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Ogiso T, Suzuki H, Matsubara H, Naito T, Yamada M, Yamamoto H, Hattori S, Aoba T, Arai Y, Urano F. A case of intraductal papillary neoplasm of the bile duct suspected to be of peribiliary glands origin. DEN OPEN 2025; 5:e70001. [PMID: 39170624 PMCID: PMC11337904 DOI: 10.1002/deo2.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/07/2024] [Accepted: 08/08/2024] [Indexed: 08/23/2024]
Abstract
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.
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Affiliation(s)
- Takuya Ogiso
- Department of GastroenterologyChutoen General Medical CenterShizuokaJapan
| | - Hirotaka Suzuki
- Department of GastroenterologyToyohashi Municipal HospitalAichiJapan
| | - Hiroshi Matsubara
- Department of GastroenterologyToyohashi Municipal HospitalAichiJapan
| | - Takehito Naito
- Department of GastroenterologyToyohashi Municipal HospitalAichiJapan
| | - Masahiro Yamada
- Department of GastroenterologyToyohashi Municipal HospitalAichiJapan
| | - Hideko Yamamoto
- Department of GastroenterologyToyohashi Municipal HospitalAichiJapan
| | - Shun Hattori
- Department of GastroenterologyToyohashi Municipal HospitalAichiJapan
| | - Taro Aoba
- Department of General SurgeryToyohashi Municipal HospitalAichiJapan
| | - Yoshifumi Arai
- Department of Pathological DiagnosisToyohashi Municipal HospitalAichiJapan
| | - Fumihiro Urano
- Department of GastroenterologyToyohashi Municipal HospitalAichiJapan
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Reshetnyak VI, Maev IV. Bile acid therapy for primary biliary cholangitis: Pathogenetic validation. World J Exp Med 2025; 15:101771. [PMID: 40115760 PMCID: PMC11718588 DOI: 10.5493/wjem.v15.i1.101771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/25/2024] [Accepted: 11/07/2024] [Indexed: 12/26/2024] Open
Abstract
Knowledge of the etiological and pathogenetic mechanisms of the development of any disease is essential for its treatment. Because the cause of primary biliary cholangitis (PBC), a chronic, slowly progressive cholestatic liver disease, is still unknown, treatment remains symptomatic. Knowledge of the physicochemical properties of various bile acids and the adaptive responses of cholangiocytes and hepatocytes to them has provided an important basis for the development of relatively effective drugs based on hydrophilic bile acids that can potentially slow the progression of the disease. Advances in the use of hydrophilic bile acids for the treatment of PBC are also associated with the discovery of pathogenetic mechanisms of the development of cholangiocyte damage and the appearance of the first signs of this disease. For 35 years, ursodeoxycholic acid (UDCA) has been the unique drug of choice for the treatment of patients with PBC. In recent years, the list of hydrophilic bile acids used to treat cholestatic liver diseases, including PBC, has expanded. In addition to UDCA, the use of obeticholic acid, tauroursodeoxycholic acid and norursodeoxycholic acid as drugs is discussed. The pathogenetic rationale for treatment of PBC with various bile acid drugs is discussed in this review. Emphasis is made on the mechanisms explaining the beneficial therapeutic effects and potential of each of the bile acid as a drug, based on the understanding of the pathogenesis of the initial stages of PBC.
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Affiliation(s)
- Vasiliy I Reshetnyak
- Department of Propaedeutics of Internal Diseases and Gastroenterology, Russian University of Medicine, Moscow 127473, Russia
| | - Igor V Maev
- Department of Propaedeutics of Internal Diseases and Gastroenterology, Russian University of Medicine, Moscow 127473, Russia
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Uski ACVR, Pedroso MHNI, Abud CP, Costa MM, Ferreira MPFD. Peribiliary cysts: uncommon mimickers of hepatic and biliary cystic lesions. Abdom Radiol (NY) 2025; 50:24-37. [PMID: 38951232 DOI: 10.1007/s00261-024-04472-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/21/2024] [Accepted: 06/22/2024] [Indexed: 07/03/2024]
Abstract
Peribiliary cysts (PC) are dilatations of the extramural peribiliary glands, with a very characteristic imaging pattern in the contexts of hepatobiliary diseases, idiopathic portal hypertension, adult-type polycystic disease of the liver and kidneys, solitary nonparasitic cysts, and systemic infections. The clinical relevance of PC is related to the fact that their presence may indicate underlying pathologies (such as those mentioned above) and may be considered as a potential marker of liver disease progression. Although imaging findings are quite characteristic, recognizing their main differential diagnoses, including malignancies, can be challenging but are essential to avoiding diagnostic errors.
