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Context: There is data about the existence of some endocrine cells in the epithelial layer of the bile duct in humans and rats. Objective: We evaluated Ghrelin-, Insulin-, Glucagon- and Somatostatin-positive cells in peribiliary glands, mast cells, and nerve fibres. Materials and methods: Wistar rats were used for dietary manipulation with a 15% fructose solution for 12 weeks. Tissue samples were elaborated with immunohistochemistry for Insulin, Glucagon, Ghrelin, and Somatostatin. Glucose and lipid parameters were studied. Results: In treated animals, Ghrelin+ and Insulin+ cells in perybiliary glands (PBGs) were significantly increased. In the male fructose group there was a significant increase of the homeostasis model assessment insulin resistance (HOMA-IR). Conclusions: Stem/progenitor cells in extrahepatic bile tree (EHBT) could be a source of Insulin-producing cells in metabolic syndrome. Fructose treatment induces the increase of Ghrelin+ and Insulin+ cells in PBGs and the elevation of Insulin and Ghrelin plasma concentration. [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is an obstructive cholangiopathy that initially affects the extrahepatic bile ducts (EHBDs) of neonates. The etiology is uncertain, but evidence points to a prenatal cause. Fetal tissues have increased levels of hyaluronic acid (HA), which plays an integral role in fetal wound healing. The objective of this study was to determine whether a program of fetal wound healing is part of the response to fetal EHBD injury. Mouse, rat, sheep, and human EHBD samples were studied at different developmental time points. Models included a fetal sheep model of prenatal hypoxia, human BA EHBD remnants and liver samples taken at the time of the Kasai procedure, EHBDs isolated from neonatal rats and mice, and spheroids and other models generated from primary neonatal mouse cholangiocytes. A wide layer of high molecular weight HA encircling the lumen was characteristic of the normal perinatal but not adult EHBD. This layer, which was surrounded by collagen, expanded in injured ducts in parallel with extensive peribiliary gland hyperplasia, increased mucus production and elevated serum bilirubin levels. BA EHBD remnants similarly showed increased HA centered around ductular structures compared with age-appropriate controls. High molecular weight HA typical of the fetal/neonatal ducts caused increased cholangiocyte spheroid growth, whereas low molecular weight HA induced abnormal epithelial morphology; low molecular weight HA caused matrix swelling in a bile duct-on-a-chip device. The fetal/neonatal EHBD, including in human EHBD remnants from Kasai surgeries, demonstrated an injury response with prolonged high levels of HA typical of fetal wound healing. The expanded peri-luminal HA layer may swell and lead to elevated bilirubin levels and obstruction of the EHBD. Biliary atresia is a pediatric cholangiopathy associated with high morbidity and mortality rates; although multiple etiologies have been proposed, the fetal response to bile duct damage is largely unknown. This study explores the fetal pathogenesis after extrahepatic bile duct damage, thereby opening a completely new avenue to study therapeutic targets in the context of biliary atresia. [Display omitted] • Fetal and neonatal extrahepatic bile ducts have high levels of hyaluronic acid, located directly around the lumen. • Damage to the fetal extrahepatic bile duct is followed by increased hyaluronic acid deposition. • Biliary atresia remnants show increased hyaluronic acid deposition around epithelial structures compared to controls. • Hyaluronic acid in neonatal extrahepatic bile ducts is degraded after injury. • Hyaluronic acid polymers of different sizes have distinct biological effects on cholangiocytes. [ABSTRACT FROM AUTHOR]

The development of cholangiopathies after liver transplantation impacts on the quality and duration of graft and patient survival, contributing to higher costs as numerous interventions are required to treat strictures and infections at the biliary tree. Prolonged donor warm ischaemia time in combination with additional cold storage are key risk factors for the development of biliary strictures. Based on this, the clinical implementation of dynamic preservation strategies is a current hot topic in the field of donation after circulatory death (DCD) liver transplantation. Despite various retrospective studies reporting promising results, also regarding biliary complications, there are only a few randomised-controlled trials on machine perfusion. Recently, the group from Groningen has published the first randomised-controlled trial on hypothermic oxygenated perfusion (HOPE), demonstrating a significant reduction of symptomatic ischaemic cholangiopathies with the use of a short period of HOPE before DCD liver implantation. The most likely mechanism for this important effect, also shown in several experimental studies, is based on mitochondrial reprogramming under hypothermic aerobic conditions, e.g. exposure to oxygen in the cold, with a controlled and slow metabolism of ischaemically accumulated succinate and simultaneous ATP replenishment. This unique feature prevents mitochondrial oxidative injury and further downstream tissue inflammation. HOPE treatment therefore supports livers by protecting them from ischaemia-reperfusion injury (IRI), and thereby also prevents the development of post-transplant biliary injury. With reduced IRI-associated inflammation, recipients are also protected from activation of the innate immune system, with less acute rejections seen after HOPE. [ABSTRACT FROM AUTHOR]

