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Frontiers in Immunology 2020Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have... (Review)
Review
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.
Topics: Animals; Biliary Atresia; Cholestasis; Cytokines; Disease Models, Animal; Disease Progression; Humans; Immunity, Humoral; Immunity, Innate; Inflammation; Macrophages; Mice; Mice, Inbred BALB C; Rotavirus; Rotavirus Infections
PubMed: 32161597
DOI: 10.3389/fimmu.2020.00329 -
Liver Transplantation : Official... Mar 2022Children with biliary atresia (BA), particularly infants, are at high risk for malnutrition attributed to a multitude of factors, including poor oral intake and... (Review)
Review
Children with biliary atresia (BA), particularly infants, are at high risk for malnutrition attributed to a multitude of factors, including poor oral intake and intolerance of enteral feeding, fat malabsorption, abnormal nutrient metabolism, and increased caloric demand. Malnutrition and sarcopenia negatively impact outcomes in BA, leading to higher pretransplant and posttransplant morbidity and mortality. This review summarizes factors contributing to nutritional deficiencies in BA and offers an organized approach to the assessment and management of malnutrition in this vulnerable population.
Topics: Biliary Atresia; Child; Enteral Nutrition; Humans; Infant; Liver Transplantation; Malnutrition; Nutritional Status; Sarcopenia
PubMed: 34669243
DOI: 10.1002/lt.26339 -
World Journal of Pediatrics : WJP May 2023Biliary atresia (BA) is one of the main causes of neonatal end-stage liver disease. Without timely diagnosis and treatment, most children with BA will develop... (Review)
Review
BACKGROUND
Biliary atresia (BA) is one of the main causes of neonatal end-stage liver disease. Without timely diagnosis and treatment, most children with BA will develop irreversible liver fibrosis within the first two months. While current theorized causes of BA include viral infection, immune disorders, and genetic defects, the comprehensive etiology is still largely unknown. Recently, biliatresone attracted much interest for its ability to induce BA in both zebrafish and mice, so we summarized the latest progress of biliatresone research in BA and tried to answer the question of whether it could provide further clues to the etiology of human BA.
DATA SOURCES
We conducted a PubMed search for any published articles related to the topic using search terms including "biliary atresia", "biliatresone", "GSH", and "HSP90". Relevant data were extracted from the original text or supplementary materials of the corresponding articles.
RESULTS
Biliatresone had shown its unique toxicity in multiple species such as zebrafish and mice, and pathogenic factors involved included glutathione (GSH), heat shock protein 90 (HSP90) and the related pathways. In combination with epidemiological evidence and recent studies on the intestinal flora in biliary atresia, a new pathogenic hypothesis that the occurrence of biliary atresia is partly due to biliatresone or its structure-like compounds depositing in human body via vegetables or/and the altered intestinal flora structure can be tentatively established.
CONCLUSIONS
Based on the existing evidence, we emphasized that GSH and HSP90 are involved in the development of BA, and the maternal diet, especially higher vegetable intake of Asian women of childbearing age, accompanied by the altered intestinal flora structure, may contribute to the occurrence of biliary atresia and the higher incidence in the Asia group. However, the evidence from large sample epidemiological research is necessary.
Topics: Child; Animals; Female; Humans; Mice; Zebrafish; Biliary Atresia; Liver Cirrhosis; Glutathione
PubMed: 36166189
DOI: 10.1007/s12519-022-00619-0 -
F1000Research 2019Biliary atresia (BA) is a neonatal liver disease characterized by progressive obstruction and fibrosis of the extrahepatic biliary tree as well as fibrosis and... (Review)
Review
Biliary atresia (BA) is a neonatal liver disease characterized by progressive obstruction and fibrosis of the extrahepatic biliary tree as well as fibrosis and inflammation of the liver parenchyma. Recent studies found that infants who will go on to develop BA have elevated direct bilirubin levels in the first few days of life, suggesting that the disease starts . The etiology and pathogenesis of BA, however, remain unknown. Here, we discuss recent studies examining potential pathogenetic mechanisms of BA, including genetic susceptibility, involvement of the immune system, and environmental insults such as viruses and toxins, although it is possible that there is not a single etiological agent but rather a large group of injurious insults that result in a final common pathway of extrahepatic bile duct obstruction and liver fibrosis. The management and diagnosis of BA have not advanced significantly in the past decade, but given recent advances in understanding the timing and potential pathogenesis of BA, we are hopeful that the next decade will bring early diagnostics and novel therapeutics.