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Affiliation(s)
- Ana Cláudia Vincenzi Raduan Uski
- Abdominal and Oncoradiology Department, A Beneficência Portuguesa de São Paulo, R. Maestro Cardim 769, São Paulo, SP, 01323-001, Brazil.
| | - Maria Helena Naves Inácio Pedroso
- Abdominal and Oncoradiology Department, A Beneficência Portuguesa de São Paulo, R. Maestro Cardim 769, São Paulo, SP, 01323-001, Brazil
| | - Carolina Pereira Abud
- Abdominal and Oncoradiology Department, A Beneficência Portuguesa de São Paulo, R. Maestro Cardim 769, São Paulo, SP, 01323-001, Brazil
| | - Marina Martini Costa
- Abdominal and Oncoradiology Department, A Beneficência Portuguesa de São Paulo, R. Maestro Cardim 769, São Paulo, SP, 01323-001, Brazil
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Reshetnyak VI, Maev IV. Mechanism of formation and significance of antimitochondrial autoantibodies in the pathogenesis of primary biliary cholangitis. EXPLORATION OF IMMUNOLOGY 2024:624-639. [DOI: 10.37349/ei.2024.00163] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 09/24/2024] [Indexed: 01/03/2025]
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic progressive liver disease associated with cholangiopathies. The detection of antimitochondrial autoantibodies (AMAs) plays an important role in the diagnosis of classical PBC. AMAs are formed against the antigenic component associated with the dihydrolipoyl transacetylase of pyruvate dehydrogenase complex (E2 PDC) localized on the inner membrane of mitochondria. The loss of immune tolerance of E2 PDC in PBC is thought to be the cause of the mechanism of AMA formation and immune-mediated destruction of biliary epithelial cells (BECs) of the small- and medium-sized intrahepatic bile ducts. E2 PDC is not only present in BECs, but is also abundant in the mitochondria of all nucleated cells. The question remains as to why E2 PDC of only small BECs is the target of autoimmune attack. There is no evidence that AMAs have a deleterious effect on BECs. New scientific data has emerged that explains the damage to BECs in PBC by the defect of the biliary bicarbonate (HCO3–) “umbrella” that protects BECs from the detergent action of bile acids under physiological conditions. Disruption of HCO3– production by BECs in PBC leads to changes in the pH of hepatic bile, accompanied by accumulation of bile acids in the small BECs. The detergent action of bile acids leads to damage of membrane structures of BECs and their apoptosis, development of ductulopenia, and intrahepatic cholestasis. For the first time, it has been suggested that under the influence of bile acids, the E2 PDC antigen may undergo conformational changes that alter its immunological properties. E2 PDC becomes a neoantigen that is recognized by the normal (“healthy”) immune system as a foreign antigen, leading to the production of AMAs. For the first time, the authors of this review provide an explanation for why only small BECs are damaged in PBC.
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Affiliation(s)
- Vasiliy Ivanovich Reshetnyak
- Department of Propaedeutics of Internal Diseases and Gastroenterology, Russian University of Medicine, 127473 Moscow, Russian Federation
| | - Igor Veniaminovich Maev
- Department of Propaedeutics of Internal Diseases and Gastroenterology, Russian University of Medicine, 127473 Moscow, Russian Federation
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Katano K, Nakanuma S, Tokoro T, Takei R, Takada S, Okazaki M, Kato K, Makino I, Harada K, Yagi S. Impact of aging on peribiliary glands in ischemia-reperfusion injury. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2024; 31:705-715. [PMID: 39011821 DOI: 10.1002/jhbp.12047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/17/2024]
Abstract
BACKGROUND The detailed mechanisms underlying the development of ischemia-type biliary lesions (ITBLs) in aged donor grafts remain unclear. In the present study we aimed to investigate the impact of aging on the response of the peribiliary gland (PBG) to ischemia-reperfusion injury (IRI) and its temporal changes. METHODS Experiments were performed using a 90-min partial warm liver ischemia model in male Wistar rats of two age groups: young (7-8 weeks old) and old (52-60 weeks old). Liver tissues were obtained 24, 72, and 168 h after IRI. Histopathological and immunohistochemical assessments of the perihilar bile duct (PHBD), including the PBG, distal to the clip-clamped site were performed. RESULTS Young rats showed little change in the bile duct tissues after IRI. However, old rats showed an increased PBG volume in the PHBD and marked PBG cell proliferation 24 h after IRI. Bile duct wall thickening with narrowing of the lumen peaked 72 h after IRI. Mucus production and oxidative stress in the PBG were significantly higher in old than in young rats after IRI. These findings showed a trend toward improvement 168 h after IRI. CONCLUSION Age-dependent differences in the response of the PBG to IRI may be related to differences in ITBL frequency.