Peribiliary glands are complex lobular structures containing mucus and serous glands, distributed along the extrahepatic and intrahepatic bile ducts. In this report, we describe a case of intraductal papillary neoplasm of the bile duct suspected to be of peribiliary glands origin. The patient was an 80-year-old man who was referred to our hospital for a hepatic mass. On further examination, a 38 × 34 mm cystic lesion with papillary growth was found in S1/4. Because the lesion was extensively bordered by both hepatic ducts and the connection was unclear, it was difficult to determine the extent of hepatic resection. To confirm the location, a peroral cholangioscopy was performed. The connection with the cyst was detected in the right hepatic duct and a villous tumor mucosa protruded through the conduit lumen. Since we found that the lesion communicated with the right hepatic duct, a right hepatectomy was subsequently performed. The postoperative pathological diagnosis was an intraductal papillary neoplasm of the blie duct with associated invasive carcinoma. The postoperative course was good, and the patient experienced no recurrence., Competing Interests: None., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

IntroductionChimerism after orthotopic liver transplantation (OLT) has largely been investigated in intrahepatic cellular constituents. However, little is known about chimerism in the extrahepatic and large intrahepatic bile ducts. Our aim was to evaluate the presence and extent of chimerism after OLT in the peribiliary glands (PBG) and the luminal epithelium of the large donor bile ducts.MethodsFor this study, we examined six extrahepatic and large intrahepatic bile ducts from livers that were re-transplanted. In all cases there was a sex-mismatch between donor and recipient (female donor organ and male recipient), which allowed to discriminate between donor- and recipient-derived cells. Specimens from female to female transplants were used as negative controls and male to male transplants as positive controls. Fluorescence in situ hybridization (FISH) for Y and X chromosomes was performed and the percentage of XY positive cells was determined among biliary epithelial cells. Immunohistochemistry was used to correlate chimerism with histological features.ResultsCholangiocellular chimerism in all studied specimens ranged from 14 to 52%. The degree of chimerism was not associated with biliary damage. Marked chimerism was present at 5 days post-OLT. Ki-67-positivity was detected in 1–8% of the epithelial cells at the time of liver re-transplantation, and this correlated inversely with the degree of chimerism.ConclusionRecipient-derived cholangiocytes are present in the large bile ducts of the donor liver after OLT. The presence of chimerism in the large bile ducts suggests that recipient-derived cells may play a role in biliary regeneration following ischemia-induced injury during OLT.

The peribiliary glands are intramural or extramural structures with multiple functions related to bile secretion. The peribiliary glands can develop cystic alterations in several conditions, such as alcohol addiction. Peribiliary cysts can enlarge till being radiologically visible and mimic cancer. We studied 217 consecutive explanted livers for end-stage alcohol-related liver disease from the Pathology Unit of the Liver Unit at the King's College Hospital in Denmark Hill, with particular focus on peribiliary glands. Our cohort consisted of 31 females and 186 males, with a median age of 51 and of 56 years respectively. 92,2% had established cirrhosis, 73,3% had only alcohol-induced liver disease, whilst 26,7% had other co-morbidities. We found a mild ectasia of the peribiliary glands (<2 mm) in 37,8% and peribiliary cysts (> = 2 mm) in 22,6% of cases. The diameter of the peribiliary glands varied from 1 mm to 8 mm. Inflammation of the peribiliary glands was found in the majority of cases with dilatation (p value = 0,000). 4,6% of the peribiliary cysts had low-grade intraductal papillary neoplasm of the bile ducts confined to the peribiliary glands. Pancreatic heterotopia was found in 10,6% and associated with the presence of ectasia. Our findings fit with what is reported in literature, such as the alcohol-induced damage at the peribiliary glands. Moreover these results underline the possible role of peribiliary glands in the development of the intraductal papillary neoplasm of the bile ducts, the biliary counterpart of the branch type intraductal mucinous neoplasm of the pancreas. [ABSTRACT FROM AUTHOR]

