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Lui VCH. Organoids in biliary atresia. WORLD JOURNAL OF PEDIATRIC SURGERY 2025; 8:e001010. [PMID: 40385243 PMCID: PMC12083310 DOI: 10.1136/wjps-2025-001010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 03/27/2025] [Indexed: 05/20/2025] Open
Abstract
Organoids are three-dimensional and self-organizing cell cultures of various lineages that resemble structures and functions of an organ in many ways, and they are versatile tools in disease modeling and patho-mechanistic study of human diseases affecting their tissues of origin. Biliary atresia (BA), a cholangiopathy affecting the bile ducts of the liver, is a heterogeneous and multifaceted liver disease of complex pathogenesis. Cholangiopathies refer to a category of liver diseases that affect the cholangiocytes, the epithelial cells lining the lumen of the biliary trees. Biliary organoids consist of cholangiocytes in a spherical monolayer epithelium, which favorably resembles the structures and functional properties of the bile duct cholangiocytes. Biliary tissue-derived cells, pluripotent stem cells or embryonic stem cells, and hepatic progenitor cells are capable of generating biliary organoids. In the last decade, a considerable advancement has been made in the generation of biliary organoids for modeling liver physiology and pathophysiology. Using biliary organoids, scientists have advanced our knowledge underlying the pathogenic roles of genetic susceptibility, dysregulated hepatobiliary development/structure, environmental factors, and dysregulated immune-inflammatory responses to an injury in BA. This review will summarize and discuss the derivation and the use of biliary organoids in the disease modeling and patho-mechanistic study of BA.
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Nagao M, Fukuda A, Kashima H, Matsuyama S, Iimori K, Nakayama S, Mizukoshi K, Kawai M, Yamakawa G, Omatsu M, Namikawa M, Masuda T, Hiramatsu Y, Muta Y, Maruno T, Nakanishi Y, Tsuruyama T, Seno H. Cholangiocyte organoids for disease, cancer, and regenerative medicine. Eur J Cell Biol 2025; 104:151472. [PMID: 39721346 DOI: 10.1016/j.ejcb.2024.151472] [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: 08/27/2024] [Revised: 11/19/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024] Open
Abstract
The biliary tract is a ductal network comprising the intrahepatic (IHBDs) and extrahepatic bile duct (EHBDs). Biliary duct disorders include cholangitis, neoplasms, and injury. However, the underlying mechanisms are not fully understood. With advancements in 3D culture technology, cholangiocyte organoids (COs) derived from primary tissues or induced pluripotent stem cells (iPSCs) can accurately replicate the structural and functional properties of biliary tissues. These organoids have become powerful tools for studying the pathogenesis of biliary diseases, such as cystic fibrosis and primary sclerosing cholangitis, and for developing new therapeutic strategies for cholangiocarcinoma. Additionally, COs have the potential to repair bile duct injuries and facilitate transplantation therapies. This review also discusses the use of organoids in genetically engineered mouse models to provide mechanistic insights into tumorigenesis and cancer progression. Continued innovation and standardization of organoid technology are crucial for advancing precision medicine for biliary diseases and cancer.
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Affiliation(s)
- Munemasa Nagao
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Akihisa Fukuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
| | - Hirotaka Kashima
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Sho Matsuyama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kei Iimori
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shinnosuke Nakayama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kenta Mizukoshi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Munenori Kawai
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Go Yamakawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Mayuki Omatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Mio Namikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Gastroenterology and Hepatology, The Japan Baptist Hospital, 47 Yamanomoto-cho, Kitashirakawa, Sakyo-ku, Kyoto 606-8273, Japan
| | - Tomonori Masuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yukiko Hiramatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yu Muta
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Takahisa Maruno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tatsuaki Tsuruyama
- Department of Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
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Hrncir HR, Goodloe B, Bombin S, Hogan CB, Jadi O, Gracz AD. Sox9 inhibits Activin A to promote biliary maturation and branching morphogenesis. Nat Commun 2025; 16:1667. [PMID: 39955269 PMCID: PMC11830073 DOI: 10.1038/s41467-025-56813-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 01/31/2025] [Indexed: 02/17/2025] Open
Abstract
Intrahepatic bile duct (IHBD) development produces a morphologically heterogeneous network of large "ducts" and small "ductules" by adulthood. IHBD formation is closely linked to developmental specification of biliary epithelial cells (BECs) starting as early as E13.5, but mechanisms regulating differential IHBD morphology remain poorly understood. Here, we show that duct and ductule development has distinct genetic requirements, with Sox9 required to form the developmental precursors to peripheral ductules in adult livers. By optimizing large-volume IHBD imaging, we find that IHBDs emerge as a homogeneous webbed structure by E15.5 and undergo morphological maturation through 2 weeks of age. Developmental knockout of Sox9 leads to decreased postnatal branching morphogenesis, resulting in adult IHBDs with normal ducts but significantly fewer ductules. In the absence of Sox9, BECs fail to mature and exhibit elevated TGF-β signaling and Activin A. Exogenous Activin A is sufficient to induce developmental gene expression and morphological defects in wild-type BEC organoids, while early postnatal inhibition of Activin A in vivo rescues IHBD morphogenesis in the absence of Sox9. Our data demonstrate that proper IHBD architecture relies on inhibition of Activin A by Sox9 to promote ductule morphogenesis, defining regulatory mechanisms underlying morphological heterogeneity.
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Affiliation(s)
- Hannah R Hrncir
- Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA, USA
- Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, GA, USA
| | - Brianna Goodloe
- Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA, USA
| | - Sergei Bombin
- Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA, USA
| | - Connor B Hogan
- Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA, USA
| | - Othmane Jadi
- School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Adam D Gracz
- Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA, USA.
- Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, GA, USA.
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Gulubova M, Tolekova A, Berbatov D, Aydogdu N. Development of pancreatic islet cells in the extrahepatic bile ducts of rats with experimentally-induced metabolic syndrome. Arch Physiol Biochem 2024; 130:669-677. [PMID: 37651586 DOI: 10.1080/13813455.2023.2252205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/27/2023] [Accepted: 08/21/2023] [Indexed: 09/02/2023]
Abstract
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.
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Affiliation(s)
- Maya Gulubova
- Department of pathology, Trakia University, Stara Zagora, Bulgaria
| | - Anna Tolekova
- Medical College, Trakia University, Stara Zagora, Bulgaria
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Bai M, Wang R, Huang C, Zhong R, Jiang N, Fu W, Mi N, Gao L, Jin Y, Ma H, Cao J, Yu H, Jing Q, Zhang C, Yue P, Zhang Y, Lin Y, Zhang H, Meng W. Biological and genetic characterization of a newly established human primary multidrug-resistant distal cholangiocarcinoma cell line, CBC3T-6. Sci Rep 2024; 14:29661. [PMID: 39613883 DOI: 10.1038/s41598-024-81392-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 11/26/2024] [Indexed: 12/01/2024] Open
Abstract
Distal cholangiocarcinoma is a rare and highly aggressive malignant tumor. The inherent tumor characteristics and growth pattern of cancer cells pose a challenge for diagnosis and treatment. Chemotherapy resistance leads to limited treatment options for patients with advanced cholangiocarcinoma. However, drug resistance studies in cholangiocarcinoma are often limited by the use of preclinical models that do not accurately replicate the essential features of the disease. In this study, we established and characterized a primary multidrug-resistant distal cholangiocarcinoma cell line, CBC3T-6. STR profiling indicated no evidence of cross-contamination. This cell line remains stable during long-term in vitro culture and is characterized by short doubling times and rapid subcutaneous tumor formation in mice. In addition, among the first-line anticancer drugs for cholangiocarcinoma, CBC3T-6 cells showed varying degrees of resistance to gemcitabine, oxaliplatin, cisplatin, and 5-FU. Whole exome sequencing analysis revealed that CBC3T-6 cells contained a variety of potentially pathogenic somatic cell mutations, such as TP53 and KRAS mutations. ABCB1 mutation as a possible therapeutic target for multidrug resistance. In conclusion, CBC3T-6 cells can be used as a useful tool to study the mechanism of cholangiocarcinoma and develop new therapeutic strategies for multidrug resistance.
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Affiliation(s)
- Mingzhen Bai
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Ruoshui Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Chongfei Huang
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Ruyang Zhong
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Ningzu Jiang
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Wenkang Fu
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Ningning Mi
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Long Gao
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Yuyao Jin
- The Sixth Clinical Medical School of Guangzhou Medical University, Guangzhou, China
| | - Haidong Ma
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Jie Cao
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Haiying Yu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, China
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, China
| | - Qiang Jing
- Department of Pathology, First Hospital of Lanzhou University, Donggang District, Lanzhou, China
| | - Chao Zhang
- Department of Orthopedics, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ping Yue
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, China
| | - Hengwei Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, China.
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, China.
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, China.
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Xie Z, Pu S, Jin S, Xiang B, Yang J, Yan L. A new clinical classification of congenital biliary dilatation - HUAXI CBD classification. BMC Pediatr 2024; 24:750. [PMID: 39563279 PMCID: PMC11575198 DOI: 10.1186/s12887-024-05220-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 11/06/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Current biliary dilatation (BD) classifications are complex and based on cases including secondary BD, leading to unclear distinctions. Notably, congenital and secondary BD differ in etiology, symptoms, and prognosis. OBJECTIVE To propose a more concise and more suitable classification of congenital biliary dilatation (CBD), and exploring the feasibility and effectiveness of this classification in diagnosis and treatment. METHODS Based on the preoperative imaging data of patients with CBD admitted to the Department of Pediatric Surgery of West China Hospital of Sichuan University, from January 2015 to December 2018, a new classification of CBD was accomplished according to the site of bile duct dilatation lesions, which was named HUAXI CBD classification. The CBD was classified into 4 types: type I (distal extra-hepatic bile duct dilatation), type II (distal extra-hepatic combined with right and left primary hepatic bile duct dilatation), type III (extra-hepatic combined with secondary and above hepatic bile duct dilatation), and type IV (intra-hepatic bile duct dilatation). Meanwhile, the feasibility and reliability of the HUAXI CBD classification were analyzed by analyzing the clinical treatment strategies, perioperative complications and long-term follow-up results of different subtypes. RESULTS A total of 300 patients with CBD were included in this study. According to the HUAXI CBD classification method, 240 cases were type I, 48 cases were type II, 10 cases were type III, and 2 cases were type IV. After treatment, patients with type I had a normal hepatobiliary function after surgery and a good prognosis; patients with type II had good recovery of liver function in 37 cases (77.1%), but 11 cases (22.9%) had postoperative complications during follow-up; patients with type III and IV had high incidence of cholangitis (6/10, 2/2, respectively) and choledocholithiasis (5/10, 2/2, respectively) after surgery, especially those with diffuse intrahepatic dilatation having a poor prognosis, eventually developing cirrhosis and necessitating liver transplantation. CONCLUSIONS The HUAXI CBD classification is consistent with treatment principles, concise and easy to remember, and more suitable for CBD clinical application.
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Affiliation(s)
- Zhenyu Xie
- Department of Pediatric Surgery, West China Hospital of Sichuan University, #37 Guo-Xue-Xiang, Chengdu, 610041, China
| | - Siyu Pu
- Department of Pediatric Surgery, West China Hospital of Sichuan University, #37 Guo-Xue-Xiang, Chengdu, 610041, China
| | - Shuguang Jin
- Department of Pediatric Surgery, West China Hospital of Sichuan University, #37 Guo-Xue-Xiang, Chengdu, 610041, China.
| | - Bo Xiang
- Department of Pediatric Surgery, West China Hospital of Sichuan University, #37 Guo-Xue-Xiang, Chengdu, 610041, China
| | - Jiayin Yang
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Lvnan Yan
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China
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Tidwell J, Wu GY. Heritable Chronic Cholestatic Liver Diseases: A Review. J Clin Transl Hepatol 2024; 12:726-738. [PMID: 39130622 PMCID: PMC11310751 DOI: 10.14218/jcth.2024.00119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/14/2024] [Accepted: 05/28/2024] [Indexed: 08/13/2024] Open
Abstract
Chronic cholestasis due to heritable causes is usually diagnosed in childhood. However, many cases can present and survive into adulthood. The time course varies considerably depending on the underlying etiology. Laboratory data usually reveal elevated conjugated hyperbilirubinemia, alkaline phosphatase, and gamma-glutamyl transpeptidase. Patients may be asymptomatic; however, when present, the typical symptoms are pruritus, jaundice, fatigue, and alcoholic stools. The diagnostic methods and management required depend on the underlying etiology. The development of genome-wide associated studies has allowed the identification of specific genetic mutations related to the pathophysiology of cholestatic liver diseases. The aim of this review was to highlight the genetics, clinical pathophysiology, presentation, diagnosis, and treatment of heritable etiologies of chronic cholestatic liver disease.
