Factors Determining ?-Bilirubin Levels in Infants With Biliary Atresia.
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ABSTRACT:
SUBMITTER: Ye W
PROVIDER: S-EPMC4409472 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
Publications
Factors Determining δ-Bilirubin Levels in Infants With Biliary Atresia.
Ye Wen W Rosenthal Philip P Magee John C JC Whitington Peter F PF
Journal of pediatric gastroenterology and nutrition 20150501 5
<h4>Objectives</h4>δ-Bilirubin (Bδ) forms when bilirubin conjugates covalently bind to albumin by way of nonenzymatic transesterification in patients with cholestasis. Infants with cholestasis with biliary atresia form Bδ. The aim of the present study was to investigate the factors determining serum Bδ concentrations in infants with biliary atresia.<h4>Methods</h4>Study patients were infants enrolled in a prospective study (PROBE: Clinicaltrials.gov NCT00061828) of biliary atresia. We acquired d ...[more]
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Project description:ObjectiveFat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia.MethodsInfants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA.ResultsThe degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998).ConclusionsWe found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, α-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.
| S-EPMC4243585 | biostudies-literature
Project description:Biliary atresia (BA) is a rare neonatal cholestatic disorder caused by obstruction of extra- and intra-hepatic bile ducts. If untreated, progressive liver cirrhosis will lead to death within 2 years. Early diagnosis and operation improve the outcome significantly. Infants with neonatal hepatitis syndrome (NHS) present similar symptoms, confounding the early diagnosis of BA. The lack of noninvasive diagnostic methods to differentiate BA from NHS greatly delays the surgery of BA infants, thus deteriorating the outcome. Here we performed a metabolomics study in plasma of BA, NHS, and healthy infants using gas chromatography-time-of-flight mass spectrometry. Scores plots of orthogonal partial least-squares discriminant analysis clearly separated BA from NHS and healthy infants. Eighteen metabolites were found to be differentially expressed between BA and NHS, among which seven (l-glutamic acid, l-ornithine, l-isoleucine, l-lysine, l-valine, l-tryptophan, and l-serine) were amino acids. The altered amino acids were quantitatively verified using ultraperformance liquid chromatography-tandem mass spectrometry. Ingenuity pathway analysis revealed the network of "Cellular Function and Maintenance, Hepatic System Development and Function, Neurological Disease" was altered most significantly. This study suggests that plasma metabolic profiling has great potential in differentiating BA from NHS, and amino acid metabolism is significantly different between the two diseases.
| S-EPMC6088235 | biostudies-literature
Project description:BackgroundAutotaxin (ATX) is a secreted glycoprotein that is involved in the development of hepatic fibrogenesis via the enzymatic production of lysophosphatidic acid. The aim of this study was to investigate hepatic expression of ATX in biliary atresia (BA) compared with non-BA liver controls and to examine the association between ATX expression and clinical outcome in BA.MethodsLiver specimens from BA infants (n = 20) were compared with samples from infants who underwent liver biopsy for reasons other than BA (n = 14) and served as controls. Relative mRNA and protein expression of ATX were quantified using real-time polymerase chain reaction (PCR) and immunohistochemistry. Masson's Trichrome staining was performed to determine the degree of liver fibrosis.ResultsQuantitative real-time PCR demonstrated overexpression of ATX mRNA in BA livers. In immunohistochemical evaluation, ATX was positively stained on the hepatic parenchyma and the biliary epithelium in BA patients, as compared to non-BA controls. The immunostaining score of ATX in BA livers was also significantly higher than that observed in non-BA livers (P < 0.001). Subgroup analysis revealed that ATX expression in the patients with poor outcomes was significantly greater than in those with good outcomes (P = 0.03). Additionally, there was a positive correlation between hepatic ATX expression and Metavir fibrosis stage in BA livers (r = 0.79, P < 0.001).DiscussionThis study found that mRNA and protein expression of ATX were increased in BA livers. High hepatic ATX expression at the time of Kasai operation was associated with liver fibrosis and outcome in BA, suggesting that ATX may serve a role as a promising biomarker of the prognosis in biliary atresia.