The larger ducts of the biliary tree contain numerous tubulo-alveolar adnexal glands that are lined with biliary epithelial cells and connected to the bile duct lumen via small glandular canals. Although these peribiliary glands (PBG) were already described in the 19th century, their exact function and role in the pathophysiology and development of cholangiopathies have not become evident until recently. While secretion of serous and mucinous components into the bile was long considered as the main function of PBG, recent studies have identified PBG as an important source for biliary epithelial cell proliferation and renewal. Activation, dilatation, and proliferation of PBG (or the lack thereof) have been associated with various cholangiopathies. Moreover, PBG have been identified as niches of multipotent stem/progenitor cells with endodermal lineage traits. This has sparked research interest in the role of PBG in the pathogenesis of various cholangiopathies as well as bile duct malignancies. Deeper understanding of the regenerative capacity of the PBG may contribute to the development of novel regenerative therapeutics for previously untreatable hepatobiliary diseases. 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. [ABSTRACT FROM AUTHOR]

Background and Aims: Dilated peribiliary glands (PBG) in patients with cirrhosis are often an incidental finding although their significance and physiopathology remain unclear. We aimed to identify clinical factors associated with dilated PBG and to perform a detailed morphometric assessment of dilated PBG in cirrhotic patients undergoing liver transplantation (LT).Methods: All consecutive cirrhotic patients undergoing LT at our institution between October 2006 and October 2011 were assessed for inclusion. Ten non-cirrhotic patients were included as controls. We performed morphometrical assessment of PBG, assessed baseline clinical factors associated with dilated PBG, immunohistochemistry staining with CK-19, MiB-1 and EpCAM, and radiological assessment of all available cases.Results: Seventy-one patients met the inclusion criteria, 24% had PBG dilatation of >1000 µm. On multivariable analysis, MELD (OR 1.11 per unit increase in MELD, p = 0.004) was the only significant factor associated with dilated PBG. Compared to PBG < 1000 µm, large PBG had a higher proportion of EpCAM-positive (69 vs. 28%, p < 0.001) and MiB-1-positive lining cells (2.8 vs. 0.55%, p = 0.036). Computed tomography and magnetic resonance imaging had high specificity but low sensitivity for the diagnosis of dilated PBG > 1000 µm (specificity 90-100%, sensitivity 25-29%).Conclusions: Dilated PBGs are a common finding in explants of cirrhotic subjects undergoing LT and are associated with liver failure although diagnostic performance of cross-sectional imaging is inconstant. The high number of proliferative and EpCAM-positive cells lining the PBG may suggest a role of PBG in organ repair during liver failure. [ABSTRACT FROM AUTHOR]

Cholangiocarcinomas (CCAs) are anatomically classified into intrahepatic, perihilar, and distal types. The gross pathological classification of intrahepatic CCAs divides them into mass-forming, periductal-infiltrating, and intraductal-growth types; and perihilar/distal CCAs into flat- and nodular-infiltrating and papillary types. Unique preinvasive lesions appear to precede individual gross types of CCA. Biliary intraepithelial neoplasia, a flat lesion, precedes periductal-, flat-, and nodular-infiltrating CCAs, whereas intraductal papillary neoplasm of the bile duct (IPNB) precedes the intraductal-growth and papillary type of CCAs. IPNBs are heterogeneous in their histological and pathological profiles along the biliary tree. Hepatobiliary cystadenomas/adenocarcinomas are reclassified as cystic IPNBs and hepatic mucinous cystic neoplasms. Peribiliary glands may participate in the development of CCAs. These latest findings present a new challenge for understanding the pathology of CCAs. [ABSTRACT FROM PUBLISHER]