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Affiliation(s)
- Jasmine Tidwell
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - George Y. Wu
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
- Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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Zhao YQ, Yang YY, Yao SY, Dong XF. Hepatic artery pseudoaneurysm: three case reports and literature review. Front Med (Lausanne) 2024; 11:1422895. [PMID: 39050537 PMCID: PMC11266017 DOI: 10.3389/fmed.2024.1422895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 06/11/2024] [Indexed: 07/27/2024] Open
Abstract
Laparoscopic surgery is extensively applied in the treatment of hepatobiliary diseases. Hepatic artery pseudoaneurysm (HAP) is a rare complication following hepatic biliary surgery through laparoscopy. The clinical manifestations of HAP are diverse and can be fatal. Given its severity, rapid assessment and management are crucial to ensuring a good prognosis. Here, we report three cases of HAP; two underwent laparoscopic surgery due to cholelithiasis, and another caused by trauma. The first case exhibited a pseudoaneurysm involving the distal portion of the right hepatic artery main trunk. The second patient had a pseudoaneurysm at the bifurcation of the left and right hepatic arteries. The third case involved a patient with a pseudoaneurysm involving a branch of the right hepatic artery. The main clinical manifestations of all three cases were bleeding from the biliary tract (the first two cases showed postoperative bleeding in the T-tube, while the third case exhibited gastrointestinal bleeding). The final diagnosis was obtained through digital subtraction angiography. The three patients underwent successful transcatheter arterial embolization operation and a follow-up revealed they were disease-free and alive. This article aims to highlight a rare complication of laparoscopic hepatobiliary surgery and share our experience in early diagnosis and treatment of HAP.
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Affiliation(s)
| | | | | | - Xiao-Feng Dong
- Department of Hepatobiliary, Pancreas and Spleen Surgery, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
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de Jong IEM, Wells RG. In Utero Extrahepatic Bile Duct Damage and Repair: Implications for Biliary Atresia. Pediatr Dev Pathol 2024; 27:291-310. [PMID: 38762769 PMCID: PMC11340255 DOI: 10.1177/10935266241247479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/20/2024]
Abstract
Biliary atresia (BA) is a cholangiopathy affecting the extrahepatic bile duct (EHBD) of newborns. The etiology and pathophysiology of BA are not fully understood; however, multiple causes of damage and obstruction of the neonatal EHBD have been identified. Initial damage to the EHBD likely occurs before birth. We discuss how different developmental stages in utero and birth itself could influence the susceptibility of the fetal EHBD to damage and a damaging wound-healing response. We propose that a damage-repair response of the fetal and neonatal EHBD involving redox stress and a program of fetal wound healing could-regardless of the cause of the initial damage-lead to either obstruction and BA or repair of the duct and recovery. This overarching concept should guide future research targeted toward identification of factors that contribute to recovery as opposed to progression of injury and fibrosis. Viewing BA through the lens of an in utero damage-repair response could open up new avenues for research and suggests exciting new therapeutic targets.
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Affiliation(s)
- Iris E. M. de Jong
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Rebecca G. Wells
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
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10
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Yang Y, Wang J, Wan J, Cheng Q, Cheng Z, Zhou X, Wang O, Shi K, Wang L, Wang B, Zhu X, Chen J, Feng D, Liu Y, Jahan-Mihan Y, Haddock AN, Edenfield BH, Peng G, Hohenstein JD, McCabe CE, O'Brien DR, Wang C, Ilyas SI, Jiang L, Torbenson MS, Wang H, Nakhleh RE, Shi X, Wang Y, Bi Y, Gores GJ, Patel T, Ji B. PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice. J Hepatol 2024; 81:120-134. [PMID: 38428643 PMCID: PMC11259013 DOI: 10.1016/j.jhep.2024.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 02/09/2024] [Accepted: 02/18/2024] [Indexed: 03/03/2024]
Abstract
BACKGROUND & AIMS The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease. METHODS The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor. RESULTS We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression. CONCLUSIONS Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA. IMPACT AND IMPLICATIONS The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.
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Affiliation(s)
- Yan Yang
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA; Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Jiale Wang
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Jianhua Wan
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Qianqian Cheng
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Zenong Cheng
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Xueli Zhou
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Oliver Wang
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Kelvin Shi
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Lingxiang Wang
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Bin Wang
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Xiaohui Zhu
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Jiaxiang Chen
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Dongfeng Feng
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Yang Liu
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | | | - Ashley N Haddock
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | | | - Guang Peng
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Chantal E McCabe
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Daniel R O'Brien
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Chen Wang
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Liuyan Jiang
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida, USA
| | - Michael S Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Huamin Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Raouf E Nakhleh
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida, USA
| | - Xuemei Shi
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Ying Wang
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Yan Bi
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Tushar Patel
- Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.
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11
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Yin T, Chen S, Zhou R, Liu W, Diao M, Li L. Relationships of serum MMP-7 and clinical characteristics in choledochal cyst children. BMC Surg 2024; 24:195. [PMID: 38914992 PMCID: PMC11194885 DOI: 10.1186/s12893-024-02488-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 06/21/2024] [Indexed: 06/26/2024] Open
Abstract
BACKGROUND Matrix metalloproteinase-7 (MMP-7) is associated with biliary injury. This study aimed to evaluate the relationships of serum MMP-7 with clinical characteristics in choledochal cysts (CDC) children. METHODS Between June 2020 and July 2022, we conducted a prospective study of CDCs who underwent one-stage definitive operation at our center. Serum MMP-7 was measured using an enzyme-linked immunosorbent assay. We evaluated the relationships between serum MMP-7 and age, laboratory tests, imaging examinations, liver fibrosis, MMP-7 expression, and perforation. RESULTS A total of 328 CDCs were enrolled in the study, with a median serum MMP-7 of 7.67 ng/mL. Higher serum MMP-7 was correlated with younger age at diagnosis (p < 0.001), larger cyst sizes (p < 0.001), higher liver fibrosis stages (p < 0.001), and higher incidence of perforation (p < 0.01). Liver MMP-7 was mainly expressed in intrahepatic and extrahepatic biliary epithelial cells. The area under the receiver operating characteristic curve (AUROC) was 0.630 (p < 0.001) for serum MMP-7 in predicting perforation. When serum MMP-7 was combined with γ-glutamyl transferase (GGT), the AUROC increased to 0.706 (p < 0.001). CONCLUSIONS Serum MMP-7 was associated with biliary obstruction in CDCs. Patients with high serum MMP-7 were more likely to have severe liver damage and biliary injury, with higher incidences of liver fibrosis and perforation.
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Affiliation(s)
- Tong Yin
- Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing, China
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Suyun Chen
- Department of Pediatric Urology, Fujian Children's Hospital, Fujian, China
| | - Ruijie Zhou
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Wei Liu
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Mei Diao
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, China.
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment, Chinese Academy of Medical Sciences 2021RU015, Beijing, China.
| | - Long Li
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, China.
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment, Chinese Academy of Medical Sciences 2021RU015, Beijing, China.
- Department of Pediatric Surgery, Tsinghua University Affiliated Beijing Tsinghua Changgung Hospital, Beijing, China.
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12
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Okumura A, Aoshima K, Tanimizu N. Generation of in vivo-like multicellular liver organoids by mimicking developmental processes: A review. Regen Ther 2024; 26:219-234. [PMID: 38903867 PMCID: PMC11186971 DOI: 10.1016/j.reth.2024.05.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/24/2024] [Accepted: 05/30/2024] [Indexed: 06/22/2024] Open
Abstract
Liver is involved in metabolic reactions, ammonia detoxification, and immunity. Multicellular liver tissue cultures are more desirable for drug screening, disease modeling, and researching transplantation therapy, than hepatocytes monocultures. Hepatocytes monocultures are not stable for long. Further, hepatocyte-like cells induced from pluripotent stem cells and in vivo hepatocytes are functionally dissimilar. Organoid technology circumvents these issues by generating functional ex vivo liver tissue from intrinsic liver progenitor cells and extrinsic stem cells, including pluripotent stem cells. To function as in vivo liver tissue, the liver organoid cells must be arranged precisely in the 3-dimensional space, closely mimicking in vivo liver tissue. Moreover, for long term functioning, liver organoids must be appropriately vascularized and in contact with neighboring epithelial tissues (e.g., bile canaliculi and intrahepatic bile duct, or intrahepatic and extrahepatic bile ducts). Recent discoveries in liver developmental biology allows one to successfully induce liver component cells and generate organoids. Thus, here, in this review, we summarize the current state of knowledge on liver development with a focus on its application in generating different liver organoids. We also cover the future prospects in creating (functionally and structurally) in vivo-like liver organoids using the current knowledge on liver development.
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Affiliation(s)
- Ayumu Okumura
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
| | - Kenji Aoshima
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
| | - Naoki Tanimizu
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
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13
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Simmons CL, Harper LK, Patel MC, Katabathina VS, Southard RN, Goncalves L, Tran E, Biyyam DR. Biliary Disorders, Anomalies, and Malignancies in Children. Radiographics 2024; 44:e230109. [PMID: 38358937 DOI: 10.1148/rg.230109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Biliary abnormalities in children are uncommon, and the spectrum of biliary disorders is broader than in adult patients. Unlike in adults, biliary disorders in children are rarely neoplastic and are more commonly rhabdomyosarcoma rather than cholangiocarcinoma. Pediatric biliary disorders may be embryologic or congenital, such as anatomic gallbladder anomalies, anomalous pancreaticobiliary tracts, various cholestatic processes, congenital cystic lesions, or genetic conditions. They may also be benign, such as biliary filling anomalies, biliary motility disorders, and biliary inflammatory and infectious disorders. Distinguishing these entities with a single imaging modality is challenging. US is the primary imaging modality for initial evaluation of biliary abnormalities in children, due to its wide availability, lack of ionizing radiation, and low cost and because it requires no sedation. Other examinations such as MRI, CT, and nuclear medicine examinations may provide anatomic and functional information to narrow the diagnosis further. Hepatobiliary-specific contrast material with MRI can provide better assessment of biliary anatomy on delayed images than can traditional MRI contrast material. MR cholangiopancreatography (MRCP) allows visualization of the intra- and extrahepatic biliary ducts, which may not be possible with endoscopic retrograde cholangiopancreatography (ERCP). Suspected biliary atresia requires multiple modalities for diagnosis and timely treatment. Determining the type of choledochal cyst calls for a combination of initial US and MRCP. Many benign and malignant biliary masses require biopsy for definitive diagnosis. Knowledge of the imaging appearances of different pediatric biliary abnormalities is necessary for appropriate imaging workup, providing a diagnosis or differential diagnosis, and guiding appropriate management. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.
