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Pathology International Dec 2022The biliary system is a highly branched tubular network consisting of intrahepatic bile ducts (IHBDs) and extrahepatic bile ducts (EHBDs). IHBDs are derived from hepatic... (Review)
Review
The biliary system is a highly branched tubular network consisting of intrahepatic bile ducts (IHBDs) and extrahepatic bile ducts (EHBDs). IHBDs are derived from hepatic progenitor cells, while EHBDs originate directly from the endoderm through a separate branching morphogenetic process. Traits that are important for cancer are often found to overlap in developmental and other processes. Therefore, it has been suggested that intrahepatic cholangiocarcinomas (iCCAs) and extrahepatic cholangiocarcinomas (eCCAs) have different developmental mechanisms. While much evidence is being gathered on the mechanism of iCCAs, the evidence for eCCA is still very limited. The main reason for this is that there are very few appropriate animal models for eCCA. We can gain important insights from these animal models, particularly genetically engineered mouse models (GEMMs). GEMMs are immunocompetent and mimic human CCA subtypes with a specific mutational pattern, allowing the development of precancerous lesions, that is, biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). This review provides a summary of the pathogenesis and mechanisms of eCCA that can be revealed by GEMMs. Furthermore, we discuss several clinical questions, such as whether BilIN and IPNB really become malignant, whether the peribiliary gland is the origin of eCCAs, and others.
Topics: Animals; Mice; Humans; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Bile Ducts, Extrahepatic; Cell Transformation, Neoplastic; Bile Pigments
PubMed: 36349994
DOI: 10.1111/pin.13287 -
PloS One 2022Bile duct integrity is essential for the maintenance of the structure and function of the biliary tree. We previously showed that cholangiocyte injury in a toxic model...
INTRODUCTION
Bile duct integrity is essential for the maintenance of the structure and function of the biliary tree. We previously showed that cholangiocyte injury in a toxic model of biliary atresia leads to increased monolayer permeability. Increased epithelial permeability was also shown in other cholangiopathies. We hypothesized that after initial cholangiocyte injury, leakage of bile acids into the duct submucosa propagates cholangiocyte damage and fibrosis. We thus aimed to determine the impact of bile acid exposure on cholangiocytes and the potential therapeutic effect of a non-toxic bile acid.
MATERIALS AND METHODS
Extrahepatic bile duct explants were isolated from adult and neonatal BALB/c mice. Explants were cultured with or without glycochenodeoxycholic acid and ursodeoxycholic acid. They were then fixed and stained.
RESULTS
Explants treated with glycochenodeoxycholic acid demonstrated cholangiocyte injury with monolayer disruption and partial lumen obstruction compared to control ducts. Masson's trichrome stains revealed increased collagen fibers. Myofibroblast marker α-SMA stains were significantly elevated in the periductal region. The addition of ursodeoxycholic acid resulted in decreased cholangiocyte injury and reduced fibrosis.
CONCLUSIONS
Bile acid leakage into the submucosa after initial cholangiocyte injury may serve as a possible mechanism of disease propagation and progressive fibrosis in cholangiopathies.
Topics: Animals; Bile Acids and Salts; Bile Ducts; Bile Ducts, Extrahepatic; Fibrosis; Glycochenodeoxycholic Acid; Mice; Ursodeoxycholic Acid
PubMed: 35294492
DOI: 10.1371/journal.pone.0265418 -
Biochimica Et Biophysica Acta.... Apr 2018Epigenomics is a fast-evolving field of research that has lately attracted considerable interest, mainly due to the reversibility of epigenetic marks. Clinically, among... (Review)
Review
Epigenomics is a fast-evolving field of research that has lately attracted considerable interest, mainly due to the reversibility of epigenetic marks. Clinically, among solid tumors, the field is still limited. In cholangiocarcinoma (CCA) it is well known that the epigenetic landscape is deregulated both during carcinogenesis and disease progression as a consequence of aberrant mechanisms leading to genome instability. In this article, we will briefly review the molecular alterations that have been described in the transformation of normal cholangiocytes into malignant derivatives, focusing on the role of non-coding RNA (ncRNA) interactions, DNA methylation, post-translational modifications (PTMs) of histones and chromatin remodeling complexes.
