cell therapies

2026-08-07 | Outcomes of Pediatric ABO-Incompatible Living Donor Liver Transplantation: A Retrospective Single-Centre Experience from India.

ABO incompatible liver transplant (ABOi-LT) is an essential alternative to blood-group-compatible liver transplant (LT) in children, and there is limited experience with this, especially from the developing world. The current analysis focuses on our experience of ABOi-LT in children. A retrospective analysis of all children undergoing ABOi-LT at our centre from January 2011 to February 2024 was performed. Their clinical profile, desensitisation protocol, post-transplant complications, patient and graft survival were analysed. We performed 35 (5%) ABOi-LTs during the above-mentioned time period. The median (interquartile range [IQR]) age at ABOi-LT was 15 (10-72) months, and the commonest aetiology was biliary atresia in 22 (63%) patients. Nineteen (54%) patients were below 18 months of age. Pre-LT plasmapheresis was offered to 24 (64%) patients, and 24 (64%) received rituximab. In children less than 18 months of age, 8 (42%) received pre-LT rituximab. None of the patients had major infections secondary to rituximab in the pre-LT period. Post-LT plasmapheresis was offered to 20 (57%) patients and 5 (15%) required immunoadsorption for persistently high antibody titres. Acute T-cell-mediated rejection was seen in 6 (17%) and 2 (5.5%) patients developed antibody-mediated rejection (AMR). No patients had hepatic artery thrombosis, anastomotic biliary strictures or bile leaks and 1 (2.7%) had chronic portal vein thrombosis. The median (IQR) duration of hospital stay was 16 (14-19.5) days. After a median follow-up of 24 months, overall survival was 34 (97%). Two patients with AMR were successfully treated and have normal graft function on follow-up. Excellent outcomes post-ABOi-LT can be achieved in children by using effective desensitisation protocols.

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2026-08-03 | Robotic-assisted Kasai portoenterostomy in biliary atresia: A case report and technical considerations

Biliary atresia is a rare and fatal cholestatic disorder characterized by progressive obliteration of the extrahepatic and intrahepatic bile ducts, typically presenting during the neonatal period. Ethology remains uncertain, although immune-mediated injury, viral triggers, and developmental anomalies have been implicated. Kasai portoenterostomy is the primary treatment for biliary atresia, with optimal outcomes achieved when performed within the first 60 days of life. Despite early intervention, many patients experience progressive cirrhosis and portal hypertension. Liver transplantation remains the definitive therapeutic option. The timing of liver transplantation in early infancy remains controversial. A primary concern is increased mortality associated with the inability to administer live childhood vaccines to infants transplanted before six months of age, thereby elevating the risk of subsequent life-threatening infections. A 6-kg infant was diagnosed with biliary atresia and underwent surgery 84 days of age. Robotic-assisted Kasai portoenterostomy was performed to maintain bile flow until transplantation and to minimize adhesion formation, both of which are beneficial for subsequent transplantation. This report presents the technical aspects of the procedure.

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2026-07-27 | [Laparoscopic Kasai portoenterostomy in children with biliary atresia in Central Asia: outcomes, learning curve and risk factors].

To evaluate technical feasibility, early clinical outcomes, learning curve, and risk factors affecting native liver preservation after laparoscopic Kasai portoenterostomy in children with biliary atresia in Uzbekistan. A retrospective single-center study involved 33 patients with BA who underwent laparoscopic Kasai portoenterostomy between July 2022 and January 2025. Demographic data, disease characteristics, native liver survival rates, incidence of cholangitis, mortality, and the need for subsequent transplantation were assessed. Data analysis included logistic regression, CUSUM, and Kaplan-Meier methods. The median age was 69 (27-148) days. Overall survival with native liver was 54.5%, patient survival - 84.8%. The incidence of postoperative cholangitis was 51.5%, and this event was an independent prognostic factor of native liver loss (odds ratio [OR] 0.035; p=0.010). The learning curve stabilized after 16-17 cases that was accompanied by shorter surgery time and better technical performance. Conversion to open surgery was required in only one case (3%). Laparoscopic Kasai portoenterostomy is a technically feasible and effective alternative to open Kasai procedure with comparable survival rates with native liver. High incidence of cholangitis remains an important issue requiring optimization of postoperative management. In the absence of pediatric liver transplantation in Uzbekistan, improving surgical techniques and preventing cholangitis are essential to improve long-term outcomes.

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2026-07-21 | Extracellular vesicles in perinatal conditions: A minimally invasive approach to regenerative medicine.

Extracellular vesicles (EVs) are lipid bilayer-delimited nanoparticles released by cells to act as mediators of intercellular communication during organ development, injury, and repair. EVs carry cargo (bioactive proteins, lipids, and nucleic acids) that reflects the status of the parent cell and is transferred to recipient cells to regulate biological processes, such as inflammation, immune responses, and tissue regeneration. These properties have made EVs promising tools for investigating disease pathogenesis, improving diagnostic and prognostic accuracy, and developing cell-free regenerative therapies for conditions characterized by dysregulation of multiple biological pathways. EVs are particularly relevant in diseases that affect the pediatric population where pathogenesis often remains poorly understood, access to affected tissues is limited, and treatment options are frequently inadequate. This review summarizes current evidence on EV applications in fetal and neonatal disorders, including necrotizing enterocolitis, congenital diaphragmatic hernia, and bronchopulmonary dysplasia, and highlights emerging data in biliary atresia, spina bifida, short bowel syndrome, and Hirschsprung's disease. In this age group, human milk and amniotic fluid represent particularly attractive biologically accessible sources of EVs, combining therapeutic potential with feasibility of clinical application. Building on robust preclinical evidence, the field is now advancing toward clinical translation, but several aspects still need to be addressed such as cargo heterogeneity, scalability of production, dosing, biodistribution, safety, and regulatory standardization. Herein, we discuss the translational challenges and future directions that will shape the clinical application of EVs in perinatal conditions.