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Affiliation(s)
- Kaoru Katano
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University Hospital, Kanazawa, Japan
| | - Shinichi Nakanuma
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University Hospital, Kanazawa, Japan
| | - Tomokazu Tokoro
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University Hospital, Kanazawa, Japan
| | - Ryohei Takei
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University Hospital, Kanazawa, Japan
| | - Satoshi Takada
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University Hospital, Kanazawa, Japan
| | - Mitsuyoshi Okazaki
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University Hospital, Kanazawa, Japan
| | - Kaichiro Kato
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University Hospital, Kanazawa, Japan
| | - Isamu Makino
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University Hospital, Kanazawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Shintaro Yagi
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University Hospital, Kanazawa, Japan
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Saikrishana E, Varshney P, Varshney VK, Soni SC, Selvakumar B, Agarwal L. En Bloc Extrahepatic Biliary Tract Excision with Triple Cholangiojejunostomy for Complex Hilar Intraductal Papillary Neoplasm of the Liver. Ann Surg Oncol 2024; 31:6947-6950. [PMID: 39085553 DOI: 10.1245/s10434-024-15954-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 07/18/2024] [Indexed: 08/02/2024]
Affiliation(s)
- E Saikrishana
- All India Institute of Medical Sciences, Jodhpur, India
| | - Peeyush Varshney
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, India.
| | - Vaibhav Kumar Varshney
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, India
| | - Subash Chandra Soni
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, India
| | - B Selvakumar
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, India
| | - Lokesh Agarwal
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, India
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Cardinale V, Paradiso S, Alvaro D. Biliary stem cells in health and cholangiopathies and cholangiocarcinoma. Curr Opin Gastroenterol 2024; 40:92-98. [PMID: 38320197 DOI: 10.1097/mog.0000000000001005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
PURPOSE OF REVIEW This review discusses evidence regarding progenitor populations of the biliary tree in the tissue regeneration and homeostasis, and the pathobiology of cholangiopathies and malignancies. RECENT FINDINGS In embryogenesis biliary multipotent progenitor subpopulation contributes cells not only to the pancreas and gall bladder but also to the liver. Cells equipped with a constellation of markers suggestive of the primitive endodermal phenotype exist in the peribiliary glands, the bile duct glands, of the intra- and extrahepatic bile ducts. These cells are able to be isolated and cultured easily, which demonstrates the persistence of a stable phenotype during in vitro expansion, the ability to self-renew in vitro, and the ability to differentiate between hepatocyte and biliary and pancreatic islet fates. SUMMARY In normal human livers, stem/progenitors cells are mostly restricted in two distinct niches, which are the bile ductules/canals of Hering and the peribiliary glands (PBGs) present inside the wall of large intrahepatic bile ducts. The existence of a network of stem/progenitor cell niches within the liver and along the entire biliary tree inform a patho-biological-based translational approach to biliary diseases and cholangiocarcinoma since it poses the basis to understand biliary regeneration after extensive or chronic injuries and progression to fibrosis and cancer.
