anti-CD20 antibody) has been established, and long-term remission has been achieved in many cases. However, the optimal immunosuppression protocol after remission of PTLD needs to be determined, and it is hoped that a treatment for refractory PTLD (e.g., PTL-NOS) will be proposed.