Explore the vast range of titles available.

Biliary atresia (BA) is a neonatal cholangiopathy that often progresses to cirrhosis despite timely Kasai portoenterostomy (KPE), and prognostic biomarkers remain undefined. Given its role in adult cholestasis, we evaluated human beta-defensin-1 (hBD1) in murine and human BA for associations with disease progression and outcome. This study analyzed hepatic expression of hBD1 and TGF-ß by qRT-PCR in BA at KPE ( n  = 36) and liver transplantation (LT, n  = 44), and compared with normal ( n  = 15) and cholestatic disease controls ( n  = 36). Serum hBD1 was measured by ELISA in BA ( n  = 23) and healthy infants ( n  = 11). Murine BD1 was assessed in a Rhesus rotavirus (RRV) BA model. BD1 was found to be upregulated in murine and human BA, with higher expression at LT than at KPE. Hepatic hBD1 correlated with TGF-ß (R 2 = 0.21), Ishak fibrosis score (R 2 = 0.36), and serum bile acids (R 2 = 0.23). Serum hBD1 was elevated in BA versus controls. Elevated hBD1 at KPE predicted persistent jaundice and reduced native liver survival (X 2 = 9.5), with ROC analysis showing good discrimination for failure of jaundice clearance at 3 months post-KPE (AUC 0.81 for liver and 0.87 for serum). Thus, hBD1 may serve as a negative predictor of jaundice clearance and native liver survival at the time of KPE.

Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000–20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50–75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60–75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.Biliary atresia is a devastating paediatric inflammatory disease of the bile ducts that restricts flow of bile from the liver. In this Primer, Tam et al. summarize current research on biliary atresia, covering its epidemiology, mechanisms, diagnosis and management, quality of life, and future directions for research.

Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have fatal consequences, when not treated in a timely manner. It is the most common indication of pediatric liver transplantation worldwide and the development of new therapies, to alleviate the need of surgical intervention, has been hindered due to its complexity and lack of understanding of the disease pathogenesis. For that reason, significant efforts have been made toward the development of experimental models and strategies to understand the etiology and disease mechanisms and to identify novel therapeutic targets. The only characterized model of BA, using a Rhesus Rotavirus Type A infection of newborn BALB/c mice, has enabled the identification of key cellular and molecular targets involved in epithelial injury and duct obstruction. However, the establishment of an unleashed chronic inflammation followed by a progressive pathological wound healing process remains poorly understood. Like T cells, macrophages can adopt different functional programs [pro-inflammatory (M1) and resolutive (M2) macrophages] and influence the surrounding cytokine environment and the cell response to injury. In this review, we provide an overview of the immunopathogenesis of BA, discuss the implication of innate immunity in the disease pathogenesis and highlight their suitability as therapeutic targets.

Biliary atresia (BA) is characterized by rapidly progressive hepatic fibrosis with unclear mechanisms. This study aimed to investigate the role of matrix metalloproteinase 7 (MMP7) in this process and its potential for targeted therapy. Serum and liver tissue samples from BA patients were collected to analyze the correlation between MMP7 and liver fibrosis. Gene set enrichment analysis (GSEA) based on GEO datasets was performed to explore MMP7-associated biological processes. Clinical samples were further used to examine the relationship between MMP7 and epithelial–mesenchymal transition (EMT) in biliary epithelial cells (BECs). The effects of MMP7 on BECs and the underlying mechanisms were validated in vitro. Finally, the profibrotic effects and therapeutic potential of MMP7 were explored in chronic BA mice. Results showed that MMP7 was positively correlated with liver fibrosis in BA patients. GSEA revealed that MMP7 was most significantly associated with EMT, which was further validated by EMT scoring in intrahepatic BECs of patients. In vitro, MMP7 induced EMT in BECs by cleaving E-cadherin and promoting β-catenin nuclear translocation. Blockade of MMP7 alleviated EMT and liver fibrosis in BA mice. In conclusion, MMP7 promotes liver fibrosis in BA by driving EMT via the E-cadherin/β-catenin pathway, and targeting MMP7 demonstrates anti-fibrotic effects.