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Affiliation(s)
| | - Savino Paradiso
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
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8
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Reshetnyak VI, Maev IV. New insights into the pathogenesis of primary biliary cholangitis asymptomatic stage. World J Gastroenterol 2023; 29:5292-5304. [PMID: 37899787 PMCID: PMC10600802 DOI: 10.3748/wjg.v29.i37.5292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/10/2023] [Accepted: 09/14/2023] [Indexed: 09/25/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic progressive liver disease and one of the most important progressive cholangiopathies in adults. Damage to cholangiocytes triggers the development of intrahepatic cholestasis, which progresses to cirrhosis in the terminal stage of the disease. Accumulating data indicate that damage to biliary epithelial cells [(BECs), cholangiocytes] is most likely associated with the intracellular accumulation of bile acids, which have potent detergent properties and damaging effects on cell membranes. The mechanisms underlying uncontrolled bile acid intake into BECs in PBC are associated with pH change in the bile duct lumen, which is controlled by the bicarbonate (HCO3-) buffer system "biliary HCO3- umbrella". The impaired production and entry of HCO3- from BECs into the bile duct lumen is due to epigenetic changes in expression of the X-linked microRNA 506. Based on the growing body of knowledge on the molecular mechanisms of cholangiocyte damage in patients with PBC, we propose a hypothesis explaining the pathogenesis of the first morphologic (ductulopenia), immunologic (antimitochondrial autoantibodies) and clinical (weakness, malaise, rapid fatigue) signs of the disease in the asymptomatic stage. This review focuses on the consideration of these mechanisms.
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Affiliation(s)
- Vasiliy Ivanovich Reshetnyak
- Department of Propaedeutics of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
| | - Igor Veniaminovich Maev
- Department of Propaedeutics of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
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9
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Tomita H, Hara A. Development of extrahepatic bile ducts and mechanisms of tumorigenesis: Lessons from mouse models. Pathol Int 2022; 72:589-605. [PMID: 36349994 PMCID: PMC10098476 DOI: 10.1111/pin.13287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 10/12/2022] [Indexed: 11/11/2022]
Abstract
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.
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Affiliation(s)
- Hiroyuki Tomita
- Department of Tumor Pathology Gifu University Graduate School of Medicine Gifu Japan
| | - Akira Hara
- Department of Tumor Pathology Gifu University Graduate School of Medicine Gifu Japan
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10
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Francis H, Kundu D, Baiocchi L. Healthy peribiliary glands are necessary for successful liver transplantation. Hepatology 2022; 75:779-781. [PMID: 35102574 PMCID: PMC8930497 DOI: 10.1002/hep.32382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 01/27/2022] [Indexed: 01/01/2023]
Affiliation(s)
- Heather Francis
- Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA.,Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA
| | - Debjyoti Kundu
- Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA
| | - Leonardo Baiocchi
- Hepatology Unit, Department of Internal MedicineUniversity PolyclinicRomeItaly
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Azmaiparashvili E, Patarashvili L, Bebiashvili I, Tsomaia K, Gvidiani S, Tananashvili D, Kakabadze M, Gusev S, Kordzaia D. Spatial architecture of biliary tree in mammals: Fractal and Euclidean geometric features. J Anat 2021; 239:682-692. [PMID: 33817796 PMCID: PMC8349449 DOI: 10.1111/joa.13441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 03/18/2021] [Accepted: 03/19/2021] [Indexed: 02/05/2023] Open
Abstract
The study of the fractal architecture of various organs and structures expanded the possibilities for determining the ranges of their functioning and structural arrangement, which, as a result, was reflected in the development of new approaches to diagnostics and therapeutic impacts. The architecture of the excretory duct systems, similar to the hemo- and lymph- circulatory beds and the bronchial tree, is considered fractal. At the same time, information about hitherto unknown structures of the biliary tree continues to appear in the literature. We aimed to study the features of the spatial geometry of the biliary tree and assess the significance of both its fractal and Euclidean characteristics for the development of approaches that facilitate comprehensive description of intrahepatic biliary tract architecture. We investigated the architecture of the biliary trees of six men, seven male canines, and seven male Wistar rats using the corrosion casting method. Corrosion casts were prepared by injecting solidifying latexes into the bile ducts. The preparations were studied using a light stereomicroscope and a scanning electron microscope. Biliary tree branching is of various types. In addition, the correlation between variations in the caliber and length of the bile ducts and their order is not significant. Therefore, the biliary tree should not be considered as a classical fractal and it consists of the main modules, represented by the network of the bile canaliculi (first nonfractal module) and a biliary tree with a fractal branching (second module) that drains the bile canaliculi mesh and the additional modules represented by the mucosal biliary glands (in mammals with the gallbladder) or the periportal biliary plexus (in mammals without a gallbladder) and the aberrant biliary ducts. Such a configuration of the biliary bed should optimally ensure the smooth implementation of the physiological function of the liver, as well as its adaptation to different pathologies accompanied by biliary hypertension. It also might be considered in the diagnosis and assessment of ductular reaction, biliary regeneration, and/or carcinogenesis.