Topics: Biliary Atresia; Humans; Infant; Inflammation; Liver Cirrhosis
PubMed: 30828434
DOI: 10.12688/f1000research.16732.1 -
Digestive Diseases (Basel, Switzerland) 2015To date, the etiology and pathogenic underpinning of the progression of the most prevalent serious neonatal liver disease, biliary atresia, remains elusive. This disease... (Review)
Review
To date, the etiology and pathogenic underpinning of the progression of the most prevalent serious neonatal liver disease, biliary atresia, remains elusive. This disease presents as an aggressive form of neonatal cholestasis characterized by the destruction and obliteration of the extrahepatic bile ducts within the first few weeks of life and a rapid progression of biliary fibrosis, likely due to unremitting cholestasis and retention of biliary constituents including bile acids. In ∼5% of patients, biliary atresia is associated with laterality features, suggesting a genetic underpinning to a disease that begins soon after birth. However, biliary atresia does not occur within families and twins are discordant, indicating an absence of strict mendelian inheritance. Despite this, genes related to bile duct dysmorphogenesis/ciliopathies overlapping with features of biliary atresia in both humans and nonhuman model systems have been proposed. Taken together, strict genetic etiologies leading to a common pathway of a neonatal cholangiopathy resulting in biliary atresia remain elusive. Contributions from fibrogenesis- and inflammation-based studies suggest that early engagement of these pathways contributes to disease progression, but a recent double-blind study did not suggest any benefit from early use of corticosteroids. However, there are genetic contributions to the adaptation and response to cholangiopathies and cholestasis that may be present in certain populations that likely impact upon the response to hepatoportoenterostomy and subsequent biliary tract function. Studies utilizing next generation sequencing technologies (e.g., exome analysis) are ongoing in several laboratories around the world; they are expected to provide insights into genetic contributions to biliary atresia outcomes. Altogether, combinations of exome sequencing and large population studies are expected to reveal causative and modifying genes relevant to patients with biliary atresia as a means to provide therapeutic targets and potential opportunities for genetic screening.
Topics: Biliary Atresia; Calmodulin-Binding Proteins; Genetic Variation; Genome-Wide Association Study; Glypicans; Humans
PubMed: 26045276
DOI: 10.1159/000371694 -
International Journal of Molecular... Jul 2022Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are... (Review)
Review
Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are incalculable for the patients, the affected families, relatives, and the healthcare system. Scientific communities have identified a rate of about 1 case per 10,000-20,000 live births, but the percentage may be higher, considering the late diagnoses. The etiology is heterogeneous. BA, which is considered in half of the causes leading to orthotopic liver transplantation, occurs in primates and non-primates. To consolidate any model, (1) more transport and cell membrane studies are needed to identify the exact mechanism of noxa-related hepatotoxicity; (2) an online platform may be key to share data from pilot projects and new techniques; and (3) the introduction of differentially expressed genes may be useful in investigating the liver metabolism to target the most intricate bilio-toxic effects of pharmaceutical drugs and toxins. As a challenge, such methodologies are still limited to very few centers, making the identification of highly functional animal models like finding a "needle in a haystack". This review compiles models from the haystack and hopes that a combinatorial search will eventually be the root for a successful pathway.
Topics: Animals; Biliary Atresia; Inflammation; Liver Transplantation
PubMed: 35887185
DOI: 10.3390/ijms23147838 -
Archives of Disease in Childhood Aug 2020To elaborate on the implementation and achievements of a biliary atresia (BA) screening programme in Shenzhen.
OBJECTIVE
To elaborate on the implementation and achievements of a biliary atresia (BA) screening programme in Shenzhen.
METHODS
In 2015, we partnered with the government in Shenzhen and attached the stool colour card (SCC) to the health handbook for mothers and children. These handbooks have been distributed through official channels to every pregnant woman in Shenzhen since 1 January 2015. A total of 118 patients diagnosed with BA at Shenzhen Children's Hospital were enrolled and divided into two cohorts based on their date of diagnosis: cohort A before and cohort B after introduction of screening. The cohorts were compared to evaluate differences in age at diagnosis, jaundice-free rate, 2-year native liver survival rate and so on.
RESULTS
After the implementation of the screening programme, the age at diagnosis decreased from 81±12 to 56±15 days old (p<0.05), the incidence of postoperative complications decreased from 58.8% to 52.6% (p<0.05), the jaundice-free rate increased from 47.1% to 54.4% (p<0.05), and the 2-year native liver survival rate increased from 44.4% to 52.6% (p<0.05). The percentage of patients who underwent surgery increased from 68.0% to 83.8% (p<0.05).
CONCLUSION
In Shenzhen, our screening programme led to earlier diagnoses and better prognoses. The latter resulted in an increased willingness to undergo the Kasai procedure. Through a hospital and government collaboration, this programme exerted a considerable influence, and guardians observed benefits with only a small cost of implementation. Our results may eventually help promote the widespread use of the SCC across the whole country.