Background Liver fibrosis in biliary atresia (BA) progresses rapidly and has distinct characteristics; however, current studies have not identified effective prevention or treatment strategies to address this issue. Methods BA liver tissues with different degrees of liver fibrosis ( n  = 4), liver tissues of choledochal cyst ( n  = 2), and liver tissues of the normal control (NC) group ( n  = 2) were selected. Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and Mendelian randomization (MR) were integrated for analysis. The clinical data of the sequenced samples, GSE176189 and GSE122340, were used to verify the results. Results The level of inflammation in the severe fibrosis group was significantly higher than that in the mild fibrosis group (adjusted P  < 0.0001). The results of MR showed that CCL2 had a causal relationship with BA (odds ratio (OR) = 1.70, confidence interval (CI): 1.19 to 2.43, P =  0.004, P false discovery rate (FDR)  = 0.117). The expression level of CCL2 in BA was significantly higher than that in NC ( P  < 0.001), and its expression level increased with the progression of fibrosis, mainly expressed in the central region of fibrosis. The pseudo-timing results of scRNA-seq showed that CXCL10 + intermediate monocytes may play a significant role in the early stages of fibrosis progression, while TREM2 + scar-associated macrophages may be more active in the later stages. OLR1 + M2 macrophages may represent a transitional state between the two cell types described above. The expression of CCL2 in these three cell subtypes was also higher than that in the others. CCL2 + monocyte-macrophage cells showed the strongest correlation with gamma-glutamyl transferase ( R  = 0.88, P  = 0.0072). The interactions between CCL2 + monocyte-macrophage cells and hepatocytes, hepatic stellate cells, and bile duct epithelial cells were significantly upregulated in BA ( P  < 0.01). These interactions were more prominent in mild fibrosis than severe fibrosis ( P  < 0.01). Conclusions Severe liver fibrosis in BA is associated with a pronounced inflammatory response. CCL2 may be crucial in the occurrence and progression of liver fibrosis in BA. Targeting CCL2 + monocyte-macrophage cells by reducing their proportion or interaction with liver fibrosis-related cells may provide a potential treatment for liver fibrosis in BA.

Key Points Biliary atresia is an inflammatory and fibrosing cholangiopathy of infancy caused by viruses, environmental toxins and targeted epithelial injury that obstructs extrahepatic bile ducts and rapidly progresses to end-stage cirrhosis Precise clinical phenotyping classifies patients into nonsyndromic and embryonic forms, and into cyst-associated and cytomegalovirus-associated variants, which might have different disease pathologies Liver tissue scoring for inflammation and fibrosis by histological features and gene expression profiles identifies different stages of disease at diagnosis Analyses of human livers and models of experimental biliary atresia suggest that a type 1 immune response has a key role in the pathogenesis of bile duct injury and obstruction The expression of type 2 cytokines promote cholangiocyte proliferation in extrahepatic bile ducts and hepatic fibrosis Clinical, histological and molecular variability of disease at presentation form a strong rationale for future trials that take into consideration the predominant biological features of affected infants Biliary atresia is a severe cholangiopathy with a poorly defined pathogenesis and treatment strategy that leads to end-stage cirrhosis in most children. The authors of this Review bring together the most up-to-date understanding of the pathogenesis of biliary atresia, how environmental and genetic factors create various clinical phenotypes and provide insights into future clinical trial design. Biliary atresia is a severe cholangiopathy of early infancy that destroys extrahepatic bile ducts and disrupts bile flow. With a poorly defined disease pathogenesis, treatment consists of the surgical removal of duct remnants followed by hepatoportoenterostomy. Although this approach can improve the short-term outcome, the liver disease progresses to end-stage cirrhosis in most children. Further improvement in outcome will require a greater understanding of the mechanisms of biliary injury and fibrosis. Here, we review progress in the field, which has been fuelled by collaborative studies in larger patient cohorts and the development of cell culture and animal model systems to directly test hypotheses. Advances include the identification of phenotypic subgroups and stages of disease based on clinical, pathological and molecular features. Stronger evidence exists for viruses, toxins and gene sequence variations in the aetiology of biliary atresia, triggering a proinflammatory response that injures the duct epithelium and produces a rapidly progressive cholangiopathy. The immune response also activates the expression of type 2 cytokines that promote epithelial cell proliferation and extracellular matrix production by nonparenchymal cells. These advances provide insight into phenotype variability and might be relevant to the design of personalized trials to block progression of liver disease.

