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BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.
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Síndrome de Alagille , Humanos , Síndrome de Alagille/complicações , Síndrome de Alagille/tratamento farmacológico , Feminino , Masculino , Estudos Retrospectivos , Criança , Lactente , Pré-Escolar , Intervalo Livre de Progressão , Adolescente , Proteínas de Transporte , Glicoproteínas de MembranaRESUMO
Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.
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Colestase Intra-Hepática , Colestase , Citrulinemia , Gastroenterologia , Doenças do Recém-Nascido , Transportadores de Ânions Orgânicos , Adolescente , Criança , Humanos , Lactente , Recém-Nascido , Colestase/diagnóstico , Colestase/etiologia , Colestase/terapia , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/etiologia , Colestase Intra-Hepática/terapia , Citrulinemia/complicações , Citrulinemia/diagnóstico , Citrulinemia/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Mutação , Transportadores de Ânions Orgânicos/genéticaRESUMO
Background and Aim: People with inflammatory bowel disease (IBD) have an increased risk of cardiovascular disease, including in younger adulthood. This may arise in part from chronic, systemic low-grade inflammation. The process of atherosclerosis may begin in childhood. We sought to determine whether pediatric IBD is associated with adverse changes in arterial structure and function as a marker of early increased cardiovascular risk. Methods: We performed a case-control study comparing children with IBD for a median disease duration of 2.49 (interquartile range 1.23, 4.38) years with healthy children. In a single visit, we collected baseline clinical and anthropometric data, and measured blood pressure, pulse wave velocity, carotid artery distensibility, and aortic and carotid intima-media thickness. High-sensitivity C-reactive protein and fasting lipids were measured. Results: We enrolled 81 children with IBD (40 with Crohn's disease, 40 with ulcerative colitis, and 1 with unspecified IBD) and 82 control participants. After adjusting for age, sex, body mass index z-score, blood pressure, and low-density lipoprotein cholesterol, there was no difference in measures of arterial structure and function in children with IBD compared with controls, nor between those with Crohn's disease or ulcerative colitis. Conclusion: We did not show any differences in arterial structure and function in children with a history of IBD for less than 5 years compared with healthy controls. IBD diagnosed in childhood may provide a window of opportunity to actively reduce standard cardiovascular risk factors and improve future cardiovascular outcomes.
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BACKGROUND: Despite reassuring clinical safety data, thrombocytosis, anemia, lymphopenia, and liver function derangements have been observed in infants born to women with inflammatory bowel disease (IBD) treated with thiopurines and biologics. We aimed to define the prevalence, course, associations, and clinical impact of hematological and biochemical abnormalities in such infants. METHODS: This multicenter prospective cohort study assessed clinical, hematologic, and biochemical outcomes of infants exposed to thiopurines or biologics in utero for management of maternal IBD. Liver transaminases, full blood examination, and infant thiopurine metabolites (where exposed) were taken at delivery and 6 weeks of age. Abnormal results were repeated until normalization. Infants were followed clinically by a pediatric gastroenterologist up to 2 years of age. RESULTS: A total of 130 infants were included. Thrombocytosis and elevated alanine transaminase (ALT) were seen in over half of infants up to 6 months of age with no significant clinical impact. Elevated ALT was associated with increasing maternal C-reactive protein in second trimester, while thrombocytosis was associated with increasing maternal C-reactive protein and fecal calprotectin in third trimester. Preceding infection and vaccination were associated with an increased risk of elevated alkaline phosphatase at 3 months. In those exposed to thiopurines, increasing maternal 6-methylmercaptopurine at delivery was associated with increased ALT to 6 months. CONCLUSIONS: Infants born to women with IBD commonly developed thrombocytosis, elevated alkaline phosphatase, and elevated ALT. These findings were associated with exposure to maternal inflammation, elevated 6-methylmercaptopurine at delivery, and infant vaccinations and infections, and had minimal clinical consequence.
