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Guo E, Yuan H, Li R, Yang J, Liu S, Liu A, Jiang X. Calcitriol ameliorates the progression of hepatic fibrosis through autophagy-related gene 16-like 1-mediated autophagy. Am J Med Sci 2024; 367:382-396. [PMID: 38431191 DOI: 10.1016/j.amjms.2024.02.010] [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: 11/29/2022] [Revised: 10/23/2023] [Accepted: 02/21/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND Calcitriol has the potential to counteract fibrotic diseases beyond its classical action of maintaining calcium and bone metabolism; however, its functional mechanism remains unknown. Autophagy-related gene 16-like 1 (Atg16l1) is one of the genes related to autophagy and is involved in protecting against fibrotic diseases. The present study aimed to explore the contribution of autophagy to the inhibition of calcitriol-induced hepatic fibrosis, as well as its potential molecular mechanism. METHODS Carbon tetrachloride (Ccl4)-treated mice were established as hepatic fibrosis models and received calcitriol treatment for 6 weeks. Quantification of Sirius red staining and measurement of key fibrotic markers (collagen-1 and α-SMA) was performed to detect hepatic fibrosis. Chloroquine (CQ) treatment was used to observe autophagic flux, and 3-methyladenine (3-MA) was used to inhibit autophagy. Furthermore, the effects of calcitriol on transforming growth factor β1 (TGFβ1)-stimulated primary hepatic stellate cells (HSCs) were detected. Downregulation of Atg16l1 or vitamin D receptor (VDR) in LX-2 cells was used to explore the mechanism of action of calcitriol in fibrosis and autophagy. Additionally, the electrophoretic mobility shift assay (EMSA) was used to investigate the interactions between VDR and ATG16L1. RESULTS Calcitriol increased the expression of VDR and ATG16L1, enhanced autophagy and attenuated hepatic fibrosis. 3-MA treatment and VDR silencing abolished the protective effects of calcitriol against fibrosis. Calcitriol-induced anti-fibrosis effects were blocked by ATG16L1 suppression. Furthermore, VDR bound to the ATG16L1 promoter and downregulation of VDR decreased the expression of ATG16L1 in LX-2 cells. CONCLUSION Calcitriol mitigates hepatic fibrosis partly through ATG16L1-mediated autophagy.
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Affiliation(s)
- Enshuang Guo
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Infectious Diseases, General Hospital of Central Theater Command of PLA, Wuhan 430070, China; Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Huixing Yuan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Renlong Li
- Department of Infectious Diseases, General Hospital of Central Theater Command of PLA, Wuhan 430070, China; Southern Medical University, Guangzhou 510515, China
| | - Jiankun Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shenpei Liu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Anding Liu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Xiaojing Jiang
- Department of Infectious Diseases, General Hospital of Central Theater Command of PLA, Wuhan 430070, China; Southern Medical University, Guangzhou 510515, China
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Trivedi PJ, Hirschfield GM, Adams DH, Vierling JM. Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts. Gastroenterology 2024; 166:995-1019. [PMID: 38342195 DOI: 10.1053/j.gastro.2024.01.049] [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] [Received: 04/25/2023] [Revised: 01/21/2024] [Accepted: 01/28/2024] [Indexed: 02/13/2024]
Abstract
Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom.
| | - Gideon M Hirschfield
- Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - David H Adams
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom
| | - John M Vierling
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, Texas.
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3
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Li J, Tian S, Ci B, Xi Y, Deng X. Serum vitamins and homocysteine levels in autoimmune liver disease: A systematic review and meta-analysis. Immun Inflamm Dis 2024; 12:e1258. [PMID: 38652023 PMCID: PMC11037259 DOI: 10.1002/iid3.1258] [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: 01/17/2024] [Revised: 03/24/2024] [Accepted: 04/12/2024] [Indexed: 04/25/2024] Open
Abstract
OBJECTIVE Vitamins and homocysteine (Hcy) are involved in liver metabolism and related to the pathogenesis of autoimmune liver disease (AILD), but consensus is lacking. This study aims to systematically summarize relevant evidence to clarify the association of serum vitamins and Hcy levels with AILD. METHODS The English and Chinese literature was searched until August 29, 2023. Studies were included if they were observational studies of investigating serum vitamins and Hcy levels in patients with AILD and their healthy comparisons. Quality assessment was performed by using the Newcastle-Ottawa Scale, and a meta-analysis was conducted using ReviewManager 5.3. The protocol was registered in the international prospective register of systematic reviews (PROSPERO), with registration number CRD42023455367. RESULTS A total of 25 case-control studies comprising 3487 patients (1673 patients and 1814 healthy controls) were included for analysis. There were 548 autoimmune hepatitis (AIH) cases, 1106 primary biliary cholangitis (PBC) cases, and 19 primary sclerosing cholangitis (PSC) cases. We found that serum A and E were decreased in both AIH and PBC/PSC; but vitamin C was reduced only in patients with PBC, not AIH. In addition, decreased content of 25(OH)D3 was found in both AIH and PBC. However, levels of 25(OH)D did not differ between the patients and controls, and were independent of disease types and the country. Only one study that met the inclusion criteria reported vitamin B6, B9, B12, and Hcy changes, and found that vitamin B6 and B9 were significantly decreased in patients with PBC, while serum vitamin B12 and Hcy levels were significantly elevated in them. One eligible study each confirmed a reduction in plasma vitamin K1 and 1,25(OH)2D3 in patients with PBC. CONCLUSION Most vitamins are deficient in AILD, so appropriate vitamin supplementation should be necessary. Further studies with larger sample sizes are needed to validate these findings.
