RESUMEN
OBJECTIVE: To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants. STUDY DESIGN: A total of 140 infants were enrolled in START, with 70 randomized to each treatment arm: steroid and placebo. Length, weight, and head circumference were obtained at baseline and follow-up visits to 24 months of age. RESULTS: Patients treated with steroids had significantly lower length and head circumference z scores during the first 3 months post-hepatoportoenterostomy (HPE), and significantly lower weight until 12 months. Growth trajectories in the steroid and placebo arms differed significantly for length (P < .0001), weight (P = .009), and head circumference (P < .0001) with the largest impact noted for those with successful HPE. Growth trajectory for head circumference was significantly lower in patients treated with steroids irrespective of HPE status, but recovered during the second 6 months of life. CONCLUSIONS: Steroid therapy following HPE in patients with biliary atresia is associated with impaired length, weight, and head circumference growth trajectories for at least 6 months post-HPE, especially impacting infants with successful bile drainage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00294684.
Asunto(s)
Corticoesteroides/efectos adversos , Atresia Biliar/tratamiento farmacológico , Atresia Biliar/cirugía , Insuficiencia de Crecimiento/inducido químicamente , Sarcopenia/inducido químicamente , Corticoesteroides/uso terapéutico , Atresia Biliar/mortalidad , Peso Corporal/efectos de los fármacos , Cefalometría/métodos , Desarrollo Infantil/efectos de los fármacos , Desarrollo Infantil/fisiología , Preescolar , Método Doble Ciego , Insuficiencia de Crecimiento/epidemiología , Insuficiencia de Crecimiento/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Monitoreo Fisiológico/métodos , Portoenterostomía Hepática/métodos , Portoenterostomía Hepática/mortalidad , Cuidados Posoperatorios/métodos , Estudios Prospectivos , Valores de Referencia , Medición de Riesgo , Sarcopenia/epidemiología , Sarcopenia/fisiopatología , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Experimental studies have shown decreased bile acid (BA) uptake and reduced excretion of cholephilic compounds in pregnant rodents. AIM: To assess the expression and function of the main BA importer, the Na(+)/taurocholate cotransporting polypeptide (Ntcp) in pregnant rats. METHODS: BA uptake and Ntcp expression were studied in control and timed-pregnant rats in late gestation. Ntcp protein, messenger RNA (mRNA) expression, and Ntcp tissue localization were determined by Northern blotting, Western analysis, and tissue immunofluorescence. The activity of three transactivators of the Ntcp promoter: hepatocyte nuclear factor 1-alpha (HNF1-alpha), nuclear receptor heterodimer retinoid X receptor:retinoid acid receptor (RXR:RAR) and signal transducer and activator of transcription 5 (Stat5) was assessed using gel electrophoretic mobility shift assays. RESULTS: A significantly reduced BA uptake and decreased Ntcp mRNA levels (-40%) and protein mass (-60%) was observed in pregnant rats. Nuclear extracts from pregnant rats showed a marked decrease of HNF1-alpha and RXR:RAR binding activities by -80 and -40% of basal activity, respectively. In contrast, binding activity of Stat-5 was increased by 50% in nuclear extracts from pregnant rats. CONCLUSIONS: Pregnancy is associated with reduced Ntcp expression and function in the rat. Our findings suggest that Ntcp down-regulation during pregnancy occurs primarily at the transcriptional level.