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Affiliation(s)
- Curtis L Simmons
- From the Department of Radiology, Phoenix Children's Hospital, 1919 E Thomas Rd, Main Tower, Phoenix, AZ 85016 (C.L.S., M.C.P., R.N.S., L.G., D.R.B.); Department of Radiology, Mayo Clinic, Phoenix, Ariz (L.K.H.); Department of Radiology, UT Health San Antonio, San Antonio, Tex (V.S.K.); and Baylor College of Medicine, Houston, Tex (E.T.)
| | - Laura K Harper
- From the Department of Radiology, Phoenix Children's Hospital, 1919 E Thomas Rd, Main Tower, Phoenix, AZ 85016 (C.L.S., M.C.P., R.N.S., L.G., D.R.B.); Department of Radiology, Mayo Clinic, Phoenix, Ariz (L.K.H.); Department of Radiology, UT Health San Antonio, San Antonio, Tex (V.S.K.); and Baylor College of Medicine, Houston, Tex (E.T.)
| | - Mittun C Patel
- From the Department of Radiology, Phoenix Children's Hospital, 1919 E Thomas Rd, Main Tower, Phoenix, AZ 85016 (C.L.S., M.C.P., R.N.S., L.G., D.R.B.); Department of Radiology, Mayo Clinic, Phoenix, Ariz (L.K.H.); Department of Radiology, UT Health San Antonio, San Antonio, Tex (V.S.K.); and Baylor College of Medicine, Houston, Tex (E.T.)
| | - Venkat S Katabathina
- From the Department of Radiology, Phoenix Children's Hospital, 1919 E Thomas Rd, Main Tower, Phoenix, AZ 85016 (C.L.S., M.C.P., R.N.S., L.G., D.R.B.); Department of Radiology, Mayo Clinic, Phoenix, Ariz (L.K.H.); Department of Radiology, UT Health San Antonio, San Antonio, Tex (V.S.K.); and Baylor College of Medicine, Houston, Tex (E.T.)
| | - Richard N Southard
- From the Department of Radiology, Phoenix Children's Hospital, 1919 E Thomas Rd, Main Tower, Phoenix, AZ 85016 (C.L.S., M.C.P., R.N.S., L.G., D.R.B.); Department of Radiology, Mayo Clinic, Phoenix, Ariz (L.K.H.); Department of Radiology, UT Health San Antonio, San Antonio, Tex (V.S.K.); and Baylor College of Medicine, Houston, Tex (E.T.)
| | - Luis Goncalves
- From the Department of Radiology, Phoenix Children's Hospital, 1919 E Thomas Rd, Main Tower, Phoenix, AZ 85016 (C.L.S., M.C.P., R.N.S., L.G., D.R.B.); Department of Radiology, Mayo Clinic, Phoenix, Ariz (L.K.H.); Department of Radiology, UT Health San Antonio, San Antonio, Tex (V.S.K.); and Baylor College of Medicine, Houston, Tex (E.T.)
| | - Evelyn Tran
- From the Department of Radiology, Phoenix Children's Hospital, 1919 E Thomas Rd, Main Tower, Phoenix, AZ 85016 (C.L.S., M.C.P., R.N.S., L.G., D.R.B.); Department of Radiology, Mayo Clinic, Phoenix, Ariz (L.K.H.); Department of Radiology, UT Health San Antonio, San Antonio, Tex (V.S.K.); and Baylor College of Medicine, Houston, Tex (E.T.)
| | - Deepa R Biyyam
- From the Department of Radiology, Phoenix Children's Hospital, 1919 E Thomas Rd, Main Tower, Phoenix, AZ 85016 (C.L.S., M.C.P., R.N.S., L.G., D.R.B.); Department of Radiology, Mayo Clinic, Phoenix, Ariz (L.K.H.); Department of Radiology, UT Health San Antonio, San Antonio, Tex (V.S.K.); and Baylor College of Medicine, Houston, Tex (E.T.)
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14
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Righini M, Mancini R, Busutti M, Buscaroli A. Autosomal Dominant Polycystic Kidney Disease: Extrarenal Involvement. Int J Mol Sci 2024; 25:2554. [PMID: 38473800 DOI: 10.3390/ijms25052554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder, but kidneys are not the only organs involved in this systemic disorder. Individuals with the condition may display additional manifestations beyond the renal system, involving the liver, pancreas, and brain in the context of cystic manifestations, while involving the vascular system, gastrointestinal tract, bones, and cardiac valves in the context of non-cystic manifestations. Despite kidney involvement remaining the main feature of the disease, thanks to longer survival, early diagnosis, and better management of kidney-related problems, a new wave of complications must be faced by clinicians who treated patients with ADPKD. Involvement of the liver represents the most prevalent extrarenal manifestation and has growing importance in the symptom burden and quality of life. Vascular abnormalities are a key factor for patients' life expectancy and there is still debate whether to screen or not to screen all patients. Arterial hypertension is often the earliest onset symptom among ADPKD patients, leading to frequent cardiovascular complications. Although cardiac valvular abnormalities are a frequent complication, they rarely lead to relevant problems in the clinical history of polycystic patients. One of the newest relevant aspects concerns bone disorders that can exert a considerable influence on the clinical course of these patients. This review aims to provide the "state of the art" among the extrarenal manifestation of ADPKD.
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Affiliation(s)
- Matteo Righini
- Nephrology and Dialysis Unit, Santa Maria delle Croci Hospital, AUSL Romagna, 48121 Ravenna, Italy
- Nephrology, Dialysis and Transplantation Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy
| | - Raul Mancini
- Nephrology, Dialysis and Transplantation Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy
| | - Marco Busutti
- Nephrology, Dialysis and Transplantation Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy
| | - Andrea Buscaroli
- Nephrology and Dialysis Unit, Santa Maria delle Croci Hospital, AUSL Romagna, 48121 Ravenna, Italy
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15
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Liu S, Li T, Yang Q, Ke X, Zhan J. Biliary atresia: the development, pathological features, and classification of the bile duct. Pediatr Surg Int 2024; 40:42. [PMID: 38289412 DOI: 10.1007/s00383-023-05627-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/26/2023] [Indexed: 02/01/2024]
Abstract
Biliary atresia is an occlusive biliary disease involving intrahepatic and extrahepatic bile ducts. Its etiology and pathogenesis are unclear. There are many manifestations of bile duct involvement in biliary atresia, but little is known about its occurrence and development. In addition, different classification methods have been proposed in different periods of biliary atresia, each with its advantages and disadvantages. The combined application of biliary atresia classification will help to improve the survival rate of patients with native liver. Therefore, this article reviews the development, pathological features, and classification of intrahepatic and extrahepatic bile ducts in biliary atresia, to provide a reference for the study of the pathogenesis and the choice of treatment methods.
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Affiliation(s)
- Shaowen Liu
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Tengfei Li
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Qianhui Yang
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Xingyuan Ke
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Jianghua Zhan
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, China.
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16
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Hrncir HR, Bombin S, Goodloe B, Hogan CB, Jadi O, Gracz AD. Sox9 links biliary maturation to branching morphogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.15.574730. [PMID: 38293117 PMCID: PMC10827067 DOI: 10.1101/2024.01.15.574730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
Branching morphogenesis couples cellular differentiation with development of tissue architecture. Intrahepatic bile duct (IHBD) morphogenesis is initiated with biliary epithelial cell (BEC) specification and eventually forms a heterogeneous network of large ducts and small ductules. Here, we show that Sox9 is required for developmental establishment of small ductules. IHBDs emerge as a webbed structure by E15.5 and undergo morphological maturation through 2 weeks of age. Developmental knockout of Sox9 leads to decreased postnatal branching morphogenesis, manifesting as loss of ductules in adult livers. In the absence of Sox9, BECs fail to mature and exhibit elevated TGF-β signaling and Activin A. Activin A induces developmental gene expression and morphological defects in BEC organoids and represses ductule formation in postnatal livers. Our data demonstrate that adult IHBD morphology and BEC maturation is regulated by the Sox9-dependent formation of precursors to ductules during development, mediated in part by downregulation of Activin A.
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Affiliation(s)
- Hannah R Hrncir
- Department of Medicine, Division of Digestive Diseases, Emory University. Atlanta, GA USA
- Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University
| | - Sergei Bombin
- Department of Medicine, Division of Digestive Diseases, Emory University. Atlanta, GA USA
| | - Brianna Goodloe
- Department of Medicine, Division of Digestive Diseases, Emory University. Atlanta, GA USA
| | - Connor B Hogan
- Department of Medicine, Division of Digestive Diseases, Emory University. Atlanta, GA USA
| | - Othmane Jadi
- School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Adam D Gracz
- Department of Medicine, Division of Digestive Diseases, Emory University. Atlanta, GA USA
- Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University
- Lead contact:
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17
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Bai M, Jiang N, Fu W, Huang C, Tian L, Mi N, Gao L, Ma H, Lu Y, Cao J, Zhang C, Yue P, Zhang Y, Lin Y, Meng W, Li X. Establishment and characterization of a novel hilar cholangiocarcinoma cell line, CBC3T-1. Hum Cell 2024; 37:364-375. [PMID: 37966669 PMCID: PMC10764469 DOI: 10.1007/s13577-023-01003-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/24/2023] [Indexed: 11/16/2023]
Abstract
Cholangiocarcinoma (CCA) is a group of malignant heterogeneous cancer arising from the biliary tree. The tumor is characterized by insidious onset, high degree of malignancy, poor prognosis, and high recurrence rate. Immortalized cancer cell lines are the best and easiest models for in vitro cancer research. Here, we established a naturally immortalized highly tumorigenic hilar cholangiocarcinoma (hCCA) cell line, CBC3T-1. The CBC3T-1 cell line was cultured for over 60 passages. Thorough analysis showed that CBC3T-1 cells share characteristics similar to original tumor cells from patients with cholangiocarcinoma and display a stable phenotype, including features of epithelial origin, stem cell-like properties, as well as a high invasive and migratory capability and tumorigenicity in mice. Furthermore, this cell line showed the best sensitivity to paclitaxel, followed by gemcitabine. RNA sequencing and whole‑exome sequencing showed that cancer-associated pathways and somatic mutations played a dominant role in the development of CCA. We established and characterized a new hCCA cell line, CBC3T-1, which contributes to a better understanding of bile duct cancer, and can be used to study tumorigenesis and progression and the role of anticancer drugs.
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Affiliation(s)
- Mingzhen Bai
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Ningzu Jiang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Wenkang Fu
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Chongfei Huang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Liang Tian
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Ningning Mi
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Long Gao
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Haidong Ma
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yawen Lu
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Jie Cao
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Chao Zhang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Ping Yue
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China.
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China.
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, Gansu, China.
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, Gansu, China
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18
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Baltaga L, Chrysikos D, Delis S, Triantopoulou C, Filippou D, Protogerou V, Troupis T. Duplicated gallbladder: an incidental anatomical variation in a patient with symptomatic cholelithiasis. Folia Med (Plovdiv) 2023; 65:834-838. [PMID: 38351768 DOI: 10.3897/folmed.65.e91397] [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: 08/08/2022] [Accepted: 09/12/2022] [Indexed: 02/16/2024] Open
Abstract
Congenital malformations of the biliary tract represent a relatively rare entity with which surgeons, radiologists and clinicians are not adequately familiarized. We present a rare case of gallbladder duplication in a 40-year-old female, with the accessory cystic duct entering the left hepatic duct, which depicts the fifth reported case in the international bibliography. Our case illustrates the importance of detailed knowledge of anatomical malformations of the biliary tree, serving the purpose of a preoperative diagnosis of symptomatic cholelithiasis. It is also of paramount importance to take under consideration biliary tract malformations to avoid inadvertent complications such as biliary duct injuries in case of laparoscopic cholecystectomy.
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Affiliation(s)
- Ludmila Baltaga
- National and Kapodistrian University of Athens, Athens, Greece
| | | | - Spiros Delis
- National and Kapodistrian University of Athens, Athens, Greece
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19
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Kamaletdinova T, Zong W, Urbánek P, Wang S, Sannai M, Grigaravičius P, Sun W, Fanaei-Kahrani Z, Mangerich A, Hottiger MO, Li T, Wang ZQ. Poly(ADP-Ribose) Polymerase-1 Lacking Enzymatic Activity Is Not Compatible with Mouse Development. Cells 2023; 12:2078. [PMID: 37626888 PMCID: PMC10453916 DOI: 10.3390/cells12162078] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 08/11/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Poly(ADP-ribose) polymerase-1 (PARP1) binds DNA lesions to catalyse poly(ADP-ribosyl)ation (PARylation) using NAD+ as a substrate. PARP1 plays multiple roles in cellular activities, including DNA repair, transcription, cell death, and chromatin remodelling. However, whether these functions are governed by the enzymatic activity or scaffolding function of PARP1 remains elusive. In this study, we inactivated in mice the enzymatic activity of PARP1 by truncating its C-terminus that is essential for ART catalysis (PARP1ΔC/ΔC, designated as PARP1-ΔC). The mutation caused embryonic lethality between embryonic day E8.5 and E13.5, in stark contrast to PARP1 complete knockout (PARP1-/-) mice, which are viable. Embryonic stem (ES) cell lines can be derived from PARP1ΔC/ΔC blastocysts, and these mutant ES cells can differentiate into all three germ layers, yet, with a high degree of cystic structures, indicating defects in epithelial cells. Intriguingly, PARP1-ΔC protein is expressed at very low levels compared to its full-length counterpart, suggesting a selective advantage for cell survival. Noticeably, PARP2 is particularly elevated and permanently present at the chromatin in PARP1-ΔC cells, indicating an engagement of PARP2 by non-enzymatic PARP1 protein at the chromatin. Surprisingly, the introduction of PARP1-ΔC mutation in adult mice did not impair their viability; yet, these mutant mice are hypersensitive to alkylating agents, similar to PARP1-/- mutant mice. Our study demonstrates that the catalytically inactive mutant of PARP1 causes the developmental block, plausibly involving PARP2 trapping.
