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Bintee B, Banerjee R, Hegde M, Vishwa R, Alqahtani MS, Abbas M, Alqahtani A, Rangan L, Sethi G, Kunnumakkara AB. Exploring bile acid transporters as key players in cancer development and treatment: Evidence from preclinical and clinical studies. Cancer Lett 2025; 609:217324. [PMID: 39571783 DOI: 10.1016/j.canlet.2024.217324] [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: 07/11/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 12/01/2024]
Abstract
Bile acid transporters (BATs) are integral membrane proteins belonging to various families, such as solute carriers, organic anion transporters, and ATP-binding cassette families. These transporters play a crucial role in bile acid transportation within the portal and systemic circulations, with expression observed in tissues, including the liver, kidney, and small intestine. Bile acids serve as signaling molecules facilitating the absorption and reabsorption of fats and lipids. Dysregulation of bile acid concentration has been implicated in tumorigenesis, yet the role of BATs in this process remains underexplored. Emerging evidence suggests that BATs may modulate various stages of cancer progression, including initiation, development, proliferation, metastasis, and tumor microenvironment regulation. Targeting BATs using siRNAs, miRNAs, and small compound inhibitors in preclinical models and their polymorphisms are well-studied for transporters like BSEP, MDR1, MRP2, OATP1A2, etc., and have shed light on their involvement in tumorigenesis, particularly in cancers such as those affecting the liver and gastrointestinal tract. While BATs' role in diseases like Alagille syndrome, biliary atresia, and cirrhosis have been extensively studied, their implications in cancer warrant further investigation. This review highlights the expression and function of BATs in cancer development and emphasizes the potential of targeting these transporters as a novel therapeutic strategy for various malignancies.
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Affiliation(s)
- Bintee Bintee
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ruchira Banerjee
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India; Applied Biodiversity Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, LE1 7RH, United Kingdom
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
| | - Athba Alqahtani
- Research Centre, King Fahad Medical City, P.O. Box: 59046, Riyadh, 11525, Saudi Arabia
| | - Latha Rangan
- Applied Biodiversity Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117699, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India.
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Bhagat P, Vij M, Raju LP, Gowrishankar G, Menon J, Shanmugam N, Kaliamoorthy I, Rammohan A, Rela M. Update on the Pathology of Pediatric Liver Tumors: A Pictorial Review. Diagnostics (Basel) 2023; 13:3524. [PMID: 38066766 PMCID: PMC10706829 DOI: 10.3390/diagnostics13233524] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/18/2023] [Accepted: 11/20/2023] [Indexed: 01/04/2025] Open
Abstract
Liver tumors in children are uncommon and show remarkable morphologic heterogeneity. Pediatric tumors may arise from either the epithelial or mesenchymal component of the liver and rarely may also show both lines of differentiation. Both benign and malignant liver tumors have been reported in children. The most common pediatric liver tumors by age are benign hepatic infantile hemangiomas in neonates and infants, malignant hepatoblastoma in infants and toddlers, and malignant hepatocellular carcinoma in teenagers. Here, we provide an up-to-date review of pediatric liver tumors. We discuss the clinical presentation, imaging findings, pathology, and relevant molecular features that can help in the correct identification of these tumors, which is important in managing these children.
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Affiliation(s)
- Priyanka Bhagat
- Department of Pathology, Choithram Hospital and Research Center, Manik Bagh Road, Indore 452014, Madhya Pradesh, India;
| | - Mukul Vij
- Department of Pathology, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (L.P.R.); (G.G.)
| | - Lexmi Priya Raju
- Department of Pathology, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (L.P.R.); (G.G.)
| | - Gowripriya Gowrishankar
- Department of Pathology, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (L.P.R.); (G.G.)
| | - Jagadeesh Menon
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (J.M.); (N.S.); (I.K.); (A.R.); (M.R.)
| | - Naresh Shanmugam
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (J.M.); (N.S.); (I.K.); (A.R.); (M.R.)
| | - Ilankumaran Kaliamoorthy
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (J.M.); (N.S.); (I.K.); (A.R.); (M.R.)
| | - Ashwin Rammohan
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (J.M.); (N.S.); (I.K.); (A.R.); (M.R.)
| | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (J.M.); (N.S.); (I.K.); (A.R.); (M.R.)
