tacrolimus and Biliary-Atresia

This review presents the author's personal perspective and contributions to the first steps, the development, the current status, and the remaining issues of pediatric liver transplantation (LT). Innumerable children around the world who have undergone LT have reached adulthood. The techniques have reached maturity. As shown by my own group's experience, grafts donated by living donors might provide the best short-term and longterm results. Debate persists about the optimal immunosuppression (IS), although the place of tacrolimus remains unchallenged. Tolerance induction protocols aiming to induce microchimerism have been tried in clinical transplantation without convincing results. Withdrawal of maintenance IS is possible in some children who underwent liver transplantation who have excellent clinical status and normal liver function tests but is not without risk of rejection and subsequent worsening of histology. The current trend favored by the Brussels' group is to minimize IS as soon after transplant as possible, aiming to obtain a state of "prope" or "almost" tolerance. Liver grafts are threatened in the long term by increasing hepatitis-related fibrosis, resulting most likely from immunological assault. Nowadays, the focus is on the longterm survival, quality of life (growth, academic performance, employment, self-fulfillment, fertility, raising a family, etc.), induction of tolerance, prevention of risks bound to decades of IS (nephrotoxicity and neurotoxicity, cardiovascular risk, de novo malignancies, etc.), and prevention of graft fibrosis. All these issues are fertile fields for younger scientists. Liver Transplantation 22 1284-1294 2016 AASLD.

Topics: Achievement; Allografts; Biliary Atresia; Child; Drug Therapy, Combination; Fibrosis; Graft Rejection; Hepatitis, Autoimmune; Hepatoblastoma; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Living Donors; Patient Selection; Preoperative Care; Quality of Life; Risk Factors; Survival Rate; Tacrolimus; Withholding Treatment

Eleven children, 4 males and 7 females, with biliary atresia receiving living related liver graft were studied. The mean age was 1.8 years and the mean body weight was 10.3 kg. The donors were 4 fathers and 7 mothers. The graft was the lateral segment or left lobe. ABO blood group matching was compatible in 9 and incompatible in 2. All patients except one were crossmatch negative. Immunosuppression at induction was triple therapy (cyclosporine, azathioprine and steroid) or FK506 plus steroid. Acute rejection episodes were treated with pulse steroids. When the signs of rejection persisted despite steroid pulse therapy, 15-deoxyspergualin (DSG) was added. The survival rate of the patients was 73%. Three patients died of portal vein thrombosis, hepatic artery thrombosis and sepsis respectively. Other major complications included hyperbilirubinemia, bile duct stenosis, bile leakage and portal vein anastomosis narrowing. Complications of the donor were sepsis in one, and liver dysfunction in two. Although there are some complications related to graft size mismatch and operative procedure, living related partial liver transplantation is an effective therapy in countries where donor source is restricted.

Topics: ABO Blood-Group System; Biliary Atresia; Child, Preschool; Female; Graft Rejection; Guanidines; Histocompatibility; Humans; Immunosuppressive Agents; Infant; Japan; Liver Transplantation; Living Donors; Male; Postoperative Complications; Survival Rate; T-Lymphocytes; Tacrolimus

Topics: Administration, Oral; Analysis of Variance; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Female; Humans; Immunosuppression Therapy; Infant; Infusions, Intravenous; Liver Transplantation; Male; Tacrolimus; Tissue Donors

To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs).. All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study.. During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred.. EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Topics: Age Factors; Anti-Allergic Agents; Biliary Atresia; Budesonide; Child; Child, Preschool; Cholestasis, Intrahepatic; Dermatitis, Atopic; Disease Progression; Drug Tapering; Enteritis; Enterocolitis; Eosinophilia; Eosinophilic Esophagitis; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Gastritis; Glucocorticoids; Graft Rejection; Humans; Hypersensitivity; Immunosuppressive Agents; Infant; Ketotifen; Liver Failure, Acute; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Viremia

BACKGROUND The number of pregnancies after liver transplantation (LT) is increasing; however, the safety and incidence of complications associated with these pregnancies are still unclear. In this report, we retrospectively assessed the influences and problems associated with post-transplant pregnancy on allografts, recipients, and fetuses. MATERIAL AND METHODS A total of 14 pregnancies were identified in 8 female recipients between 2005 and 2018. The original disease was biliary atresia in all recipients. We provide a basic guide for the management of planned pregnancies in female recipients. RESULTS Of the 7 planned pregnancies, no recipients took mycophenolate mofetil (MMF) or had allograft liver dysfunction. Among the 7 unplanned conceptions, we judged that the pregnancy was inadequate to continue in 4 recipients due to taking MMF and 2 recipients due to allograft liver dysfunction at conception. However, 4 recipients who immediately stopped taking MMF continued with their pregnancies. Ten pregnancies resulted in live 11 births. Among obstetric complications or fetal and neonatal complications, gestational diabetes mellitus in 3 recipients was the most common. There were 3 miscarriages and 1 planned termination because of MMF medication and liver dysfunction. CONCLUSIONS Planned pregnancies in LT recipients can lead to the birth of a healthy baby and no influence on either the allograft or the recipient. However, unplanned pregnancies in LT recipients, such as recipients who take MMF or have allograft liver dysfunction, may have an adverse influence on the fetus.

