RESUMO
OBJECTIVES: To assess outcomes following liver transplantation for maple syrup urine disease by determining attainment and sustainability of metabolic control and apply an "ideal" outcome composite in long-term survivors. STUDY DESIGN: A single center, retrospective review collected clinical data including branched-chain amino acid (leucine, isoleucine, and valine) levels following liver transplant and determined achievement of an ideal long-term outcome profile of a first allograft stable on immunosuppression monotherapy, normal growth, and absence of common transplant-related sequelae. RESULTS: Of 77 patients meeting inclusion criteria identified, 23 were long-term (≥10-year) survivors and were additionally assessed for ideal outcome attainment. Patient and graft survival were 100% and 99%, respectively, and all patients were on an unrestricted protein intake diet. Although significant variation was noted in mean isoleucine (P < .01) and leucine (P < .05) levels postliver transplantation, no difference was seen in valine (P = .29) and overall clinical impact was likely negligible as metabolic stability was achieved and sustained beyond 3 years postliver transplantation and no metabolic crises were identified. Of 23 long-term survivors with available data, 9 (39%) achieved all composite metrics determined to define "ideal" outcomes in pediatric postliver transplantation populations. CONCLUSIONS: Liver transplant enables long-term metabolic stability for patients with maple syrup urine disease. A combination of experience and improvement in both pre- and postliver transplantation care has enabled excellent survival and minimal comorbidities following transplant.
Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Transplante de Fígado , Doença da Urina de Xarope de Bordo/metabolismo , Doença da Urina de Xarope de Bordo/cirurgia , Adolescente , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Lactente , Masculino , Doença da Urina de Xarope de Bordo/diagnóstico , Doença da Urina de Xarope de Bordo/mortalidade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Sobreviventes , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Portal hypertension (PHT) and its complications in children are thought to be distinct from adult PHT in several areas, including the underlying bio-physiology of a child in which PHT develops, but also because of the pediatric-specific etiologies that drive disease progression. And yet pharmacologic approaches to PHT in children are mainly based on adult data, modified for pediatric practice. This reality has been driven by a lack of data specific to children. AREAS COVERED: The authors discuss current therapeutic approaches to PHT in children, including management of acute gastrointestinal variceal bleed, pharmacotherapy in prophylaxis, and established and emerging therapies to combat systemic co-morbidities that result from PHT. The few areas where pediatric-specific data exist are highlighted and the many gaps in knowledge that remain unresolved are underscored. EXPERT OPINION: Despite decades of experience, optimal management of pediatric PHT remains undefined. In large part, this can be directly linked to a lack of basic understanding related to the unique pathophysiology and natural history that defines PHT in children. As a result, meaningful research into the utility and effectiveness of pharmacotherapy in children with PHT remains in its infancy. Large, multi-center, prospective studies will be needed to begin to establish an infrastructure on which a pediatric-specific research agenda can be built.
Assuntos
Hipertensão Portal , Adulto , Criança , Previsões , Hemorragia Gastrointestinal , Humanos , Hipertensão Portal/tratamento farmacológico , Estudos ProspectivosAssuntos
Hiperamonemia , Hepatopatias , Benzoatos , Criança , Método Duplo-Cego , Humanos , Benzoato de SódioRESUMO
BACKGROUND AND AIMS: We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years. APPROACH AND RESULTS: Unbound ("free") bilirubin (Bf ) was measured in patient sera to characterize the binding of unconjugated bilirubin (BT ) to albumin (A) and validate their molar concentration ratio (BT /A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep BT /A at least 30% below intravascular BT binding capacity (i.e., BT /A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (Lf ) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to BT (R2 = 0.71) and BT /A (R2 = 0.76), and Bf as a percentage of BT correlated inversely to the bilirubin-albumin equilibrium association binding constant (R2 = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak BT ≥ 30 mg/dL and BT /A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 µW/cm2 â¢nm for 9.2 ± 1.1 hours/day kept BT and BT /A within safe limits throughout childhood, but BT increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized BT and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe. CONCLUSION: Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.