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2026-07-06 | Mesenchymal stem cells in intrahepatic and extrahepatic biliary diseases: mechanisms and therapeutic applications.

Mesenchymal stem cells (MSCs) have emerged as promising therapeutic candidates for a wide range of intrahepatic and extrahepatic biliary diseases. However, their clinical application remains limited by an incomplete understanding of underlying mechanisms and heterogeneous therapeutic outcomes. This review provides a comprehensive overview of recent advances in MSC-based therapies for biliary system diseases, including primary biliary cholangitis, intrahepatic biliary fibrosis and cirrhosis, biliary atresia, primary sclerosing cholangitis, and cholangiocarcinoma. We summarize both preclinical and clinical evidence and focus on key therapeutic mechanisms, including immunomodulation, antifibrotic activity, regulation of bile acid metabolism, and protection of biliary epithelial cells.

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small molecules

2026-08-15 | Hepatic methionine-cycle dysregulation is associated with immune-inflammatory and fibrogenic remodeling in biliary atresia.

Biliary atresia (BA) is a progressive fibroinflammatory cholangiopathy leading to liver failure in infancy. The contribution of methionine metabolism to BA remains incompletely defined. This study investigated hepatic methionine-cycle alterations and the potential therapeutic effects of S-adenosylmethionine (SAMe). Public bulk transcriptomic and single-cell RNA sequencing datasets were analyzed to characterize methionine-cycle-related alterations in BA. Selected genes were validated in clinical liver tissues. Methionine-cycle metabolites, oxidative stress indicators, and histopathological changes were assessed in human liver samples. The effects of SAMe were examined in BA-derived liver mononuclear cells (LMNCs) and further evaluated in a rhesus rotavirus-induced BA mouse model using methionine-cycle metabolite quantification, liver transcriptomics, multiplex immunofluorescence, cytokine measurement, oxidative stress assays, and histological analysis. Methionine metabolism-related genes were dysregulated in BA, highlighting alterations in the one-carbon-methionine cycle-transsulfuration axis. Single-cell analysis localized these alterations to both hepatocyte and immune-cell compartments. Human BA liver tissues exhibited methionine-cycle imbalance, with increased methionine, S-adenosylhomocysteine, and homocysteine levels and reduced S-adenosylmethionine levels, accompanied by oxidative stress and fibrogenic responses. SAMe modulated cytokine secretion in BA-derived LMNCs. In BA mice, SAMe partially normalized methionine-cycle metabolite levels, improved hepatic redox status, reduced inflammatory immune infiltration, attenuated cytokine responses, and alleviated early fibrogenic remodeling. Hepatic methionine-cycle dysregulation is a prominent metabolic feature of BA and is associated with oxidative stress, immune-inflammatory alterations, and fibrogenic remodeling. SAMe partially alleviated these abnormalities in ex vivo and animal-model experiments, supporting further investigation of the therapeutic relevance of methionine metabolism in BA.

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2026-08-11 | Biliary atresia-related liver fibrosis

Biliary atresia (BA) is a devastating cholestatic disease of infancy characterized by progressive fibro-obliterative cholangiopathy, which, without timely intervention, inexorably leads to end-stage liver disease and the need for liver transplantation. Hepatic fibrosis constitutes not only the histopathological cornerstone of BA but also the principal determinant of disease trajectory, native liver survival, and long-term outcomes. This review provides a comprehensive synthesis of the current understanding and unmet clinical needs in BA-associated liver fibrosis, systematically addressing three interconnected domains: pathogenesis, diagnostic modalities, and therapeutic strategies. In the pathogenic realm, we dissect the multilayered molecular architecture-from genetic susceptibility loci (including ciliopathy-related PKD1L1, developmental regulators ADD3,GPC1, and immune-modulating polymorphisms) through aberrant cellular activation (biliary epithelial cells undergoing ductular reaction and epithelial-mesenchymal transition, hepatic stellate cells and portal fibroblasts transdifferentiating into myofibroblasts, and immune cells polarizing toward pro-fibrotic phenotypes), to the integrated signaling network of TGF-β/Smad, Wnt/β-catenin, Hippo/YAP, and Notch pathways, further sustained by epigenetic modifications involving DNA methylation, histone remodeling, and non-coding RNAs. In diagnostics, we evaluate conventional ultrasound, emerging shear wave elastography, serum matrix metalloproteinase-7 as a promising biomarker, and risk-stratification algorithms, while critically comparing their strengths and limitations. In therapeutics, we assess the enduring role of Kasai portoenterostomy (KPE), the limitations of current adjunctive therapies, and the evolving landscape of pharmacological interventions-including ileal bile acid transporter inhibitors (odevixibat), farnesoid X receptor agonists (obeticholic acid), eicosapentaenoic acid, and N-acetylcysteine-alongside ongoing clinical trials. We further highlight how single-cell and spatial transcriptomic technologies are revolutionizing our comprehension of cellular heterogeneity and intercellular crosstalk within the fibrotic niche, offering unprecedented opportunities for molecular subtyping and precision medicine. By bridging mechanistic insights with clinical translation, this review provides a conceptual framework to guide future research, improve diagnostic precision, and develop rationally targeted combination therapies for BA-associated liver fibrosis.