Introduction Heterotopic pancreas (HP) has rarely been identified in the wall of choledochal cyst (CC). Methods Retrospectively we screened 200 excised specimens of CC received at our Institute over a period of last eight years and looked for presence of HP rests in them. All the specimens were processed in their entirety. Result HP was identified in the wall of 13 (6.5%) CCs, out of which 11 were Heinrich Type 2, and two were Heinrich Type 1. In half of the cases peribiliary mucous glands were observed intermingled with the HP rests. Features of chronic fibrosing pancreatitis were identified in these rests, with ulceration of overlying cyst lining. Conclusions HP rests in the wall of CC though rare; their coexistence with peribiliary glands may possibly indicate their common embryonic origin. As a common site of inflammation, HP rest may be one of the common causes of CC. [ABSTRACT FROM AUTHOR]

A tumorigenic role of peribiliary glands (PBGs) has been suggested recently. This study was performed to clarify the histological characteristics of PBGs showing cystic and micropapillary epithelial changes. From histological sections of a total of 938 autopsy livers, cases with cystic and micropapillary changes of the epithelial cells of intrahepatic PBGs were collected. PBGs with cystic change that lacked micropapillary epithelial changes were referred to as cystic lesion. Mucin staining and immunohistochemical analysis were performed, and the results were compared between cystic and micropapillary (C-P) lesions and cystic lesions. C-P and cystic lesions were observed in 9 (1 %) and 40 (4 %) , respectively. The atypia of micropapillary epithelium was usually mild, but in a single case, invasive adenocarcinoma accompanied a C-P lesion. Abundant mucin expression was observed in all cases of C-P lesion, which was similar to mucinous acini of normal PBGs rather than serous acini. Immunohistochemical analysis showed that MUC5AC was more frequently expressed in C-P lesions than in cystic lesions. Immunohistochemical expression of cyclin D1 and S100P was characteristically found in C-P lesions. Mean Ki-67 labeling index of C-P lesions was significantly higher than that of cystic lesions. The immunoprofile of C-P lesions was similar to that of the branch-type intraductal papillary mucinous neoplasm of the pancreas. These results suggest that C-P lesions may have neoplastic features and might represent a precursor of biliary epithelial neoplasms, including branch-type intraductal papillary neoplasm of the bile duct as well as mucin-producing cholangiocarcinoma, a concept that we have recently proposed. [ABSTRACT FROM AUTHOR]

Peribiliary glands (PBGs) in bile duct walls, and pancreatic duct glands (PDGs) associated with pancreatic ducts, in humans of all ages, contain a continuous, ramifying network of cells in overlapping maturational lineages. We show that proximal (PBGs)-to-distal (PDGs) maturational lineages start near the duodenum with cells expressing markers of pluripotency (NANOG, OCT4, and SOX2), proliferation (Ki67), self-replication (SALL4), and early hepato-pancreatic commitment (SOX9, SOX17, PDX1, and LGR5), transitioning to PDG cells with no expression of pluripotency or self-replication markers, maintenance of pancreatic genes (PDX1), and expression of markers of pancreatic endocrine maturation (NGN3, MUC6, and insulin). Radial-axis lineages start in PBGs near the ducts' fibromuscular layers with stem cells and end at the ducts' lumens with cells devoid of stem cell traits and positive for pancreatic endocrine genes. Biliary tree-derived cells behaved as stem cells in culture under expansion conditions, culture plastic and serum-free Kubota's Medium, proliferating for months as undifferentiated cells, whereas pancreas-derived cells underwent only approximately 8-10 divisions, then partially differentiated towards an islet fate. Biliary tree-derived cells proved precursors of pancreas' committed progenitors. Both could be driven by three-dimensional conditions, islet-derived matrix components and a serum-free, hormonally defined medium for an islet fate (HDM-P), to form spheroids with ultrastructural, electrophysiological and functional characteristics of neoislets, including glucose regulatability. Implantation of these neoislets into epididymal fat pads of immunocompromised mice, chemically rendered diabetic, resulted in secretion of human C-peptide, regulatable by glucose, and able to alleviate hyperglycemia in hosts. The biliary tree-derived stem cells and their connections to pancreatic committed progenitors constitute a biological framework for life-long pancreatic organogenesis. S tem C ells 2013;31:1966-1979 [ABSTRACT FROM AUTHOR]