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Affiliation(s)
- Tatiana Kamaletdinova
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), 07745 Jena, Germany; (T.K.); (P.U.); (M.S.); (P.G.); (Z.F.-K.)
| | - Wen Zong
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China; (W.Z.); (S.W.); (W.S.); (T.L.)
| | - Pavel Urbánek
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), 07745 Jena, Germany; (T.K.); (P.U.); (M.S.); (P.G.); (Z.F.-K.)
| | - Sijia Wang
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China; (W.Z.); (S.W.); (W.S.); (T.L.)
| | - Mara Sannai
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), 07745 Jena, Germany; (T.K.); (P.U.); (M.S.); (P.G.); (Z.F.-K.)
| | - Paulius Grigaravičius
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), 07745 Jena, Germany; (T.K.); (P.U.); (M.S.); (P.G.); (Z.F.-K.)
| | - Wenli Sun
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China; (W.Z.); (S.W.); (W.S.); (T.L.)
| | - Zahra Fanaei-Kahrani
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), 07745 Jena, Germany; (T.K.); (P.U.); (M.S.); (P.G.); (Z.F.-K.)
| | - Aswin Mangerich
- Molecular Toxicology, Department of Biology, University of Konstanz, 78464 Konstanz, Germany;
- Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, 14469 Potsdam, Germany
| | - Michael O. Hottiger
- Department of Molecular Mechanisms of Disease, University of Zürich, 8057 Zürich, Switzerland;
| | - Tangliang Li
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China; (W.Z.); (S.W.); (W.S.); (T.L.)
| | - Zhao-Qi Wang
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), 07745 Jena, Germany; (T.K.); (P.U.); (M.S.); (P.G.); (Z.F.-K.)
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China; (W.Z.); (S.W.); (W.S.); (T.L.)
- Faculty of Biological Sciences, Friedrich Schiller University of Jena, 07743 Jena, Germany
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Yoshihara M, Takahashi S. Recent advances in in situ Notch signaling measurement. Front Cell Dev Biol 2023; 11:1244105. [PMID: 37576594 PMCID: PMC10416437 DOI: 10.3389/fcell.2023.1244105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 07/21/2023] [Indexed: 08/15/2023] Open
Abstract
Notch signaling is necessary for the development of many organ systems, including the nervous system, biliary system, and visual and auditory sensory systems. This signaling pathway is composed of DSL ligands and Notch receptors. Upon the interaction of those components between neighboring cells, the intracellular domain of the Notch receptor is cleaved from the cell membrane to act as a transcription factor. To date, many mechanistic insights, including lateral inhibition and lateral induction, have been proposed from observation of patterning morphogenesis and expression profiles of Notch signaling-associated molecules. The lack of a direct measurement method for Notch signaling, however, has impeded the examination of those mechanistic insights. In this mini-review, recent advances in the direct measurement of Notch signaling are introduced with a focus on the application of genetic modification of Notch receptors with the components of the Cre/loxP system and Gal4/UAS system. The combination of such conventional genetic techniques is opening a new era in Notch signaling biology by direct visualization of Notch "signaling" in addition to Notch signaling-associated molecules.
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Affiliation(s)
- Masaharu Yoshihara
- Department of Primary Care and Medical Education, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Satoru Takahashi
- Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
- Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
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21
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Chen S, Yin T, Li L, Diao M, Huang T. Correlation of ectopic distal location of papilla of Vater and clinical characteristics in pediatric choledochal cysts. Pediatr Surg Int 2023; 39:201. [PMID: 37191896 DOI: 10.1007/s00383-023-05486-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/10/2023] [Indexed: 05/17/2023]
Abstract
PURPOSE Ectopic distal location of papilla of Vater (EDLPV) is an obvious pathological feature of choledochal cyst (CDC). This study aimed to investigate the correlation between EDLPV and clinical characteristics of CDCs. METHODS Three groups were studied: Group 1 (G1), papilla in the middle third of second part of duodenum (n = 38); Group 2 (G2), papilla from the distal third of second part to the beginning of third part of duodenum (n = 168); Group 3 (G3), papilla from the middle of third part to fourth part of duodenum (n = 121). Relative variables among three groups were compared. RESULTS Compared with G1 and G2, G3 patients had the largest cysts (relative diameter: 1.18 vs. 1.60 vs. 2.62, p < 0.001), the youngest age (20.52 vs. 19.47 vs. -3.40 months, p < 0.001), the highest rate of prenatal diagnosis (26.32% vs. 36.31% vs. 62.81%, p < 0.001), the lowest occurrence of protein plugs in common channel (44.74% vs. 38.69% vs. 16.53%, p < 0.001), and the most elevated total bilirubin level (7.35 vs. 9.95 vs. 28.70 μmol/L, p < 0.001). Prenatally diagnosed G3 patients had heavier liver fibrosis than G2 (13.16% vs. 1.67%, p = 0.015). CONCLUSION The more distal papilla location, the more severe clinical characteristics of CDCs, suggesting a crucial role in its pathogenesis.
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Affiliation(s)
- Suyun Chen
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing, China
| | - Tong Yin
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing, China
| | - Long Li
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China.
- Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing, China.
- Department of Pediatric Surgery, Tsinghua University Affiliated Beijing Tsinghua Changgung Hospital, Beijing, China.
| | - Mei Diao
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing, China
| | - Ting Huang
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Children's Hospital Capital Institute of Pediatrics, Graduate School of Peking Union Medical College, Beijing, China
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22
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Renzulli M, Brandi N, Brocchi S, Balacchi C, Lanza C, Pettinari I, Stefanini B, Carrafiello G, Piscaglia F, Golfieri R, Marasco G. Association between anatomic variations of extrahepatic and intrahepatic bile ducts: Do look up! J Anat 2023; 242:683-694. [PMID: 36670522 PMCID: PMC10008292 DOI: 10.1111/joa.13808] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/06/2022] [Accepted: 12/06/2022] [Indexed: 01/22/2023] Open
Abstract
Biliary anatomic variations are usually asymptomatic, but they may cause problems in diagnostic investigations and interventional and surgical procedures, increasing both their technical difficulty and their postoperative complication rates. The aim of the present study was to evaluate the prevalence of anatomic variations in the intrahepatic biliary ducts (IHBD) in relation to demographical and clinical characteristics in a large study population requiring magnetic resonance cholangiopancreatography (MRCP) for various clinical conditions. The possible association between IHBD and extrahepatic biliary ducts (EHBD) variants was then explored. From January 2017 to May 2019, 1004 patients underwent MRCP. Demographical and clinical data were collected. IHBD and EHBD anatomy were recorded and the EHBD anatomy was classified using both qualitative and quantitative classifications. The presence of a type 3 EHBD variant (an abnormal proximal cystic duct [CD] insertion) in both qualitative and quantitative classifications and an intrapancreatic CD were associated with the presence of IHBD variants at univariate analysis (p = 0.008, p = 0.019, and p = 0.001, respectively). The presence of a posterior or medial insertion of the CD into the EHBD was a strong predictive factor of the presence of IHBD variants both at uni- and multivariate analysis (p = 0.002 and p = 0.003 for posterior insertion and p = 0.002 and p = 0.002 for medial insertion, respectively). The presence of gallstones on MRCP resulted in a strong predictor of the presence of an anatomical variant of the IHBD both at uni- and multivariate analysis (p = 0.027 and p = 0.046, respectively). In conclusion, the presence of a type 3 variant of the EHBD, an intrapancreatic CD and, especially, a posterior/medial CD insertion into the EHBD represent predictive factors of the concomitant presence of IHBD variants, thus radiologists must be vigilant when encountering these EHBD configurations and always remember to "look up" at the IHBD. Finally, the presence of an IHBD variant is a strong predictive factor of gallstones.
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Affiliation(s)
- Matteo Renzulli
- Department of RadiologyIRCCS Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | - Nicolò Brandi
- Department of RadiologyIRCCS Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | - Stefano Brocchi
- Department of RadiologyIRCCS Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | - Caterina Balacchi
- Department of RadiologyIRCCS Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | - Carolina Lanza
- Diagnostic and Interventional Radiology Department, Fondazione IRCCS Cà GrandaOspedale Maggiore PoliclinicoMilanItaly
| | - Irene Pettinari
- Department of RadiologyIRCCS Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | - Bernardo Stefanini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic DiseasesIRCCS Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | - Giampaolo Carrafiello
- Diagnostic and Interventional Radiology Department, Fondazione IRCCS Cà GrandaOspedale Maggiore PoliclinicoMilanItaly
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic DiseasesIRCCS Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | - Rita Golfieri
- Department of RadiologyIRCCS Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | - Giovanni Marasco
- Internal Medicine and Digestive Physiopathology UnitIRCCS Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
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23
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Davenport M, Kronfli R, Makin E. Advances in understanding of biliary atresia pathogenesis and progression - a riddle wrapped in a mystery inside an enigma. Expert Rev Gastroenterol Hepatol 2023; 17:343-352. [PMID: 36908275 DOI: 10.1080/17474124.2023.2191188] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
INTRODUCTION Biliary atresia is a potentially fatal condition of the bile ducts - both intra- and extrahepatic, for which we have no cure. Though principally a cholestatic condition, much of its pathology stems from its tendency to aggressively induce liver fibrosis and ultimately cirrhosis, only partially restrained by the portoenterostomy. AREAS COVERED This review is based on the current literature exploring the heterogeneous nature of biliary atresia. Thus, there are various phenotypes or variants of biliary atresia, each potentially with different etiological backgrounds caused by a number of hypothetical pathological mechanisms thought to be important in the genesis of the condition. Search methodology: the review (Oct. - Nov. 2022) is based on a search of PubMed (NLM) using main keyword 'biliary atresia' with supplementary searches using 'fibrosis'; 'inflammation'; 'BASM'; 'genetics'; 'surgery'; 'experimental'; 'etiology'; 'virology'; 'cases'; and 'syndromes.' EXPERT OPINION Future developments will be made on matching clinical variants with a more distinct pathophysiological discrimination and those pathways linking the initial cholestatic phase of biliary atresia to the early stages of fibrosis.
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Affiliation(s)
- Mark Davenport
- Department of Paediatric Surgery, Kings College Hospital, London, UK
| | - Rania Kronfli
- Department of Paediatric Surgery, Kings College Hospital, London, UK
| | - Erica Makin
- Department of Paediatric Surgery, Kings College Hospital, London, UK
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24
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Laitman JT, Smith HF. The Anatomical Record digests new findings on the twists and turns and surprises of the gastrointestinal system in a new Special Issue. Anat Rec (Hoboken) 2023; 306:937-940. [PMID: 36734640 DOI: 10.1002/ar.25156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 01/04/2023] [Indexed: 02/04/2023]
Affiliation(s)
- Jeffrey T Laitman
- Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Heather F Smith
- Department of Anatomy, Midwestern University, Glendale, Arizona, USA.,School of Human Evolution and Social Change, Arizona State University, Tempe, Arizona, USA
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25
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Correlation between Pancreatic Duct Variation and Related Diseases: An Effective Method Observing the Dual-Energy CT with Low-keV Monoenergetic Images. Diagnostics (Basel) 2023; 13:diagnostics13030520. [PMID: 36766625 PMCID: PMC9914045 DOI: 10.3390/diagnostics13030520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/18/2023] [Accepted: 01/25/2023] [Indexed: 02/04/2023] Open
Abstract
PURPOSE Pancreatic duct variation can affect the secretory function of the pancreas. We aimed to explore the pancreatic duct variation, observed using low-keV monoenergetic images [MEI (+)] of dual-energy CT (DECT), and its relationship with related diseases. We further sought to compare pancreatic duct imaging using low-keV MEI (+) of DECT and magnetic resonance cholangiopancreatography (MRCP). MATERIALS AND METHODS The DECT and MRCP images of 854 patients were evaluated retrospectively. The 808 patients' pancreatic duct types were classified according to the anatomy and the opening of the pancreatic ducts, and the correlation with related diseases was analyzed. The DECT and MRCP images of 852 patients were graded according to the sharpness of the pancreatic ducts for evaluation. RESULTS A higher prevalence of acute pancreatitis (AP), chronic pancreatitis (CP), and duodenal papillary carcinoma (DPC) was observed in the variant group. Of the 27 AP cases in the variant group, 9 patients (33.3%) were Type 3c. Additionally, Type 4a was significantly correlated with AP and CP (p < 0.05). Low-keV MEI (+) of DECT outperformed the MRCP images in the sharpness of the pancreatic ducts in 852 patients. CONCLUSIONS Pancreatic duct variation is associated with AP, CP, and DPC. Low-keV MEI (+) DECT is an effective method to observe the pancreatic duct system.