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2026-08-07 | Ganciclovir Improves Transplant-Free Liver Survival in Children With Biliary Atresia and Concurrent Cytomegaloviral Infection: A Pilot Study.

To investigate the effect of post-operative ganciclovir therapy on transplant-free liver survival in children with biliary atresia (BA) complicated by cytomegalovirus (CMV) infection, and to propose an intervention mechanism hypothesis based on the 'CMV-hepatic stellate cell-fibrosis-long-term prognosis' pathogenic axis. This retrospective study included children diagnosed with BA complicated by CMV infection at a tertiary children's hospital between January 2017 and October 2023. Patients were divided into a treatment group and a non-treatment group based on whether ganciclovir was administered for ≥ 1 week within 3 months after Kasai portoenterostomy (KPE). All patients had follow-up of at least 2 years by 1 October 2025. Baseline characteristics and clinical outcomes (transplant-free liver survival time and 3-month post-operative jaundice clearance rate) were compared between groups. Kaplan-Meier analysis was used to generate survival curves, and differences were assessed using the Log-Rank test. Evidence from basic and clinical research was integrated to construct a mechanistic hypothesis diagram for CMV-driven hepatic fibrosis and antiviral intervention. A total of 17 children with BA were included, with 6 in the treatment group and 11 in the non-treatment group. Baseline characteristics indicated no significant differences between the two groups in terms of sex, hepatic fibrosis stage, age at surgery, preoperative DBIL and other clinical indicators, demonstrating balanced comparability (p > 0.05). Comparison of clinical outcomes and Kaplan-Meier survival curves showed that transplant-free liver survival time was significantly longer in the treatment group than in the non-treatment group: 1518 (217, 2825) versus 190 (83, 265) days, p = 0.035; the survival curve showed an improving trend (Log-Rank p = 0.087). The 3-month post-operative jaundice clearance rate did not differ significantly between groups (p > 0.05). The mechanistic hypothesis diagram suggested that CMV may activate hepatic stellate cells via multiple pathways, including CCL19/CCR7 and TGF-β, accelerating fibrosis progression, while ganciclovir may block this process. Ganciclovir antiviral therapy may be associated with improved transplant-free liver survival in CMV-positive children with BA, exerting a specific effect on long-term fibrosis progression rather than short-term bile drainage. This clinical observation aligns with the 'CMV-fibrosis-long-term prognosis' pathogenic axis hypothesis and provides preliminary evidence for clinical antiviral treatment.

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2026-08-07 | Hepatoprotective Effects of Imeglimin Are Associated With Preserved Mitochondrial Bioenergetics and Reduced Oxidative Stress in a Murine Cholestasis Model.

Biliary atresia is a cholestatic liver disease that causes persistent inflammation and reduces the hepatic reserve. New therapeutic concepts are crucial to improve native liver survival. We investigated whether imeglimin, a mitochondria-targeting agent, has hepatoprotective effects on cholestatic liver disease using a murine bile duct ligation (BDL) model. BDL was performed in 4-5-week-old mice. After BDL, the mice received intraperitoneal imeglimin or vehicle injections. Sham-operated mice received vehicle. Blood and liver samples were collected on days 7 and 14 for biochemical and histological analysis. Mitochondrial morphology was examined by transmission electron microscopy. Quantitative PCR and immunoblotting were performed for inflammation and mitochondrial stress markers. Metabolomic profiling was conducted using capillary electrophoresis-mass spectrometry. Transcriptome was analyzed by RNA sequencing. Seahorse assays, ATP quantification, and MitoSOX staining were used to evaluate mitochondrial function and oxidative stress. Imeglimin improved survival after BDL, and reduced serum AST, ALT, and bilirubin levels. Tissue fibrosis and Col1a1 and Acta2 expression were attenuated in imeglimin-treated livers. Glycolysis, amino acid metabolism, and mitochondrial electron transport activity were enhanced. Expression of genes associated with mitochondrial function, antioxidant defense, and metabolic regulation was upregulated. Mitochondrial morphology was preserved, and mitochondrial number and size increased. Imeglimin elevated oxygen consumption, extracellular acidification rates, and ATP levels of BDL mice livers, while reducing mitochondrial superoxide and oxidative protein modification by 4-hydroxynonenal. Expression levels of Il1β, Il6, and Tnf decreased. Imeglimin exerted hepatoprotective effects on BDL-operated mice, which are associated with preserved mitochondrial bioenergetic function and reduced oxidative stress.

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2026-07-30 | Impact of bacterial infection on native liver survival in children with cirrhosis due to biliary atresia.

Biliary atresia (BA) is a common cause of cirrhosis in children, and serious bacterial infections may worsen clinical outcomes. To study the characteristics, associated factors, and outcomes of infections in children with cirrhosis secondary to BA. A retrospective cohort study was conducted in children aged <18 years with cirrhosis due to BA between 2014 and 2023. Patients were categorized as having proven/suspected bacterial infection, presumed viral infection, or no documented infection. The clinical characteristics, associated risk factors, predictive models, and native liver survival outcomes, including liver transplantation (LT) and death, were analyzed. Among 150 children, 94 (62.7%) had 222 infection episodes and 249 had infection-related diagnosis. Of the 222 episodes, 143 (64.4%) were classified as proven/suspected bacterial infections; cholangitis was the most common bacterial diagnosis (39.7%). Univariate analysis showed that proven/suspected bacterial infection was associated with higher pediatric end-stage liver disease scores at the first visit and during fever episodes and with higher total and direct bilirubin levels during fever episodes. C-reactive protein (CRP) cutoff of 31 mg/L yielded 75.4% sensitivity, 68.2% specificity, and an area under the receiver operating characteristic curve of 0.80 (95% confidence interval [CI], 0.69-0.90) for distinguishing proven/suspected bacterial from presumed viral infections. Overall, 54% of patients underwent LT, 24% survived with their native liver, 8% died, and 14% were lost to follow-up. After adjustment for disease severity and infection history before referral, proven/suspected bacterial infection was associated with lower native liver survival (adjusted hazard ratio, 1.88; 95% CI, 1.51-2.33). Infections are common in children with cirrhosis due to BA. Serum CRP may help distinguish proven/suspected bacterial from other infections. Bacterial infections were associated with lower native liver survival; therefore, appropriate management and prevention may improve native liver survival.