| S-EPMC6063256 | biostudies-literature
Project description:Importance:Treating biliary atresia in newborns earlier can delay or prevent the need for liver transplant; however, treatment typically occurs later because biliary atresia is difficult to detect during its early stages. Objective:To determine the diagnostic yield of newborn screening for biliary atresia with direct or conjugated bilirubin measurements and to evaluate the association of screening implementation with clinical outcomes. Design, Setting, and Participants:A cross-sectional screening study of 124?385 infants born at 14 Texas hospitals between January 2015 and June 2018; and a pre-post study of 43 infants who underwent the Kasai portoenterostomy as treatment for biliary atresia at the region's largest pediatric hepatology center before (January 2008-June 2011) or after (January 2015-June 2018) screening implementation. Final follow-up occurred on July 15, 2019. Exposures:Two-stage screening with direct or conjugated bilirubin measurements. In stage 1, all newborns were tested within the first 60 hours of life, with a positive screening result defined as bilirubin levels exceeding derived 95th percentile reference intervals. In stage 2, infants who had a positive screening result in stage 1 were retested at or before the 2-week well-child visit, with a positive screening result defined as bilirubin levels greater than the stage 1 result or greater than 1 mg/dL. Main Outcomes and Measures:The primary outcomes of the screening study were sensitivity, specificity, positive predictive value, and negative predictive value based on infants testing positive in both stages. The reference standard was biliary atresia diagnosed at the region's pediatric hepatology centers. The primary outcome of the pre-post study was the age infants underwent the Kasai portoenterostomy for treatment of biliary atresia. Results:Of 124?385 newborns in the screening study, 49.2% were female, 87.6% were of term gestational age, 70.0% were white, and 48.1% were Hispanic. Screening identified the 7 known infants with biliary atresia with a sensitivity of 100% (95% CI, 56.1%-100.0%), a specificity of 99.9% (95% CI, 99.9%-99.9%), a positive predictive value of 5.9% (95% CI, 2.6%-12.2%), and a negative predictive value of 100.0% (95% CI, 100.0%-100.0%). In the pre-post study, 24 infants were treated before screening implementation and 19 infants were treated after screening implementation (including 6 of 7 from the screening study, 7 from screening at nonstudy hospitals, and 6 from referrals because of clinical symptoms). The age infants underwent the Kasai portoenterostomy was significantly younger after screening was implemented (mean age, 56 days [SD, 19 days] before screening implementation vs 36 days [SD, 22 days] after screening implementation; between-group difference, 19 days [95% CI, 7-32 days]; P?=?.004). Conclusions and Relevance:Newborn screening with direct or conjugated bilirubin measurements detected all known infants with biliary atresia in the study population, although the 95% CI around the sensitivity estimate was wide and the study design did not ensure complete ascertainment of false-negative results. Research is needed in larger populations to obtain more precise estimates of diagnostic yield and to better understand the clinical outcomes and cost-effectiveness of this screening approach.
| S-EPMC7093763 | biostudies-literature
Project description: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.
