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Nature Reviews. Gastroenterology &... May 2019Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they... (Review)
Review
Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they participate in bile production and homeostasis. Cholangiocytes are damaged in a variety of human diseases termed cholangiopathies, often causing advanced liver failure. The regulation of cholangiocyte transport properties is increasingly understood, as is their anatomical and functional heterogeneity along the biliary tract. Furthermore, cholangiocytes are pivotal in liver regeneration, especially when hepatocyte regeneration is compromised. The role of cholangiocytes in innate and adaptive immune responses, a critical subject relevant to immune-mediated cholangiopathies, is also emerging. Finally, reactive ductular cells are present in many cholestatic and other liver diseases. In chronic disease states, this repair response contributes to liver inflammation, fibrosis and carcinogenesis and is a subject of intense investigation. This Review highlights advances in cholangiocyte research, especially their role in development and liver regeneration, their functional and biochemical heterogeneity, their activation and involvement in inflammation and fibrosis and their engagement with the immune system. We aim to focus further attention on cholangiocyte pathobiology and the search for new disease-modifying therapies targeting the cholangiopathies.
Topics: Adaptive Immunity; Bile Duct Diseases; Bile Ducts; Epithelial Cells; Fibrosis; Humans; Immunity, Innate; Inflammation; Liver Failure; Liver Regeneration
PubMed: 30850822
DOI: 10.1038/s41575-019-0125-y -
Annals of Hepatology 2022Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it... (Review)
Review
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA). The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types. When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor. In order to ameliorate patients' survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.
Topics: Bile Duct Neoplasms; Bile Ducts, Extrahepatic; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Humans; Klatskin Tumor
PubMed: 35809836
DOI: 10.1016/j.aohep.2022.100737 -
Methods in Molecular Biology (Clifton,... 2022Cholangiopathies affect the biliary tree via various pathophysiological mechanisms. Research on biliary physiology and pathology, however, is hampered by a lack of...
Cholangiopathies affect the biliary tree via various pathophysiological mechanisms. Research on biliary physiology and pathology, however, is hampered by a lack of physiologically relevant in vitro models. Conventional models, such as two-dimensional (2D) monolayers and organoids, fail to replicate the structural organization of the bile duct, and both the size of the duct and position of cells are difficult to manipulate in a controllable way. Here, we describe a bile duct-on-a-chip (BDOC) that phenocopies the open-ended tubular architecture of the bile duct in three dimensions which, when seeded with either a cholangiocyte cell line or primary cells, demonstrates barrier function similar to bile ducts in vivo. This device represents an in vitro platform to study the pathophysiology of the bile duct using cholangiocytes from a variety of sources.
Topics: Bile Ducts; Epithelial Cells; Lab-On-A-Chip Devices; Organoids
PubMed: 34520006
DOI: 10.1007/978-1-0716-1693-2_4 -
Digestive Surgery 2020Bile duct injury (BDI) is a devastating complication following cholecystectomy. After initial management of BDI, patients stay at risk for late complications including...
BACKGROUND
Bile duct injury (BDI) is a devastating complication following cholecystectomy. After initial management of BDI, patients stay at risk for late complications including anastomotic strictures, recurrent cholangitis, and secondary biliary cirrhosis.
METHODS
We provide a comprehensive overview of current literature on the long-term outcome of BDI. Considering the availability of only limited data regarding treatment of anastomotic strictures in literature, we also retrospectively analyzed patients with anastomotic strictures following a hepaticojejunostomy (HJ) from a prospectively maintained database of 836 BDI patients.
RESULTS
Although clinical outcomes of endoscopic, radiologic, and surgical treatment of BDI are good with success rates of around 90%, quality of life (QoL) may be impaired even after "clinically successful" treatment. Following surgical treatment, the incidence of anastomotic strictures varies from 5 to 69%, with most studies reporting incidences around 10-20%. The median time to stricture formation varies between 11 and 30 months. Long-term BDI-related mortality varies between 1.8 and 4.6%. Of 91 patients treated in our center for anastomotic strictures after HJ, 81 (89%) were treated by percutaneous balloon dilatation, with a long-term success rate of 77%. Twenty-four patients primarily or secondarily underwent surgical revision, with recurrent strictures occurring in 21%.