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antibodies

2026-04-01 | P41 Cost effectiveness of fat soluble vitamin preparations in children with biliary atresia

A course of steroids is also given to reduce coronary artery complications. 1 These are given alongside aspirin for its antiplatelet and anti-inflammatory effects. 1 In refractory cases of Kawasaki disease, infliximab can be used, which prevents inflammation by inhibiting tumour necrosis factor alpha (TNF-alpha). 1 Our patient is a 3-month-old male, presenting with a 5 day history of fever, alongside red and cracked lips, widespread maculopapular rash, prominent left lymph node and red sclera.IVIG was administered on day 7 following a delay due to difficult intravenous (IV) access requiring a midline insertion.Aspirin 10mg/kg 4 times a day was also started at this time alongside methylprednisolone.The patient remained afebrile, however bradycardic and hypertensive (deemed to be because of methylprednisolone).An echocardiogram on day 9 showed coronary artery aneurysms.The patient was then started on prophylactic enoxaparin 0.5mg/kg twice a day (dose as per British National Formulary for Children [BNFc]) and given two doses of IV infliximab 6mg/kg (dose as per health board guideline) one week apart.Due to extreme difficulty in obtaining and maintaining IV access, we looked at adalimumab, another biologic medication which inhibits TNF-alpha, however can be given subcutaneously.It is licensed in children over 2 years old with polyarticular juvenile idiopathic arthritis, with studies utilising a 24mg/m 2 dose. 3ollowing a multi-disciplinary team discussion, involving dosage discussions with Scottish Paediatric and Adolescent Rheumatology Network (SPARN) and colleagues from other areas, adalimumab was started for our patient 6 weeks after first presentation for a 3-to-6-month course.The dose prescribed was 24mg/m 2 , which equated to 9mg.For ease of administration, 10mg every 2 weeks was prescribed, and dispensed as the 20mg in 0.4ml pre-filled syringe of which 0.2ml was decanted and given.The course of treatment was stopped after 5 months due to low adalimumab levels (<0.4microgram/ml) and high adalimumab antibodies (>200AU/ml).Follow up echocardiograms have shown the aneurysms have reduced in size.While it is impossible to tell if our patient benefitted from the adalimumab due to the low levels and high antibodies.This trial shows problem solving by practitioners using a multi-disciplinary approach which opens the possibility for other practitioners to utilise this drug in this context.

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2026-02-16 | Interferon-gamma blocking as a promising treatment for severe liver dysfunction in secondary hemophagocytic lymphohistiocytosis after liver transplantation.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that can occur after solid organ transplantation but remains underrecognized in this setting. The diagnosis is often delayed due to overlapping clinical manifestations with infection, rejection, or malignancy, and management becomes particularly challenging when accompanied by severe hepatic dysfunction. Here, we describe a pediatric patient who developed Epstein-Barr virus (EBV)-associated secondary HLH following liver re-transplantation for biliary atresia. On postoperative Day 10, the patient presented with high fever, cytopenia, hypertriglyceridemia, hypofibrinogenemia, and marked hyperferritinemia, accompanied by rapidly worsening liver injury. Bone marrow biopsy confirmed hemophagocytosis. Given the severe hepatic impairment and persistent inflammation, the patient received three doses of emapalumab (1 mg/kg), a monoclonal antibody blocking interferon-γ, combined with corticosteroids, intravenous immunoglobulin, and antimicrobial prophylaxis. The treatment led to a rapid decline in ferritin levels, reversal of liver dysfunction, and complete clinical recovery without opportunistic infections. The patient has remained stable with normal liver function and negative EBV DNA for over 2 years of follow-up. This case demonstrates that early interferon-γ blockade can safely and effectively reverse HLH-related liver injury after transplantation, offering a promising therapeutic strategy for the management of secondary HLH complicated by severe hepatic dysfunction.

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2026-02-06 | Liver fibrosis in biliary atresia: identification of the key gene EDIL3 via integrated bioinformatics.