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Affiliation(s)
- Elza Azmaiparashvili
- Department of Clinical Anatomy, Faculty of MedicineIvane Javakhishvili Tbilisi State University (TSUTbilisiGAUSA
| | - Leila Patarashvili
- Department of Clinical Anatomy, Faculty of MedicineIvane Javakhishvili Tbilisi State University (TSUTbilisiGAUSA
| | - Irakli Bebiashvili
- Department of Clinical Anatomy, Faculty of MedicineIvane Javakhishvili Tbilisi State University (TSUTbilisiGAUSA
| | - Keti Tsomaia
- Department of Clinical Anatomy, Faculty of MedicineIvane Javakhishvili Tbilisi State University (TSUTbilisiGAUSA
- Department of Clinical Anatomy and Experimental ModelingTSU Alexander Natishvili Institute of MorphologyTbilisiGAUSA
| | - Salome Gvidiani
- Department of Clinical Anatomy, Faculty of MedicineIvane Javakhishvili Tbilisi State University (TSUTbilisiGAUSA
| | | | - Manana Kakabadze
- Department of Clinical Anatomy, Faculty of MedicineIvane Javakhishvili Tbilisi State University (TSUTbilisiGAUSA
- Department of Clinical Anatomy and Experimental ModelingTSU Alexander Natishvili Institute of MorphologyTbilisiGAUSA
| | - Sergey Gusev
- Federal Research & Clinical Center of Physical‐Chemical MedicineFederal Medical Biological AgencyMoscowRussia
| | - Dimitri Kordzaia
- Department of Clinical Anatomy, Faculty of MedicineIvane Javakhishvili Tbilisi State University (TSUTbilisiGAUSA
- Department of Clinical Anatomy and Experimental ModelingTSU Alexander Natishvili Institute of MorphologyTbilisiGAUSA
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Heme Oxygenase-1-Modified Bone Marrow Mesenchymal Stem Cells Combined with Normothermic Machine Perfusion Repairs Bile Duct Injury in a Rat Model of DCD Liver Transplantation via Activation of Peribiliary Glands through the Wnt Pathway. Stem Cells Int 2021; 2021:9935370. [PMID: 34285696 PMCID: PMC8275434 DOI: 10.1155/2021/9935370] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/28/2021] [Accepted: 06/21/2021] [Indexed: 02/08/2023] Open
Abstract
Livers from donors after circulatory death (DCD) are inevitably exposed to a longer warm ischemic period, which might increase the incidence of postoperative bile duct complications. Bone marrow mesenchymal stem cells (BMMSCs) have tissue repair properties. The present study was aimed at exploring the repair effect of heme oxygenase-1- (HO-1-) modified BMMSCs (HO-1/BMMSCs) combined with normothermic machine perfusion (NMP) on bile duct injury after DCD liver transplantation and at revealing the underlying mechanisms. Rat livers were exposed to in situ warm ischemia for 30 min; then, NMP was performed through the portal vein for 4 h with BMMSCs, HO-1/BMMSCs, or neither before implantation. Obvious bile duct histological damage and liver functional damage were observed postoperatively. In the group treated with HO-1/BMMSCs combined with NMP (HBP group), liver functions and bile duct histology were improved; meanwhile, cell apoptosis was reduced and cell proliferation was active. A large number of regenerative cells appeared at the injured site, and the defective bile duct epithelium was restored. Dilatation of peribiliary glands (PBGs), proliferation of PBG cells, high expression of vascular endothelial growth factor (VEGF), and increased proportion of bile duct progenitor cells with stem/progenitor cells biomarkers were observed. Blocking Wnt signaling significantly inhibited the repair effect of HO-1/BMMSCs on bile duct injury. In conclusion, HO-1/BMMSCs combined with NMP were relevant to the activation of biliary progenitor cells in PBGs which repaired bile duct injury in DCD liver transplantation via the Wnt signaling pathway. Proliferation and differentiation of PBG cells were involved in the renewal of the injured biliary epithelium.