| S-EPMC6365098 | biostudies-literature
Project description:OBJECTIVES:Diagnosing biliary atresia (BA) quickly is critical, because earlier treatment correlates with delayed or reduced need for liver transplantation. However, diagnosing BA quickly is also difficult, with infants usually treated after 60 days of life. In this study, we aim to accelerate BA diagnosis and treatment, by better understanding factors influencing the diagnostic timeline. METHODS:Infants born between 2007 and 2014 and diagnosed with BA at our institution were included (n?=?65). Two periods were examined retrospectively: P1, the time from birth to specialist referral, and P2, the time from specialist referral to treatment. How sociodemographic factors associate with P1 and P2 were analyzed with Kaplan-Meier curves and Cox proportional hazard models. In addition, to better characterize P2, laboratory results and early tissue histology were studied. RESULTS:P1 associated with race/ethnicity, with shorter times in non-Hispanic white infants compared to non-Hispanic black and Hispanic infants (P?=?0.007 and P?=?0.004, respectively). P2 associated with referral age, with shorter times in infants referred after 30, 45, or 60 days of life (P?<?0.001, P?<?0.001, and P?=?0.001, respectively). One potential reason for longer P2 in infants referred ?30 days is that aminotransferase levels were normal or near-normal. However, despite reassuring laboratory values, tissue histology in early cases showed key features of BA. CONCLUSIONS:Our findings suggest 2 opportunities to accelerate BA diagnosis and treatment. First, to achieve prompt referrals for all races/ethnicities, universal screening strategies should be considered. Second, to ensure efficient evaluations independent of age, algorithms designed to detect early features of BA can be developed.
| S-EPMC5963977 | biostudies-literature
Project description:ObjectivesTo prospectively assess the value of serum total bilirubin (TB) within 3 months of hepatoportoenterostomy (HPE) in infants with biliary atresia as a biomarker predictive of clinical sequelae of liver disease in the first 2 years of life.Study designInfants with biliary atresia undergoing HPE between June 2004 and January 2011 were enrolled in a prospective, multicenter study. Complications were monitored until 2 years of age or the earliest of liver transplantation (LT), death, or study withdrawal. TB below 2 mg/dL (34.2 μM) at any time in the first 3 months (TB <2.0, all others TB ≥ 2) after HPE was examined as a biomarker, using Kaplan-Meier survival and logistic regression.ResultsFifty percent (68/137) of infants had TB < 2.0 in the first 3 months after HPE. Transplant-free survival at 2 years was significantly higher in the TB < 2.0 group vs TB ≥ 2 (86% vs 20%, P < .0001). Infants with TB ≥ 2 had diminished weight gain (P < .0001), greater probability of developing ascites (OR 6.4, 95% CI 2.9-14.1, P < .0001), hypoalbuminemia (OR 7.6, 95% CI 3.2-17.7, P < .0001), coagulopathy (OR 10.8, 95% CI 3.1-38.2, P = .0002), LT (OR 12.4, 95% CI 5.3-28.7, P < .0001), or LT or death (OR 16.8, 95% CI 7.2-39.2, P < .0001).ConclusionsInfants whose TB does not fall below 2.0 mg/dL within 3 months of HPE were at high risk for early disease progression, suggesting they should be considered for LT in a timely fashion. Interventions increasing the likelihood of achieving TB <2.0 mg/dL within 3 months of HPE may enhance early outcomes.Trial registrationClinicalTrials.gov: NCT00061828 and NCT00294684.
| S-EPMC4826612 | biostudies-literature
Project description:BackgroundPreliminary studies have shown that diffusion tensor imaging (DTI) is helpful in evaluating liver disorders. However, there is no published literature on the use of DTI in the diagnosis of biliary atresia (BA). This study aimed to investigate the diagnostic value of the liver average apparent diffusion coefficient (ADC) and fractional anisotropy (FA) measured using DTI for BA in neonates and infants.MethodsFifty-nine patients with infant jaundice were included in this study. DTI was performed with b factors of 0 and 1000 s/mm2. Liver fibrosis in the BA group was determined and graded (F0, F1, F2, F3, F4) based on the pathological findings. Statistical analyses were performed to determine the diagnostic accuracy of DTI for BA.ResultsThe ADC value was significantly lower in the BA group [(1.262±0.127)×10-3 mm2/s] than in the non-BA group [(1.430±0.149)×10-3 mm2/s, (P<0.001)]. The area under the receiver operating characteristic curve was 0.805±0.058 (P<0.001) for ADC. With a cut-off value of 1.317×10-3 mm2/s, ADC achieved a sensitivity of 75% and a specificity of 81.5% for the differential diagnosis of BA and non-BA. In the BA group, the ADC value was significantly correlated with fibrotic stage. Further analysis showed that the ADC value of stage F0 was significantly higher than that of stages F1, F2, F3 and F4, whereas there were no significant differences among stages F1, F2, F3 and F4.ConclusionHepatic ADC measured with DTI can be used as an adjunct to other noninvasive imaging methods in the differential diagnosis of BA and non-BA. ADC was helpful in detecting liver fibrosis but not in differentiating the fibrotic grades.