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Vij M, Menon J, Subbiah K, Raju LP, Gowrisankar G, Shanmugum N, Kaliamoorthy I, Rammohan A, Rela M. Pathologic and Immunophenotypic Characterization of Syncytial Giant Cell Variant of Pediatric Hepatocellular Carcinoma. A Distinct Subtype. Fetal Pediatr Pathol 2023; 42:709-718. [PMID: 37071763 DOI: 10.1080/15513815.2023.2201318] [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: 02/06/2023] [Revised: 04/01/2023] [Accepted: 04/04/2023] [Indexed: 04/20/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) in pediatrics has a uniformly poor prognosis. Complete surgical resection or liver transplantation remain the only curative options. In contrast to adult HCC, literature on pediatric HCC is sparse and a majority of the distinct subtypes are undefined with regards to their histology, immunohistochemistry and prognosis. CASE REPORT Two infants, one with biliary atresia and another with transaldolase deficiency, underwent living donor liver transplants. Explant-liver histopathology revealed tumor with diffuse neoplastic syncytial giant cell pattern. Immunophenotypic characterization highlighted expression of epithelial cell adhesion molecule, alpha fetoprotein and metallothionein. CONCLUSION HCC with syncytial giant cells variant can occur in infants with underlying liver disease, specifically in our experience, with biliary atresia and another with transaldolase deficiency.
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr. Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Jagadeesh Menon
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Komalavalli Subbiah
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Lexmi Priya Raju
- Department of Pathology, Dr. Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Gowripriya Gowrisankar
- Department of Pathology, Dr. Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Naresh Shanmugum
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Ilankumaran Kaliamoorthy
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Ashwin Rammohan
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
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Biyoukar M, Corpechot C, El Mouhadi S, Chambenois E, Vanderbecq Q, Barbu V, Dong C, Lemoinne S, Tordjman M, Jomaah R, Chazouilleres O, Arrivé L. ABCB4 variant is associated with hepatobiliary MR abnormalities in people with low phospholipid associated cholelithiasis syndrome. JHEP Rep 2022; 4:100590. [PMID: 36277956 PMCID: PMC9582794 DOI: 10.1016/j.jhepr.2022.100590] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/09/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022] Open
Affiliation(s)
- Moustafa Biyoukar
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Sanaâ El Mouhadi
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Edouard Chambenois
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Quentin Vanderbecq
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Véronique Barbu
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Catherine Dong
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Sara Lemoinne
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Mickael Tordjman
- Department of Radiology, Raymond Poincaré Hospital, Assistance Publique – Hôpitaux de Paris (APHP), Garches, France
| | - Raphel Jomaah
- Faculty of Arts and Science, University of Toronto, Toronto, ON, Canada
| | - Olivier Chazouilleres
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Lionel Arrivé
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
- Corresponding author. Address: Department of Radiology, Saint-Antoine Hospital, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France. Tel.: +33-149282257.
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Vitale G, Mattiaccio A, Conti A, Turco L, Seri M, Piscaglia F, Morelli MC. Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature. Cancers (Basel) 2022; 14:cancers14143421. [PMID: 35884482 PMCID: PMC9322180 DOI: 10.3390/cancers14143421] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 02/06/2023] Open
Abstract
The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
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Affiliation(s)
- Giovanni Vitale
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
- Correspondence:
| | - Alessandro Mattiaccio
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University di Bologna, 40138 Bologna, Italy
| | - Amalia Conti
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
| | - Laura Turco
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
| | - Marco Seri
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University di Bologna, 40138 Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Maria Cristina Morelli
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