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Muacevic A, Adler JR. Variant Biliary Anatomy in Biological Siblings. Cureus 2023; 15:e34199. [PMID: 36843766 PMCID: PMC9955506 DOI: 10.7759/cureus.34199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2023] [Indexed: 01/26/2023] Open
Abstract
Laparoscopic cholecystectomy is the standard of care for cholecystolithiasis but carries an increased risk of biliary injury compared to open cholecystectomy. Complications from laparoscopic cholecystectomy can be related to several factors. These include - (i) technical factors that depend on the skill of the surgeon, (ii) pathologic factors such as associated inflammation and adhesions, and (iii) anatomic factors such as biliary anatomy. Aberrant biliary anatomy is a major cause of bile duct injury during surgery. To the best of our knowledge familial aberrant biliary anatomy has not been previously reported in the literature. We report a case series of two biological sisters with isolated posterior right duct syndrome and present a brief literature review of this medical condition.
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Affiliation(s)
- Alexander Muacevic
- Department of Gastroenterology and Hepatology, University of Connecticut Health, Farmington, USA
| | - John R Adler
- Department of Gastroenterology and Hepatology, University of Connecticut Health, Farmington, USA
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27
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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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28
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Spain HN, Penninck DG, Thelen M. Ultrasonographic prevalence and proposed morphologic classification of bilobed gallbladder in cats. J Feline Med Surg 2022; 24:986-993. [PMID: 34709081 PMCID: PMC10812300 DOI: 10.1177/1098612x211055629] [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] [Accepted: 10/05/2021] [Indexed: 11/16/2022]
Abstract
OBJECTIVES Morphologic anomalies of the feline gallbladder (GB) have been previously reported in the literature. These morphologic variants are frequently encountered on routine abdominal ultrasound examination. The aim of this study was to provide an ultrasonographic classification system of these variants and document the overall incidence in the feline population. METHODS A prospective, descriptive study was undertaken; cats that had an abdominal ultrasound examination that included at least one sagittal and transverse plane image of the GB were included. GB shape was evaluated and categorized based on a classification scheme of morphologic variants modified from the human literature. Septated (S), bilobed (B1, B2, B3), duplex (D) and complex (C) categories were described. RESULTS Of 516 cats included in the study, 389 had normal GB morphology, while 127 had anomalous GB morphology. The overall incidence rate of anomalous GB morphology was 24.61%. When examined by morphologic type, the septated (S) morphology had an incidence of 9.69%. A bilobed (B) morphology was the most commonly observed classification; incidence was 14.35% within our population; incidence of B1, B2 and B3 subtypes were 2.91%, 6.98% and 4.46%, respectively. Duplex GBs only made up 0.39% of the total population. The incidence of complex (C) morphologies was 0.19%. CONCLUSIONS AND RELEVANCE The incidence of GB morphologic anomalies was higher in our population than previously reported. Identification of these anomalies on routine ultrasound evaluation is common; numerous different morphologies can be identified and a standardized classification scheme is proposed. Complete evaluation of morphology can be challenging, particularly with regard to cystic duct anatomy. Clinical significance is uncertain and future studies are warranted to determine the relationship between morphologic variants and hepatobiliary disease.
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Affiliation(s)
- Heather N Spain
- Department of Radiology, BluePearl, The Pet Specialists of Monterey, Del Rey Oaks, CA, USA
| | - Dominique G Penninck
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA, USA
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29
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Norcia LF, Watanabe EM, Hamamoto Filho PT, Hasimoto CN, Pelafsky L, de Oliveira WK, Sassaki LY. Polycystic Liver Disease: Pathophysiology, Diagnosis and Treatment. Hepat Med 2022; 14:135-161. [PMID: 36200122 PMCID: PMC9528914 DOI: 10.2147/hmer.s377530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/07/2022] [Indexed: 11/25/2022] Open
Abstract
Polycystic liver disease (PLD) is a clinical condition characterized by the presence of more than 10 cysts in the liver. It is a rare disease Of genetic etiology that presents as an isolated disease or assoc\iated with polycystic kidney disease. Ductal plate malformation, ciliary dysfunction, and changes in cell signaling are the main factors involved in its pathogenesis. Most patients with PLD are asymptomatic, but in 2-5% of cases the disease has disabling symptoms and a significant reduction in quality of life. The diagnosis is based on family history of hepatic and/or renal polycystic disease, clinical manifestations, patient age, and polycystic liver phenotype shown on imaging examinations. PLD treatment has evolved considerably in the last decades. Somatostatin analogues hold promise in controlling disease progression, but liver transplantation remains a unique curative treatment modality.
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Affiliation(s)
- Luiz Fernando Norcia
- Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Erika Mayumi Watanabe
- Department of Radiology, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Pedro Tadao Hamamoto Filho
- Department of Neurology, Psychology and Psychiatry, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Claudia Nishida Hasimoto
- Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Leonardo Pelafsky
- Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Walmar Kerche de Oliveira
- Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Ligia Yukie Sassaki
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
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Hrncir HR, Gracz AD. Cellular and transcriptional heterogeneity in the intrahepatic biliary epithelium. GASTRO HEP ADVANCES 2022; 2:108-120. [PMID: 36593993 PMCID: PMC9802653 DOI: 10.1016/j.gastha.2022.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/19/2022] [Indexed: 01/05/2023]
Abstract
Epithelial tissues comprise heterogeneous cellular subpopulations, which often compartmentalize specialized functions like absorption and secretion to distinct cell types. In the liver, hepatocytes and biliary epithelial cells (BECs; also called cholangiocytes) are the two major epithelial lineages and play distinct roles in (1) metabolism, protein synthesis, detoxification, and (2) bile transport and modification, respectively. Recent technological advances, including single cell transcriptomic assays, have shed new light on well-established heterogeneity among hepatocytes, endothelial cells, and immune cells in the liver. However, a "ground truth" understanding of molecular heterogeneity in BECs has remained elusive, and the field currently lacks a set of consensus biomarkers for identifying BEC subpopulations. Here, we review long-standing definitions of BEC heterogeneity as well as emerging studies that aim to characterize BEC subpopulations using next generation single cell assays. Understanding cellular heterogeneity in the intrahepatic bile ducts holds promise for expanding our foundational mechanistic knowledge of BECs during homeostasis and disease.
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Affiliation(s)
- Hannah R. Hrncir
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia
- Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia
| | - Adam D. Gracz
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia
- Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia
- Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, Georgia
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31
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Boushehry R, Husain F, Saleem A, Alshamali M, Alhammadi F, Mohammad K. Congenital absence of the cystic duct: Case report of a rare anomaly and review of the literature. Int J Surg Case Rep 2022; 96:107353. [PMID: 35780648 PMCID: PMC9284068 DOI: 10.1016/j.ijscr.2022.107353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/22/2022] [Accepted: 06/22/2022] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION AND IMPORTANCE Congenital absence of the cystic duct is one of the rare types of anomalies associated with the extrahepatic biliary tract (EHBT). It is often an incidental finding intraoperatively leading to significant implications during the perioperative period. CASE PRESENTATION A 25-year-old lady was admitted for an elective laparoscopic cholecystectomy indicated for recurrent symptoms of right upper quadrant pain with evidence of cholelithiasis on ultrasound. During laparoscopy, the cystic duct could not be identified. After retrieval of the gallbladder, a blind ending orifice resembling an obliterated cystic duct was discovered. CLINICAL DISCUSSION Absence of the cystic duct can result from a congenital or an acquired process. In both cases, they are difficult to diagnose pre-operatively even though magnetic resonance cholangiopancreatography (MRCP) has shown great potential in delineating the EHBT. It confers an increased risk of injury to the surrounding biliary tract during cholecystectomy. Therefore, the surgical approach depends on the surgeon's operative competency and knowledge related to EHBT anomalies. CONCLUSION Definitive treatment for patients with symptomatic absent cystic duct is an open cholecystectomy, given its increased likelihood of iatrogenic morbidity. Nonetheless, it is important to highlight that laparoscopic cholecystectomy may be performed if the surgeon carries sufficient skills.
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Sharbidre K, Zahid M, Venkatesh SK, Bhati C, Lalwani N. Imaging of fibropolycystic liver disease. Abdom Radiol (NY) 2022; 47:2356-2370. [PMID: 35670875 DOI: 10.1007/s00261-022-03565-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/14/2022] [Accepted: 05/17/2022] [Indexed: 11/01/2022]
Abstract
Fibropolycystic liver diseases (FLDs) make up a rare spectrum of heritable hepatobiliary diseases resulting from congenital ductal plate malformations (DPMs) due to the dysfunction of proteins expressed on the primary cilia of cholangiocytes. The embryonic development of the ductal plate is key to understanding this spectrum of diseases. In particular, DPMs can result in various degrees of intrahepatic duct involvement and a wide spectrum of cholangiopathies, including congenital hepatic fibrosis, Caroli disease, polycystic liver disease, and Von Meyenberg complexes. The most common clinical manifestations of FLDs are portal hypertension, cholestasis, cholangitis, and (in rare cases) cholangiocarcinoma. This article reviews recent updates in the pathophysiology, imaging, and clinical management of FLDs.
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Affiliation(s)
- Kedar Sharbidre
- Department of Abdominal Imaging, University of Alabama at Birmingham, Birmingham, AB, USA.
| | - Mohd Zahid
- Department of Abdominal Imaging, University of Alabama at Birmingham, Birmingham, AB, USA
| | | | - Chandra Bhati
- Department of Transplant Surgery, University of Maryland Medical Center, Baltimore, ML, USA
| | - Neeraj Lalwani
- Department of Abdominal Imaging, Virginia Commonwealth University, Richmond, VA, USA
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Kinoshita IHB, Torres US, Zanini LAP, Pinto MF, Veloso JDCV, de Siqueira GRS, D'Ippolito G. The Ductal Plate From the Inside Out: An Illustrated Review of Fibropolycystic Liver Disease. Semin Ultrasound CT MR 2022; 43:510-516. [DOI: 10.1053/j.sult.2022.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Roos FJM, van Tienderen GS, Wu H, Bordeu I, Vinke D, Albarinos LM, Monfils K, Niesten S, Smits R, Willemse J, Rosmark O, Westergren-Thorsson G, Kunz DJ, de Wit M, French PJ, Vallier L, IJzermans JNM, Bartfai R, Marks H, Simons BD, van Royen ME, Verstegen MMA, van der Laan LJW. Human branching cholangiocyte organoids recapitulate functional bile duct formation. Cell Stem Cell 2022; 29:776-794.e13. [PMID: 35523140 DOI: 10.1016/j.stem.2022.04.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 02/25/2022] [Accepted: 04/14/2022] [Indexed: 12/13/2022]
Abstract
Human cholangiocyte organoids show great promise for regenerative therapies and in vitro modeling of bile duct development and diseases. However, the cystic organoids lack the branching morphology of intrahepatic bile ducts (IHBDs). Here, we report establishing human branching cholangiocyte organoid (BRCO) cultures. BRCOs self-organize into complex tubular structures resembling the IHBD architecture. Single-cell transcriptomics and functional analysis showed high similarity to primary cholangiocytes, and importantly, the branching growth mimics aspects of tubular development and is dependent on JAG1/NOTCH2 signaling. When applied to cholangiocarcinoma tumor organoids, the morphology changes to an in vitro morphology like primary tumors. Moreover, these branching cholangiocarcinoma organoids (BRCCAOs) better match the transcriptomic profile of primary tumors and showed increased chemoresistance to gemcitabine and cisplatin. In conclusion, BRCOs recapitulate a complex process of branching morphogenesis in vitro. This provides an improved model to study tubular formation, bile duct functionality, and associated biliary diseases.