Topics: Adolescent; Adult; Biliary Atresia; Female; Humans; Immunosuppressive Agents; Japan; Liver Transplantation; Prednisolone; Pregnancy; Pregnancy Outcome; Retrospective Studies; Tacrolimus; Young Adult

Allergy and other immune-mediated diseases are more frequently reported in children who have undergone liver transplantation. Furthermore, autoantibodies are also prevalent, suggesting a state of immune dysregulation in these patients. Whether or not these processes occur simultaneously in the same individual has not been studied previously.. A cohort of 43 children who had undergone liver transplantation for nonautoimmune liver disease at median age of 1.3 years was investigated for allergy and autoimmune disease. Sensitization to food and inhalant allergens was assessed, and autoantibodies were measured.. The prevalence of food allergy was 26% and that of respiratory allergy was 23%, whereas 33% and 26% of the subjects were sensitized to food and inhalant allergens, respectively. Autoimmune disease (ie, autoimmune hepatitis) occurred in a single individual (2%), whereas autoantibodies were present in 44% of the children. Food allergy and autoantibodies occurred concomitantly in 19% of the children, which was almost twice the frequency expected by chance (11%, P = 0.04). Respiratory allergy and the presence of autoantibodies were unrelated (12% concurrence versus the expected 10%, P = 0.73). In the logistic regression analysis, autoantibody formation was associated with discontinued immunosuppression and food allergy, with odds ratios of 13 (P = 0.01) and 7.1 (P = 0.03), respectively.. In contrast to respiratory allergy, food allergy and autoantibody formation occurred together in the same children who underwent liver transplantation at a frequency higher than would be expected by chance. This may reflect an underlying immune dysregulation that impairs immune tolerance to both food allergens and autoantigens.

Topics: Adolescent; Allergens; Autoantibodies; Autoantigens; Autoimmune Diseases; Biliary Atresia; Child; Child, Preschool; Cross-Sectional Studies; End Stage Liver Disease; Female; Follow-Up Studies; Food Hypersensitivity; Humans; Immunosuppression Therapy; Infant; Liver Transplantation; Male; Odds Ratio; Postoperative Complications; Prevalence; Tacrolimus

Topics: Biliary Atresia; Child; Color; Dentition, Permanent; Female; Humans; Hyperbilirubinemia; Pigmentation; Portal Vein; Prednisone; Splenomegaly; Tacrolimus; Venous Thrombosis

Topics: Administration, Sublingual; Age Factors; Biliary Atresia; Calcineurin Inhibitors; Child; Child, Preschool; Drug Monitoring; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Retrospective Studies; Tacrolimus; Treatment Outcome

Drugs and xenobiotics that inhibit the CYP-450 isoenzyme 3A4 are associated with increased serum tacrolimus levels. We sought to determine whether there was a temporal association between initiation of dexmedetomidine and increased serum tacrolimus levels. An interaction has not been previously documented. We reviewed tacrolimus levels and dosing in a pediatric patient aged 8 months who had undergone deceased-donor liver transplantation for biliary atresia and later required sedation with dexmedetomidine continuous infusion during the POD (212-216). Serum tacrolimus trough levels increased 4-fold from 3.4 to 13.1 ng/mL (tacrolimus regimen: 1 mg every 12 h) within 21 h of initiating dexmedetomidine. During dexmedetomidine infusion, serum tacrolimus trough levels were maintained with doses that were 25% of baseline tacrolimus dose. Tacrolimus trough levels decreased to below goal range within 30-40 h of discontinuation of dexmedetomidine. Data submitted to the U.S. Food and Drug Administration demonstrate that dexmedetomidine inhibits CYP 3A4 and may produce adequate liver concentrations that could interfere with tacrolimus metabolism. We suggest that tacrolimus levels should be carefully monitored in children receiving prolonged infusions of dexmedetomidine to avoid adverse events associated with elevated tacrolimus levels.