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Özçay F, Balci Sezer O, Sarialioğlu F, Boyvat F, Coşkun M, Haberal Reyhan N, Haberal M. Seventeen Years of Pediatric Liver Transplantation Experience for Cirrhosis and Hepatocellular Carcinoma. EXP CLIN TRANSPLANT 2022. [PMID: 35297328 DOI: 10.6002/ect.2021.0469] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES This was a retrospective analysis of liver transplant for pediatric patients with liver cirrhosis and hepatocellular carcinoma. MATERIALS AND METHODS Fourteen pediatric patients with chronic liver disease and hepatocellular carcinoma underwent liver transplant from 2004 to 2021. Preexisting diseases were tyrosinemia (n = 6), progressive familial intrahepatic cholestasis type 2 (n = 2) and type 3 (n = 3), cryptogenic cirrhosis (n = 2), hepatitis B and D (n = 1), and biliary atresia (n = 1). RESULTS Mean age was 9.43 ± 4.9 years (range, 13 months to 16 years). Three patients had 1 tumor, 4 had 2 tumors, and 7 had multiple (≥3) lesions. Six patients were classified as Pretreatment Extent of Disease Staging System for Hepatoblastoma (PRETEXT) stage IV, 3 as stage II, and 5 as stage I. Some patients received systemic chemotherapy before (n = 4) or after transplant (n = 3) or transarterial chemoembolization and microwave ablation pretransplant (n = 1). Hepatocellular carcinoma posttransplant recurrence was observed at 23, 47, and 108 months in 3 patients (21%). Recurrence sites were omentum (n = 1) and liver graft (n = 2). One patient was treated with hepatic resection, radiofrequency ablation, and radiotherapy, while the other received radiofrequency ablation and chemotherapy for graft tumor recurrence. Relapse-free patient survival rates were 92%, 82.5%, and 72.2% at 2, 4, and 10 years, respectively. Four recipients (28.5%) died; posttransplant cause of death was infection at 19 (n = 1) and 188 months (n = 1) or hepatocellular carcinoma recurrence at 79 (n = 1) and 165 months (n = 1). Median follow-up was 178 months (range, 13-204 months). Mean estimated survival was 171.25 ± 16.6 months. Overall patient posttransplant survival was 100%, 92.3%, 92.3%, 83%, and 72% at 1, 2, 5, 10, and 15 years, respectively. CONCLUSIONS Hepatocellular carcinoma was mainly associated with inherited liver diseases in our pediatric series. Liver transplant provided a long-term survival advantage to pediatric patients with preexisting cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Figen Özçay
- From the Department of Pediatric Gastroenterology, Başkent University, Ankara, Turkey
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Abstract
PURPOSE Pediatric hepatocellular carcinoma is rarely seen in childhood. It constitutes approximately 1% of childhood solid organ malignancies. Pediatric hepatocellular carcinoma is the second most common malignant liver tumor after hepatoblastoma in children. In this review, we aimed to review the diagnosis and treatment of pediatric hepatocellular carcinoma in the light of the latest literature. METHODS We reviewed the literature in terms of the diagnosis and treatment of pediatric hepatocellular carcinoma. RESULTS Hepatocellular carcinoma (HCC) and hepatoblastoma constitute 0.5-1.5% of all childhood malignant tumors. HCC is responsible for 27% of all liver tumors and 4% of all pediatric liver transplantations. While 99.6% of HCC is seen in adults, only 0.4% of it is seen in pediatric patients. Etiological predisposition and biological behavior are different from adults. In a child with cirrhosis or liver disease, HCC should be suspected in the presence of a high level of AFP and an abnormal nodule on ultrasonography. Hepatoblastoma should be considered first in the differential diagnosis. CONCLUSION Treatment of pediatric HCC is challenging. Complete surgical resection is essential for the cure. To this end, different neoadjuvant chemotherapy protocols have been designed to convert non-resectable tumors into resectable tumors. For tumors that cannot be resected, liver transplantation for each patient with childhood HCC should be decided individually.
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Affiliation(s)
- Fatma İlknur Varol
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, Inonu University, 244280, Malatya, Turkey.
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Sticova E, Jirsa M. ABCB4 disease: Many faces of one gene deficiency. Ann Hepatol 2021; 19:126-133. [PMID: 31759867 DOI: 10.1016/j.aohep.2019.09.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 09/04/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023]
Abstract
ATP-binding cassette (ABC) subfamily B member 4 (ABCB4), also known as multidrug resistance protein 3 (MDR3), encoded by ABCB4, is involved in biliary phospholipid secretion, protecting hepatobiliary system from deleterious detergent and lithogenic properties of the bile. ABCB4 mutations altering canalicular ABCB4 protein function and expression may have variable clinical presentation and predispose to several human liver diseases. Well-established phenotypes of ABCB4 deficit are: progressive familial intrahepatic cholestasis type 3, gallbladder disease 1 (syn. low phospholipid associated cholelithiasis syndrome), high ɣ-glutamyl transferase intrahepatic cholestasis of pregnancy, chronic cholangiopathy, and adult biliary fibrosis/cirrhosis. Moreover, ABCB4 aberrations may be involved in some cases of drug induced cholestasis, transient neonatal cholestasis, and parenteral nutrition-associated liver disease. Recently, genome-wide association studies have documented occurrence of malignant tumours, predominantly hepatobiliary malignancies, in patients with ABCB4/MDR3 deficit. The patient's age at the time of the first presentation of cholestatic disease, as well as the severity of liver disorder and response to treatment are related to the ABCB4 allelic status. Mutational analysis of ABCB4 in patients and their families should be considered in all individuals with cholestasis of unknown aetiology, regardless of age and/or time of onset of the first symptoms.