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13
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Sarcognato S, Sacchi D, Fassan M, Fabris L, Cadamuro M, Zanus G, Cataldo I, Covelli C, Capelli P, Furlanetto A, Guido M. Benign biliary neoplasms and biliary tumor precursors. Pathologica 2021; 113:147-157. [PMID: 34294933 PMCID: PMC8299320 DOI: 10.32074/1591-951x-251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 01/04/2021] [Indexed: 12/21/2022] Open
Abstract
Benign biliary tumor are common lesions that are often an incidental finding in subjects who undergo medical imaging tests for other conditions. Most are true neoplasms while few result from reactive or malformative proliferation. Benign tumors have no clinical consequences, although the premalignant nature or potential for malignant transformation is of concern in some cases. The main practical problem for pathologists is the need to differentiate them from malignant biliary tumours, which is not always straightforward. Premalignant lesions of the bile duct have been described, although their incidence has been poorly characterized. These lesions include biliary mucinous cystic neoplasms, intraductal papillary neoplasms of the bile duct, and biliary intraepithelial neoplasia. In this article, histopathology of benign biliary tumors and biliary tumor precursors is discussed, with a focus on the main diagnostic criteria.
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Affiliation(s)
| | - Diana Sacchi
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Matteo Fassan
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Luca Fabris
- Department of Molecular Medicine - DMM, University of Padova, Padova, Italy
| | | | - Giacomo Zanus
- 4 Surgery Unit, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Department of Surgery, Oncology and Gastroenterology - DISCOG, University of Padova, Padova, Italy
| | - Ivana Cataldo
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Claudia Covelli
- Pathology Unit, Fondazione IRCCS “Casa Sollievo della Sofferenza”, San GiovanniRotondo, Italy
| | - Paola Capelli
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | | | - Maria Guido
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Department of Medicine - DIMED, University of Padova, Padova, Italy
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14
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Intraductal Papillary Neoplasm of Bile Duct: Updated Clinicopathological Characteristics and Molecular and Genetic Alterations. J Clin Med 2020; 9:jcm9123991. [PMID: 33317146 PMCID: PMC7763595 DOI: 10.3390/jcm9123991] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Intraductal papillary neoplasm of the bile duct (IPNB), a pre-invasive neoplasm of the bile duct, is being established pathologically as a precursor lesion of invasive cholangiocarcinoma (CCA), and at the time of surgical resection, approximately half of IPNBs show stromal invasion (IPNB associated with invasive carcinoma). IPNB can involve any part of the biliary tree. IPNB shows grossly visible, exophytic growth in a dilated bile duct lumen, with histologically villous/papillary neoplastic epithelia with tubular components covering fine fibrovascular stalks. Interestingly, IPNB can be classified into four subtypes (intestinal, gastric, pancreatobiliary and oncocytic), similar to intraductal papillary mucinous neoplasm of the pancreas (IPMN). IPNBs are classified into low-grade and high-grade based on lining epithelial features. The new subclassification of IPNB into types 1 (low-grade dysplasia and high-grade dysplasia with regular architecture) and 2 (high-grade dysplasia with irregular architecture) proposed by the Japan–Korea pathologist group may be useful in the clinical field. The outcome of post-operative IPNBs is more favorable in type 1 than type 2. Recent genetic studies using next-generation sequencing have demonstrated the existence of several groups of mutations of genes: (i) IPNB showing mutations in KRAS, GNAS and RNF43 belonged to type 1, particularly the intestinal subtype, similar to the mutation patterns of IPMN; (ii) IPNB showing mutations in CTNNB1 and lacking mutations in KRAS, GNAS and RNF43 belonged to the pancreatobiliary subtype but differed from IPMN. IPNB showing mutation of TP53, SMAD4 and PIK3CA might reflect complicated and other features characterizing type 2. The recent recognition of IPNBs may facilitate further clinical and basic studies of CCA with respect to the pre-invasive and early invasive stages.
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15
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Balloon Extraction of an Intraductal Tubulopapillary Neoplasm of the Bile Duct During Endoscopic Retrograde Cholangiopancreatography. ACG Case Rep J 2020; 7:e00481. [PMID: 33269290 PMCID: PMC7685965 DOI: 10.14309/crj.0000000000000481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 07/17/2020] [Indexed: 11/17/2022] Open
Abstract
Intraductal tubulopapillary neoplasm (ITPN) of the bile duct is a rare type of intraductal neoplasm of the bile duct that has mainly been described in the literature in case reports and small case series. Only within the past decade has ITPN of the bile duct been identified as its own entity and have definitive diagnostic criteria been established. Given its rarity, there is no standard of care for treatment. Here, we describe a case report of biliary ITPN diagnosed in a unique manner.