Topics: Adrenergic alpha-2 Receptor Agonists; Biliary Atresia; Cyclooxygenase Inhibitors; Cytochrome P-450 CYP3A; Dexmedetomidine; Drug Interactions; Female; Humans; Immunosuppressive Agents; Infant; Liver; Liver Transplantation; Tacrolimus; Time Factors

PTMS describes the presence of ≥3 cardiometabolic risk factors that include obesity, hypertension, dyslipidemia, and IR. The prevalence of the clustering of ≥3 cardiometabolic risk factors or central obesity has not been studied in pediatric LT recipients. Single-center, cross-sectional study.. LT recipients 2-18 yr-old, at least one yr post-LT.. recipients of liver retransplants or multivisceral transplants. Eighty-seven patients were identified. Median age was 9.8 yr (range 2-18), median time since LT was 6.9 yr (range 1-17). The most common indication for LT was biliary atresia (56%), and the most frequently used immunosuppressant was tacrolimus (80%). The prevalence of overweight and obesity was 21% and 5%, respectively. Central obesity affected 14%, hypertension 44%, IR 27%, low HDL 20%, and hypertriglyceridemia 39% of patients. The prevalence of ≥3 cardiometabolic risk factors was 19%. Fifty percent of the overweight/obese patients had ≥3 risk factors. Time since transplant, immunosuppression and renal function were not different between those with <3 or ≥3 risk factors. Clustering of cardiometabolic risk factors is prevalent in pediatric LT recipients, suggesting an increased risk of future CV events.

Topics: Adolescent; Biliary Atresia; Cardiovascular Diseases; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Male; Obesity, Abdominal; Overweight; Prevalence; Risk Factors; Tacrolimus

Tacrolimus is prescribed to prevent allograft rejection in pediatric liver transplant recipients; however, its metabolism through the cytochrome P-450 enzyme system presents a multitude of challenges in regard to drug interactions. Here, we describe four children (ages 1.4-8.7 yr) who acutely developed supra-therapeutic serum tacrolimus trough concentrations, despite standard dosing, while on concomitant nicardipine therapy following liver transplantation. Even though tacrolimus regimens were altered (dosage reductions and held doses), serum tacrolimus concentrations remained elevated. Resolution of high tacrolimus concentrations was achieved only after the discontinuation of nicardipine. Following the termination of nicardipine, all children eventually required dosage increases in their tacrolimus regimens to re-achieve target serum concentrations. We conclude that concomitant use of tacrolimus and nicardipine can result in high tacrolimus concentrations due to the inhibition of cytochrome p450 enzymes responsible for the metabolism of tacrolimus. We encourage clinicians to consider alternative antihypertensive options in children on tacrolimus therapy. If nicardipine therapy is necessary, we recommend a 50% reduction in tacrolimus dose and daily serum concentration monitoring.

Topics: Alagille Syndrome; Antihypertensive Agents; Biliary Atresia; Carcinoma, Hepatocellular; Child; Child, Preschool; Cholestasis, Intrahepatic; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Liver Neoplasms; Liver Transplantation; Male; Nicardipine; Reoperation; Tacrolimus

To summarize the clinical characteristics, early diagnosis, comprehensive treatment and prognosis of 6 cases of children with post-transplantation lymphoproliferative disorder (PTLD) after liver transplantation.. Data of 6 cases with PTLD seen between January 2011 and December 2013 were retrospectively analyzed. The anti-rejection drug dose adjustments, the effect of rituximab, antiviral therapy and comprehensive treatment program after surgery were explored.. (1) The diagnosis of PTLD was confirmed by histologic findings. Six cases of PTLD including 3 males and 3 females were diagnosed as congenital biliary atresia and underwent split liver transplantation. The occurrence rate of PTLD was 2.9%. (2) The median time to the development of PTLD was less than 6 months. The initial symptom of PTLD in all patients was fever and clinical manifestations of PTLD were non-specific, depending on the involving organs. Five cases of PTLD developed gastrointestinal symptoms, including diarrhea, abdominal pain, and abdominal distension. One case developed respiratory symptoms, including cough and tachypnea. Three cases had lymph node involvement. In 2 cases pathophysiology involved polymorphic lymphocyte proliferation and in 4 cases B lymphocyte proliferation. (3) Two cases died, in whom EBV DNA was not detected and were diagnosed as PTLD by surgical pathology before death. Four survived cases had high EBV-DNA load and then were diagnosed as PTLD by biopsy pathology. (4) Of the 6 cases of PTLD, 2 cases died and 4 cases survived. The overall mortality was 33%. The dead cases were only treated with laparotomy because of intestinal obstruction or perforation and the survived cases were treated with tacrolimus at reduced doses or discontinuation and rituximab. In 2 cases antiviral therapy (acyclovir) was continued, including 1 cases of intestinal obstruction treated with surgical repair. All the survived patients were followed up for 4 months to 1 year and no evidence has been found.. EBV infection is the high risk factor for PTLD after liver transplantation. Close clinical surveillance of EBV DNA for pediatric liver transplantation was important for the early diagnosis of PTLD. Reducing doses of immunosuppressive agents and rituximab is the initial therapy for PTLD. A reduction in the dose of tacrolimus is suggested. Operation therapy can also play a role in the management of local complications.