Hematological and biochemical abnormalities have been observed in infants born to women with inflammatory bowel disease. This prospective study shows that thrombocytosis and elevated alanine transaminase are common in infants to 6 months of age and are associated with maternal inflammation, rather than with in utero medication exposures.
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BACKGROUND AND AIMS: The risk of intrahepatic cholestasis of pregnancy [ICP] is increased in thiopurine-exposed pregnancies. Thiopurine 'shunting', with a 6-methylmercaptopurine [MMP] to 6-thioguanine [TGN] ratio ofâ >11, progresses over pregnancy, and may promote ICP development. We aimed to explore the association between thiopurine exposure and ICP, including the hypothesised impact of thiopurine shunting, and identify risk minimisation strategies. METHODS: This prospective multicentre cohort study compared thiopurine and biologic monotherapy-exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids, and transaminases were obtained before conception, in each trimester, at delivery, and postpartum. Thiopurine dose management was at the discretion of the treating physician. RESULTS: Included were 131 thiopurine and 147 biologic monotherapy-exposed pregnancies. MMP/TGN ratio increased from preconception to third trimester [pâ <0.01], with approximately 25% of participants shunting in pregnancy. Second trimester split dosing led to a decrease in the median MMP/TGN ratio from 18 (interquartile range [IQR] 6-57) to 3 [IQR 2-3.5] at delivery [pâ =â 0.04]. The risk of ICP was increased in thiopurine-exposed pregnancies (6.7% [7/105] vs 0% [0/112], pâ <0.001), with all ICP cases occurring in the setting of antenatal thiopurine shunting. Thiopurine dose increases (risk ratio [RR] 8.10, 95% confidence interval [CI] 1.88-34.85, pâ =â 0.005) and shunting in third trimester [6.20, 1.21-30.73, pâ =â 0.028] and at delivery [14.18, 1.62-123.9, pâ =â 0.016] were associated with an increased risk of ICP. CONCLUSIONS: Thiopurine exposure is associated with an increased risk of ICP, particularly following dose increases antenatally and with shunting in late pregnancy. The latter may be effectively managed with split dosing, although further studies are warranted.
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Colestase Intra-Hepática , Doenças Inflamatórias Intestinais , Mercaptopurina , Complicações na Gravidez , Humanos , Gravidez , Feminino , Complicações na Gravidez/tratamento farmacológico , Adulto , Colestase Intra-Hepática/induzido quimicamente , Estudos Prospectivos , Mercaptopurina/análogos & derivados , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Imunossupressores/efeitos adversos , Imunossupressores/administração & dosagem , Tioguanina/administração & dosagem , Tioguanina/efeitos adversos , Azatioprina/efeitos adversos , Azatioprina/administração & dosagem , Fatores de RiscoRESUMO
INTRODUCTION: Hepatic artery complications (HACs), such as a thrombosis or stenosis, are serious causes of morbidity and mortality after paediatric liver transplantation (LT). This study will investigate the incidence, current management practices and outcomes in paediatric patients with HAC after LT, including early and late complications. METHODS AND ANALYSIS: The HEPatic Artery stenosis and Thrombosis after liver transplantation In Children (HEPATIC) Registry is an international, retrospective, multicentre, observational study. Any paediatric patient diagnosed with HAC and treated for HAC (at age <18 years) after paediatric LT within a 20-year time period will be included. The primary outcomes are graft and patient survivals. The secondary outcomes are technical success of the intervention, primary and secondary patency after HAC intervention, intraprocedural and postprocedural complications, description of current management practices, and incidence of HAC. ETHICS AND DISSEMINATION: All participating sites will obtain local ethical approval and (waiver of) informed consent following the regulations on the conduct of observational clinical studies. The results will be disseminated through scientific presentations at conferences and through publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: The HEPATIC registry is registered at the ClinicalTrials.gov website; Registry Identifier: NCT05818644.