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Pathologica Jun 2021Autoimmune cholestatic liver diseases are rare hepato-biliary disorders characterized by a progressive, inflammatory destruction of bile ducts. Primary biliary... (Review)
Review
Autoimmune cholestatic liver diseases are rare hepato-biliary disorders characterized by a progressive, inflammatory destruction of bile ducts. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. Both may evolve into secondary biliary cirrhosis and its complications. Therapeutic options are limited and liver transplantation remains the only definitive treatment for PBC and PSC. Most PBC and PSC patients have a typical presentation, which does not require liver biopsy. However, in routine clinical practice, important variants or specific subgroups that benefit from liver biopsy for proper management may be observed. Herein, we provide a general overview of clinical and pathological characteristic of PBC and PSC, highlighting the most important features for routine diagnostic practice.
Topics: Autoimmune Diseases; Cholangitis, Sclerosing; Humans; Liver Cirrhosis, Biliary
PubMed: 34294935
DOI: 10.32074/1591-951X-245 -
EBioMedicine Dec 2021Biliary Atresia is a devastating pediatric cholangiopathy affecting the bile ducts of the liver. In this review, we describe recent progress in the understanding of... (Review)
Review
Biliary Atresia is a devastating pediatric cholangiopathy affecting the bile ducts of the liver. In this review, we describe recent progress in the understanding of liver development with a focus on cholangiocyte differentiation and how use of technical platforms, including rodent, zebrafish and organoid models, advances our understanding of Biliary Atresia. This is followed by a description of potential pathomechanisms, such as autoimmune responses, inflammation, disturbed apical-basal cell polarity, primary cilia dysfunction as well as beta-amyloid accumulation. Finally, we describe current and emerging diagnostic opportunities and recent translation breakthroughs for Biliary Atresia in the area of emerging therapy development, including immunomodulation and organoid-based systems for liver and bile duct repair.
Topics: Animals; Bile Ducts; Biliary Atresia; Cell Differentiation; Disease Models, Animal; Epithelial Cells; Humans; Organoids
PubMed: 34781099
DOI: 10.1016/j.ebiom.2021.103689 -
Clinical Gastroenterology and... Jul 2023Primary biliary cholangitis (PBC) is an archetypal autoimmune disease. Chronic lymphocytic cholangitis is associated with interface hepatitis, ductopenia, cholestasis,... (Review)
Review
Primary biliary cholangitis (PBC) is an archetypal autoimmune disease. Chronic lymphocytic cholangitis is associated with interface hepatitis, ductopenia, cholestasis, and progressive biliary fibrosis. People living with PBC are frequently symptomatic, experiencing a quality-of-life burden dominated by fatigue, itch, abdominal pain, and sicca complex. Although the female predominance, specific serum autoantibodies, immune-mediated cellular injury, as well as genetic (HLA and non-HLA) risk factors, identify PBC as autoimmune, to date treatment has focused on cholestatic consequences. Biliary epithelial homeostasis is abnormal and contributes to disease. The impact of cholangiocyte senescence, apoptosis, and impaired bicarbonate secretion enhances chronic inflammation and bile acid retention. First-line therapy is a non-specific anti-cholestatic agent, ursodeoxycholic acid. For those with residual cholestasis biochemically, obeticholic acid is introduced, and this semisynthetic farnesoid X receptor agonist adds choleretic, anti-fibrotic, and anti-inflammatory activity. Future PBC licensed therapy will likely include peroxisome proliferator activated receptor (PPAR) pathway agonists, including specific PPAR-delta agonism (seladelpar), as well as elafibrinor and saroglitazar (both with broader PPAR agonism). These agents dovetail the clinical and trial experience for off-label bezafibrate and fenofibrate use. Symptom management is essential, and encouragingly, PPAR agonists reduce itch; IBAT inhibition (eg, linerixibat) also appears promising for pruritus. For those where liver fibrosis is the target, NOX inhibition is being evaluated. Earlier stage therapies in development include therapy to impact immunoregulation in patients, as well other approaches to treating pruritus (eg, antagonists of MrgprX4). Collectively the PBC therapeutic landscape is exciting. Therapy goals are increasingly proactive and individualized and aspire to rapidly achieve normal serum tests and quality of life with prevention of end-stage liver disease.
