-
Comprehensive Physiology Jul 2013Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile... (Review)
Review
Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (∼1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions.
Topics: Animals; Bile; Bile Acids and Salts; Bile Ducts; Biological Transport; Gastroenterology; Hepatocytes; History, 20th Century; Humans; Liver; Membrane Transport Proteins; Signal Transduction
PubMed: 23897680
DOI: 10.1002/cphy.c120027 -
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 -
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 -
World Journal of Gastroenterology Oct 2022Biliodigestive anastomosis between the extrahepatic bile duct and the intestine for bile duct disease is a gastrointestinal reconstruction that abolishes duodenal... (Review)
Review
Biliodigestive anastomosis between the extrahepatic bile duct and the intestine for bile duct disease is a gastrointestinal reconstruction that abolishes duodenal papilla function and frequently causes retrograde cholangitis. This chronic inflammation can cause liver dysfunction, liver abscess, and even bile duct cancer. Although research has been conducted for over 100 years to directly repair bile duct defects with alternatives, no bile duct substitute (BDS) has been developed. This narrative review confirms our understanding of why bile duct alternatives have not been developed and explains the clinical applicability of BDSs in the near future. We searched the PubMed electronic database to identify studies conducted to develop BDSs until December 2021 and identified studies in English. Two independent reviewers reviewed studies on large animals with 8 or more cases. Four types of BDSs prevail: Autologous tissue, non-bioabsorbable material, bioabsorbable material, and others (decellularized tissue, 3D-printed structures, ). In most studies, BDSs failed due to obstruction of the lumen or stenosis of the anastomosis with the native bile duct. BDS has not been developed primarily because control of bile duct wound healing and regeneration has not been elucidated. A BDS expected to be clinically applied in the near future incorporates a bioabsorbable material that allows for regeneration of the bile duct outside the BDS.
Topics: Animals; Bile Ducts; Bile Ducts, Extrahepatic; Bile Duct Diseases; Cholangitis; Anastomosis, Surgical; Constriction, Pathologic
PubMed: 36338889
DOI: 10.3748/wjg.v28.i39.5707 -
Asian Journal of Surgery Oct 2023Bile leak is a rare complication after Laparoscopic Cholecystectomy. Subvesical bile duct (SVBD) injury is the second cause of minor bile leak, following the... (Review)
Review
Bile leak is a rare complication after Laparoscopic Cholecystectomy. Subvesical bile duct (SVBD) injury is the second cause of minor bile leak, following the unsuccessful clipping of the cystic duct stump. The aim of this study is to pool available data on this type of biliary tree anatomical variation to summarize incidence of injury, methods used to diagnose and treat SVBD leaks after LC. Articles published between 1985 and 2021 describing SVBD evidence in patients operated on LC for gallstone disease, were included. Data were divided into two groups based on the intra or post-operative evidence of bile leak from SVBD after surgery. This systematic report includes 68 articles for a total of 231 patients. A total of 195 patients with symptomatic postoperative bile leak are included in Group 1, while Group 2 includes 36 patients describing SVBD visualized and managed during LC. Outcomes of interest were diagnosis, clinical presentation, treatment, and outcomes. The management of minor bile leak is controversial. In most of cases diagnosed postoperatevely, Endoscopic Retrograde Cholangio-Pancreatography (ERCP) is the best way to treat this complication. Surgery should be considered when endoscopic or radiological approaches are not resolutive.
Topics: Humans; Cholecystectomy, Laparoscopic; Postoperative Complications; Cholangiopancreatography, Endoscopic Retrograde; Bile Ducts; Bile Duct Diseases; Biliary Tract Diseases
PubMed: 37127504
DOI: 10.1016/j.asjsur.2023.04.031 -
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 -
Biomedicine & Pharmacotherapy =... Oct 2023Cholangiocarcinoma (CCA), a heterogeneous malignancy of bile duct epithelial cells, is characterized by aggressiveness, difficult diagnosis, and poor prognosis due to... (Review)
Review
Cholangiocarcinoma (CCA), a heterogeneous malignancy of bile duct epithelial cells, is characterized by aggressiveness, difficult diagnosis, and poor prognosis due to limited understanding and lack of effective therapeutic strategies. Genetic and epigenetic alterations accumulated in CCA cells can cause the aberrant regulation of oncogenes and tumor suppressors. Epigenetic alterations with histone modification, DNA methylation, and noncoding RNA modulation are associated with the carcinogenesis of CCA. Mutation or silencing of genes by various mechanisms can be a frequent event during CCA development. Alterations in histone acetylation/deacetylation at the posttranslational level, DNA methylation at promoters, and noncoding RNA regulation contribute to the heterogeneity of CCA and drive tumor development. In this review article, we mainly focus on the roles of epigenetic regulation in cholangiocarcinogenesis. Alterations in epigenetic modification can be potential targets for the therapeutic management of CCA, and epigenetic targets may become diagnostic biomarkers of CCA.
Topics: Humans; Epigenesis, Genetic; Bile Duct Neoplasms; Cholangiocarcinoma; Bile Ducts; Bile Ducts, Intrahepatic
PubMed: 37557012
DOI: 10.1016/j.biopha.2023.115290 -
Biochimica Et Biophysica Acta.... Apr 2018Chronic cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis,... (Review)
Review
Chronic cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, and, ultimately, to the development of cirrhosis. However, the precise relationship between cholestasis, in its broad meaning, and liver tissue fibrosis is still poorly defined. Fibrogenesis is currently viewed as a dynamic process that appears strictly related to the extent and duration of parenchymal injury. This relationship is clearly evident in the presence of reiterative hepatocellular necrosis due to viral infection or alcohol abuse. It appears that "pure" intralobular intrahepatic cholestasis secondary to biliary secretory failure of the hepatocyte, in absence of hepatocellular damage, lobular inflammation and bile duct damage and/or proliferation, is not associated with marked and/or progressive liver tissue fibrosis. In contrast, marked and progressive liver tissue fibrosis always follows liver diseases characterized by chronic inflammatory bile duct damage as seen in PBC and PSC or chronic mechanical obstruction of the biliary tree. Overall, the fibrogenic process in these clinical conditions appears to be related to a more complex interaction between immune/inflammatory mechanisms, cytokine networks and the derangement of the homeostasis between epithelial and mesenchymal cells. The elucidation of these mechanisms is indeed crucial for the identification of potential diagnostic and therapeutic targets.
Topics: Bile Ducts; Cholangitis; Cytokines; Epithelial Cells; Fibrosis; Humans; Liver; Liver Cirrhosis, Biliary; Stromal Cells
PubMed: 28754450
DOI: 10.1016/j.bbadis.2017.07.026