CONCLUSIONS
The long-term impact of BDI is considerable, both in terms of clinical outcomes and QoL. Treatment should be performed in tertiary expert centers to optimize outcomes. Patients require a long-term follow-up to detect anastomotic strictures. Strictures should initially be managed by percutaneous dilatation, with surgical revision as a next step in treatment.
Topics: Anastomosis, Roux-en-Y; Bile Ducts; Cholangitis; Cholecystectomy; Constriction, Pathologic; Dilatation; Humans; Iatrogenic Disease; Jejunum; Liver Cirrhosis, Biliary; Prognosis; Quality of Life; Recurrence; Reoperation; Retrospective Studies
PubMed: 30654363
DOI: 10.1159/000496432 -
Journal of Hepatology Dec 2022Cholangiocarcinomas are cancers arising from bile ducts, either found within the liver (intrahepatic) or outside the liver (extrahepatic). In Western countries, deaths... (Review)
Review
Cholangiocarcinomas are cancers arising from bile ducts, either found within the liver (intrahepatic) or outside the liver (extrahepatic). In Western countries, deaths due to intrahepatic cancers are rising at a higher rate than deaths due to extrahepatic cancers. This may be due to rising cases of liver disease and misclassification of the different cancer types.
Topics: Humans; Cholangiocarcinoma; Bile Ducts; Liver; Bile Duct Neoplasms; Bile Ducts, Intrahepatic
PubMed: 35977611
DOI: 10.1016/j.jhep.2022.07.022 -
Science (New York, N.Y.) Feb 2021Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the...
Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However, cholangiocyte organoids remain plastic and resume their in vivo signatures when transplanted back in the biliary tree. We then utilize a model of cell engraftment in human livers undergoing ex vivo normothermic perfusion to demonstrate that this property allows extrahepatic organoids to repair human intrahepatic ducts after transplantation. Our results provide proof of principle that cholangiocyte organoids can be used to repair human biliary epithelium.
Topics: Animals; Bile; Bile Duct Diseases; Bile Ducts; Bile Ducts, Intrahepatic; Cell- and Tissue-Based Therapy; Common Bile Duct; Epithelial Cells; Gallbladder; Gene Expression Regulation; Humans; Liver; Liver Transplantation; Mesenchymal Stem Cell Transplantation; Mice; Organoids; RNA-Seq; Tissue and Organ Procurement; Transcriptome
PubMed: 33602855
DOI: 10.1126/science.aaz6964 -
Biochimica Et Biophysica Acta.... Apr 2018Drug-induced liver injury includes a spectrum of pathologies, some related to the mode of injury, some to the cell type primarily damaged. Among these, drug-induced bile... (Review)
Review
Drug-induced liver injury includes a spectrum of pathologies, some related to the mode of injury, some to the cell type primarily damaged. Among these, drug-induced bile duct injury is characterized by the destruction of the biliary epithelium following exposure to a drug. Most of the drugs associated with bile duct injury cause immune-mediated lesions to the epithelium of interlobular ducts. These share common histopathological features with primary biliary cholangitis, such as inflammation and necrosis at the expense of cholangiocytes and, if the insult persists, bile duct loss and biliary cirrhosis. Some drugs selectively target larger ducts. Such injury is often dose-dependent and thought to be the result of intrinsic drug toxicity. The histological changes resemble those seen in primary sclerosing cholangitis. This overview focuses on the clinical and pathological features of bile duct injury associated with drug treatment and on the immunological and biochemical effects that drugs exert on the biliary epithelium. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
Topics: Amoxicillin-Potassium Clavulanate Combination; Bile Acids and Salts; Bile Ducts; Biomarkers; Biotransformation; Carbamazepine; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestasis; Epithelial Cells; Humans; Liver