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16
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Kobayashi S, Kozaka K, Gabata T, Matsui O, Koda W, Okuda M, Okumura K, Sugiura T, Ogi T. Pathophysiology and Imaging Findings of Bile Duct Necrosis: A Rare but Serious Complication of Transarterial Therapy for Liver Tumors. Cancers (Basel) 2020; 12:cancers12092596. [PMID: 32932894 PMCID: PMC7565329 DOI: 10.3390/cancers12092596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/09/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Bile duct necrosis (BDN) is rare but serious complication of transarterial therapy for liver tumors. During development of BDN, ischemia of the peribiliary vascular plexus (PBP) induces the disruption of the bile duct epithelial protection mechanism, causing necrosis of the surrounding tissue by the detergent action of exuded bile acids, and eventually a biloma forms. Once BDN starts, persistent tissue damage to the surrounding bile duct is induced by imbibed bile acids, and portal vein thrombosis may also be observed. On CT images, BDN shows similar findings to intrahepatic bile duct dilatation, and, therefore, it is sometimes misdiagnosed. Clinicians should be aware that although BDN and biloma can usually be treated conservatively, in the presence of symptoms such as moderate or severe infection or interval growth of the biloma, prompt treatment is essential to avoid lethal abscess formation and sepsis. Abstract Bile duct necrosis (BDN) with biloma formation is a type of ischemic bile duct injury that is one of the serious complications associated with transarterial therapies, such as transcatheter chemoembolization therapy (TACE), and radioembolization for hepatocellular carcinoma (HCC) and hepatic arterial infusion chemotherapy (HAIC) for metastatic liver cancer from colorectal carcinoma. In terms of the occurrence of BDN and subsequent biloma formation, ischemic injury to the peribiliary vascular plexus (PBP), the supporting vessel of bile duct epithelium, is thought to be intimately associated. In this paper, we first describe the anatomy, blood supply, and function of the intrahepatic bile duct, and then illustrate the pathophysiology of BDN, and finally present the imaging findings of BDN. Under the process of BDN formation, ischemia of the PBP induces the disruption of the bile duct epithelial protection mechanism that causes coagulation and fibrinoid necrosis of the surrounding tissue by the detergent action of exuded bile acids, and eventually a biloma forms. Once BDN occurs, persistent tissue damage to the surrounding bile duct is induced by imbibed bile acids, and portal vein thrombosis may also be observed. On pre-contrast and contrast-enhanced computed tomography (CT), BDN shows similar findings to intrahepatic bile duct dilatation, and, therefore, it is sometimes misdiagnosed. Differentiation of imaging findings on CT and ultrasound (US)/magnetic resonance (MR) imaging/MR cholangiopancreatography (MRCP) is important for correct diagnosis of BDN.
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17
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Safarikia S, Carpino G, Overi D, Cardinale V, Venere R, Franchitto A, Onori P, Alvaro D, Gaudio E. Distinct EpCAM-Positive Stem Cell Niches Are Engaged in Chronic and Neoplastic Liver Diseases. Front Med (Lausanne) 2020; 7:479. [PMID: 32984373 PMCID: PMC7492539 DOI: 10.3389/fmed.2020.00479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/15/2020] [Indexed: 12/12/2022] Open
Abstract
In normal human livers, EpCAMpos cells are mostly restricted in two distinct niches, which are (i) the bile ductules and (ii) the mucous glands present inside the wall of large intrahepatic bile ducts (the so-called peribiliary glands). These EpCAMpos cell niches have been proven to harbor stem/progenitor cells with great importance in liver and biliary tree regeneration and in the pathophysiology of human diseases. The EpCAMpos progenitor cells within bile ductules are engaged in driving regenerative processes in chronic diseases affecting hepatocytes or interlobular bile ducts. The EpCAMpos population within peribiliary glands is activated when regenerative needs are finalized to repair large intra- or extra-hepatic bile ducts affected by chronic pathologies, including primary sclerosing cholangitis and ischemia-induced cholangiopathies after orthotopic liver transplantation. Finally, the presence of distinct EpCAMpos cell populations may explain the histological and molecular heterogeneity characterizing cholangiocarcinoma, based on the concept of multiple candidate cells of origin. This review aimed to describe the precise anatomical distribution of EpCAMpos populations within the liver and the biliary tree and to discuss their contribution in the pathophysiology of human liver diseases, as well as their potential role in regenerative medicine of the liver.
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Affiliation(s)
- Samira Safarikia
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico," Rome, Italy
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Rosanna Venere
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
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