Assuntos
Bilirrubina , Encefalopatias , Síndrome de Crigler-Najjar , Cirrose Hepática , Fototerapia/métodos , Albumina Sérica/análise , Adolescente , Bilirrubina/sangue , Bilirrubina/metabolismo , Encefalopatias/sangue , Encefalopatias/diagnóstico , Encefalopatias/etiologia , Encefalopatias/prevenção & controle , Síndrome de Crigler-Najjar/sangue , Síndrome de Crigler-Najjar/genética , Síndrome de Crigler-Najjar/fisiopatologia , Síndrome de Crigler-Najjar/terapia , Feminino , Glucuronosiltransferase/genética , Homozigoto , Humanos , Recém-Nascido , Estimativa de Kaplan-Meier , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/etiologia , Cirrose Hepática/terapia , Transplante de Fígado/métodos , Transplante de Fígado/estatística & dados numéricos , Masculino , Medição de Risco , Estados UnidosRESUMO
Indications for liver transplantation (LT) in metabolic disease are evolving. We reviewed the US experience with primary LT for metabolic disease in the Scientific Registry for Transplant Recipients (October 1987 to June 2017) to determine the following: temporal changes in indications, longterm outcomes, and factors predicting survival. Patients were grouped by the presence of structural liver disease (SLD) and whether the defect was confined to the liver. There were 5996 patients who underwent LT for metabolic disease, 2354 (39.3%) being children. LT for metabolic disease increased in children but not in adults. Children experienced a 6-fold increase in LT for metabolic disease without SLD. Indications for LT remained stable in adults. Living donor liver transplantation increased between era 1 and era 3 from 5.6% to 7.6% in children and 0% to 4.5% in adults. Patient and graft survival improved with time. The latest 5-year patient survival rates were 94.5% and 81.5% in children and adults, respectively. Outcomes were worse in adults and in those with extrahepatic disease (P < 0.01), whereas SLD did not affect outcomes. Survival improved with younger age at LT until age <2 years. On multivariate analysis, diagnostic category, inpatient status, age at LT, and transplant era significantly predicted outcomes in all ages with male sex predicting survival in childhood only. Children without structural disease were less likely to die awaiting LT and had improved post-LT survival compared with children with chronic liver disease. In conclusion, LT for metabolic disease is increasingly used for phenotypic correction in children; extrahepatic manifestations significantly impact survival at all ages; where indicated, transplantation should not be unnecessarily delayed; and the development of new allocation models may be required.
Assuntos
Doença Hepática Terminal/cirurgia , Transplante de Fígado/tendências , Doenças Metabólicas/cirurgia , Seleção de Pacientes , Adulto , Fatores Etários , Criança , Pré-Escolar , Doença Hepática Terminal/etiologia , Doença Hepática Terminal/mortalidade , Feminino , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Transplante de Fígado/normas , Transplante de Fígado/estatística & dados numéricos , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/mortalidade , Pessoa de Meia-Idade , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Taxa de Sobrevida , Sobreviventes/estatística & dados numéricos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
Propionic acidemia (PA) and methylmalonic acidemia (MMA) comprise the most common organic acidemias and account for profound morbidity in affected individuals. Although liver transplantation (LT) has emerged as a bulk enzyme-replacement strategy to stabilize metabolically fragile patients, it is not a metabolic cure because patients remain at risk for disease-related complications. We retrospectively studied LT and/or liver-kidney transplant in 9 patients with PA or MMA with additional focus on the optimization of metabolic control and management in the perioperative period. Metabolic crises were common before transplant. By implementing a strategy of carbohydrate minimization with gradual but early lipid and protein introduction, lactate levels significantly improved over the perioperative period (P < 0.001). Posttransplant metabolic improvement is demonstrated by improvements in serum glycine levels (for PA; P < 0.001 × 10-14 ), methylmalonic acid levels (for MMA; P < 0.001), and ammonia levels (for PA and MMA; P < 0.001). Dietary restriction remained after transplant. However, no further metabolic crises have occurred. Other disease-specific comorbidities such as renal dysfunction and cardiomyopathy stabilized and improved. In conclusion, transplant can provide a strategy for altering the natural history of PA and MMA providing stability to a rare but metabolically brittle population. Nutritional management is critical to optimize patient outcomes.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/cirurgia , Transplante de Fígado , Assistência Perioperatória/métodos , Acidemia Propiônica/cirurgia , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Biomarcadores/sangue , Bases de Dados Factuais , Metabolismo Energético , Nutrição Enteral , Feminino , Gastrostomia , Sobrevivência de Enxerto , Humanos , Recém-Nascido , Transplante de Rim , Transplante de Fígado/efeitos adversos , Masculino , Estado Nutricional , Assistência Perioperatória/efeitos adversos , Complicações Pós-Operatórias/terapia , Acidemia Propiônica/sangue , Acidemia Propiônica/diagnóstico , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
We report a case of glycogen storage disease type 1b that was successfully treated with bone marrow transplantation after life-threatening complications related to neutropenia and thrombocytopenia. Concomitant reduction in inflammatory bowel disease-related symptoms and improved metabolic stability were also observed.