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ABSTRACT: Pediatric acute liver failure (PALF) is a rare, rapidly progressive clinical syndrome with significant morbidity and mortality. The phenotype of PALF manifests as abrupt onset liver dysfunction, which can be brought via disparate etiology. Management is reliant upon intensive clinical care and support, often provided by the collaborative efforts of hepatologists, critical care specialists, and liver transplant surgeons. The construction of an age-based diagnostic approach, the identification of a potential underlying cause, and the prompt implementation of appropriate therapy can be lifesaving; however, the dynamic and rapidly progressive nature of PALF also demands that diagnostic inquiries be paired with monitoring strategies for the recognition and treatment of common complications of PALF. Although liver transplantation can provide a potential life-saving therapeutic option, the ability to confidently determine the certainness that liver transplant is needed for an individual child has been hampered by a lack of adequately tested clinical decision support tools and accurate predictive models. Given the accelerated progress in understanding PALF, we will provide clinical guidance to pediatric gastroenterologists and other pediatric providers caring for children with PALF by presenting the most recent advances in diagnosis, management, pathophysiology, and associated outcomes.
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Gastroenterologia , Falência Hepática Aguda , Transplante de Fígado , Criança , Humanos , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/terapia , América do Norte , Estado NutricionalRESUMO
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.
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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.
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Hipertensão Portal , Adulto , Criança , Previsões , Hemorragia Gastrointestinal , Humanos , Hipertensão Portal/tratamento farmacológico , Estudos ProspectivosRESUMO
OBJECTIVES: To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. STUDY DESIGN: The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. RESULTS: We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. CONCLUSIONS: Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.
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Colestase Intra-Hepática/complicações , Hipertensão Portal/etiologia , Deficiência de alfa 1-Antitripsina/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Hipertensão Portal/cirurgia , Lactente , Recém-Nascido , Transplante de Fígado , Estudos Longitudinais , Masculino , Adulto Jovem , Deficiência de alfa 1-Antitripsina/sangueRESUMO
OBJECTIVES: The aim of the study was to assess neurodevelopmental outcomes among children with biliary atresia (BA) surviving with their native liver at ages 3 to 12 years and evaluate variables that associate with neurodevelopment. METHODS: Participants (ages 3-12 years) in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with Weschler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III, ages 3-5 years) and Weschler Intelligence Scale for Children, 4th edition (WISC-IV, ages 6-12 years). Continuous scores were analyzed using Kolmogorov-Smironov tests compared with a normal distribution (meanâ=â100â±â15). Effect of covariates on Full-Scale Intelligence Quotient (FSIQ) was analyzed using linear regression. RESULTS: Ninety-three participants completed 164 WPPSI-III (mean age 3.9) and 51 WISC-IV (mean age 6.9) tests. WPPSI-III FSIQ (104â±â14, Pâ<â0.02), Verbal IQ (106â±â14, Pâ<â0.001), and General Language Composite (107â±â16, Pâ<â0.001) distributions were shifted higher compared with test norms. WISC-IV FSIQ (105â±â12, Pâ<â0.01), Perceptual Reasoning Index (107â±â12, Pâ<â0.01), and Processing Speed Index (105â±â10, Pâ<â0.02) also shifted upwards. In univariate and multivariable analysis, parent education (Pâ<â0.01) was a significant predictor of FSIQ on WPPSI-III and positively associated with WISC-IV FSIQ. Male sex and higher total bilirubin and gamma glutamyl transferase (GGT) predicted lower WPPSI-III FSIQ. Portal hypertension was predictive of lower WISC-IV FSIQ. CONCLUSIONS: This cohort of children with BA and native liver did not demonstrate higher prevalence of neurodevelopmental delays. Markers of advanced liver disease (higher total bilirubin and GGT for age ≤5 years; portal hypertension for age ≥6) correlate with lower FSIQ and may identify a vulnerable subset of patients who would benefit from intervention.
