Biliary Atresia – emerging diagnostic and therapy opportunities⁎
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ABSTRACT:
SUBMITTER: Lendahl U
PROVIDER: S-EPMC8604670 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The diagnosis of biliary atresia (BA) remains a clinical challenge because affected infants have signs, symptoms, and serum liver biochemistry that are also seen in those with other causes of neonatal cholestasis (non-BA). However, an early diagnosis and prompt surgical treatment are required to improve clinical outcome. Recently, the relative abundance of serum matrix metalloproteinase-7 (MMP-7) was suggested to have discriminatory features for infants with BA. To test the hypothesis that elevated serum concentration of MMP-7 is highly diagnostic for BA, we determined the normal serum concentration of MMP-7 in healthy control infants, and then in 135 consecutive infants being evaluated for cholestasis. The median concentration for MMP-7 was 2.86 ng/mL (interquartile range, IQR: 1.32-5.32) in normal controls, 11.47 ng/mL (IQR: 8.54-24.55) for non-BA, and 121.1 ng/mL (IQR: 85.42-224.4) for BA (P < 0.0001). The area under the curve of MMP-7 for the diagnosis of BA was 0.9900 with a cutoff value of 52.85 ng/mL; the diagnostic sensitivity and specificity were 98.67% and 95.00%, respectively, with a negative predictive value of 98.28%. Conclusion: Serum MMP-7 assay has high sensitivity and specificity to differentiate BA from other neonatal cholestasis, and may be a reliable biomarker for BA.
| S-EPMC6519383 | 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: Biliary atresia (BA) is a devastating pediatric liver disease. Early diagnosis is important for timely intervention and better prognosis. Using clinical parameters for non-invasive and efficient BA diagnosis, we aimed to establish an artificial neural network (ANN). Methods: A total of 2,384 obstructive jaundice patients from 2012 to 2017 and their 137 clinical parameters were screened for eligibility. A standard binary classification feed-forward ANN was employed. The network was trained and validated for accuracy. Gamma-glutamyl transpeptidase (GGT) level was used as an independent predictor and a comparison to assess the network effectiveness. Results: We included 46 parameters and 1,452 patients for ANN modeling. Total bilirubin, direct bilirubin, and GGT were the most significant indicators. The network consisted of an input layer, 3 hidden layers with 12 neurons each, and an output layer. The network showed good predictive property with a high area under curve (AUC) (0.967, sensitivity 97.2% and specificity 91.0%). Five-fold cross validation showed the mean accuracy for training data of 93.2% and for validation data of 88.6%. Conclusions: The high accuracy and efficiency demonstrated by the ANN model is promising in the noninvasive diagnosis of BA and could be considered as in a low-cost and independent expert diagnosis system.
| S-EPMC7438882 | biostudies-literature
Project description:BackgroundBiliary atresia (BA) is a severe inflammatory obliterative cholangiopathy of infancy that requires early diagnosis and prompt surgical intervention. In this study, we aimed to obtain comprehensive evidence on the diagnostic performance of liver stiffness measurement by ultrasound elastography in the detection of BA through a meta-analysis.MethodsThe PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched for studies that investigated the diagnostic performance of ultrasound elastography in the detection of BA up to January 10, 2022. In this study, in order to summarize the diagnostic performance of ultrasound elastography, the summary receiver operating characteristic (SROC) modeling was constructed. Heterogeneity was estimated with the I 2 statistic. Multiple subgroup analyses were also performed.ResultsFourteen studies from eleven articles, including 774 BA patients, 850 non-BA patients, and 173 controls were included in the present meta-analysis. The summary sensitivity and specificity of ultrasound elastography for liver stiffness were 85% [95% confidence interval (CI): 79-89%] and 82% (95% CI: 73-88%) with the I 2 value of 82.90 and 84.33%, respectively. The area under the SROC curve (AUROC) using ultrasound elastography for diagnosing BA was 0.90 (95% CI: 0.87-0.92). In addition, a subgroup analysis of 9 two-dimensional shear wave elastography studies was also performed. Subgroup analysis revealed that the summary sensitivity and specificity were 85% (95% CI: 77-91%) and 79% (95% CI: 71-86%), respectively, and the summary AUROC was 0.89 (95% CI: 0.86-0.92).ConclusionsUltrasound elastography exhibits good diagnostic accuracy for BA and can be served as a non-invasive tool to facilitate the differential diagnosis of BA.
| S-EPMC9643747 | biostudies-literature
Project description:Aim:Increasing evidence indicates that hepatic subcapsular flow (HSF) can serve as a noninvasive ultrasonographic marker for the early diagnosis of biliary atresia (BA). However, results regarding its diagnostic accuracy are inconsistent and inconclusive. We conducted this meta-analysis with an aim to systematically evaluate the diagnostic value of HSF in predicting BA. Methods:A comprehensive literature search of four databases was conducted to identify the eligible studies. All analyses were performed using STATA 12.0. Results:Nine studies from eight articles containing 368 patients and 469 controls were included in our meta-analysis. Briefly, the values for pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.95 (95% CI 0.88-0.98), 0.92 (95% CI 0.85-0.96), 11.6 (95% CI 6.3-21.5), 0.06 (95% CI 0.02-0.14), 201 (95% CI 59-689), and 0.98 (95% CI 0.96-0.99), respectively. Additionally, metaregression along with subgroup analysis based on various covariates revealed the potential sources of heterogeneity and the detailed diagnostic value in each subgroup. Conclusion:Our meta-analysis showed that HSF assay could provide high accuracy in predicting BA patients and non-BA individuals. However, further studies with better design and larger sample size are required to support the results of the present study.