Topics: Bile Duct Neoplasms; Bile Ducts; Cell Transformation, Neoplastic; Cholangiocarcinoma; Chromatin Assembly and Disassembly; DNA Methylation; Disease Progression; Epigenesis, Genetic; Epithelial Cells; Gene Expression Regulation, Neoplastic; Genomic Instability; Histones; Humans; Protein Processing, Post-Translational; RNA, Untranslated
PubMed: 28645654
DOI: 10.1016/j.bbadis.2017.06.014 -
Canadian Journal of Surgery. Journal... Sep 2017Common bile duct (CBD) injury is the most serious complication of laparoscopic cholecystectomy. Recently, laparoscopic techniques have been used in the management of... (Review)
Review
Common bile duct (CBD) injury is the most serious complication of laparoscopic cholecystectomy. Recently, laparoscopic techniques have been used in the management of postoperative bile leak and CBD injury; this literature has not been reviewed. We reviewed the literature on CBD injury, the approach to its diagnosis and management, and reports of laparoscopic management techniques. We combined this review with our experience in laparoscopic methods to highlight diagnostic and therapeutic options. Laparoscopic techniques can be used to prevent, diagnose and treat CBD injuries. Intraoperatively, CBD injury can be prevented in the case of short cystic duct with the use of a loop ligature or transfixing suture, and it can be diagnosed using intraoperative cholangiography or other visualization techniques. When CBD injury is suspected postoperatively, repeat laparoscopy can be used to control sepsis with abdominal washout; as a diagnostic tool to guide management; and, in some settings, as a therapeutic tool for suturing small duct leaks, drain insertion and postoperative endoscopic retrograde cholangiopancreatography with sphincterotomy. Definitive laparoscopic repair is possible when certain criteria are met. Open surgery should be considered when the CBD is small, the injury occurred more than 72 hours previously, injury or anatomy are complex, port positioning is awkward for repair, or local experience is limited with laparoscopic management. There is an emerging role for laparoscopy in the management of CBD injuries. More case reports and series are needed to show the safety and efficacy of this technique, encourage its wider adoption, and allow outcomes assessment on a larger scale.
Topics: Bile Duct Diseases; Bile Ducts; Humans; Laparoscopy; Postoperative Complications
PubMed: 28930036
DOI: 10.1503/cjs.003317 -
World Journal of Gastroenterology Aug 2023Current abdominal surgery has several approaches for biliary reconstruction. However, the creation of functional and clinically applicable bile duct substitutes still...
Current abdominal surgery has several approaches for biliary reconstruction. However, the creation of functional and clinically applicable bile duct substitutes still represents an unmet need. In the paper by Miyazawa and colleagues, approaches to the creation of bile duct alternatives were summarized, and the reasons for the lack of development in this area were explained. The history of bile duct surgery since the nineteenth century was also traced, leading to the conclusion that the use of bioabsorbable materials holds promise for the creation of bile duct substitutes in the future. We suggest three ideas that may stimulate progress in the field of bile duct substitute creation. First, a systematic analysis of the causative factors leading to failure or success in the creation of bile duct substitutes may help to develop more effective approaches. Second, the regeneration of a bile duct is delicately balanced between epithelialization and subsequent submucosal maturation within limited time frames, which may be more apparent when using quantitative models to estimate outcomes. Third, the utilization of the organism's endogenous regeneration abilities may enhance the creation of bile duct substitutes. We are convinced that an interdisciplinary approach, including quantitative methods, machine learning, and deep retrospective analysis of the causes that led to success and failure in studies on the creation of bile duct substitutes, holds great value. Additionally, more attention should be directed towards the balance of epithelialization and submucosal maturation rates, as well as induced angiogenesis. These ideas deserve further investigation to pave the way for bile duct restoration with physiologically relevant outcomes.
Topics: Humans; Retrospective Studies; Bile Ducts; Biliary Tract Surgical Procedures; Machine Learning; Metaplasia
PubMed: 37662863
DOI: 10.3748/wjg.v29.i30.4701 -
Transplantation Jun 2023End-ischemic ex situ normothermic machine perfusion (NMP) enables assessment of donor livers prior to transplantation. The objective of this study was to provide support...
BACKGROUND
End-ischemic ex situ normothermic machine perfusion (NMP) enables assessment of donor livers prior to transplantation. The objective of this study was to provide support for bile composition as a marker of biliary viability and to investigate whether bile ducts of high-risk human donor livers already undergo repair during NMP.