There are peribiliary glands around the biliary tract, and these glands drain into the bile duct lumen. Interestingly, small amounts of pancreatic exocrine acini are intermingled with these glands. Experimental studies using animals suggest that the biliary tract shows some potential for pancreatic differentiation. It is noteworth that the biliary tract and pancreas have similar pathological features. IgG4-related sclerosing cholangitis and autoimmune pancreatitis are representative inflammatory diseases with similar features. Intraductal papillary neoplasms are found in the biliary tract and also in the pancreas: intraductal papillary neoplasm of the bile duct (IPNB) and intraductal papillary mucinous neoplasm of the pancreas (IPMN). IPNB and IPMN share common histologic and phenotypic features and biological behaviors. Interestingly, mucinous cystic neoplasm (MCN) arises in both the pancreas and the heaptobiliary system. Intraductal tubular neoplasia is found in both the biliary tract and pancreas as well. Intraepithelial neoplasm is found in the biliary tract and pancreas: biliary intraepithelial neoplasm (BilIN) and pancreatic intraepithelial neoplasm (PanIN). BilIN and PanIN are followed by conventional invasive adenocarcinoma, while IPNB and IPMN are followed by tubular adenocarcinoma and mucinous carcinoma in both organs. Further study of the biliary tract's pathophysiology based on its similarity to pancreatic counterparts is warranted. [ABSTRACT FROM AUTHOR]

Liver cirrhosis is reportedly one of the conditions preceding peripheral-type intrahepatic cholangiocarcinoma but not hilar/perihilar cholangiocarcinoma. Herein, we report a case of perihilar cholangiocarcinoma arising in a hepatitis C virus-related cirrhotic liver. The patient was a 69-year-old man. He was diagnosed with hepatitis C virus-related chronic hepatitis at the age of 56 years, and 9 years later, multiple hepatocellular carcinomas were detected by imaging modalities. Despite treatments, including chemotherapy, he died of hepatic failure at the age of 69 years. At autopsy, in addition to multiple nodules of hepatocellular carcinoma, we found a white mucinous and fibrous tumor spreading from the hepatic hilum to the periphery along the left lateral segmental bile ducts in the advanced cirrhotic liver. This tumor was histologically a cholangiocarcinoma that involved mainly the peribiliary glands and showed variable cystic dilation, suggesting that it might have been derived from these peribiliary glands. Immunohistochemically, the cholangiocarcinoma cells were positive for cytokeratin 7 and mucin core protein 1, and negative for cytokeratin 20 and mucin core protein 2. Hilar/perihilar cholangiocarcinoma arising in hepatitis C virus-related liver cirrhosis has rarely been reported. This case warrants further studies to clarify the possible involvement of hepatitis C virus in tumorigenesis of hilar/perihilar cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Discusses the case of peribiliary cysts, initially thought to represent Caroli's disease, in a 36-year-old man presented with a perforated cecal mass, and underwent a right hemicolectomy. Diagnosis of peribiliary cysts, otherwise known as cystic dilatation of the peribiliary glands; Histology of the lesion; Management of the condition.

Trefoil factor family (TFF) 1, 2, and 3 is a mucin-associated protein involved in the maintenance of mucosal barrier and restitution of lining epithelial cells. In this study, the expression of TFF1, 2, and 3 and MUC mucins were examined immunohistochemically in hepatolithiasis and control livers. The expression of TFF1, 2, and 3 were augmented markedly in biliary mucosa in hepatolithiasis in coordinate with gel-forming mucin. TFF3 was detected in hepatic bile samples of hepatolithiasis. Augmented expression and secretion of TFF in biliary mucosa in hepatolithiasis may play a role in lithogenesis together with gel-forming mucin in addition to mucosal defense and repair. [Copyright &y& Elsevier]