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Affiliation(s)
- Floris J M Roos
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Gilles S van Tienderen
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Haoyu Wu
- Radboud University, Department of Molecular Biology, Nijmegen, the Netherlands
| | - Ignacio Bordeu
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | - Dina Vinke
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Laura Muñoz Albarinos
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Kathryn Monfils
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Sabrah Niesten
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Ron Smits
- Erasmus MC, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands
| | - Jorke Willemse
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Oskar Rosmark
- Lung Biology, Department Experimental Medical Science, Lund University, Lund, Sweden
| | | | - Daniel J Kunz
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, University of Cambridge, Cambridge, UK
| | - Maurice de Wit
- Erasmus MC, University Medical Center Rotterdam, Department of Pathology, Rotterdam, the Netherlands
| | - Pim J French
- Erasmus MC, University Medical Center Rotterdam, Cancer Treatment Screening Facility, Department of Neurology, Rotterdam, the Netherlands
| | - Ludovic Vallier
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Jan N M IJzermans
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Richard Bartfai
- Radboud University, Department of Molecular Biology, Nijmegen, the Netherlands
| | - Hendrik Marks
- Radboud University, Department of Molecular Biology, Nijmegen, the Netherlands
| | - Ben D Simons
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | - Martin E van Royen
- Erasmus MC, University Medical Center Rotterdam, Department of Pathology, Rotterdam, the Netherlands
| | - Monique M A Verstegen
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Luc J W van der Laan
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands.
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Xu J, Hao S, Shi Q, Deng Q, Jiang Y, Guo P, Yuan Y, Shi X, Shangguan S, Zheng H, Lai G, Huang Y, Wang Y, Song Y, Liu Y, Wu L, Wang Z, Cheng J, Wei X, Cheng M, Lai Y, Volpe G, Esteban MA, Hou Y, Liu C, Liu L. Transcriptomic Profile of the Mouse Postnatal Liver Development by Single-Nucleus RNA Sequencing. Front Cell Dev Biol 2022; 10:833392. [PMID: 35465320 PMCID: PMC9019599 DOI: 10.3389/fcell.2022.833392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 03/11/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Jiangshan Xu
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Shijie Hao
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Quan Shi
- BGI-Shenzhen, Shenzhen, China
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Qiuting Deng
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Yujia Jiang
- BGI-Shenzhen, Shenzhen, China
- BGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Pengcheng Guo
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
- Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yue Yuan
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Xuyang Shi
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Shuncheng Shangguan
- Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Joint School of Life Sciences, Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Huiwen Zheng
- BGI-Shenzhen, Shenzhen, China
- BGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Guangyao Lai
- Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Joint School of Life Sciences, Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | | | | | | | | | - Liang Wu
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | | | - Jiehui Cheng
- Guangdong Hospital of Traditional Chinese Medicine, Zhuhai, China
| | | | - Mengnan Cheng
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Yiwei Lai
- Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Giacomo Volpe
- Hematology and Cell Therapy Unit, IRCCS-Istituto Tumori‘Giovanni Paolo II’, Bari, Italy
| | - Miguel A. Esteban
- BGI-Shenzhen, Shenzhen, China
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
- Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
| | | | | | - Longqi Liu
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
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Brahee DD, Lampl BS. Neonatal diagnosis of biliary atresia: a practical review and update. Pediatr Radiol 2022; 52:685-692. [PMID: 34331566 DOI: 10.1007/s00247-021-05148-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/03/2021] [Accepted: 06/28/2021] [Indexed: 02/02/2023]
Abstract
Biliary atresia is challenging to diagnose because many of the clinical and imaging features of this condition overlap with those of other causes of cholestasis in newborns. When jaundice persists beyond 2 weeks of age, the neonate should be evaluated for cholestasis, and biliary atresia - the most common cause of neonatal cholestasis - should be considered. It is critical to diagnose biliary atresia early because failure to treat can result in hepatic fibrosis and death in less than 1 year. In this paper, we review the current diagnostic imaging methods, differential considerations and treatment options for biliary atresia.
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Affiliation(s)
- Deborah D Brahee
- Department of Radiology, Cleveland Clinic, 9500 Euclid Ave., Mail Code L10, Cleveland, OH, 44193, USA.
| | - Brooke S Lampl
- Department of Radiology, Cleveland Clinic, 9500 Euclid Ave., Mail Code L10, Cleveland, OH, 44193, USA
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Vij M, Puri Y, Rammohan A, G G, Rajalingam R, Kaliamoorthy I, Rela M. Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review. World J Gastrointest Oncol 2022; 14:607-627. [PMID: 35321284 PMCID: PMC8919011 DOI: 10.4251/wjgo.v14.i3.607] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/13/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Yogesh Puri
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ashwin Rammohan
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Gowripriya G
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Rajesh Rajalingam
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ilankumaran Kaliamoorthy
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
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Aburawi E, Dakilah F. An extremely rare case of bonneau syndrome with novel cardiac and eye manifestations. SAUDI JOURNAL OF MEDICINE AND MEDICAL SCIENCES 2022; 10:166-169. [PMID: 35602397 PMCID: PMC9121694 DOI: 10.4103/sjmms.sjmms_122_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 08/25/2021] [Accepted: 03/09/2022] [Indexed: 11/24/2022] Open
Abstract
Bonneau or cardio-ducto-polysyndactyly syndrome is an extremely rare, life-threatening developmental defect, which has only been reported in eight patients previously. Here, we describe one such case of Bonneau syndrome in a newborn with additional novel manifestations. This late preterm (35 weeks of gestation) neonate born to parents of consanguineous marriage following a pregnancy complicated by polyhydramnios was symmetrically small for date at birth (<3rd centile for weight, length, and occipitofrontal circumference). She had the typical Bonneau syndrome features such as facial dysmorphism and polysyndactyly in addition to novel eye manifestations (microphthalmia, cataract, and vitreous hemorrhage) and cardiac defects such as D-transposition of the great arteries and pulmonary valve stenosis. The chromosomal study was normal (46, XX). The multiple congenital anomalies made the cardiac defects inoperable, and the patient died at the age of 16 days due to uncontrolled cardiac failure. A very high index of suspicion is required by pediatricians/neonatologists to identify this very rare syndrome based on presentation with known features.
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Feng J, Zhu R, Yin Y, Wang S, Zhou L, Lv F, Zhao D. Re-Recognizing the Cellular Origin of the Primary Epithelial Tumors of the Liver. J Hepatocell Carcinoma 2021; 8:1537-1563. [PMID: 34917552 PMCID: PMC8668194 DOI: 10.2147/jhc.s334935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 11/25/2021] [Indexed: 11/29/2022] Open
Abstract
The primary epithelial tumors of the liver (PETL) are composed of a series of heterogeneous tumors. Although the classification of PETLs has been updated several times by the World Health Organization, the cellular origins of some tumors in this family remain to be precisely depicted. In addition, certain tumors in different categories have similar histology, molecular phenotypes and biological characteristics, suggesting that they may have the same cellular origin. In this work, a narrative review method was adopted to review the relevant papers. By comparing the expression profiles of biomarkers of liver epithelium at different lineages and stages of differentiation, the cells-of-origin of some major members of the PETL family were reassessed. We propose that 1) hepatic adenomas, hepatocellular carcinomas (HCCs) and pure fetal hepatoblastomas (HBs) share the same spectrum in their cellular origin including the hepatocytic-committed progenitors (HCP) and their differentiated descendants. 2) Bile duct adenomas, peribiliary cysts and intrahepatic cholangiocellular carcinomas (ICCs) can share the same spectrum in their cellular origin including the cholangiocytic-committed progenitors (CCP) and their differentiated descendants. 3) The cells-of-origin of embryonal HBs include liver stem cells (LSCs), hepatoblasts, and transitional cells between them. Embryonal HB with small cell element, small cell undifferentiated HB and small cell neuroendocrine carcinoma of the liver can have the same or similar cells-of-origin from LSC. Embryonal HB lacking the small cell component of the LSC phenotype and presenting both hepatocytic and bile duct/ductule components may originate from actual hepatoblasts/hepatic progenitor cells (HPCs) as the combined HCC-ICC does. 4) Teratoid hepatoblastoma and mixed epithelial/mesenchymal HBs can be derived from the LSCs or even less committed extrahepatic pluripotent stem cell. 5) Many members of the PETLs family, including those derived from LSCs, hepatoblasts/HPCs, early HCPs and CCPs, have neuroendocrine potentiality. Except for those primary hepatic neuroendocrine tumor (PHNET) exhibit hepatocytic and/or cholangiocytic phenotypes, other PHNETs subtype may be derived from the descendants of LSC that differentiate towards the upper digestive tract, pancreas or other lineages.
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Affiliation(s)
- Jiliang Feng
- Clinical-Pathology Center, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China
- Correspondence: Jiliang Feng Clinical-Pathology Center, Beijing You-An Hospital, Capital Medical University, No. 8, Xitoutiao, Youanmenwai Street, FengTai District, Beijing, 100069, People’s Republic of ChinaTel +86-10-83997342Fax +86-10-83997343 Email
| | - Ruidong Zhu
- General Surgical Center, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China
| | - Yu Yin
- Department of Pathology, Anhui Medical University, Hefei, 230032, People’s Republic of China
| | - Shanshan Wang
- Clinical-Pathology Center, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China
| | - Lei Zhou
- Department of Pathology, First Affiliated Hospital of Bengbu Medical College/Bengbu Medical College, Bengbu, 233004, People’s Republic of China
| | - Fudong Lv
- Clinical-Pathology Center, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China
| | - Dawei Zhao
- Department of Medical Imaging, Capital Medical University, Beijing, 100069, People’s Republic of China
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Jarrar MS, Masmoudi W, Barka M, Chermiti W, Zaghouani H, Youssef S, Naouar N, Hamila F, Ghannouchi S. Anatomic variations of the extrahepatic biliary tree. A monocentric study and review of the literature. LA TUNISIE MEDICALE 2021; 99:652-661. [PMID: 35244918 PMCID: PMC8795998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION The study of the anatomy of the extra hepatic bile ducts has demonstrated the existence of a significant number of variants which can be explained by hepato-biliary embryology. A good knowledge of this anatomy is essential for the interpretation of radiological examinations, and for a good practice of hepato-biliary and pancreatic surgery. Several imaging methods are used to study the anatomy of the bile ducts, including classical cholangiography, which is still practiced and very useful. AIM To study the modal anatomy (the most frequent) and the anatomical variants of the extrahepatic bile ducts through the interpretation of postoperative cholangiograms and to examine their implication on the surgical practice. METHODS This is a monocentric, retrospective observational study. It concerned any patient who underwent hepato-biliary or pancreatic surgery at the Department of General and Digestive Surgery of Farhat Hached University Hospital of Sousse between 2007 and 2016, and who received postoperative cholangiography. A data form was fulfilled for each patient. RESULTS Out of a total population of 293 patients, we identified 158 patients (53.9%) with anatomic variants of the extrahepatic bile ducts. The common bile duct was modally implanted in the second duodenum in 96.2% of cholangiographies and in the genu inferius in 3.8% of cases. The main pancreatic duct had a V-shaped implantation in 87.1% of cholangiograms, a U-shaped implantation in 4.2% of cases and a Y-shaped implantation in 7.1% of cases. The common bile duct had a modal aspect in 71.3% of cholangiograms, with 28.7% of anatomic variants, organized in 4 models. The cystic duct had a modal presentation in 80.9% of cases, and we recorded 6 other branching models (19.1% of cases). No significant difference was observed between the presence of anatomic variants on the one hand, and age, sex, conversion rate, intraoperative incidents, postoperative complications, postoperative hospital stay and overall hospital stay on the other hand. CONCLUSION Conventional cholangiography constitutes a more or less precise tool for detecting these anatomic variants and is therefore very useful in the practice of hepato-biliary surgery even after the advent of new techniques in this field. However, it also requires a more extensive and in-depth knowledge of these anatomic variants, which nevertheless remain quite frequent, and represent a source of surgical difficulties.