METHODS
Forty-two livers that were initially declined for transplantation were included in our NMP clinical trial. After NMP, livers were either secondary declined (n = 17) or accepted for transplantation (n = 25) based on the chemical composition of bile and perfusate samples. Bile duct biopsies were taken before and after NMP and assessed using an established histological injury severity scoring system and a comprehensive immunohistochemical assessment focusing on peribiliary glands (PBGs), vascular damage, and regeneration.
RESULTS
Bile ducts of livers that were transplanted after viability testing during NMP showed better preservation of PBGs, (micro)vasculature, and increased cholangiocyte proliferation, compared with declined livers. Biliary bicarbonate, glucose, and pH were confirmed as accurate biomarkers of bile duct vitality. In addition, we found evidence of PBG-based progenitor cell differentiation toward mature cholangiocytes during NMP.
CONCLUSIONS
Favorable bile chemistry during NMP correlates well with better-preserved biliary microvasculature and PBGs, with a preserved capacity for biliary regeneration. During NMP, biliary tree progenitor cells start to differentiate toward mature cholangiocytes, facilitating restoration of the ischemically damaged surface epithelium.
Topics: Humans; Liver Transplantation; Living Donors; Liver; Bile Ducts; Perfusion; Bile Duct Diseases; Organ Preservation
PubMed: 36721302
DOI: 10.1097/TP.0000000000004531 -
Biochimica Et Biophysica Acta.... May 2019Cholestasis is a frequent clinical condition initiating or complicating chronic liver diseases, particularly cholangiopathies, where the biliary epithelium is the... (Review)
Review
Cholestasis is a frequent clinical condition initiating or complicating chronic liver diseases, particularly cholangiopathies, where the biliary epithelium is the primary target of the pathogenetic sequence. Until a few decades ago, understanding of cholestasis relied mostly on the experimental model of bile duct ligation in rodents. However, a simple model of biliary obstruction cannot reproduce the complex mechanisms and networks leading to cholestasis in cholangiopathies. These networks are underpinned by an intricate dysregulation of pro-inflammatory and pro-fibrotic signals involving besides cholangiocytes, multiple cell elements of both innate and adaptive immunity. Therefore, in the last years, a wide range of animal models of biliary injury have been developed, mostly in mice, following three main approaches, chemical induction, immunization and genetic manipulation. In this review, we will give an update of the animal models of the two main cholangiopathies, primary sclerosing cholangitis and primary biliary cholangitis, which have provided us with the most relevant insights into the pathogenesis of these still controversial diseases.
Topics: Animals; Bile Ducts; Cholangitis; Cholestasis; Disease Models, Animal; Humans
PubMed: 30398152
DOI: 10.1016/j.bbadis.2018.07.025 -
Surgical Endoscopy Jun 2021Recently new standards for reporting outcomes of bile duct injury (BDI) have been proposed. It is unclear how these treatment outcomes are reflected in quality of life...
INTRODUCTION
Recently new standards for reporting outcomes of bile duct injury (BDI) have been proposed. It is unclear how these treatment outcomes are reflected in quality of life (QOL). The aim of this study was to report outcomes and QOL after repair of major BDI and compare repairs by hepatobiliary surgeon to repairs by non-hepatobiliary surgeons.
METHODS
This was a retrospective study of patients treated for major (Strasberg E-type) BDI after cholecystectomy at a tertiary hepatobiliary center. Outcomes were assessed using Cho-Strasberg proposed standards. QOL was assessed using Short Form Health Survey (SF-36) and the gastrointestinal QOL-index (GIQLI). Patients undergoing uneventful cholecystectomy matched by age, urgency, and duration of follow-up were used as controls.
RESULTS
Fifty-two patients with major BDI treated between 2000 and 2016 were included (42% male, median age 53 years). Thirty-seven (71%) patients attained primary patency (29 (83%) if primarily operated by a hepatobiliary surgeon). Actuarial primary patency rate (grade A result) at 1, 3, and 5 years was 58%, 56%, and 53% in the whole cohort, and 83%, 80%, and 80% in patients primary treated by a hepatobiliary surgeon, respectively. At 3-year follow-up 6 (11.5%) patients obtained grade B, 10 (19.2%) grade C, and 7 (13.5%) grade D result. QOL was similar in patients with BDI and controls (median SF-36 physical component 51.7 and 53.6, p = 1.0, mental component 53.3 and 53.4, p = 1.0, GIQLI 109.0 and 123.0, p = 0.174, respectively) at median 90 (IQR 70-116) months from cholecystectomy. QOL was similar regardless of outcome grade.