Biliary atresia (BA) is one of the most destructive liver and biliary diseases in neonates and is characterized by progressive fibrous inflammatory obstruction of the intrahepatic and extrahepatic bile ducts, ultimately leading to liver fibrosis and liver failure. This study aimed to use integrated bioinformatics methods to identify differentially expressed genes (DEGs) in BA liver tissue, identify key genes, and explore their mechanisms in liver fibrosis. We obtained data from the gene expression omnibus (GEO) dataset GSE122340 [171 BA patients and 7 normal controls (NCs)]. DEGs were screened via the limma package, followed by gene ontology (GO)/kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. A protein-protein interaction (PPI) network was constructed via STRING and Cytoscape, and core genes were selected via the maximum clique centrality (MCC), maximum neighborhood component (MNC), and degree algorithms from the CytoHubba plugin. Further focus was placed on the key gene EGF-like repeats and discoidin I-like domains 3 (EDIL3) through gene set enrichment analysis (GSEA), expression validation, subcellular localization analysis, and clinical tissue sample validation. To minimize batch effects, we performed ComBat correction on the combined gene expression data of GSE122340 and the validation dataset GSE46960 before interdataset comparison. We identified a total of 3706 DEGs, including 2774 upregulated DEGs and 932 downregulated DEGs. The functional enrichment analysis revealed that the DEGs were involved mainly in biological processes such as the cell cycle, DNA replication, and extracellular matrix organization, as well as signaling pathways such as herpes simplex virus infection, phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT), and tumor necrosis factor (TNF). Protein-protein interaction (PPI) network analysis revealed 7 core genes (BRCA1, TOP2A, BRCA2, BUB1B, HSP90AA1, PLK4, and EDIL3), with EDIL3 showing the greatest increase in BA. EDIL3 is located on chromosome 5, and its encoded protein is expressed primarily in the cell membrane and extracellular region. GSEA indicated that high EDIL3 expression was significantly associated with apoptosis and activation of the PI3K-AKT signaling pathway. Clinical sample validation revealed that EDIL3 expression was significantly elevated in BA liver tissue, and its high expression was significantly negatively correlated with the survival rate of patients' native livers. Discoidin I-like domain 3 is a novel gene with a potentially key role in BA-related liver fibrosis, possibly influencing the proliferation and apoptosis of cholangiocytes by regulating the PI3K-AKT signaling pathway, thereby participating in the occurrence and development of liver fibrosis. This study provides new insights into the molecular mechanisms and potential treatment strategies for BA.

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2025-10-30 | Membrane Attack Complex in Biliary Atresia: New Insight for Etiopathogenesis

Purpose Biliary atresia (BA) is the most common cause of neonatal cholestasis (NC); nevertheless, there is a lack of an established etiology. Understanding etiopathogenesis opens the way to adjuvant medical therapy. Membrane attack complex (MAC) is the terminal step in the complement cascade and was found to share in the pathogenesis in some hepatic diseases. So, we aimed to study the MAC immunostaining in liver sections of BA. Methods In this retrospective case-control study, 165 NC cases that underwent liver biopsy from January 2017 to December 2019 in our Institute were checked. Their liver biopsy paraffin blocks were retrieved. Those with insufficient tissue and those without sufficient data within the patients' files were excluded. Finally, 66 cases were included (35 cases of BA and 31 cases of non-BA cholestasis). Clinical, laboratory, and radiological data were registered from the patients' files. All liver sections were examined for MAC by immunostaining using anti-human C5b-9 monoclonal antibody. Results No significant difference was found between the studied groups regarding age (p = 0.452) and sex (p = 0.56). Portal MAC immunostaining was significantly (p = 0.004) associated with BA (54%) than non-BA cholestasis (19%). On the other hand, hepatocellular MAC immunostaining was higher in the non-BA group (p = 0.039). MAC-positive BA cases had significantly higher (p = 0.04) gamma-glutamyl transferase (GGT) than MAC-negative BA. Conclusion MAC is significantly expressed in the portal structures of BA. MAC is a proposed pathophysiologic mechanism for developing the fibro-obliterative process of the biliary tree in BA. Assessment of targeting MAC-mediated pathophysiological process in MAC-positive BA cases is warranted.

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2025-08-26 | Inflammatory factor CCL2 enhances the interaction between monocyte-macrophage cells and liver parenchymal cells to promote liver inflammation and fibrosis in biliary atresia.

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. 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. 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). 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.

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proteins

2026-05-11 | Clinical features of biliary atresia complicated by cytomegalovirus infection and prognostic analysis after Kasai portoenterostomy.

To explore the unique clinical characteristics of biliary atresia (BA) combined with cytomegalovirus (CMV) infection and its impact on early and late prognosis after Kasai portoenterostomy (KPE). This was a retrospective study involving children diagnosed with BA and treated with KPE at the Children's Hospital of Jiangxi Province from January 2017 to October 2023. Based on the presence or absence of CMV infection, the patients were divided into a CMV infection group and a CMV non-infection group. The follow-up period ended on October 1, 2025, with a minimum follow-up duration of >2 years. Data were collected and analyzed, including basic characteristics, core disease features, core laboratory indicators, treatment-related indicators, surgical success within 3 months postoperatively, and native liver survival status after more than 2 years. A total of 70 BA patients were included, with 19 in the CMV infection group and 51 in the CMV non-infection group. In the CMV infection group, 31.6% (6/19) had successful operation, while in the non-infection group, 47.1% (24/51) had successful operation. In the CMV infection group, 78.9% (15/19) experienced native liver failure (NLF), whereas in the non-infection group, 51.0% (26/51) experienced NLF. Differential analysis showed significant differences between the CMV infection group and the non-infection group in terms of age at admission, surgical age, hepatomegaly, surgical weight, GLO levels, AST levels, DBIL levels, gallbladder ejection fraction, postoperative antiviral treatment (P < 0.05), while no significant differences were found in gender, ALB, ALP, ALT, GGT, PLT, splenomegaly, BASM, other associated malformations, BA anatomical classification, early postoperative cholangitis, and total postoperative steroid dose (P > 0.05). Univariate and multivariate analyses showed that CMV infection is an independent risk factor for long-term NLF postoperatively (HR = 1.998, 95% CI:1.008,3.994, P = 0.047), but it had no significant effect on the short-term success rate of KPE (OR = 2.118, 95% CI: 0.644, 6.967, P = 0.217). Kaplan Meier plotter showed that the cumulative incidence of NLF events was significantly higher in the CMV infection group, and the median native liver survival time was significantly shorter (Log-Rank P < 0.05). Although CMV infection does not affect the early success rate of KPE, it is an independent risk factor for long-term NLF, significantly reducing the long-term survival rate of native liver in BA patients. Therefore, in the future, CMV status can be used as an important indicator for risk stratification and long-term follow-up of BA patients.