PubMed: 28882625
DOI: 10.1016/j.bbadis.2017.08.033 -
The British Journal of Radiology Sep 2021Cholangitis refers to inflammation of the bile ducts with or without accompanying infection. When intermittent or persistent inflammation lasts 6 months or more, the... (Review)
Review
Cholangitis refers to inflammation of the bile ducts with or without accompanying infection. When intermittent or persistent inflammation lasts 6 months or more, the condition is classified as chronic cholangitis. Otherwise, it is considered an acute cholangitis. Cholangitis can also be classified according to the inciting agent, complete mechanical obstruction, which is the leading cause of acute cholangitis, longstanding partial mechanical blockage, or immune-mediated bile duct damage that results in chronic cholangitis.The work-up for cholangitis is based upon medical history, clinical presentation, and initial laboratory tests. Whereas ultrasound is the first-line imaging modality used to identify bile duct dilatation in patients with colicky abdominal pain, cross-sectional imaging is preferable when symptoms cannot be primarily localised to the hepatobiliary system. CT is very useful in oncologic, trauma, or postoperative patients. Otherwise, magnetic resonance cholangiopancreatography is the method of choice to diagnose acute and chronic biliary disorders, providing an excellent anatomic overview and, if gadoxetic acid is injected, simultaneously delivering morphological and functional information about the hepatobiliary system. If brush cytology, biopsy, assessment of the prepapillary common bile duct, stricture dilatation, or stenting is necessary, then endoscopic ultrasound and/or retrograde cholangiography are performed. Finally, when the pathologic duct is inaccessible from the duodenum or stomach, percutaneous transhepatic cholangiography is an option. The pace of the work-up depends upon the severity of cholestasis on presentation. Whereas sepsis, hypotension, and/or Charcot's triad warrant immediate investigation and management, chronic cholestasis can be electively evaluated.This overview article will cover the common cholangitides, emphasising our clinical experience with the chronic cholestatic liver diseases.
Topics: Bile Ducts; Cholangitis; Diagnostic Imaging; Humans
PubMed: 34233488
DOI: 10.1259/bjr.20210417 -
HPB : the Official Journal of the... Oct 2022
Topics: Humans; Bile Ducts; Cholecystectomy, Laparoscopic; Bile Duct Diseases
PubMed: 35654672
DOI: 10.1016/j.hpb.2022.05.001 -
Biochimica Et Biophysica Acta.... Apr 2018Cholangiocytes are epithelial cells that line the intra- and extrahepatic biliary tree. They serve predominantly to mediate the content of luminal biliary fluid, which... (Review)
Review
Cholangiocytes are epithelial cells that line the intra- and extrahepatic biliary tree. They serve predominantly to mediate the content of luminal biliary fluid, which is controlled via numerous signaling pathways influenced by endogenous (e.g., bile acids, nucleotides, hormones, neurotransmitters) and exogenous (e.g., microbes/microbial products, drugs etc.) molecules. When injured, cholangiocytes undergo apoptosis/lysis, repair and proliferation. They also become senescent, a form of cell cycle arrest, which may prevent propagation of injury and/or malignant transformation. Senescent cholangiocytes can undergo further transformation to a senescence-associated secretory phenotype (SASP), where they begin secreting pro-inflammatory and pro-fibrotic signals that may contribute to disease initiation and progression. These and other concepts related to cholangiocyte pathobiology will be reviewed herein. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
Topics: Animals; Apoptosis; Bile; Bile Acids and Salts; Bile Duct Diseases; Bile Ducts; Cell Proliferation; Cellular Senescence; Cilia; Epithelial Cells; Humans; MicroRNAs; Signal Transduction
PubMed: 28716705
DOI: 10.1016/j.bbadis.2017.06.024