Neoplastic transformation of epithelial cells is commonly associated with alterations in the synthesis and structures of mucin. Mucin protein epitopes and mRNA levels were frequently altered in adenocarcinomas compared to corresponding normal tissues. Clinically, hepatolithiasis has been regarded as a risk factor for cholangiocarcinoma. The aims of this study were to determine the possible alteration of mucin gene expression in stone-containing intrahepatic bile ducts and cholangiocarcinomas and to try to predict whether or not hepatolithiasis has a predisposition to development of cholangiocarcinoma. In situ hybridization with DIG-tailed oligonucleotides was performed on sections of paraffin-embedded tissues of stone-containing intrahepatic bile ducts, cholangiocarcinomas, and normal controls to identify the expression of MUC2, MUC3, MUC4, MUC5B, and MUC5AC in nonneoplastic and neoplastic biliary epithelium. The findings showed that (1) while multiple diverse mucin genes were expressed in the biliary epithelium, MUC3 and MUC5B mRNA were the main mucin genes expressed in the biliary epithelium of stone-containing intrahepatic bile ducts and normal controls; (2) absent or decreased expression of MUC2, MUC3, and MUC5B of mRNA was found in cholangiocarcinomas in contrast to nonneoplastic biliary epithelium; and (3) increased expression of MUC4 and MU5AC of mRNA was found in cholangiocarcinomas and the biliary epithelium, especially for dysplastic cells of stone-containing intrahepatic bile ducts compared with normal controls. In this study, using in situ hybridization we demonstrated that neoplastic transformation of the biliary epithelium is accompained by alterations in mucin gene expression, the altered mucin gene expression in dysplastic cells of stone-containing intrahepatic bile ducts may reflect a higher potential for malignant transformation in these cells, and it could be a precursor of cholangiocarcinoma in the presence of hepatolithiasis. [ABSTRACT FROM AUTHOR]

Aims/Background: Nerve growth factor (NGF) has recently been shown to influence the survival and function of non-neuronal inflammatory cells, possibly through its activity as a colony-stimulating factor. It may also play an important role in acute inflammation and tissue repair. However, no prior report has focused on NGF in chronic inflammatory diseases of the gastrointestinal and biliary tracts. The aim of this study was to examine the expression of NGF in hepatolithiasis. Methods: Twenty-six liver specimens resected from 22 patients with intrahepatic calcium bilirubinate stones and from 4 patients with intrahepatic cholesterol stones were examined immunohistochemically. Results: The 22 patients with calcium bilirubinate stones demonstrated NGF immunoreactivity associated with surrounding inflammatory cells that was localized to the epithelia of proliferative peribiliary glands in the ductal wall. However, neither the surface lining of the bile duct nor hepatocytes expressed detectable NGF immunoreactivity. In the cholesterol stones cases in contrast, peribiliary glandular elements and inflammatory cell infiltration were less extensive than those observed in cases of calcium bilirubinate stones, and NGF immunoreactivity was not noted. Conclusions: These observations suggest that proliferative peribiliary glands express NGF protein in chronic proliferative cholangitis. This is characteristic of intrahepatic calcium bilirubinate stones. [ABSTRACT FROM AUTHOR]

Although primary sclerosing cholangitis (PSC) is not a common disease, it is important in the differential diagnosis of hepatobiliary tract diseases in clinical practice. A diagnosis of PSC should be made only after the exclusion of similar diseases with well known etiologies or pathogeneses. In this review, the pathology of classical PSC and its variants or related diseases is highlighted. PSC is histologically characterized by progressive periductal fibrosis with luminal stenosis or obliteration, along with the formation of a fibrous core, as well as dilatation (cholangiectasis). Its etiology is unknown. Bacterial ascending cholangitis is superimposed on its long clinical course. Such a heterogeneous distribution of biliary lesions with biliary obliteration and cholangiectasis is responsible for the radiological demonstration of biliary abnormalities, particularly the beaded appearance. Sampling variability is common in needle or wedge biopsied specimens. As a result of biliary damage, the liver shows progressive cholestatic change followed by biliary fibrosis and cirrhosis, and this hepatic progression is divisible into four stages. There are several variants of PSC or related diseases, such as localized biliary sclerosis and stenosis, sclerosing cholangitis associated with inflammatory pseudotumor, and PSC-autoimmune hepatitis overlapping syndrome. Cholelithiasis, including secondary hepatolithiasis and, to a lesser degree, biliary carcinoma and dysplasia, are also known to develop at the perihilar bile ducts as a late complication of PSC. [ABSTRACT FROM AUTHOR]