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2025-07-12 | Impending arterial thrombosis in pediatric liver transplantation: Initial experience with alteplase - A case report.

Early hepatic artery thrombosis is a serious complication following pediatric liver transplantation, often associated with high morbidity and mortality. While surgical revascularization and retransplantation are the standard treatments, thrombolytic therapy has emerged as a potential alternative. However, clinical reports remain limited and standardized protocols are lacking. A 13-month-old infant with biliary atresia post-Kasai procedure underwent living donor liver transplantation. On postoperative day 9, Doppler ultrasound detected signs of impending hepatic artery thrombosis, which was confirmed by computed tomography angiography. The patient was treated with intravenous alteplase at a dose of 0.3 mg/kg/h. After 3.5 hours of infusion, Doppler ultrasound showed improved hepatic artery flow. The infusion was stopped early due to intra-abdominal bleeding, which was managed conservatively. The patient stabilized without surgical intervention and was discharged on postoperative day 32 with stable hepatic artery flow. At six-month follow-up, the hepatic artery remained patent, and the patient was clinically stable. This case supports the effectiveness of alteplase administration in treating incomplete hepatic artery thrombosis, despite its bleeding risk. We recommend lower dose regimens to reduce hemorrhagic complications. However, further studies are needed to optimize the alteplase dosage. Thrombolytic therapy with alteplase is a possible and effective alternative in managing eHAT, particularly where conventional options are not indicated or limited.

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2024-12-24 | Biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics.

EGF-containing fibulin extracellular matrix protein 1 (EFEMP1, also called fibulin-3) is an extracellular matrix protein linked in a genome-wide association study to biliary atresia, a fibrotic disease of the neonatal extrahepatic bile duct. Fibulin-3 is deposited in most tissues and Efemp1 null mice have decreased elastic fibers in visceral fascia; however, fibulin-3 does not have a role in the development of large elastic fibers and its overall function in the extrahepatic bile ducts remains unclear. We used staining and histology to define the amount and organization of key extracellular matrix components in the extrahepatic bile ducts. We also repurposed pressure myography, a technique heretofore applied to the vasculature, to determine the contribution of elastin and fibulin-3 to extrahepatic bile duct mechanics. We examined extrahepatic bile duct structure and mechanics in three models: neonatal vs. adult rat ducts (n = 6 each), elastase-treated adult rat ducts (n = 6-7 each), and Efemp1 +/- vs. wild-type mouse ducts (n = 6 each). We demonstrated that fibulin-3 is expressed in the submucosa of both neonatal and adult mouse, rat and human extrahepatic bile ducts and that, in adult Efemp1 +/- mouse ducts, elastin organization into fibers is decreased by approximately half. Pressure myography showed that Efemp1 +/- ducts have altered mechanics compared to control ducts, with Efemp1 +/- ducts displaying significant stretch compared to controls (p = 0.0376); these changes in stretch are similar to those observed in elastase-treated vs. normal ducts (p <0.0001) and in neonatal ducts vs. adult ducts (p <0.0001). Fibulin-3 has an important role in the formation of elastic fibers and the mechanical properties of the extrahepatic bile duct. This provides functional relevance for the biliary atresia susceptibility gene EFEMP1. The gene EFEMP1 was found via a genome-wide association study to be a susceptibility gene for the neonatal disease biliary atresia. EFEMP1 encodes the protein fibulin-3, which regulates elastic fiber organization in the extrahepatic bile duct (EHBD), the major site of disease in biliary atresia. We showed that neonatal EHBDs as well as mice heterozygous for Efemp1 have decreased numbers of elastic fibers, and that this alters EHBD mechanics. This work is important for understanding the mechanism of biliary atresia, in particular susceptibility to obstruction.

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2024-08-12 | Specific binding sites on Rhesus rotavirus capsid protein dictate the method of endocytosis inducing the murine model of biliary atresia.

Biliary atresia (BA) is the leading indication for pediatric liver transplantation. Rhesus rotavirus (RRV)-induced murine BA develops an obstructive cholangiopathy that mirrors the human disease. We have previously demonstrated the "SRL" motif on RRV's VP4 protein binds to heat shock cognate 70 protein (Hsc70) facilitating entry into cholangiocytes. In this study, we analyzed how binding to Hsc70 affects viral endocytosis, intracellular trafficking, and uniquely activates the signaling pathway that induces murine BA. Inhibition of clathrin- and dynamin-mediated endocytosis in cholangiocytes following infection demonstrated that blocking dynamin decreased the infectivity of RRV, whereas clathrin inhibition had no effect. Blocking early endosome trafficking resulted in decreased viral titers of RRV, whereas late endosome inhibition had no effect. After infection, TLR3 expression and p-NF-κB levels increased in cholangiocytes, leading to increased release of CXCL9 and CXCL10. Infected mice knocked out for TLR3 had decreased levels of CXCL9 and CXCL10, resulting in reduced NK cell numbers. Human patients with BA experienced an increase in CXCL10 levels, suggesting this as a possible pathway leading to biliary obstruction. Viruses that use Hsc70 for cell entry exploit a clathrin-independent pathway and traffic to the early recycling endosome uniquely activating NF-κB through TLR3, leading to the release of CXCL9 and CXCL10 and inducing NK cell recruitment. These results define how the "SRL" peptide found on RRV's VP4 protein modulates viral trafficking, inducing the host response leading to bile duct obstruction.NEW & NOTEWORTHY In this study, we have determined that the presence of the "SRL" peptide on RRV alters its method of endocytosis and intracellular trafficking through viral binding to heat shock cognate 70 protein. This initiates an inflammatory pathway that stimulates the release of cytokines associated with biliary damage and obstruction.