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Atresia Biliar/psicologia , Transtornos do Neurodesenvolvimento/epidemiologia , Atresia Biliar/sangue , Atresia Biliar/patologia , Bilirrubina/sangue , Criança , Desenvolvimento Infantil , Pré-Escolar , Escolaridade , Feminino , Humanos , Hipertensão Portal/etiologia , Hipertensão Portal/psicologia , Fígado/patologia , Estudos Longitudinais , Masculino , Transtornos do Neurodesenvolvimento/etiologia , Prevalência , Estudos Prospectivos , Fatores de Risco , Escalas de Wechsler , gama-Glutamiltransferase/sangueRESUMO
Diffusion of cholera and other diarrheal diseases in an informal settlement is a product of multiple behavioral, environmental and spatial risk factors. One of the most important components is the spatial interconnections among water points, drainage ditches, toilets and the intervening environment. This risk is also longitudinal and variable as water points fluctuate in relation to bacterial contamination. In this paper we consider part of this micro space complexity for three informal settlements in Port au Prince, Haiti. We expand on more typical epidemiological analysis of fecal coliforms at water points, drainage ditches and ocean sites by considering the importance of single point location fluctuation coupled with recording micro-space environmental conditions around each sample site. Results show that spatial variation in enteric disease risk occurs within neighborhoods, and that while certain trends are evident, the degree of individual site fluctuation should question the utility of both cross-sectional and more aggregate analysis. Various factors increase the counts of fecal coliform present, including the type of water point, how water was stored at that water point, and the proximity of the water point to local drainage. Some locations fluctuated considerably between being safe and unsafe on a monthly basis. Next steps to form a more comprehensive contextualized understanding of enteric disease risk in these environments should include the addition of behavioral factors and local insight.
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Cólera/epidemiologia , Diarreia/epidemiologia , Cidades , Sistemas de Informação Geográfica , Haiti , Humanos , Fatores de RiscoRESUMO
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.
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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
Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual-energy X-ray absorptiometry (DXA) analysis was performed in children with intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha-1 antitrypsin deficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height-adjusted and weight-adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height-adjusted and weight-adjusted subtotal BMC Z scores were lower in ALGS participants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.
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Densidade Óssea , Colestase/etiologia , Transtornos do Crescimento/etiologia , Hepatopatias/complicações , Hepatopatias/fisiopatologia , Absorciometria de Fóton , Adolescente , Criança , Doença Crônica , Correlação de Dados , Feminino , Humanos , Estudos Longitudinais , MasculinoRESUMO
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.
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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
Liver transplant (LT) decisions in pediatric acute liver failure (PALF) are complex. Three phases of the PALF registry, containing data on 1,144 participants over 15 years, were interrogated to characterize clinical features associated with listing status. A decrease in the cumulative incidence of listing (P < 0.005) and receiving (P < 0.05) LT occurred without an increase in the cumulative incidence of death (P = 0.67). Time to listing was constant and early (1 day; quartiles 1-3 = 0-2; P = 0.88). The most frequent reasons for not listing were "not sick enough" and "medically unsuitable." Participants listed for LT were more likely male, with coma grade scores >0; had higher international normalized ratio, bilirubin, lactate, and venous ammonia; and had lower peripheral lymphocytes and transaminase levels compared to those deemed "not sick enough." Participants listed versus those deemed "medically unsuitable" were older; had higher serum aminotransferase levels, bilirubin, platelets, and albumin; and had lower lactate, venous ammonia, and lymphocyte count. An indeterminate diagnosis was more prevalent in listed participants. Ventilator (23.8%) and vasopressor (9.2%) support occurred in a significant portion of listed participants but less frequently than in those who were not "medically suitable." Removal from the LT list was a rare event. Conclusion: The cumulative incidence of listing for and receiving LT decreased throughout the PALF study without an increase in the cumulative incidence of death. While all participants fulfilled entry criteria for PALF, significant differences were noted between participants listed for LT and those deemed "not sick enough" as well as those who were "medically unsuitable." Having an indeterminate diagnosis and a requirement for cardiopulmonary support appeared to influence decisions toward listing; optimizing listing decisions in PALF may reduce the frequency of LT without increasing the frequency of death.