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Affiliation(s)
- Mohamed Salah Jarrar
- 1- Department of General and Digestive Surgery – Farhat Hached University Hospital - Sousse / Faculty of Medicine of Sousse
| | - Wafa Masmoudi
- 1- Department of General and Digestive Surgery – Farhat Hached University Hospital - Sousse / Faculty of Medicine of Sousse
| | - Malek Barka
- 1- Department of General and Digestive Surgery – Farhat Hached University Hospital - Sousse / Faculty of Medicine of Sousse
| | - Wajdi Chermiti
- 2- Department of Anatomy / Faculty of Medicine of Sousse
| | - Hounaida Zaghouani
- 3- Department of Radiology - Farhat Hached University Hospital - Sousse / Faculty of Medicine of Sousse
| | - Sabri Youssef
- 1- Department of General and Digestive Surgery – Farhat Hached University Hospital - Sousse / Faculty of Medicine of Sousse
| | - Nader Naouar
- 2- Department of Anatomy / Faculty of Medicine of Sousse
| | - Fehmi Hamila
- 1- Department of General and Digestive Surgery – Farhat Hached University Hospital - Sousse / Faculty of Medicine of Sousse
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La Pergola E, Zen Y, Davenport M. Developmental histology of the portal plate in biliary atresia: observations and implications. Pediatr Surg Int 2021; 37:715-721. [PMID: 33646373 DOI: 10.1007/s00383-021-04861-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/09/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE The key characteristic of biliary atresia (BA) is obliteration of the extrahepatic bile ducts at the level of the porta hepatis. We aimed to relate the immunohistochemical features of remnant biliary ductules at the porta hepatis with clinical features and outcomes. METHODS Samples were immunostained with anti-cytokeratin 20 (CK20), vimentin and alpha-smooth muscle actin (aSMA). Primary outcome was set as clearance of jaundice (bilirubin ≤ 20 μmol/L) following Kasai portoenterostomy (KPE). RESULTS Eighty-two cases were classified into syndromic BA (n = 10), cystic BA (n = 7), CMV IgM+ BA (n = 9) and isolated BA (n = 56). CK20 expression was confirmed in 40/82 (49%), and vimentin expression in 19/82 (23%). aSMA was negative in all cases studied. CK20 expression was less common in isolated BA (n = 20/56, 36%) compared to CMV IgM+ BA (n = 8/9, 89%), cystic BA (n = 7/7, 100%) (isolated BA vs non-isolated BA, P = 0.0008). There was no difference in vimentin expression among the sub-groups (isolated BA vs. non-isolated BA; P = 0.39). CoJ was achieved in 52/82 (63%) overall with significant difference depending simply on sub-group [e.g. syndromic BA 9/10 (90%)]. CK20 expression was associated with a diminished rate of CoJ in the entire cohort [CK20+ 32/56 (57%) vs. CK20- 20/26 (77%); P = 0.04]. By contrast no correlation was observed between vimentin expression and CoJ (P = 0.13). CONCLUSION CK20+ expression was associated with reduced clearance of jaundice in BA and a trend towards reduced native liver survival.
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Affiliation(s)
- Enrico La Pergola
- Department of Paediatric Surgery, Kings College Hospital, Denmark Hill, London, SE5 9RS, UK
- Department of Pediatric Surgery, Università degli Studi di Padova, Padua, Italy
| | - Yoh Zen
- Institute of Liver Studies, Kings College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Mark Davenport
- Department of Paediatric Surgery, Kings College Hospital, Denmark Hill, London, SE5 9RS, UK.
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Hayata Y, Nakagawa H, Kurosaki S, Kawamura S, Matsushita Y, Hayakawa Y, Suzuki N, Hata M, Tsuboi M, Kinoshita H, Miyabayashi K, Mizutani H, Nakagomi R, Ikenoue T, Hirata Y, Arita J, Hasegawa K, Tateishi K, Koike K. Axin2 + Peribiliary Glands in the Periampullary Region Generate Biliary Epithelial Stem Cells That Give Rise to Ampullary Carcinoma. Gastroenterology 2021; 160:2133-2148.e6. [PMID: 33465373 DOI: 10.1053/j.gastro.2021.01.028] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 01/11/2021] [Accepted: 01/11/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts, have been suggested as biliary epithelial stem/progenitor cell niche; however, evidence to support this claim is limited because of a lack of PBG-specific markers. We therefore sought to identify PBG-specific markers to investigate the potential role of PBGs as stem/progenitor cell niches, as well as an origin of cancer. METHODS We examined the expression pattern of the Wnt target gene Axin2 in extrahepatic bile ducts. We then applied lineage tracing to investigate whether Axin2-expressing cells from PBGs contribute to biliary regeneration and carcinogenesis using Axin2-CreERT mice. RESULTS Wnt signaling activation, marked by Axin2, was limited to PBGs located in the periampullary region. Lineage tracing showed that Axin2-expressing periampullary PBG cells are capable of self-renewal and supplying new biliary epithelial cells (BECs) to the luminal surface. Additionally, the expression pattern of Axin2 and the mature ductal cell marker CK19 were mutually exclusive in periampullary region, and fate tracing of CK19+ luminal surface BECs showed gradual replacement by CK19- cells, further supporting the continuous replenishment of new BECs from PBGs to the luminal surface. We also found that Wnt signal enhancer R-spondin3 secreted from Myh11-expressing stromal cells, corresponding to human sphincter of Oddi, maintained the periampullary Wnt signal-activating niche. Notably, introduction of PTEN deletion into Axin2+ PBG cells, but not CK19+ luminal surface BECs, induced ampullary carcinoma whose development was suppressed by Wnt inhibitor. CONCLUSION A specific cell population receiving Wnt-activating signal in periampullary PBGs functions as biliary epithelial stem/progenitor cells and also the cellular origin of ampullary carcinoma.
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Affiliation(s)
- Yuki Hayata
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan.
| | | | - Satoshi Kawamura
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Yuki Matsushita
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Nobumi Suzuki
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Masahiro Hata
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Mayo Tsuboi
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Hiroto Kinoshita
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan; Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Chuo-ku, Tokyo, Japan
| | - Koji Miyabayashi
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Hiroya Mizutani
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Ryo Nakagomi
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Tsuneo Ikenoue
- Division of Clinical Genome Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yoshihiro Hirata
- Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Keisuke Tateishi
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
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Lasagni A, Cadamuro M, Morana G, Fabris L, Strazzabosco M. Fibrocystic liver disease: novel concepts and translational perspectives. Transl Gastroenterol Hepatol 2021; 6:26. [PMID: 33824930 DOI: 10.21037/tgh-2020-04] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022] Open
Abstract
Fibrocystic liver diseases (FLDs) comprise a heterogeneous group of rare diseases of the biliary tree, having in common an abnormal development of the embryonic ductal plate caused by genetically-determined dysfunctions of proteins expressed in the primary cilia of cholangiocytes (and therefore grouped among the "ciliopathies"). The ductal dysgenesis may affect the biliary system at multiple levels, from the small intrahepatic bile ducts [congenital hepatic fibrosis (CHF)], to the larger intrahepatic bile ducts [Caroli disease (CD), or Caroli syndrome (CS), when CD coexists with CHF], leading to biliary microhamartomas and segmental bile duct dilations. Biliary changes are accompanied by progressive deposition of abundant peribiliary fibrosis. Peribiliary fibrosis and biliary cysts are the fundamental lesions of FLDs and are responsible for the main clinical manifestations, such as portal hypertension, recurrent cholangitis, cholestasis, sepsis and eventually cholangiocarcinoma. Furthermore, FLDs often associate with a spectrum of disorders affecting primarily the kidney. Among them, the autosomal recessive polycystic kidney disease (ARPKD) is the most frequent, and the renal function impairment is central in disease progression. CHF, CD/CS, and ARPKD are caused by a number of mutations in polycystic kidney hepatic disease 1 (PKHD1), a gene that encodes for fibrocystin/polyductin, a protein of unclear function, but supposedly involved in planar cell polarity and other fundamental cell functions. Targeted medical therapy is not available yet and thus the current treatment aims at controlling the complications. Interventional radiology or surgical treatments, including liver transplantation, are used in selected cases.
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Affiliation(s)
- Alberto Lasagni
- Department of Molecular Medicine, University of Padua, Padua, Italy
| | | | - Giovanni Morana
- Division of Radiology, Treviso Regional Hospital, Treviso, Italy
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua, Padua, Italy.,Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
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Tomita H, Tanaka K, Hirata A, Okada H, Imai H, Shirakami Y, Ohnishi K, Sugie S, Aoki H, Hatano Y, Noguchi K, Kanayama T, Niwa A, Suzui N, Miyazaki T, Tanaka T, Akiyama H, Shimizu M, Yoshida K, Hara A. Inhibition of FGF10-ERK signal activation suppresses intraductal papillary neoplasm of the bile duct and its associated carcinomas. Cell Rep 2021; 34:108772. [PMID: 33626352 DOI: 10.1016/j.celrep.2021.108772] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 12/31/2020] [Accepted: 01/28/2021] [Indexed: 02/07/2023] Open
Abstract
Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking, and IPNB pathogenesis remains unclear. Here, we use a doxycycline-inducible tetracycline (Tet)-on mice model to control fibroblast growth factor 10 (FGF10) expression, which regulates branching and tubule formation. FGF10-induced IPNB mimics the multifocal and divergent human IPNB phenotypes via the FGF10-FGF receptor 2 (FGFR2)-RAS-extracellular-signal-regulated kinase (ERK) signaling pathway. A paracrine/autocrine growth factor is sufficient to initiate and maintain IPNB originating from the peribiliary glands, including biliary stem/progenitor cells. With KrasG12D, p53, or p16 mutations or both, Fgf10-induced IPNB shows stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes and progression are suppressed by the inhibition of the FGF10-FGFR2-RAS-ERK signaling pathway, demonstrating that the signal is a therapeutic target for IPNB and associated carcinoma.
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Affiliation(s)
- Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
| | - Kaori Tanaka
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Akihiro Hirata
- Division of Animal Experiment, Life Science Research Center, Gifu University, Gifu 501-1194, Japan
| | - Hideshi Okada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Hisashi Imai
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Yohei Shirakami
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Kotaro Ohnishi
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Shigeyuki Sugie
- Department of Pathology, Asahi University Hospital, Gifu 500-8523, Japan
| | - Hitomi Aoki
- Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Yuichiro Hatano
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Kei Noguchi
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Tomohiro Kanayama
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Ayumi Niwa
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Natsuko Suzui
- Department of Pathology, Gifu University Hospital, Gifu 501-1194, Japan
| | | | - Takuji Tanaka
- Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu 500-8513, Japan
| | - Haruhiko Akiyama
- Department of Orthopedic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
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Moeini A, Haber PK, Sia D. Cell of origin in biliary tract cancers and clinical implications. JHEP Rep 2021; 3:100226. [PMID: 33665585 PMCID: PMC7902553 DOI: 10.1016/j.jhepr.2021.100226] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022] Open
Abstract
Biliary tract cancers (BTCs) are aggressive epithelial malignancies that can arise at any point of the biliary tree. Albeit rare, their incidence and mortality rates have been rising steadily over the past 40 years, highlighting the need to improve current diagnostic and therapeutic strategies. BTCs show high inter- and intra-tumour heterogeneity both at the morphological and molecular level. Such complex heterogeneity poses a substantial obstacle to effective interventions. It is widely accepted that the observed heterogeneity may be the result of a complex interplay of different elements, including risk factors, distinct molecular alterations and multiple potential cells of origin. The use of genetic lineage tracing systems in experimental models has identified cholangiocytes, hepatocytes and/or progenitor-like cells as the cells of origin of BTCs. Genomic evidence in support of the distinct cell of origin hypotheses is growing. In this review, we focus on recent advances in the histopathological subtyping of BTCs, discuss current genomic evidence and outline lineage tracing studies that have contributed to the current knowledge surrounding the cell of origin of these tumours.