Two distinct stem/progenitor cell populations of biliary origin have been identified in the adult liver and biliary tree. Hepatic Stem/progenitor Cells (HpSCs) are bipotent progenitor cells located within the canals of Hering and can be differentiated into mature hepatocytes and cholangiocytes; Biliary Tree Stem/progenitor Cells (BTSCs) are multipotent stem cells located within the peribiliary glands of large intrahepatic and extrahepatic bile ducts and able to differentiate into hepatic and pancreatic lineages. HpSCs and BTSCs are endowed in a specialized niche constituted by supporting cells and extracellular matrix compounds. The actual contribution of these stem cell niches to liver and biliary tree homeostatic regeneration is marginal; this is due to the high replicative capabilities and plasticity of mature parenchymal cells (i.e., hepatocytes and cholangiocytes). However, the study of human liver and biliary diseases disclosed how these stem cell niches are involved in the regenerative response after extensive and/or chronic injuries, with the activation of specific signaling pathways. The present review summarizes the contribution of stem/progenitor cell niches in human liver diseases, underlining mechanisms of activation and clinical implications, including fibrogenesis and disease progression. [ABSTRACT FROM AUTHOR]

Peribiliary glands (PBGs) represent the niche of biliary tree stem/progenitor cells (BTSCs) [1]. BTSCs are multipotent stem cells able to differentiate into hepatocytes, cholangiocytes, and pancreatic islets. Primary sclerosing cholangitis (PSC) is a chronic inflammation involving extra-hepatic biliary tree, and is complicated by the risk of cholangiocarcinoma (CCA) development [2]. We aimed to evaluate the involvement of PBGs and BTSCs in PSC and their role in CCA insurgence [2]. Specimens from normal liver (N=5), PSC (N=20), and CCA arising in PSC patients (N=20) were included and processed for histology, immunohistochemistry and immunofluorescence. In vitro experiments were performed on human BTSCs and primary CCA cell cultures. PSC-affected ducts were characterized by the activation of BTSCs and by PBG hyperplasia. In PSC, ducts showed higher microvascular density around PBGs compared to normal ducts. In CCA arising in PSC patients, PBGs showed dysplastic and neoplastic aspects. Compared to non-cancerous ducts, neoplastic ducts showed higher inflammation, wall thickness, and PBG activation. CCAs were characterized by higher expression of epithelial-to-mesenchymal transition (EMT) traits in PBGs and by the absence of primary cilia in BTSCs compared to control ducts. In vitro study confirmed that human BTSCs, under inflammatory milieu, increased proliferation rate and expression of EMT traits, and lost primary cilia compared to control conditions. In conclusion, patients affected by PSC are characterized by PBG involvement and activation of BTSC niche; the insurgence of CCA was characterized by involvement of PBG niche, suggesting a key role of this cell compartment in progressive tumorigenesis. [ABSTRACT FROM AUTHOR]

Some biliary diseases mimic pancreatic diseases pathologically as well as pathogenetically. Such diseases can be called "biliary diseases with pancreatic counterparts". Biliary intraepithelial neoplasm (BilIN), intraductal papillary neoplasm of bile ducts (IPNB), hepatobiliary mucinous cystic neoplasm (hMCN), and IgG4-inflammatory pseudotumor represent the biliary counterparts of pancreatic intraepithelial neoplasm (PanIN), intraductal papillary mucinous neoplasm of pancreas (IPMN), pancreatic MCN, and mass forming type 1 autoimmune pancreatitis (AIP), respectively. BilIN and PanIN represent pre-invasive intraepithelial stages of nodular sclerosing cholangiocarcinoma and pancreatic ductal adenocarcinoma, respectively. IPNB and IPMN are grossly visible, predominant papillary, intraductal neoplasms that may progress to invasive carcinoma. Morphologically similar MCNs with subepithelial ovarian-like stroma occur in both the hepatobiliary system as well as the pancreas. IgG4-inflammatory pseudotumor, usually of the lymphoplasmacytic type, and mass forming type 1 AIP represent IgG4-related disease in the biliary tree and pancreas respectively. The biliary tract, which is associated with the peribiliary glands, including the pancreatic acini, can be regarded as an incomplete pancreas, so several diseases mimicking pancreatic diseases may be expected to occur in the biliary tract (biliary diseases with pancreatic counterparts)., (Copyright © 2017. Published by Elsevier Inc.)