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Affiliation(s)
- Eva Sticova
- Institute for Clinical and Experimental Medicine, Videnska, Prague, Czech Republic; Pathology Department, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Srobarova, Prague, Czech Republic.
| | - Milan Jirsa
- Institute for Clinical and Experimental Medicine, Videnska, Prague, Czech Republic; Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and Faculty General Hospital, U Nemocnice, Prague, Czech Republic
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Evans HM, Siew SM. Neonatal liver disease. J Paediatr Child Health 2020; 56:1760-1768. [PMID: 33197975 DOI: 10.1111/jpc.15064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 06/22/2020] [Accepted: 06/22/2020] [Indexed: 12/01/2022]
Abstract
Neonatal liver disease encompasses many diagnoses, including structural and genetic aetiologies. Many have significant health implications requiring long-term specialist treatment including liver transplantation. Jaundice is a common presenting feature. The ability of health-care professionals to differentiate neonatal liver disease from benign diagnoses such as physiological jaundice is very important. Persistent (more than 2 weeks) of conjugated jaundice always warrants investigation. Severe unconjugated jaundice (requiring prolonged phototherapy) should also be promptly investigated. Recent advances in genomics have enabled previously elusive, precise diagnoses in some patients with neonatal liver disease. This review paper discusses the commoner causes, with a focus on early detection and need for referral to paediatric liver services.
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Affiliation(s)
- Helen M Evans
- Department of Paediatric Gastroenterology and Hepatology, Starship Child Health, Auckland, New Zealand.,Department of Paediatrics, University of Auckland, Auckland, New Zealand
| | - Susan M Siew
- Department of Gastroenterology and James Fairfax Institute of Paediatric Nutrition, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
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Siew SM, Cunningham SC, Zhu E, Tay SS, Venuti E, Bolitho C, Alexander IE. Prevention of Cholestatic Liver Disease and Reduced Tumorigenicity in a Murine Model of PFIC Type 3 Using Hybrid AAV-piggyBac Gene Therapy. Hepatology 2019; 70:2047-2061. [PMID: 31099022 DOI: 10.1002/hep.30773] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 05/06/2019] [Indexed: 12/14/2022]
Abstract
Recombinant adeno-associated viral (rAAV) vectors are highly promising vehicles for liver-targeted gene transfer, with therapeutic efficacy demonstrated in preclinical models and clinical trials. Progressive familial intrahepatic cholestasis type 3 (PFIC3), an inherited juvenile-onset, cholestatic liver disease caused by homozygous mutation of the ABCB4 gene, may be a promising candidate for rAAV-mediated liver-targeted gene therapy. The Abcb4-/- mice model of PFIC3, with juvenile mice developing progressive cholestatic liver injury due to impaired biliary phosphatidylcholine excretion, resulted in cirrhosis and liver malignancy. Using a conventional rAAV strategy, we observed markedly blunted rAAV transduction in adult Abcb4-/- mice with established liver disease, but not in disease-free, wild-type adults or in homozygous juveniles prior to liver disease onset. However, delivery of predominantly nonintegrating rAAV vectors to juvenile mice results in loss of persistent transgene expression due to hepatocyte proliferation in the growing liver. Conclusion: A hybrid vector system, combining the high transduction efficiency of rAAV with piggyBac transposase-mediated somatic integration, was developed to facilitate stable human ABCB4 expression in vivo and to correct juvenile-onset chronic liver disease in a murine model of PFIC3. A single dose of hybrid vector at birth led to life-long restoration of bile composition, prevention of biliary cirrhosis, and a substantial reduction in tumorigenesis. This powerful hybrid rAAV-piggyBac transposon vector strategy has the capacity to mediate lifelong phenotype correction and reduce the tumorigenicity of progressive familial intrahepatic cholestasis type 3 and, with further refinement, the potential for human clinical translation.