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Key Words
- ARID1A, AT-rich interactive domain-containing protein 1A
- BAP1, BRCA1-associated protein 1
- BRAF, v-Raf murine sarcoma viral oncogene homolog B
- BTC, biliary tract cancer
- Biliary tract cancers
- CCA, cholangiocarcinoma
- CDKN2A/B, cyclin-dependent kinase inhibitor 2A/B
- CK, cytokeratin
- CLC, cholangiolocarcinoma
- Cell of origin
- Cholangiocarcinoma
- CoH, Canal of Hering
- DCR, disease control rate
- ER, estrogen receptor
- ERBB2/3, Erb-B2 Receptor Tyrosine Kinase 2/3
- FGFR, fibroblast growth factor receptor
- FGFR2, Fibroblast Growth Factor Receptor 2
- GBC, gallbladder cancer
- GEMM, genetically engineered mouse models
- Genomics
- HCC, hepatocellular carcinoma
- HPCs, hepatic progenitor cells
- IDH, isocitrate dehydrogenase
- KRAS, Kirsten Rat Sarcoma Viral Oncogene Homolog
- Lineage tracing
- MET, Hepatocyte Growth Factor Receptor
- MST1, Macrophage Stimulating 1
- NA, not applicable
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NGS, next-generation sequencing
- NR, not reported
- NTRK, Neurotrophic Receptor Tyrosine Kinase 1
- ORR, objective response rate
- OS, overall survival
- PBG, peribiliary gland
- PFS, progression- free survival
- PIK3CA, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha
- PLC, primary liver cancer
- PRKACA/B, Protein Kinase CAMP-Activated Catalytic Subunit Alpha/Beta
- PROM1, Prominin 1
- PSC, primary sclerosing cholangitis
- Personalized therapy
- RNF43, Ring Finger Protein 43
- SMAD4, SMAD Family Member 4
- TBG, thyroid binding globulin
- TP53, Tumor Protein P53
- WHO, World Health Organization
- dCCA, distal cholangiocarcinoma
- eCCA, extrahepatic cholangiocarcinoma
- iCCA, intrahepatic cholangiocarcinoma
- mo, months
- pCCA, perihilar cholangiocarcinoma
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Affiliation(s)
- Agrin Moeini
- Cancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, UK
| | - Philipp K Haber
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Daniela Sia
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
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Naeem MQ, Ahmed MS, Hamid K, Shazlee MK, Qureshi F, Asad Ullah M. Prevalence of Different Hepatobiliary Tree Variants on Magnetic Resonance Cholangiopancreatography in Patients Visiting a Tertiary Care Teaching Hospital in Karachi. Cureus 2020; 12:e12329. [PMID: 33520527 PMCID: PMC7837639 DOI: 10.7759/cureus.12329] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Introduction Hepatobiliary tree variant anatomy is crucial to understand the preoperative planning of hepatobiliary surgeries. Although the presence of variant anatomy is not an absolute contraindication for liver transplantation, inadvertent mapping can lead to postoperative biliary complications. These variants are also important to be recognized in various hepatobiliary surgeries and interventional procedures. Magnetic resonance cholangiopancreatography (MRCP) is an excellent non-invasive imaging tool that can identify biliary anatomy. The purpose of the current study is focused on determining anatomical variants of the biliary tree on MRCP in our population visiting a teaching hospital in Karachi. Methods This cross-sectional study was conducted on patients referred to Dr. Ziauddin Hospital for MRCP. MRCP was performed on MAGNETOM Avanto, SIEMENS, Belgium, Germany. Images were analyzed on a workstation by two radiologists and a postgraduate trainee. A senior radiologist reviewed equivocal cases. SPSS 22.0 (SPSS Inc., Chicago, IL) was used for statistical analysis. Chi-square test was used to see the link between anatomical variants of biliary tree and gender. P-value of ≤0.05 was considered as statistically significant. Results We recruited 369 patients undergoing MRCP consecutively for our study. Out of 369, 342 patients were eligible for analysis (139 males and 203 females). Standard anatomy was found to be prevalent in 65.8%. Type 3 was the leading variant. A statistically significant difference was recorded for the type 2 anatomic variant which was more frequent in males than females (p-value <0.001), while types 1, 3, and 4 anatomic variants were found to be more in females than males but this difference was not statistically significant. Few other variants were also recorded. Conclusion This study is robust evidence regarding biliary variants in Pakistan. It is important to consider these variants in our region, owing to an increased trend of liver transplants and other hepatobiliary procedures.
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Tanaka T, Nakada T, Ito T, Kominami R, Sonomura T, Kagaya M, Kawai K, Honma S. Topographical relationship between the accessory hepatic duct and the hepatic artery system. Anat Sci Int 2020; 96:112-118. [PMID: 32914370 DOI: 10.1007/s12565-020-00568-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 09/01/2020] [Indexed: 10/23/2022]
Abstract
Hepatic biliary injury is one of the most common complications in cholecystectomy and is frequently accompanied by arterial injuries. Because there are several anatomical variations of the hepatic ducts, including the accessory hepatic ducts (AHDs), it is important to consider not only the anatomical position of the hepatic ducts but also those of the AHDs in cholecystectomy. However, the topographical relationships between the AHDs and the hepatic arteries are still poorly understood. In the present study we show that AHDs were observed in 7 out of 59 (11.9%) of the cadavers. There was a single AHD in the 6 out of the 7 cadavers and double AHDs in one. In these cases, the right AHDs emerged from the anterior medial segment of the liver piercing the parenchyma, while the left AHDs emerged directly from the anterior part of the caudate lobe. The right AHDs ran anterior to the right hepatic artery, while the left AHDs ran posterior to the hepatic arteries. The topographical relationship between the AHD and the hepatic artery system was thus reversed in the cases of the right and the left AHDs.
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Affiliation(s)
- Takashi Tanaka
- Department of Anatomy II, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan
| | - Takayuki Nakada
- Anatomy Center, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan
| | - Tetsufumi Ito
- Department of Anatomy II, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan
| | - Rieko Kominami
- Department of Anatomy II, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan
| | - Takahiro Sonomura
- Department of Anatomy, School of Dentistry, Asahi University, 1851 Hozumi, Mizuho, Gifu, 501-0296, Japan
| | - Miyuki Kagaya
- Department of Anatomy II, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan
| | - Katsushi Kawai
- Department of Anatomy II, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan
| | - Satoru Honma
- Department of Anatomy II, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan.
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Couinaud Type A communicating accessory bile duct: report of a case. Surg Radiol Anat 2020; 42:1485-1488. [PMID: 32683481 DOI: 10.1007/s00276-020-02533-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/11/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Communicating accessory bile ducts are defined as ducts that communicate between major biliary channels but do not drain individual segments of the liver. The Couinaud Type A communicating accessory bile duct is a rare anomaly where an aberrant duct connects the right main hepatic duct to the common hepatic duct without segmental drainage. There are very few reports of this anomaly in the literature to date. CASE PRESENTATION A 75-year-old male who died of ischemic heart disease donated his body for cadaveric dissection, which included careful attention to the anatomy of the hepatic hilum. During dissection, it was found that the right hepatic duct was duplicated and an accessory duct drained directly into the common hepatic duct. Although rare and difficult to visualize even with modern preoperative imaging techniques, sound knowledge of this rare anatomic variation is imperative to avoid inadvertent intraoperative biliary injuries which can lead to severe morbidity. CONCLUSIONS An aberrant bile duct from the right hepatic duct to the common hepatic duct (Couinaud Type A) is an uncommon accessory bile duct that one must be aware of when performing complex hepatobiliary procedures such as right liver resection for living-related donation. Detailed preoperative imaging and careful dissection with anticipation of anomalous anatomy are of the utmost importance for the safe conduct of hepatic surgery.
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Wang X, Yang L, Wang YC, Xu ZR, Feng Y, Zhang J, Wang Y, Xu CR. Comparative analysis of cell lineage differentiation during hepatogenesis in humans and mice at the single-cell transcriptome level. Cell Res 2020; 30:1109-1126. [PMID: 32690901 PMCID: PMC7784864 DOI: 10.1038/s41422-020-0378-6] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 06/23/2020] [Indexed: 12/17/2022] Open
Abstract
During embryogenesis, the liver is the site of hepatogenesis and hematopoiesis and contains many cell lineages derived from the endoderm and mesoderm. However, the characteristics and developmental programs of many of these cell lineages remain unclear, especially in humans. Here, we performed single-cell RNA sequencing of whole human and mouse fetal livers throughout development. We identified four cell lineage families of endoderm-derived, erythroid, non-erythroid hematopoietic, and mesoderm-derived non-hematopoietic cells, and defined the developmental pathways of the major cell lineage families. In both humans and mice, we identified novel markers of hepatic lineages and an ID3+ subpopulation of hepatoblasts as well as verified that hepatoblast differentiation follows the “default-directed” model. Additionally, we found that human but not mouse fetal hepatocytes display heterogeneity associated with expression of metabolism-related genes. We described the developmental process of erythroid progenitor cells during human and mouse hematopoiesis. Moreover, despite the general conservation of cell differentiation programs between species, we observed different cell lineage compositions during hematopoiesis in the human and mouse fetal livers. Taken together, these results reveal the dynamic cell landscape of fetal liver development and illustrate the similarities and differences in liver development between species, providing an extensive resource for inducing various liver cell lineages in vitro.
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Affiliation(s)
- Xin Wang
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Department of Human Anatomy, Histology, and Embryology, and School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, 100871, China
| | - Li Yang
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Department of Human Anatomy, Histology, and Embryology, and School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, 100871, China
| | - Yan-Chun Wang
- Haidian Maternal & Child Health Hospital, Beijing, 100080, China
| | - Zi-Ran Xu
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Department of Human Anatomy, Histology, and Embryology, and School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, 100871, China
| | - Ye Feng
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Department of Human Anatomy, Histology, and Embryology, and School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, 100871, China
| | - Jing Zhang
- Haidian Maternal & Child Health Hospital, Beijing, 100080, China
| | - Yi Wang
- Haidian Maternal & Child Health Hospital, Beijing, 100080, China
| | - Cheng-Ran Xu
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Department of Human Anatomy, Histology, and Embryology, and School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, 100871, China.
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50
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Adachi T, Adachi T, Nakagaki T, Ono S, Hidaka M, Ito S, Kanetaka K, Takatsuki M, Nishida N, Eguchi S. Difference in driver gene expression patterns between perihilar and peripheral intrahepatic cholangiocarcinoma in an experimental mouse model. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2020; 27:477-486. [PMID: 32463951 DOI: 10.1002/jhbp.772] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 03/29/2020] [Accepted: 04/01/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND The prognosis of intrahepatic cholangiocarcinoma (ICC) is based on tumor localization; however, the mechanism remains unknown. Therefore, we investigated the biological characteristics of perihilar and peripheral ICC in a mouse model. METHODS The model was established by the administration of three oncogenic plasmids harboring myristoylated AKT, mutated human YAP, and pCMV-Sleeping Beauty into the mice. The perihilar and peripheral ICC tumors that developed in the same mouse were assessed for the expression of cell adhesion factors and driver genes with immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). RESULTS The perihilar ICC tumors were irregularly shaped, whereas the peripheral tumors were mostly circular, similar to the differences found in patients. Alpha-smooth muscle actin was strongly expressed in the perihilar tumors at 10 weeks, and vimentin expression was significantly up-regulated in the perihilar ICC at 14 weeks. Fgfr2 level significantly increased in peripheral ICC at 10 weeks, whereas Idh2 expression was up-regulated in perihilar ICC. CONCLUSIONS Despite diffuse injection of oncogenic plasmid, expression of driver genes and oncogenes in ICC tumor cells differs depending on the tumor localization, resulting in changes in epithelial-mesenchymal transition, which may explain the different outcomes of patients with peripheral and perihilar ICC.
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Affiliation(s)
- Toshiyuki Adachi
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Tomohiko Adachi
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Takehiro Nakagaki
- Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shinichiro Ono
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Shinichiro Ito
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Kengo Kanetaka
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Mitsuhisa Takatsuki
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Noriyuki Nishida
- Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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