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Affiliation(s)
- Jiahuan Li
- Department of Infectious Diseases, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Shan Tian
- Department of Infectious Diseases, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Bai Ci
- Division of Gastroenterology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yuwen Xi
- Division of Gastroenterology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiaoling Deng
- Division of Gastroenterology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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Abdelrahman BA, El-Khatib AS, Attia YM. Insights into the role of vitamin D in targeting the culprits of non-alcoholic fatty liver disease. Life Sci 2023; 332:122124. [PMID: 37742738 DOI: 10.1016/j.lfs.2023.122124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/12/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
Vitamin D (VD) is a secosteroid hormone that is renowned for its crucial role in phospho-calcium homeostasis upon binding to the nuclear vitamin D receptor (VDR). Over and above, the pleiotropic immunomodulatory, anti-inflammatory, and metabolic roles VD plays in different disease settings started to surface in the past few decades. On the other hand, a growing body of evidence suggests a correlation between non-alcoholic fatty liver disease (NAFLD) and its progressive inflammatory form non-alcoholic steatohepatitis (NASH) with vitamin D deficiency (VDD) owing to the former's ingrained link with obesity and metabolic syndrome. Accordingly, a better understanding of the contribution of disrupted VDR signalling to NAFLD incidence and progression would provide further insights into its diagnosis, treatment modalities, and prognosis. This is especially significant as, hitherto, no drug for NAFLD has been approved. This review, therefore, sought to set forth the likely contribution of VDR signalling in NAFLD and how it might influence its multiple drivers.
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Affiliation(s)
- Basma A Abdelrahman
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
| | - Aiman S El-Khatib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Yasmeen M Attia
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
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Pop TL, Sîrbe C, Benţa G, Mititelu A, Grama A. The Role of Vitamin D and Vitamin D Binding Protein in Chronic Liver Diseases. Int J Mol Sci 2022; 23:ijms231810705. [PMID: 36142636 PMCID: PMC9503777 DOI: 10.3390/ijms231810705] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/09/2022] [Accepted: 09/12/2022] [Indexed: 11/24/2022] Open
Abstract
Vitamin D (calciferol) is a fat-soluble vitamin that has a significant role in phospho-calcium metabolism, maintaining normal calcium levels and bone health development. The most important compounds of vitamin D are cholecalciferol (vitamin D3, or VD3) and ergocalciferol (vitamin D2, or VD2). Besides its major role in maintaining an adequate level of calcium and phosphate concentrations, vitamin D is involved in cell growth and differentiation and immune function. Recently, the association between vitamin D deficiency and the progression of fibrosis in chronic liver disease (CLD) was confirmed, given the hepatic activation process and high prevalence of vitamin D deficiency in these diseases. There are reports of vitamin D deficiency in CLD regardless of the etiology (chronic viral hepatitis, alcoholic cirrhosis, non-alcoholic fatty liver disease, primary biliary cirrhosis, or autoimmune hepatitis). Vitamin D binding protein (VDBP) is synthesized by the liver and has the role of binding and transporting vitamin D and its metabolites to the target organs. VDBP also plays an important role in inflammatory response secondary to tissue damage, being involved in the degradation of actin. As intense research during the last decades revealed the possible role of vitamin D in liver diseases, a deeper understanding of the vitamin D, vitamin D receptors (VDRs), and VDBP involvement in liver inflammation and fibrogenesis could represent the basis for the development of new strategies for diagnosis, prognosis, and treatment of liver diseases. This narrative review presents an overview of the evidence of the role of vitamin D and VDBP in CLD, both at the experimental and clinical levels.