| S-EPMC7072104 | 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:AbstractThe diagnosis of biliary atresia (BA) remains a clinical challenge, reliable biomarkers that can easily distinguish BA and other forms of intrahepatic cholestasis (IC) are urgently needed.Differentially expressed genes were identified by R software. The least absolute shrinkage and selection operator regression and support vector machine algorithms were used to filter the diagnostic biomarkers of BA. The candidate biomarkers were further validated in another independent cohort of patients with BA and IC. Then CIBERSORT was used for estimating the fractions of immune cell types in BA. Gene set enrichment analyses were conducted and the correlation between diagnostic genes and immune cells was analyzed.A total of 419 differentially expressed genes in BA were detected and 2 genes (secreted phosphoprotein 1 [SPP1] and ankyrin repeat domain [ANKRD1]) among them were selected as diagnostic biomarkers. The SPP1 yielded an area under the curve (AUC) value of 0.798 (95% confidence interval [CI]: 0.742-0.854) to distinguish patients with BA from those with IC, and ANKRD1 exhibited AUC values of 0.686 (95% CI: 0.616-0.754) in discriminating BA patients and those with IC. Further integrating them into one variable resulted in a higher AUC of 0.830 (95% CI: 0.777-0.879). The regulatory T cells, M2 macrophages cells, CD4 memory T cells, and dendritic cells may be involved in the BA process. The ANKRD1 and SPP1 was negatively correlated with regulatory T cells.In conclusion, the ANKRD1 and SPP1 could potentially provide extra guidance in discriminating BA and IC. The immune cell infiltration of BA gives us new insight to explore its pathogenesis.
| S-EPMC8678012 | biostudies-literature
Project description:The diagnosis of biliary atresia is still terrifying at the 3rd decade of the 21st century. In a department of neonatal intensive care unit, parents and physicians face a challenge with a jaundiced baby, who may or may not have a surgically correctable hepatopathy. The approach has been systematically evaluated, but the etiology remains ambiguous. The study of families with recurrent biliary atresia has been undertaken at a molecular level. The primary interest with this disease is to identify the etiology and change the treatment from symptomatic to curative. The occurrence of this obstructive cholangio-hepatopathy in well-known genetic syndromes has suggested just coincidental finding, but the reality can be more intriguing because some of these diseases may have some interaction with the development of the intrahepatic biliary system. Several genes have been investigated thoroughly, including ADD3 and GPC1 shifting the interest from viruses to genetics. In this review, the intriguing complexities of this hepatobiliary disease are highlighted.
| S-EPMC8870870 | biostudies-literature
Project description:The treatment of biliary atresia (BA) is predominantly surgical with firstly an attempt at restoration of bile flow from the native liver by wide excision of the obstructed, obliterated extrahepatic biliary tree to the level of the porta hepatis and a portoenterostomy using a long Roux loop-Kasai portoenterostomy (KPE). Liver transplantation is reserved for those that fail this and for those where surgery is considered futile for reasons of age or stage of disease. As the aetiology of BA remains ill-defined, so adjuvant treatment has been largely based on pragmatism, trial and error. Systematic analysis of the few randomized placebo-controlled trial data and less well-controlled cohort studies have suggested benefit from post-operative high-dose steroids and ursodeoxycholic acid (UDCA) while the benefit of long-term prophylactic antibiotics, bile acid sequestrants (e.g., colestyramine) or probiotics remains unproven. Newer modalities such as antiviral therapy (AVT), immunoglobulin, FXR agonists (e.g., obeticholic acid), ileal bile acid transporter (IBAT) antagonists (e.g., maralixibat) remain unproven. This article reviews the current evidence for the efficacy of adjuvant medical therapy in BA.
| S-EPMC7347763 | biostudies-literature
Project description:In patients with biliary atresia (BA), the extent of intrahepatic biliary fibrosis negatively correlates with successful surgical bypass of the congenital cholangiopathy as well as subsequent transplant-free survival. We recently linked the expansion of a population of prominin-1 (Prom1)-expressing hepatic progenitor cells to biliary fibrogenesis. Herein, we hypothesized that Prom1-expressing progenitor cells play a role in BA-associated fibrosis. Rhesus rotavirus (RRV)-mediated experimental BA was induced in newborn mice homozygous for the transgene Prom1cre-ert2-nlacz , which was knocked in to the Prom1 gene locus, thus creating functional Prom1 knockout (KO) mice, and their wildtype (WT) littermates. Clinical data and tissue samples from BA infants from the Childhood Liver Disease Research Consortium were analyzed. Extrahepatic biliary obliteration was present in both WT and KO mice; there was no difference in serum total bilirubin (TBili) levels. The intrahepatic periportal expansion of the PROM1pos cell population, typically observed in RRV-induced BA, was absent in KO mice. RRV-treated KO mice demonstrated significantly fewer cytokeratin-19 (CK19)-positive ductular reactions (P = 0.0004) and significantly less periportal collagen deposition (P = 0.0001) compared with WT. RRV-treated KO mice expressed significantly less integrin-β6, which encodes a key biliary-specific subunit of a transforming growth factor (TGF) β activator (P = 0.0004). Infants with successful biliary drainage (Tbili ≤1.5 mg/dL within 3 months postoperatively), which is highly predictive of increased transplant-free survival, expressed significantly less hepatic PROM1, CK19, and COLLAGEN-1α compared with those with TBili >1.5 (P < 0.05). Conclusion: Prom1 plays an important role in biliary fibrogenesis, in part through integrin-mediated TGF pathway activation.
| S-EPMC6541523 | biostudies-literature