Topics: Antiviral Agents; Biliary Atresia; DNA, Viral; Drug Therapy, Combination; Early Diagnosis; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Pediatrics; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus

Post-transplant lymphoproliferative disorders of T-cell origin are quite uncommon, and the vast majority represent neoplasms of mature, post-thymic T- or natural killer cells. Here, we report a rare case of T-cell acute lymphoblastic leukaemia (T-ALL), which occurred in an 18-year-old man who had undergone three liver transplants, initially for biliary atresia and subsequently for graft failure due to chronic rejection. He had received immunosuppression with cyclosporine and tacrolimus, as well as short-term treatment with OKT3. The T-ALL occurred 16 years after the first liver transplant. This case highlights the challenge for classifying rare neoplasms occurring in recipients of solid organ transplants that are currently not recognized to lie within the spectrum of post-transplant lymphoproliferative disorders. Given the long interval between the liver transplants and the development of T-ALL, a coincidental occurrence of the leukaemia cannot be ruled out. However, the potential roles of immunosuppressive therapy and other co-morbid conditions of the individual as possible risk factors for the pathogenesis of T-ALL are discussed.

Topics: Adolescent; Biliary Atresia; Causality; Clone Cells; Comorbidity; Cyclosporine; Diagnosis, Differential; Disease Susceptibility; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Radiation-Induced; Liver Transplantation; Lymphoproliferative Disorders; Male; Muromonab-CD3; Postoperative Complications; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Radiography; Remission Induction; Reoperation; Tacrolimus; Time Factors

Leukoencephalopathy syndrome is a neurologic complication after organ transplantation caused predominantly by the neurotoxic effects of immunosuppressive agents on cerebral white matter. We determined the incidence and features of leukoencephalopathy syndrome in recipients after living-donor liver transplantations.. We retrospectively investigated 205 patients who had a living-donor liver transplantation performed at our institution between August 1998 and October 2008.. Leukoencephalopathy syndrome developed in 7 of 205 patients (3.9%) and in 4.7% of the 150 patients treated with tacrolimus-based immunosuppression after their living-donor liver transplantation. The underlying diseases were alcoholic cirrhosis in 3 cases, viral cirrhosis in 2, biliary atresia in 1, and Wilson disease in 1. Time to clinical onset after tacrolimus medication was 15.6 days (range, 6-30 days). The neurologic symptoms included headache, confusion, myoclonus, seizures, and visual disturbances. The mean serum trough level of tacrolimus at clinical onset was not very high (11.7 ng/mL [range, 6.0-14.2 ng/mL]). T2-weighted magnetic resonance imaging in all cases showed diffuse high signal in the white matter of the frontal, parieto-occipital, and temporal lobes. Treatment with antihypertensives, anticonvulsants, and withdrawal of tacrolimus resulted in amelioration of symptoms and magnetic resonance imaging abnormalities. Six patients showed complete recovery, while the seventh had residual rigidity and cognitive impairment caused by hypoxia during a convulsion.. Tacrolimus neurotoxicity can occur despite low trough levels; it depends on variations in pharmacokinetics, such as absorption and maximum concentration level. Early diagnosis and treatment of leukoencephalopathy syndrome should contribute to complete remission.

Topics: Anticonvulsants; Antihypertensive Agents; Biliary Atresia; Child; Contraindications; Female; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Leukoencephalopathies; Liver Cirrhosis; Liver Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Syndrome; Tacrolimus; Treatment Outcome

Although an LDLT can successfully treat biliary atresia (BA), some patients develop liver fibrosis or inflammation. To study the incidence and risk factors associated with these complications, we performed serial protocol biopsies. Twenty-four patients with BA who received a pediatric LDLT underwent protocol biopsies. All patients received standard tacrolimus-based immunosuppression and steroids. The last available biopsies were assessed. The mean age at the time of transplant was 4.8yr and the follow-up period ranged from 1.2 to 12.3yr. The GRWR ranged from 0.8% to 4.5%. The mean time from transplantation to the latest biopsy was 4.7yr. No complications occurred with the biopsy protocol. The last available biopsies for 13 (54%) and 4 (17%) patients indicated grade 1 and grade 2 portal fibrosis, respectively, and 14 patients (54%) had inflammation. No ductopenia was detected. A younger age at LDLT was significantly correlated with graft fibrosis (p=0.036). These results indicate that biopsy-proven fibrosis can be detected in patients with BA after LDLT, even in the context of normal liver function blood tests. Therefore, a serial biopsy is a safe and effective follow-up procedure for pediatric LDLT.