Topics: Humans; Female; Male; Liver Cirrhosis, Biliary; Quality of Life; Peroxisome Proliferator-Activated Receptors; Ursodeoxycholic Acid; Cholangitis; Cholestasis; Pruritus
PubMed: 36809835
DOI: 10.1016/j.cgh.2023.02.005 -
Clinics in Liver Disease Aug 2022Biliary atresia is a rare disease but remains the most common indication for pediatric liver transplantation as there are no effective medical therapies to slow... (Review)
Review
Biliary atresia is a rare disease but remains the most common indication for pediatric liver transplantation as there are no effective medical therapies to slow progression after diagnosis. Variable contribution of genetic, immune, and environmental factors contributes to disease heterogeneity among patients with biliary atresia. Developing a deeper understanding of the disease mechanism will help to develop targeted medical therapies and improve patient outcomes.
Topics: Biliary Atresia; Child; Humans; Infant; Liver Transplantation
PubMed: 35868678
DOI: 10.1016/j.cld.2022.03.001 -
Hepatology (Baltimore, Md.) Jan 2022Biliary atresia is a severe inflammatory and fibrosing cholangiopathy of neonates of unknown etiology. The onset of cholestasis at birth implies a prenatal onset of... (Observational Study)
Observational Study
BACKGROUND AND AIMS
Biliary atresia is a severe inflammatory and fibrosing cholangiopathy of neonates of unknown etiology. The onset of cholestasis at birth implies a prenatal onset of liver dysfunction. Our aim was to investigate the mechanisms linked to abnormal cholangiocyte development.
APPROACH AND RESULTS
We generated biliary organoids from liver biopsies of infants with biliary atresia and normal and diseased controls. Organoids emerged from biliary atresia livers and controls and grew as lumen-containing spheres with an epithelial lining of cytokeratin-19 albumin SOX17 cholangiocyte-like cells. Spheres had similar gross morphology in all three groups and expressed cholangiocyte-enriched genes. In biliary atresia, cholangiocyte-like cells lacked a basal positioning of the nucleus, expressed fewer developmental and functional markers, and displayed misorientation of cilia. They aberrantly expressed F-actin, β-catenin, and Ezrin, had low signals for the tight junction protein zonula occludens-1 (ZO-1), and displayed increased permeability as evidenced by a higher Rhodamine-123 (R123) signal inside organoids after verapamil treatment. Biliary atresia organoids had decreased expression of genes related to EGF signaling and FGF2 signaling. When treated with EGF+FGF2, biliary atresia organoids expressed differentiation (cytokeratin 7 and hepatocyte nuclear factor 1 homeobox B) and functional (somatostatin receptor 2, cystic fibrosis transmembrane conductance regulator [CFTR], aquaporin 1) markers, restored polarity with improved localization of F-actin, β-catenin and ZO-1, increased CFTR function, and decreased uptake of R123.
CONCLUSIONS
Organoids from biliary atresia are viable and have evidence of halted epithelial development. The induction of developmental markers, improved cell-cell junction, and decreased epithelial permeability by EGF and FGF2 identifies potential strategies to promote epithelial maturation and function.
Topics: Adolescent; Bile Ducts; Biliary Atresia; Biopsy; Case-Control Studies; Cells, Cultured; Child; Child, Preschool; Cholestasis; Epithelial Cells; Healthy Volunteers; Humans; Infant; Infant, Newborn; Organoids; Primary Cell Culture; Tight Junctions
PubMed: 34392560
DOI: 10.1002/hep.32107 -
Hepatology Communications Jun 2023Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked...
Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. The incidence and prevalence of PBC vary widely in different regions and time periods, and although disproportionally more common among White non-Hispanic females, contemporary data show a higher prevalence in males and racial minorities than previously described. Outcomes largely depend on early recognition of the disease and prompt institution of treatment, which, in turn, are directly influenced by provider bias and socioeconomic factors. Ursodeoxycholic acid remains the initial treatment of choice for PBC, with obeticholic acid and fibrates (off-label therapy) reserved as add-on therapy for the management of inadequate responders or those with ursodeoxycholic acid intolerance. Novel and repurposed drugs are currently at different stages of clinical development not only for the treatment of PBC but also for its symptomatic management. Here, we summarize the most up-to-date data regarding the epidemiology, prognosis, and treatment of PBC, providing clinically useful information for its holistic management.
Topics: Male; Female; Humans; Ursodeoxycholic Acid; Liver Cirrhosis, Biliary; Cholangitis; Prognosis; Cholestasis
PubMed: 37267215
DOI: 10.1097/HC9.0000000000000179 -
Seminars in Interventional Radiology Aug 2021The hepatobiliary system is known to have high anatomic variability, as studies have shown variant rates of over 40% among individuals. This review will describe biliary... (Review)
Review
The hepatobiliary system is known to have high anatomic variability, as studies have shown variant rates of over 40% among individuals. This review will describe biliary anatomy and the most common anatomic variants, knowledge of which is critical to ensuring safe and effective biliary interventions.
PubMed: 34393334
DOI: 10.1055/s-0041-1731085 -
Drugs Jul 2021Cholestatic liver disease is a disease that causes liver damage and fibrosis owing to bile stasis. It is represented by primary biliary cholangitis (PBC) and primary... (Review)
Review
Cholestatic liver disease is a disease that causes liver damage and fibrosis owing to bile stasis. It is represented by primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), but the pathophysiological pathways that cause bile stasis in both diseases are different. The pathogenesis of the disease is still unclear, although autoimmune mechanisms have been postulated and partially elucidated. Although the disease may progress slowly with only mild liver dysfunction, it may progress to liver cirrhosis or liver failure, which require liver transplantation. As a medical treatment, ursodeoxycholic acid is widely used for PBC and has proved to be very effective against disease progression in cases of PBC. On the other hand, its efficacy is limited in cases of PSC, and the research and development of various drugs are underway. Furthermore, the clinical course of both diseases is quite variable, making the design of clinical trials fairly difficult. In this review, we present the general natural history of PBC and PSC, and provide information on the latest drug therapies currently available and those that are under investigation.
Topics: Anti-Bacterial Agents; Bezafibrate; Cholagogues and Choleretics; Cholangitis, Sclerosing; Fibroblast Growth Factors; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Peroxisome Proliferator-Activated Receptors; Probiotics; Receptors, Cytoplasmic and Nuclear; Tumor Necrosis Factor-alpha
PubMed: 34142342
DOI: 10.1007/s40265-021-01545-7 -
World Journal of Gastrointestinal... Dec 2021Choledochoscopy, or cholangioscopy, is an endoscopic procedure for direct visualization within the biliary tract for diagnostic or therapeutic purposes. Since its... (Review)
Review
Choledochoscopy, or cholangioscopy, is an endoscopic procedure for direct visualization within the biliary tract for diagnostic or therapeutic purposes. Since its conception in 1879, many variations and improvements are made to ensure relevance in diagnosing and managing a range of intrahepatic and extrahepatic biliary pathologies. This ranges from improved visual impression and optical guided biopsies of indeterminate biliary strictures and clinically indistinguishable pathologies to therapeutic uses in stone fragmentation and other ablative therapies. Furthermore, with the evolving understanding of biliary disorders, there are significant innovative ideas and techniques to fill this void, such as nuanced instances of biliary stenting and retrieving migrated ductal stents. With this in mind, we present a review of the current advancements in choledo-choscopy with new supporting evidence that further delineates the role of choledochoscopy in various diagnostic and therapeutic interventions, complications, limitations and put forth areas for further study.
PubMed: 35070020
DOI: 10.4253/wjge.v13.i12.571