Background Biliary atresia (BA) is a rare condition of unknown origin in newborns with jaundice. In BA bile ducts are non-functional, causing neonatal cholestasis and following liver fibrosis and failure. Methods This retrospective study included liver biopsies of 14 infants with BA aged [mean ± SD] 63 ± 23 days. Patients were grouped according to the clinical course (jaundice-free vs recurrent jaundice vs required liver transplantation or liver fibrosis (Ishak fibrosis score)) and followed for 1.61–5.64 years (mean 4.03). Transcriptome profiles were assessed using a panel of 768 fibrosis-specific genes, reanalyzed via qRT-PCR, and confirmed via immunostaining. Plasma from an additional 30 BA infants and 10 age-matched controls were used for amyloid precursor protein (APP) quantification by ELISA. Results Different clinical outcome groups showed a homogeneous mRNA expression. Altered amyloid-metabolism-related gene expression was found between cases with Ishak fibrosis score greater than 4. Immunostaining confirmed a distinct presence of APP in the livers of all BA subjects. APP plasma levels were higher in BA than in age-matched controls and correlated with the histological fibrosis grade. Conclusions These results suggest that amyloidosis may contribute to BA and liver fibrosis, indicating that APP could serve as a potential liquid biomarker for these conditions. Impact Biliary atresia patients with higher fibrosis scores according to Ishak have higher hepatic expression of amyloid-related genes while amyloid precursor protein accumulates in the liver and increases in the circulation. After a recent study revealed beta-amyloid deposition as a mechanism potentially involved in biliary atresia, we were able to correlate amyloid-metabolism-related transcript levels as well as amyloid precursor protein tissue and plasma levels with the degree of hepatic fibrosis. These findings suggest that amyloid precursor protein is a fibrosis marker in infants with biliary atresia, reinforcing the role of amyloid metabolism in the pathogenesis of this serious disease.

It is still challenging to make accurate diagnosis of biliary atresia (BA) with sonographic gallbladder images particularly in rural area without relevant expertise. To help diagnose BA based on sonographic gallbladder images, an ensembled deep learning model is developed. The model yields a patient-level sensitivity 93.1% and specificity 93.9% [with areas under the receiver operating characteristic curve of 0.956 (95% confidence interval: 0.928-0.977)] on the multi-center external validation dataset, superior to that of human experts. With the help of the model, the performances of human experts with various levels are improved. Moreover, the diagnosis based on smartphone photos of sonographic gallbladder images through a smartphone app and based on video sequences by the model still yields expert-level performances. The ensembled deep learning model in this study provides a solution to help radiologists improve the diagnosis of BA in various clinical application scenarios, particularly in rural and undeveloped regions with limited expertise. It is still challenging to make accurate diagnosis of biliary atresia (BA) with sonographic gallbladder images particularly in rural areas without relevant expertise. Here, the authors develop a diagnostic deep learning model which favourable performance in comparison with human experts in multi-center external validation.

Injury to the biliary epithelium triggers inflammation and fibrosis, which can result in severe liver diseases and may progress to malignancy. Development of a type 1 immune response has been linked to biliary injury pathogenesis; however, a subset of patients with biliary atresia, the most common childhood cholangiopathy, exhibit increased levels of Th2-promoting cytokines. The relationship among different inflammatory drivers, epithelial repair, and carcinogenesis remains unclear. Here, we determined that the Th2-activating cytokine IL-33 is elevated in biliary atresia patient serum and in the livers and bile ducts of mice with experimental biliary atresia. Administration of IL-33 to WT mice markedly increased cholangiocyte proliferation and promoted sustained cell growth, resulting in dramatic and rapid enlargement of extrahepatic bile ducts. The IL-33-dependent proliferative response was mediated by an increase in the number of type 2 innate lymphoid cells (ILC2s), which released high levels of IL-13 that in turn promoted cholangiocyte hyperplasia. Induction of the IL-33/ILC2/IL-13 circuit in a murine biliary injury model promoted epithelial repair; however, induction of this circuit in mice with constitutive activation of AKT and YAP in bile ducts induced cholangiocarcinoma with liver metastases. These findings reveal that IL-33 mediates epithelial proliferation and suggest that activation of IL-33/ILC2/IL-13 may improve biliary repair and disruption of the circuit may block progression of carcinogenesis.

Biliary atresia is a rare disease of infancy, which has changed within 30 years from being fatal to being a disorder for which effective palliative surgery or curative liver transplantation, or both, are available. Good outcomes for infants depend on early referral and timely Kasai portoenterostomy, and thus a high index of suspicion is needed for investigation of infants with persistent jaundice. In centres with much experience of treating this disorder, up to 60% of children will achieve biliary drainage after Kasai portoenterostomy and will have serum bilirubin within the normal range within 6 months. 80% of children who attain satisfactory biliary drainage will reach adolescence with a good quality of life without undergoing liver transplantation. Although much is known about management of biliary atresia, many aspects are poorly understood, including its pathogenesis. Several hypotheses exist, implicating genetic predisposition and dysregulation of immunity, but the cause is probably multifactorial, with obliterative extrahepatic cholangiopathy as the common endpoint. Researchers are focused on identification of relevant genetic and immune factors and understanding serum and hepatic factors that drive liver fibrosis after Kasai portoenterostomy. These factors might become therapeutic targets to halt the inevitable development of cirrhosis and need for liver transplantation.