Topics: Adolescent; Adult; Biliary Atresia; Biopsy; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Inflammation; Liver Cirrhosis; Liver Transplantation; Living Donors; Male; Tacrolimus

The objective of this study was to identify the incidence of posttransplantation lymphoproliferative disease (PTLD) among children within 1 year after liver transplantation.. This retrospective review analyzed information in medical charts of pediatric (younger than 18 years of age) recipients of liver transplants between September 2000 and December 2007.. Seventy-one patients underwent a liver transplantation and 7 (9.85%) developed PTLD. Among this group, 6 children were girls and 1 was a boy. The median age at transplantation was 35.14 months. Indications that led the children to have their transplantation were 1 case of hemangioendothelioma, 1 case of autoimmune hepatic cirrhosis, 1 case of alpha-1-antitrypsin deficiency, and 4 cases of biliary atresia. The most frequent symptoms were splenomegaly, diarrhea, and fever. The median time from the first symptoms to the initial treatment was 9.7 days. The standard treatment was withdrawal of immunosuppression and close observation of tacrolimus levels and liver function tests associated with antiviral drugs and chemotherapy. Four among 7 children died; 3 children recovered. All 3 children who recovered has presented at the transplantation center within 5 days of initiation of symptoms (P = .033896).. Despite its rarity, when it occurs, PTLD shows a high mortality rate. Therefore, it is necessary to have interdisciplinary work between the medical team that performs the transplantation and those promoting the primary care to diagnose the disease early and treat it effectively.

Topics: alpha 1-Antitrypsin Deficiency; Biliary Atresia; Child; Child, Preschool; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Splenomegaly; Tacrolimus

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation that has been linked to Epstein-Barr virus (EBV) infection. The aim of this article was to describe a single-center experience with the multiplicity of clinical presentations of PTLD. Among 350 liver transplantations performed in 303 children, 13 survivor children displayed a histological diagnosis of PTLD (13/242 survivors; 5.4%). The age at diagnosis ranged from 12 to 258 months (median, 47), and the time from transplantation ranged from 1 to 84 months (median, 13). Ten of these children (76.9%) were EBV-naïve prior to transplantation. Fever was present in all cases. The clinical signs at presentation were anemia (92.3%), diarrhea and vomiting (69.2%), recurrent upper airway infections (38.4%), Waldeyer ring lymphoid tissue hypertrophy (23.0%), abdominal mass lesions (30.7%), massive cervical and mediastinal adenopathy (15.3%), or gastrointestinal and respiratory symptoms (30.7%). One child developed fulminant hepatic allograft failure secondary to graft involvement by PTLD. Polymorphic PTLD was diagnosed in 6 patients; 7 had the diagnosis of lymphoma. Treatment consisted of stopping immunosuppression as well as starting intravenous gancyclovir and anti-CD20 monoclonal antibody therapy. The mortality rate was 53.8%. The clinical presentation of PTLD varied from fever of unknown origin to fulminant hepatic failure. The other symptoms that may be linked to the diagnosis of PTLD are pancytopenia, tonsil and adenoid hypertrophy, cervical or mediastinal lymph node enlargement, as well as abdominal masses. Despite numerous advances, the optimal treatment approach for PTLD is not completely known and the mortality rate is still high.

Topics: Biliary Atresia; Child; Child, Preschool; Colonic Neoplasms; Cyclosporine; Drug Therapy, Combination; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymph Nodes; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Postoperative Complications; Prednisone; Retrospective Studies; Survivors; Tacrolimus

To evaluate the outcome of pediatric patients who underwent liver transplantation between Oct. 2002 and May 2005 in the Pediatric Hospital.. Eight cases aged from 4 to 67 months who underwent liver transplantation were analyzed retrospectively. Four of the patients were boys and 4 girls, whose body weight at the time of liver transplantation was 6-19 kg. The underlying diseases were biliary atresia, congenital cholestasis, drug-induced cholestatic cirrhosis and cryptogenic cirrhosis. These patients had been followed up for blood routine examinations, liver and renal function, serum electrolytes and blood concentration of tacrolimus for 16 to 43 months after liver transplantation. Results of serological studies for viral etiology, liver biopsy, growth and mental development were also recorded.. One-year survival rate was 75.0% with the longest survival time being 43 months after transplantation. One patient died from renal failure due to postoperative bleeding 24 hours after the surgery and another case died of variceal hemorrhage 8 months after transplantation. Posttransplantation complications included acute cellular rejection, viral infection and hypoalbuminemia. Viral infections included cytomegalovirus infection in 3 cases, Epstein-Barr virus infection in 1 and hepatitis B virus infection in 1. Surgical complications of portal vein thrombosis and stenosis of inferior vena cava and hepatic vein occurred in 2 cases respectively. Side effects of tacrolimus including hypertension, renal damage, liver damage and diarrhea were observed. Significant growth-retardation was not often seen. A self-reported high quality of life was common.. Close follow-up and management of patients after liver transplantation may significantly increase the survival rate and improve quality of life in children with end-stage liver diseases.