CONCLUSION
First attempt to repair a severe BDI should be undertaken by a hepatobiliary surgeon. However, long-term QOL is not affected even by severe BDI, and QOL is not associated with the grade of the outcome.
Topics: Bile Duct Diseases; Bile Ducts; Female; Follow-Up Studies; Humans; Male; Middle Aged; Quality of Life; Retrospective Studies
PubMed: 32572630
DOI: 10.1007/s00464-020-07726-x -
Physiological Reports Jul 2022Infants with neonatal cholestasis are prone to neurodevelopmental deficits, however, the underlying pathogenesis is unclear. Lipid malabsorption and accumulation of...
Infants with neonatal cholestasis are prone to neurodevelopmental deficits, however, the underlying pathogenesis is unclear. Lipid malabsorption and accumulation of potentially neurotoxic molecules in the blood such as bile acids are important yet relatively unexplored pathways. Here, we developed a translational piglet model to understand how the molecular bile acid and lipid composition of the brain is affected by this disease and relates to motor function. Piglets (8-days old) had bile duct ligation or sham surgery and were fed a formula diet for 3 weeks. Alongside sensory-motor deficits observed in bile duct-ligated animals, we found a shift toward a more hydrophilic and conjugated bile acid profile in the brain. Additionally, comprehensive lipidomics of the cerebellum revealed a decrease in total lipids including phosphatidylinositols and phosphatidylserines and increases in lysophospholipid species. This was paralleled by elevated cerebellar expression of genes related to inflammation and tissue damage albeit without significant impact on the brain transcriptome. This study offers new insights into the developing brain's molecular response to neonatal cholestasis indicating that bile acids and lipids may contribute in mediating motor deficits.
Topics: Animals; Bile Acids and Salts; Bile Ducts; Brain; Cholestasis; Humans; Lipids; Swine
PubMed: 35822260
DOI: 10.14814/phy2.15368 -
World Journal of Gastroenterology Oct 2023Intraductal papillary neoplasms of the bile duct (IPNBs) represent a rare variant of biliary tumors characterized by a papillary growth within the bile duct lumen. Since... (Review)
Review
Intraductal papillary neoplasms of the bile duct (IPNBs) represent a rare variant of biliary tumors characterized by a papillary growth within the bile duct lumen. Since their first description in 2001, several classifications have been proposed, mainly based on histopathological, radiological and clinical features, although no specific guidelines addressing their management have been developed. Bile duct neoplasms generally develop through a multistep process, involving different precursor pathways, ranging from the initial lesion, detectable only microscopically, biliary intraepithelial neoplasia, to the distinctive grades of IPNB until the final stage represented by invasive cholangiocarcinoma. Complex and advanced investigations, mainly relying on magnetic resonance imaging (MRI) and cholangioscopy, are required to reach a correct diagnosis and to define an adequate bile duct mapping, which supports proper treatment. The recently introduced subclassifications of types 1 and 2 highlight the histopathological and clinical aspects of IPNB, as well as their natural evolution with a particular focus on prognosis and survival. Aggressive surgical resection, including hepatectomy, pancreaticoduodenectomy or both, represents the treatment of choice, yielding optimal results in terms of survival, although several endoscopic approaches have been described. IPNBs are newly recognized preinvasive neoplasms of the bile duct with high malignant potential. The novel subclassification of types 1 and 2 defines the histological and clinical aspects, prognosis and survival. Diagnosis is mainly based on MRI and cholangioscopy. Surgical resection represents the mainstay of treatment, although endoscopic resection is currently applied to nonsurgically fit patients. New frontiers in genetic research have identified the processes underlying the carcinogenesis of IPNB, to identify targeted therapies.
Topics: Humans; Bile Ducts; Cholangiocarcinoma; Bile Duct Neoplasms; Biliary Tract Neoplasms; Bile Ducts, Intrahepatic
PubMed: 37900587
DOI: 10.3748/wjg.v29.i38.5361