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2023-11-06 | The association of immune-related genes and the potential role of IL10 with biliary atresia.

Biliary atresia (BA) is a severe immune-related disease that is characterized by biliary obstruction and cholestasis. The etiology of BA is unclear, our aim was to explore the relationship between biliary tract inflammation and immune-related genes. We selected 14 SNPs in 13 immune-related genes and investigated their associations with BA by using a large case‒control cohort with a total of 503 cases and 1473 controls from southern China. SNP rs1518111 in interleukin10 (IL10) was identified as associated with BA (P = 5.79E-03; OR: 0.80; 95% CI: 0.68-0.94). The epistatic effects of the following pairwise interactions among these SNPs were associated with BA: signal transducer and activator of transcription 4 (STAT4) and chemokine (C-X-C motif) ligand 3 (CXCL3); STAT4 and damage-regulated autophagy modulator1 (DRAM1); CXCL3 and RAD51 paralog B (RAD51B); and interferon gamma (IFNG) and interleukin26 (IL26). Furthermore, we explored the potential role of IL-10 in the pathogenesis of the neonatal mouse model of BA. IL-10 effectively prevented biliary epithelial cell injury and biliary obstruction in murine BA as well as inhibit the activation of BA-related immune cells. In conclusion, this study provided strong evidence implicating IL10 as a susceptibility gene for BA in the southern Chinese population. This study provided strong evidence implicating IL10 as a susceptibility gene for BA in the southern Chinese population. This study could infer that IL-10 may play a protective role in BA mouse model. We found that four SNPs (rs7574865, rs352038, rs4622329, and rs4902562) have genetic interactions.

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2026-05-14 | LncRNA H19 as a key regulator in biliary atresia: insights into pathogenesis and potential therapeutic targets.

Biliary atresia (BA) is a devastating cholangiopathy, characterized by onset of persistent cholestatic jaundice during the neonatal period. The etiology of BA remains incompletely understood and is considered multifactorial. Recent evidence has identified that the long non-coding RNA H19 (H19) is among the critical regulators involved in this pathological process. This review summarizes the current understanding of the H19 in the pathogenesis of BA. The pathogenesis of BA is considered to be closely associated with impaired biliary epithelial barrier function. This barrier defect renders cholangiocytes more susceptible to injury and promotes bile acid retention. Within this pathological microenvironment, multiple factors such as bile acids and estrogen significantly upregulate H19 expression, with its level showing a positive correlation with the severity of BA. Up-regulated H19 is predominantly enriched in cholangiocytes and can be delivered to adjacent hepatocytes, hepatic stellate cells, macrophages, and liver sinusoidal endothelial cells, where it orchestrates cellular activities via diverse signaling pathways. By integrating and amplifying injury signals, H19 ultimately exacerbates inflammatory responses and fibrotic processes, driving the development and progression of BA. Additionally, emerging evidence suggests that certain traditional Chinese medicines exert anti-fibrotic effects by targeting H19, further highlighting its potential as a therapeutic target. This review comprehensively and systematically delineates the key regulatory network of H19 in BA, highlighting its translational potential as a novel therapeutic target and laying a theoretical foundation for future mechanistic exploration and clinical translation.

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2026-04-29 | Determining the Early Clues for the Outcome of Biliary Atresia Patients After Kasai's Operation

Purpose: Kasai's operation is still the initial step in the management of biliary atresia (BA). This study aims to identify the early factors predicting the event-free survival after Kasai portoenterostomy (KPE).Materials and Methods: In this retrospective study, records of 35 cases that underwent KPE between 2000 and 2012 were reviewed. Cases who died or needed liver transplantation were defined as the poor prognosis group (PPG) (n=21) and cases with event-free survival were defined as the good prognosis group (GPG)(n=14). Demographic data, preoperative and postoperative liver function test results, and pathology reports were analyzed. Non-parametric and receiver operating characteristic (ROC) tests for cut-off values were used.Results: Serum levels of total bilirubin (TB) and direct bilirubin (DB) after KPE were 10.9 mg/dL (6.6-22.3 mg/dL) and 8.6 mg/dL (5.1-16.1 mg/dL) for PPG, and 8.3 mg/dL (4.0-14.2 mg/dL) and 5.7 mg/dL (2.9-10.2 mg/dL) in GPG; both showed significant difference (p=0.004, p=0.003). The ROC analyses determined the optimal cut-off values were 8.84 mg/dL for TB with 75% sensitivity and 62% specificity; and 7.21 mg/dL for DB with 79% sensitivity and 65% specificity. Ductal plate malformation (DPM) was reported in 4 cases (29%) in GPG and in none of the cases of PPG (p = 0.047).Conclusion: Serum DB and TB levels early after KPE may be reliable early predictors of event-free survival. DPM may be a good prognostic factor, but larger case groups should be studied.

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2026-04-23 | Maternal risk factors for biliary atresia in neonates: a systematic review and meta-analysis.