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Affiliation(s)
- Susan M Siew
- Department of Gastroenterology and James Fairfax Institute of Pediatric Nutrition, Sydney Children's Hospitals Network, Westmead, Australia
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, Australia
| | - Sharon C Cunningham
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, Australia
| | - Erhua Zhu
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, Australia
| | - Szun S Tay
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, Australia
| | - Elena Venuti
- Department of Gastroenterology and James Fairfax Institute of Pediatric Nutrition, Sydney Children's Hospitals Network, Westmead, Australia
| | - Christine Bolitho
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, Australia
| | - Ian E Alexander
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, Australia
- Discipline of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Westmead, Australia
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Henkel SAF, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019; 11:450-463. [PMID: 31183005 PMCID: PMC6547292 DOI: 10.4254/wjh.v11.i5.450] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/19/2019] [Accepted: 04/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes, resulting in a hepatocellular form of cholestasis. While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause, recent scientific advancements have uncovered multiple specific responsible proteins. The variety of identified defects has resulted in an ever-broadening phenotypic spectrum, ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.
AIM To review current data on defects in bile acid homeostasis, explore the expanding knowledge base of genetic based diseases in this field, and report disease characteristics and management.
METHODS We conducted a systemic review according to PRISMA guidelines. We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding, diagnosis, and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC. English only articles were accessed in full. The manual search included references of retrieved articles. We extracted data on disease characteristics, associations with other diseases, and treatment. Data was summarized and presented in text, figure, and table format.
RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults. A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.
CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1 (ATP8B1), BSEP (ABCB11), and MDR3 (ABCB4) transporter deficiencies, as well as more recently described gene mutations -- TJP2 (TJP2), FXR (NR1H4), MYO5B (MYO5B), and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.
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Affiliation(s)
- Sarah AF Henkel
- Division of Gastroenterology, Hepatology, and Nutrition, Emory School of Medicine, Atlanta, GA 30322, United States
| | - Judy H Squires
- Department of Radiology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Mary Ayers
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Armando Ganoza
- Division of Pediatric Transplantation, Department of Surgery, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Patrick Mckiernan
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - James E Squires
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
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Ishizawa T, Makino N, Kakizaki Y, Ando Y, Matsuda A, Kobayashi T, Ikeda C, Sugahara S, Tsunoda M, Sato H, Murakami R, Ueno Y. A novel pathogenic variant of ATP-binding cassette subfamily B member 4 causing gallstones in a young adult. Clin J Gastroenterol 2019; 12:637-641. [DOI: 10.1007/s12328-019-00991-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 04/27/2019] [Indexed: 12/12/2022]
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Vij M, Valamparampil J, Shanmugum N, Reddy SM, Rajindrajith S, Rela M. Paucity of Interlobular Bile Ducts in Multidrug-Resistant P-Glycoprotein 3 (MDR3) Deficiency. Int J Surg Pathol 2019; 27:343-347. [PMID: 30222019 DOI: 10.1177/1066896918799941] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2023]
Abstract
Multidrug-resistant P-glycoprotein 3 (MDR3) is a phospholipid translocator encoded by the ABCB4 gene located on chromosome 7. MDR3 mediates the translocation of phosphatidylcholine across the canalicular membrane of the hepatocyte into bile. Severe MDR3 deficiency typically occurs during childhood with progressive cholestasis evolving to cirrhosis and liver failure, requiring liver transplantation. In this article, we report 2 pediatric cases of severe MDR3 deficiency with paucity of interlobular bile ducts. Both underwent living donor liver transplantation at our center for decompensated liver disease and portal hypertension. We diagnosed severe MDR3 deficiency in both the cases with negative MDR3 immunostaining in the explanted liver. Genetic studies revealed homozygous deletion single base pair deletion in exon 24 of the ABCB4 gene in the second child. The patients are on regular follow-up after liver transplant and are doing well. Our report highlights that cholangiopathy in MDR3 deficiency can lead to ductopenia in pediatric livers.