Aim: To investigate the roles of peribiliary glands around the bile ducts in the pathophysiology of the biliary tract., Methods: The expression of fetal pancreatic markers, pancreatic duodenal homeobox factor 1 (PDX1) and hairy and enhancer of split 1 (HES1) and endodermal stem/progenitor (S/P) cell markers [CD44s, chemokine receptor type 4 (CXCR4), SOX9 and epithelial cell adhesion molecule (EpCAM)] were examined immunohistochemically in 32 normal adult livers (autopsy livers) and 22 hepatolithiatic livers (surgically resected livers). The latter was characterized by the proliferation of the peribiliary glands. Immunohistochemistry was performed using formalin-fixed, paraffin-embedded tissue sections after deparaffinization. Although PDX1 and HES1 were expressed in both the nucleus and cytoplasm of epithelial cells, only nuclear staining was evaluated. SOX9 was expressed in the nucleus, while CD44s, CXCR4 and EpCAM were expressed in the cell membranes. The frequency and extent of the expression of these molecules in the lining epithelia and peribiliary glands were evaluated semi-quantitatively based on the percentage of positive cells: 0, 1+ (focal), 2+ (moderate) and 3+ (extensive)., Results: In normal livers, PDX1 was infrequently expressed in the lining epithelia, but was frequently expressed in the peribiliary glands. In contrast, HES1 was frequently expressed in the lining epithelia, but its expression in the peribiliary glands was focal, suggesting that the peribiliary glands retain the potential of differentiation toward the pancreas and the lining epithelia exhibit properties to inhibit such differentiation. This unique combination was also seen in hepatolithiatic livers. The expression of endodermal S/P cell markers varied in the peribiliary glands in normal livers: SOX9 and EpCAM were frequently expressed, CD44s infrequently, and CXCR4 almost not at all. The expression of these markers, particularly CD44s and CXCR4, increased in the peribiliary glands and lining epithelia in hepatolithiatic livers. This increased expression of endodermal S/P cell markers may be related to the increased production of intestinal and gastric mucin and also to the biliary neoplasia associated with the gastric and intestinal phenotypes reported in hepatolithiasis., Conclusion: The unique expression pattern of PDX1 and HES1 and increased expression of endodermal S/P cell markers in the peribiliary glands may be involved in biliary pathophysiologies.

Cholangiocarcinomas (CCs) show intraluminal spread to bile ducts and periductal infiltration associated with vascular, lymphatic and perineural invasion in addition to direct penetration. Recently, the peribiliary gland networks located around the hilar and extrahepatic bile ducts have been reportedly to be involved in a variety of biliary diseases. However, the pathological features and roles of these networks in the carcinogenesis and progression of CCs remain to be explored. Recently, we experienced two cases of hilar CC showing a nodular sclerosing growth grossly and histologically well-differentiated adenocarcinomas, with an extensive involvement of the peribiliary gland networks. In situ like spread of carcinoma cells in the bile duct lumen was focal in one case and not identifiable in the other. In contrast, other 4 cases of ordinary hilar CC which were also well-differentiated adenocarcinomas, showed variable intraductal luminal spread and also extensive periductal infiltration irrespective of the peribiliary gland network. In conclusion, the present study showed a unique form of periductal spread of CCs with preferential and extensive involvement of the peribiliary gland networks.

Recent histological and molecular characterization of cholangiocarcinoma (CCA) highlights the heterogeneity of this cancer that may emerge at different sites of the biliary tree and with different macroscopic or morphological features. Furthermore, different stem cell niches have been recently described in the liver and biliary tree, suggesting this as the basis of the heterogeneity of intrahepatic (IH)- and extrahepatic (EH)-CCAs, which are two largely different tumors from both biological and epidemiological points of view. The complexity of the organization of the liver stem cell compartments could underlie the CCA clinical-pathological heterogeneity and the criticisms in classifying primitive liver tumors. These recent advances highlight a possible new classification of CCAs based on cells of origin and this responds to the need of generating homogenous diagnostic, prognostic and, hopefully, therapeutic categories of IH- and EH-CCAs.

Cholangiocarcinoma (CCA) is a malignant tumour that arises from biliary epithelium at any portion of the biliary tree. CCA is currently classified as intra-hepatic or extra-hepatic CCA (EH-CCA). Recent evidences suggest that intra-hepatic CCA (IH-CCA) and EH-CCA are biologically different cancers, giving further support to a number of recent epidemiological studies showing large differences in terms of incidence, mortality and risk factors. The purpose of this manuscript is to review recent literature dealing with the descriptive epidemiology and risk factors of CCA with a special effort to compare IH- with EH-CCA.