Topics: Biliary Atresia; Child; Child, Preschool; Constriction, Pathologic; Female; Graft Rejection; Hepatitis B; Herpesvirus 4, Human; Humans; Hypertension; Immunosuppressive Agents; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Pediatrics; Postoperative Complications; Survival Rate; Tacrolimus; Treatment Outcome; Vena Cava, Inferior; Venous Thrombosis

Since the advent of transplantation as a life-saving procedure for patients with end-stage liver disease, more than 15,000 children and adolescents have received liver transplants. With the improvements in long-term posttransplant survival offered by advances in medical and surgical therapy, the concept of transplantation outcome has expanded beyond simple patient and graft survival rates. The quality of the life years restored, the long-term complications of transplant immunosuppression, and the overall cost of care have been increasingly recognized as important components of liver transplantation outcome. This review focuses on the efforts of a single pediatric transplant center to examine the incidence of, and risk factors for, common posttransplantation complications, to characterize posttransplantation health-related quality of life, to describe the cost of posttransplant care, and to implement novel programs to improve health care delivery. Together, these projects set the future course for research and care improvement initiatives in this population and encourage us to "keep the end in mind" when considering pediatric liver transplantation.

Topics: Adolescent; Biliary Atresia; Bone Density; Bone Diseases; Calcineurin Inhibitors; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Cyclosporine; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Information Services; Kidney Failure, Chronic; Length of Stay; Liver Failure, Acute; Liver Transplantation; Male; Ohio; Postoperative Complications; Quality of Life; Risk Factors; Tacrolimus; Treatment Outcome

Organ transplant recipients are generally considered to be at greater risk for developing malignant disorders because of prolonged immunosuppression for organ grafting, but acute leukemia is a rare complication after organ transplantation (0.2 -2.5%). We encountered two girls with acute promyelocytic leukemia (APL) after living donor partial orthotopic liver transplantation. In one patient, APL developed 21 months after liver transplantation for ornithine transcarbamylase deficiency. She had been administered tacrolimus for prophylaxis of graft-versus-host reaction. In the other patient, APL was diagnosed 46 months after liver transplantation for congenital biliary atresia. Both patients were successfully treated by chemotherapy including all-trans retinoic acid (ATRA), and after reaching complete remission, they have subsequently been in continuous remission. Although leukemia after liver transplantation is generally thought of as a rare complication, increases in survival rate following liver transplantation is likely to lead to more such cases, and documentation of these cases is therefore of importance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biliary Atresia; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Promyelocytic, Acute; Liver Transplantation; Living Donors; Ornithine Carbamoyltransferase Deficiency Disease; Remission Induction; Tacrolimus; Tretinoin

The toxicities associated with the chronic use of tacrolimus are well described in the literature; however, little is known about the management during an acute overdose. Phenobarbital is a long-acting barbiturate metabolized in the liver by the cytochrome p450 3a4 system. It is known to enhance the rate of metabolism of itself and the clearance of drugs metabolized by p450 3a4. Because tacrolimus is a substrate of this particular isoenzyme, phenobarbital can be considered a potential option when rapid decreases in tacrolimus whole-blood levels are desired. We hereby report our experience using intravenous phenobarbital in the management of two infants with acute elevations in their tacrolimus whole-blood concentration following liver transplantation. Phenobarbital, through its up-regulation of hepatic cytochrome p450 system increases the elimination of whole-blood tacrolimus concentration in acute overdose situations.

Topics: Biliary Atresia; Half-Life; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Phenobarbital; Tacrolimus

Occurrences of allergic reactions induced by various foods have been reported in pediatric liver graft recipients receiving tacrolimus immunosuppression. We describe herein a female infant, who was admitted to our hospital with life-threatening angioedema because of banana hypersensitivity, 8 months after orthotopic liver transplantation. Food allergies should be screened in all tacrolimus-immunosuppressed pediatric liver recipients who show suggestive clinical symptoms. Banana must be added to allergen batteries during etiologic investigations. Cyclosporine represents an option for drug conversion to prevent organ rejection.

Topics: Biliary Atresia; Cyclosporine; Female; Food Hypersensitivity; Humans; Immunoglobulin E; Immunosuppressive Agents; Infant; Liver Transplantation; Musa; Tacrolimus; Tomography, X-Ray Computed; Trachea; Treatment Outcome

Topics: Agglutinins; Anemia, Hemolytic; Autoantibodies; Biliary Atresia; Child; Cryoglobulins; Cyclosporine; Drug Therapy, Combination; Family; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Methylprednisolone; Postoperative Complications; Tacrolimus; Treatment Outcome

The purpose of this study was to assess the overall results of recipients undergoing transplantation for biliary atresia (BA), according to age, surgical techniques, and transplant eras, and to identify the prognostic factors affecting outcome.. Between 1984 and 2000, 328 pediatric recipients with BA who underwent orthotopic liver transplantation (OLT) were reviewed. Median age at OLT was 1.5 years (range, 0.4-14.5 years). Kasai hepatoportoenterostomy (KHPE) had been previously performed in 285 (87%) children. Regarding surgical techniques, 125 (38%) children received a whole-liver graft, 128 (39%) received a reduced-size graft, 16 (5%) received a split-liver graft, and 59 (18%) received a living-related (LR) donor graft.. Overall actuarial patient survivals were 87%, 83%, and 81% at 1, 5, and 10 years, respectively. One-year patient survivals in children undergoing transplantation at the different age ranges were 85% (under 1 year), 86% (1-3 years), 83% (3-6 years), 100% (6-10 years), and 100% (beyond 10 years) (not significant). One-year patient survivals for the different transplant eras were 75% (1984-1988), 85% (1989-1992), 93% (1993-1996), and 98% (1997-2000) (P=0.0001). Multivariate analysis demonstrated that pretransplant recipient weight (P=0.004), indication for OLT (P=0.083), and age at OLT (P=0.024) predicted patient survival. The type of baseline calcineurin inhibitor (tacrolimus) and the age at OLT (beyond 6 years) were significantly associated with a better graft survival.. Best results in children undergoing transplantation beyond 6 years indicate the importance of performing a KHPE as the first therapeutic step in BA; innovative surgical techniques, particularly LR donor graft, allowed successful transplantation in infants with early failure of KHPE.