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Affiliation(s)
- Mukul Vij
- 1 Gleneagles Global Health City, Chennai, India
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14
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Cholangiocyte death in ductopenic cholestatic cholangiopathies: Mechanistic basis and emerging therapeutic strategies. Life Sci 2019; 218:324-339. [DOI: 10.1016/j.lfs.2018.12.044] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 12/26/2018] [Indexed: 02/07/2023]
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Yeap SP, Harley H, Thompson R, Williamson KD, Bate J, Sethna F, Farrell G, Hague WB. Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy: Diagnostic and management implications. J Gastroenterol Hepatol 2019; 34:425-435. [PMID: 29992621 DOI: 10.1111/jgh.14376] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 06/19/2018] [Accepted: 06/20/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Clinical syndromes associated with biallelic mutations of bile acid (BA) transporters usually present in childhood. Subtle mutations may underlie intrahepatic cholestasis of pregnancy (ICP) and oral contraceptive steroid (OCS) induced cholestasis. In five women with identified genetic mutations of such transporters, with eight observed pregnancies complicated by ICP, we examined relationships between transporter mutations, clinical phenotypes, and treatment outcomes. METHODS Gene mutation analysis for BA transporter deficiencies was performed using Next Generation/Sanger sequencing, with analysis for gene deletions/duplications. RESULTS Intrahepatic cholestasis of pregnancy was early-onset (9-32 weeks gestation) and severe (peak BA 74-370 μmol/L), with premature delivery (28+1 -370 weeks gestation) in 7/8 pregnancies, in utero passage of meconium in 4/8, but overall good perinatal outcomes, with no stillbirths. There was generally no response to ursodeoxycholic acid and variable responses to rifampicin and chelation therapies; naso-biliary drainage appeared effective in 2/2 episodes persisting post-partum in each of the two sisters. Episodic jaundice occurring spontaneously or provoked by non-specific infections, and OCS-induced cholestasis, had previously occurred in 3/5 women. Two cases showed biallelic heterozygosity for several ABCB11 mutations, one was homozygous for an ABCB4 mutation and a fourth case was heterozygous for another ABCB4 mutation. CONCLUSIONS Early-onset or recurrent ICP, especially with previous spontaneous or OCS-induced episodes of cholestasis and/or familial cholestasis, may be attributable to transporter mutations, including biallelic mutations of one or more transporters. Response to standard therapies for ICP is often incomplete; BA sequestering therapy or naso-biliary drainage may be effective. Optimized management can produce good outcomes despite premature birth and evidence of fetal compromise.
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Affiliation(s)
- Sze Pheh Yeap
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Hugh Harley
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.,Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | | | | | - John Bate
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Farah Sethna
- Department of Obstetrics and Gynaecology, Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Geoffrey Farrell
- Liver Research Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia.,The Australian National University Medical School, Canberra, Australian Capital Territory, Australia
| | - William Bill Hague
- Obstetric Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia.,Robinson Research Institute, University of Adelaide, North Adelaide, South Australia, Australia
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16
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Khanna R, Verma SK. Pediatric hepatocellular carcinoma. World J Gastroenterol 2018; 24:3980-3999. [PMID: 30254403 PMCID: PMC6148423 DOI: 10.3748/wjg.v24.i35.3980] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 07/11/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Pediatric hepatocellular carcinoma (HCC) is the second common malignant liver tumor in children after hepatoblastoma. It differs from the adult HCC in the etiological predisposition, biological behavior and lower frequency of cirrhosis. Perinatally acquired hepatitis-B virus, hepatorenal tyrosinemia, progressive familial intrahepatic cholestasis, glycogen storage disease, Alagille’s syndrome and congenital portosystemic shunts are important predisposing factors. Majority of children (87%) are older than 5 years of age. Following mass immunization against hepatitis-B, there has been a drastic fall in the incidence of new cases of pediatric HCC in the Asia-Pacific region. Management is targeted on complete surgical removal either by resection or liver transplantation. There is a trend towards improving survival of children transplanted for HCC beyond Milan criteria. Chemotherapeutic regimens do not offer good results but may be helpful for down-staging of advanced HCC. Surveillance of children with chronic liver diseases with ultrasound and alpha-fetoprotein may be helpful in timely detection, intervention and overall improvement in outcome of HCC.
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Affiliation(s)
- Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | - Sanjeev Kumar Verma
- Department of Pediatrics, King George Medical University, Uttar Pradesh 226003, India
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Vij M, Shanmugam NP, Reddy MS, Sankaranarayanan S, Rela M. Paediatric hepatocellular carcinoma in tight junction protein 2 (TJP2) deficiency. Virchows Arch 2017; 471:679-683. [PMID: 28733884 DOI: 10.1007/s00428-017-2204-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 06/30/2017] [Accepted: 07/12/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Mukul Vij
- Department of Pathology, Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, Tamil Nadu, 600100, India.
| | - Naresh P Shanmugam
- Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, Tamil Nadu, 600100, India
| | - Mettu Srinivas Reddy
- Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, Tamil Nadu, 600100, India
| | | | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, Tamil Nadu, 600100, India
- National Foundation for Liver Research, Chennai, Tamil Nadu, India
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