| S-EPMC5167545 | biostudies-literature
Project description:ObjectiveCholestasis predisposes to fat-soluble vitamin (FSV) deficiencies. A liquid multiple FSV preparation made with tocopheryl polyethylene glycol-1000 succinate (TPGS) is frequently used in infants with biliary atresia (BA) because of ease of administration and presumed efficacy. In this prospective multicenter study, we assessed the prevalence of FSV deficiency in infants with BA who received this FSV/TPGS preparation.MethodsInfants received FSV/TPGS coadministered with additional vitamin K as routine clinical care in a randomized double-blinded, placebo-controlled trial of corticosteroid therapy after hepatoportoenterostomy (HPE) for BA (identifier NCT 00294684). Levels of FSV, retinol binding protein, total serum lipids, and total bilirubin (TB) were measured 1, 3, and 6 months after HPE.ResultsNinety-two infants with BA were enrolled in this study. Biochemical evidence of FSV insufficiency was common at all time points for vitamin A (29%-36% of patients), vitamin D (21%-37%), vitamin K (10%-22%), and vitamin E (16%-18%). Vitamin levels were inversely correlated with serum TB levels. Biochemical FSV insufficiency was much more common (15%-100% for the different vitamins) in infants whose TB was ≥2 mg/dL. At 3 and 6 months post HPE, only 3 of 24 and 0 of 23 infants, respectively, with TB >2 mg/dL were sufficient in all FSV.ConclusionsBiochemical FSV insufficiency is commonly observed in infants with BA and persistent cholestasis despite administration of a TPGS containing liquid multiple FSV preparation. Individual vitamin supplementation and careful monitoring are warranted in infants with BA, especially those with TB >2 mg/dL.
| S-EPMC3428752 | biostudies-literature
Project description:Biliary atresia (BA) is characterized by the inflammation and obstruction of the extrahepatic bile ducts (EHBDs) in newborn infants. SOX17 is a master regulator of fetal EHBD formation. In mouse Sox17+/- BA models, SOX17 reduction causes cell-autonomous epithelial shedding together with the ectopic appearance of SOX9-positive cystic duct-like epithelia in the gallbladder walls, resulting in BA-like symptoms during the perinatal period. However, the similarities with human BA gallbladders are still unclear. In the present study, we conducted phenotypic analysis of Sox17+/- BA neonate mice, in order to compare with the gallbladder wall phenotype of human BA infants. The most characteristic phenotype of the Sox17+/- BA gallbladders is the ectopic appearance of SOX9-positive peribiliary glands (PBGs), so-called pseudopyloric glands (PPGs). Next, we examined SOX17/SOX9 expression profiles of human gallbladders in 13 BA infants. Among them, five BA cases showed a loss or drastic reduction of SOX17-positive signals throughout the whole region of gallbladder epithelia (SOX17-low group). Even in the remaining eight gallbladders (SOX17-high group), the epithelial cells near the decidual sites were frequently reduced in the SOX17-positive signal intensity. Most interestingly, the most characteristic phenotype of human BA gallbladders is the increased density of PBG/PPG-like glands in the gallbladder body, especially near the epithelial decidual site, indicating that PBG/PPG formation is a common phenotype between human BA and mouse Sox17+/- BA gallbladders. These findings provide the first evidence of the potential contribution of SOX17 reduction and PBG/PPG formation to the early pathogenesis of human BA gallbladders.This article has an associated First Person interview with the joint first authors of the paper.
| S-EPMC7132780 | biostudies-literature