Topics: Adolescent; Aging; Biliary Atresia; Body Weight; Calcineurin Inhibitors; Child; Child, Preschool; Female; Graft Survival; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Living Donors; Male; Multivariate Analysis; Portoenterostomy, Hepatic; Prognosis; Survival Analysis; Tacrolimus; Treatment Outcome

Topics: Adolescent; Age Distribution; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Female; Humans; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Liver Diseases; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome

Immunosuppression by cyclosporin A (CsA) is associated with adverse side-effects, including nephrotoxicity, neurotoxicity and gingival overgrowth. Tacrolimus (TAC/FK506) is a new immunosuppressive agent, recently approved for use in solid-organ transplants. The mode of action of TAC is similar to that of CsA and the toxicity profile of CsA is duplicated by TAC. The effect of TAC on the gingival tissue is not yet conclusive.. Gingival overgrowth was assessed in 30 liver transplant children, 20 boys and 10 girls, aged 2-19 years. Seventeen children (10 boys, seven girls) were on a CsA-based immunosuppressive regimen whereas 13 children (10 boys, three girls) were on TAC for at least 1 year (mean 4.3 +/- 2.7).. In the CsA group, 35% of children exhibited gingival overgrowth characterized by one or more units with increased sulcus probing depth (> or = 4 mm), i.e. pseudopockets. In contrast to the CsA group, none of the children in the TAC group exhibited gingival overgrowth. The occurrence of enamel hypoplasia was observed in 11 children (36%) and enamel opacities were found in 23 children (76%). Six of the 12 children (50%) with hyperbilirubinaemia biliary atresia exhibited a marked greenish discoloration of the teeth. Caries experience (dmft/DMFT) among these children was 2.0 +/- 2.8.. No difference in caries experience or enamel defect was observed between the CsA and TAC group.

Topics: Adolescent; Adult; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Dental Enamel; Dental Enamel Hypoplasia; Dental Plaque Index; DMF Index; Female; Follow-Up Studies; Gingival Overgrowth; Gingivitis; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Liver Transplantation; Male; Mouth Diseases; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Statistics as Topic; Statistics, Nonparametric; Tacrolimus; Tooth Discoloration; Tooth Diseases

Topics: Acidosis, Renal Tubular; Bicarbonates; Biliary Atresia; Bilirubin; Child, Preschool; Creatinine; Electrolytes; Female; Glomerular Filtration Rate; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Living Donors; Postoperative Complications; Tacrolimus

We report the occurrence of epididymitis and orchitis 1 week after the onset of Listeriosis in an 11-month-old boy receiving an orthotopic liver transplantation for biliary atresia. Immunologic implications of Listeria monocytogenes-induced testicular inflammation are discussed, and the potential role of immunosuppression with tacrolimus is also discussed.

Topics: Biliary Atresia; Epididymitis; Humans; Immunosuppressive Agents; Infant; Listeriosis; Liver Transplantation; Male; Orchitis; Tacrolimus

Newer surgical techniques and immunosuppressive therapies have resulted in paediatric liver transplantation being available for most children with end-stage liver disease and has resulted in a greater than 80% 5-year survival rate. The most common indications for paediatric liver transplantation are biliary atresia (43%), metabolic disease (13%) and acute hepatic necrosis (11%). For approximately 75% of children with acute hepatic failure, the cause is unknown. Timing of liver transplantation not only affects survival rate, but may influence neurodevelopmental outcome. Fortunately, numerous types of donors, such as reduced-sized, living related or unrelated and blood-type mismatched, have reduced the mortality of children who are waiting for liver transplantation. However, the mortality and morbidity before and after liver transplantation remain high for children who have fulminant hepatic failure or are less than 5 months of age at the time of transplantation. The principle medical complications after liver transplantation are rejection and infection. Although use of newer immunosuppressive regimens has reduced the rate of rejection, Epstein-Barr virus infection with associated lymphoproliferative disorder remains the principle cause for morbidity and mortality after the initial 3 months post-liver transplant.