Topics: Biliary Atresia; China; Early Diagnosis; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Liver Transplantation; Male; Neonatal Screening; Patient Acceptance of Health Care; Patient Education as Topic; Portoenterostomy, Hepatic; Prognosis
PubMed: 32518136
DOI: 10.1136/archdischild-2019-317787 -
Nature Communications Jan 2022Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life remains unknown. We...
Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life remains unknown. We hypothesized that feeding butyrate to pregnant mice influences the newborn's susceptibility to biliary atresia, a severe cholangiopathy of neonates. Here, we show that butyrate administration to mothers renders newborn mice resistant to inflammation and injury of bile ducts and improves survival. The prevention of hepatic immune cell activation and survival trait is linked to fecal signatures of Bacteroidetes and Clostridia and increases glutamate/glutamine and hypoxanthine in stool metabolites of newborn mice. In human neonates with biliary atresia, the fecal microbiome signature of these bacteria is under-represented, with suppression of glutamate/glutamine and increased hypoxanthine pathways. The direct administration of butyrate or glutamine to newborn mice attenuates the disease phenotype, but only glutamine renders bile duct epithelial cells resistant to cytotoxicity by natural killer cells. Thus, maternal intake of butyrate influences the fecal microbial population and metabolites in newborn mice and the phenotypic expression of experimental biliary atresia, with glutamine promoting survival of bile duct epithelial cells.
Topics: Animals; Animals, Newborn; Bile Ducts; Biliary Atresia; Cholestasis; Disease Models, Animal; Epithelial Cells; Female; Gastrointestinal Microbiome; Humans; Infant, Newborn; Inflammation; Killer Cells, Natural; Liver; Mice; Mice, Inbred BALB C; Pregnancy
PubMed: 35013245
DOI: 10.1038/s41467-021-27689-4 -
Current Opinion in Pediatrics Jun 2015The purpose of this study is to review advances in both the pathogenesis and clinical management of biliary atresia. (Review)
Review
PURPOSE OF REVIEW
The purpose of this study is to review advances in both the pathogenesis and clinical management of biliary atresia.
RECENT FINDINGS
Immunologic studies have further characterized roles of helper T-cells, B-cells, and natural killer cells in the immune dysregulation following viral replication within and damage of biliary epithelium. Prominin-1-expressing portal fibroblasts may play an integral role in the biliary fibrosis associated with biliary atresia. A number of genetic polymorphisms have been characterized as leading to susceptibility for biliary atresia. Postoperative corticosteroid therapy is not associated with greater transplant-free survival. Newborn screening may improve outcomes of infants with biliary atresia and may also provide a long-term cost benefit.
SUMMARY
Although recent advances have enhanced our understanding of pathogenesis and clinical management, biliary atresia remains a significant challenge requiring further investigation.
Topics: Bile Ducts, Intrahepatic; Biliary Atresia; Child; Child, Preschool; Early Diagnosis; Humans; Infant; Infant, Newborn; Liver Transplantation; Portoenterostomy, Hepatic; Prognosis; Treatment Outcome
PubMed: 25944310
DOI: 10.1097/MOP.0000000000000214 -
Current Opinion in Gastroenterology Jan 2012New knowledge on rotavirus infection in children and well established mouse models has renewed interest in whether rotavirus could cause biliary atresia, an idiopathic,... (Review)
Review
PURPOSE OF REVIEW
New knowledge on rotavirus infection in children and well established mouse models has renewed interest in whether rotavirus could cause biliary atresia, an idiopathic, obliterative infantile disease of bile ducts that is the primary indication for liver transplant in children.
RECENT FINDINGS
Studies in the rotavirus mouse model of biliary atresia indicate that infection of biliary epithelium is an inaugural event leading to biliary inflammation and obstruction, which is preceded by systemic spread of rotavirus, which also occurs during human rotavirus enteric infections. Viral factors, including rotavirus gene 4, are important for biliary infection and biliary atresia in mice. Specific host factors related to inflammatory processes (natural killer and T cells, interferon) are also critical, and a paucity of regulatory T cells in neonates may play a key role in pathogenesis in experimental biliary atresia. Rotavirus vaccination has substantially decreased rotavirus diarrheal disease worldwide and might enable demonstration of a cause-effect relationship between rotavirus infection and biliary atresia in humans.
SUMMARY
Rotavirus can be detected in the serum of mice and children and causes biliary atresia in neonatal mice. Approaches to re-examine whether rotavirus causes biliary atresia in children are discussed based on concepts from the mouse model of biliary atresia and rotavirus vaccination programs.
Topics: Animals; Bile Ducts; Biliary Atresia; Global Health; Humans; Incidence; Infant; Risk Factors; Rotavirus; Rotavirus Infections
PubMed: 22123643
DOI: 10.1097/MOG.0b013e32834c7ae4