The risk factors for neonatal biliary atresia remain unclear. This study aimed to systematically analyze maternal risk factors associated with the development of neonatal biliary atresia (BA). A systematic search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library to retrieve relevant literature published from database inception to December 31, 2025, focusing on maternal risk factors for neonatal biliary atresia. Stata (Version 18.0) was used for meta-analysis. A total of 10 retrospective studies were included in the meta-analysis. The results identified several statistically significant risk factors for the development of biliary atresia (BA), including maternal urogenital tract infection (OR = 1.21, 95% CI: 1.02-1.43), maternal diabetes mellitus (OR = 1.55, 95% CI: 1.20-2.00), preterm birth (OR = 2.64, 95% CI: 1.66-4.22), and low birth weight (OR = 1.66, 95% CI: 1.28-2.16). Additionally, the incidence of BA was significantly lower in neonates of White/Caucasian ethnicity (OR = 0.67, 95% CI: 0.46-0.98). By contrast, maternal smoking history, neonatal sex, maternal age (with 35 years as the cutoff), mode of delivery, and fetal number (singleton/multiple pregnancy) did not show statistically significant associations in this meta-analysis. The pathogenesis of neonatal biliary atresia is associated with multiple factors, including genetics, intrauterine infection, and maternal environmental exposures. Heightened vigilance for biliary atresia in neonates with high-risk characteristics is warranted to facilitate early diagnosis and treatment. However, due to the limited number of included studies, our findings require further validation through research with larger sample sizes.

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2024-09-12 | A narrative review of genes associated with liver fibrosis in biliary atresia.

Biliary atresia (BA) is characterized by biliary inflammation and obstruction. In the later phase, liver fibrosis occurs. Although the etiology of BA is believed to be multi-factorial, genetic predisposition has been proposed to play a critical role in the pathogenesis. This review aimed to provide an updated summary of the genes that have been reported to be involved in BA-associated liver fibrosis. The review was conducted via evaluation of MalaCards (BA disease: MalaCards-research articles, drugs, genes, clinical trials) which is a universally applied website including various human disease database. The database of genes that are involved in liver fibrosis were studied. Thirty-one genes that are associated with BA according to the disease relevance score were reviewed after further evaluations. Eleven genes (GPT, NR1H4, TGF-B1, MMP7, CCN2, TIMP1, SPP1, ADD3, KRT7, ADD3-AS1, SOX9) that are specific and with a potential association with liver fibrosis were selected for detailed description. Increased expression of GPT, TGF-B1, MMP7, CCN2, TIMP1, SPP1, ADD3, KRT7 and ADD3-AS1 maybe associated with the development of liver fibrosis in BA patients, while the expression of NR1H4 and SOX9 are more likely to suppress liver fibrosis. Current scientific evidence using gene database has revealed a close association between genetic anomalies and the pathogenesis of liver fibrosis in BA. With a better understanding of these anomalies, therapy targeting these related genes may be a new therapeutic approach to alleviate liver fibrosis in BA.

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2024-08-01 | IDDF2024-ABS-0285 Ferritinophagy activation and sideroflexin3-dependent mitochondrial iron overload contribute to biliary epithelial cells epithelial-mesenchymal transition and liver fibrosis in biliary atresia

Biliary atresia (BA) is a severe liver disease in neonates, which is caused by obliteration of the intra- and the extrahepatic biliary duct leading to cholestasis, and progressive liver injury and fibrosis. Epithelial-mesenchymal transformation (EMT) of bile duct epithelial cells is considered to be a key mechanism in the pathogenesis of liver fibrosis. The present study aimed to explore the role and underlying mechanism of ferroptosis in EMT and liver fibrosis. Thirty-four cases of BA liver tissue and twenty-two cases of adjacent normal liver tissue from hepatoblastoma were subjected to RNA-sequencing and proteomic analysis to verify the expression differences of EMT and fibrosis between BA and non-BA liver tissues, as well as the correlation between the expression level of the differential gene SFXN3 in BA and clinical pathological characteristics. A mouse liver model of biliary atresia induced by rotavirus in rhesus monkeys was constructed to verify the expression differences of EMT and fibrosis-related genes. A fibrosis model was constructed by inducing cholangiocytes with TGF-β, and the effects of SFXN3 knockdown and overexpression on cellular ferroptosis, EMT, and fibrosis were studied. We found that EMT-related molecules were significantly upregulated in BA patients. In addition, RT-PCR and Western blot experiments on liver of BA mice also revealed significant activation of fibrosis and EMT-related molecules In terms of mechanism, we found that SFXN3 was significantly upregulated in the fibrotic liver of patients (IDDF2024-ABS-0285 Figure 1). And it is positively correlated with the degree of fibrosis, EMT and clinical assay index. We discovered through colocalization that SFXN3 is localized to the biliary epithelial cells (IDDF2024-ABS-0285 Figure 2). Mechanically, we found that nuclear receptor coactivator NCOA4, a master regulator of ferritin phagocytosis, significantly activates and degrades ferritin during EMT, thereby releasing large amounts of ferrous, further leading to SFXN3-dependent mitochondrial iron overload. Conversely, knockdown of NCOA4 or SFXN3 with small interfering RNAs could effectively ameliorate ferroptotic cell death, cellular or mitochondrial iron overload and lipid peroxides accumulation (IDDF2024-ABS-0285 Figure 3). Overall, our findings underscore that ferritinophagy activation and SFXN3-dependent mitochondrial iron overload play critical roles in ferroptosis and EMT in biliary atresia.

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