Topics: Adolescent; Adult; Age Factors; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Hepatic Encephalopathy; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Tacrolimus

Topics: Azathioprine; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Emulsions; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Methylprednisolone; Tacrolimus

Topics: ABO Blood-Group System; Biliary Atresia; Blood Group Incompatibility; Child; Child, Preschool; Cyclosporine; Drug Administration Schedule; Female; Guanidines; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Living Donors; Male; Muromonab-CD3; Parents; Plasma Exchange; Plasmapheresis; Tacrolimus

The authors report on experience with liver transplantation for infants younger than 1 year of age.. Over the last 15 years, orthotopic liver transplant has become the only lifesaving procedure available for infants with end-stage liver disease. Many transplant centers initially required infants to reach a specific weight or age to minimize morbidity and mortality. Size-appropriate infant donors also were uncommon. As a result, many children, in the first few years of life, died of their disease. The availability of reduced-size cadaveric and living-related liver transplants has offered the ability to transplant the young infant with liver failure.. The authors instituted a program to aggressively transplant infants with liver failure in the first year of life using both cadaveric and living-related liver donors.. Between June 1991 and January 1995, 13 infants were transplanted for rapidly progressive liver failure. Infant age ranged from 4 to 11 months (mean, 7.5 months). The cause of liver failure included biliary atresia (11), alpha 1-antitrypsin deficiency (1), and liver failure secondary to echovirus 7 (1). The United Network for Organ Sharing status at the time of transplant ranged from status 4, intensive care unit bound (4 patients); status 3, hospitalized (4 patients); or status 2, failing at home (5 patients). Six patients (46%) received cadaveric whole organ (2) or segmental transplants (4). Seven patients (54%) received left lateral segment living-related transplants from parental donors. After operation, patients received cyclosporine or FK506-based immunosuppression. Three patients (23%) required four retransplants (two cadaveric for primary nonfunction; one living-related for graft thrombosis in the face of fungal infection and bile leak). Postoperative complications included primary nonfunction (15%), rejection (85%), graft vascular thrombosis (15%, two of three revascularized successfully), bacterial and fungal infections (77%), and viral infections (46%). Epstein-Barr virus-associated lymphoproliferative developed in two patients (15%). Intestinal perforation requiring reoperation developed in two patients (15%). Bile leaks requiring reoperation or transhepatic stinting or both developed in three patients (23%). Two patients died in the perioperative period (< 1 month) from a combination of primary nonfunction or graft thrombosis and sepsis. Overall survival was 85%, ranging from 11.0 months to 4.5 years.. Orthotopic liver transplantation in infants younger than 1 year of age poses significant challenges from technical and infectious complications. Despite these barriers, overall patient survival is comparable to that of older children and adults.

Topics: Biliary Atresia; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

Two infants with biliary atresia who exhibited three-fold increased trough levels of tacrolimus and required reduced doses during episodes of acute infantile diarrhea within 5 months of liver transplantation are described. The cause of the increase was not explained simply by hemoconcentration as a result of significant loss of extracellular fluid during these episodes. It does highlight an important issue: that of the continuing need to carefully monitor the trough levels of tacrolimus in such infants.

Topics: Acute Disease; Biliary Atresia; Diarrhea, Infantile; Female; Humans; Immunosuppressive Agents; Infant; Jaundice; Liver Transplantation; Portoenterostomy, Hepatic; Tacrolimus

Topics: Amino Acid Metabolism, Inborn Errors; Biliary Atresia; Child; Child, Preschool; Contraindications; Drug Interactions; Erythromycin; Female; Hepatic Encephalopathy; Humans; Liver Transplantation; Male; Propionates; Rifampin; Tacrolimus

The authors performed 20 liver transplantations from living related donors between June 1990 and July 1991. The 20 pediatric patients (14 biliary atresia, two Budd-Chiari syndrome, one liver cirrhosis after hepatitis C viral infection (HCV hepatitis), 1 progressive intrahepatic cholestasis, 1 liver cirrhosis, 1 protoporphyria) were transplanted with 11 left lobes, eight left lateral segments, and one right lobe. The choice of donors was restricted to the parents of the recipients. The immunosuppressive treatment consisted of FK 506 and steroids. Seventeen recipients are alive, 15 of whom are well and at home. Two recipients, who underwent emergency transplantation, died of postoperative complications. Another recipient died of accidental asphyxia at 6 months after the transplantation. All 20 donors had uneventful postoperative courses and were able to resume their normal social lives. The arterial ketone body ratio (AKBR) increased to above 1.0 within 2 days after the transplantation in all cases. Relatively mild rejection episodes were encountered in only two cases transplanted with ABO-compatible grafts, and these were treated successfully with steroids and FK 506.

Topics: Adolescent; Biliary Atresia; Child; Child, Preschool; Female; Graft Rejection; Humans; Infant; Liver Diseases; Liver Transplantation; Male; Methylprednisolone; Parents; Postoperative Complications; Survival Rate; Tacrolimus; Tissue Donors