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Affiliation(s)
- Tudor Lucian Pop
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Claudia Sîrbe
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence:
| | - Gabriel Benţa
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Alexandra Mititelu
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Alina Grama
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
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Ravaioli F, Pivetti A, Di Marco L, Chrysanthi C, Frassanito G, Pambianco M, Sicuro C, Gualandi N, Guasconi T, Pecchini M, Colecchia A. Role of Vitamin D in Liver Disease and Complications of Advanced Chronic Liver Disease. Int J Mol Sci 2022; 23:ijms23169016. [PMID: 36012285 PMCID: PMC9409132 DOI: 10.3390/ijms23169016] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 12/12/2022] Open
Abstract
Vitamin D is a crucial nutrient with many pleiotropic effects on health and various chronic diseases. The purpose of this review is to provide a detailed report on the pathophysiological mechanisms underlying vitamin D deficiency in patients with chronic liver disease, addressing the different liver etiologies and the condition of advanced chronic liver disease (cirrhosis) with related complications. To date, patients with liver disease, regardless of underlying etiology, have been shown to have reduced levels of vitamin D. There is also evidence of the predictive role of vitamin D values in complications and progression of advanced disease. However, specific indications of vitamin D supplementation are not conclusive concerning what is already recommended in the general population. Future studies should make an effort to unify and validate the role of vitamin D supplementation in chronic liver disease.
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Affiliation(s)
- Federico Ravaioli
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40128 Bologna, Italy
- Correspondence:
| | - Alessandra Pivetti
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Lorenza Di Marco
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Christou Chrysanthi
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Gabriella Frassanito
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Martina Pambianco
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Chiara Sicuro
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Noemi Gualandi
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Tomas Guasconi
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Maddalena Pecchini
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Antonio Colecchia
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
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Aggeletopoulou I, Thomopoulos K, Mouzaki A, Triantos C. Vitamin D–VDR Novel Anti-Inflammatory Molecules—New Insights into Their Effects on Liver Diseases. Int J Mol Sci 2022; 23:ijms23158465. [PMID: 35955597 PMCID: PMC9369388 DOI: 10.3390/ijms23158465] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/26/2022] [Accepted: 07/28/2022] [Indexed: 02/05/2023] Open
Abstract
There is consistent evidence that vitamin D deficiency is strongly associated with liver dysfunction, disease severity, and poor prognosis in patients with liver disease. Vitamin D and its receptor (VDR) contribute to the regulation of innate and adaptive immune responses. The presence of genetic variants of vitamin D- and VDR-associated genes has been associated with liver disease progression. In our recent work, we summarized the progress in understanding the molecular mechanisms involved in vitamin D–VDR signaling and discussed the functional significance of VDR signaling in specific cell populations in liver disease. The current review focuses on the complex interaction between immune and liver cells in the maintenance of liver homeostasis and the development of liver injury, the interplay of vitamin D and VDR in the development and outcome of liver disease, the role of vitamin D- and VDR-associated genetic variants in modulating the occurrence and severity of liver disease, and the therapeutic value of vitamin D supplementation in various liver diseases. The association of the vitamin D–VDR complex with liver dysfunction shows great potential for clinical application and supports its use as a prognostic index and diagnostic tool.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, GR-26504 Patras, Greece;
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
- Correspondence:
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, GR-26504 Patras, Greece;
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
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Neamatallah M, Serria MS, El‐Bendary M, El‐Gilany A, Alhawarey A, Abed S, Setate YA, Ammar OA. Association of Vitamin D Gene Polymorphisms With HCV Infection Outcome. Br J Biomed Sci 2022; 79:10237. [PMID: 35996514 PMCID: PMC8983825 DOI: 10.3389/bjbs.2021.10237] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/02/2021] [Indexed: 11/13/2022]
Abstract
Background: Vitamin D derivatives and their receptor (VDR) are immune-response modulators in many diseases including malignancies, metabolic conditions, and infections. We hypothesized that one or more variants of VDR single nucleotide polymorphisms (SNPs) are associated with hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) cirrhotic patients. Materials and Methods: A total of 861 subjects were recruited and classified as spontaneous viral clearance (SVC, n = 127), chronic hepatic cirrhosis (CHC, n = 392), and HCC (n = 342). Standard routine laboratory tests were performed and clinical features noted. All individuals were genotyped for seven SNPs spanning the VDR using real-time PCR. Results: Genotype frequencies of SNPs rs7970376, rs11568820, rs4516035, rs2228570 (Fok1), rs1544410 (Bsm-1), and rs731236 (Taq1), but not rs739837, were variously altered in CHC and HCC compared with SVC, and in HCC compared to CHC (all p < 0.001). The most powerful was rs7970376, which brought an OR (95% CI) of 7.14 (4.64-10.98) for HCC compared to SVC (p = 0.001). The carriage of the AGTAC haplotype of five SNPs were linked to CHC compared to SVC at OR 2.88 [95% CI 1.2-6.9] (p = 0.017) and with HCC compared to CHC at OR 1.54 [95% CI = 1.04-2.27 (p = 0.031). Conclusion: SNPs in VDR may have a potential role in the outcomes of patients with HCV infection. VDR SNPs; rs7970376, rs11568820, rs4516035, rs2228570 (Fok1), rs1544410 (Bsm-1), and rs731236 (Taq1) could be used as molecular markers to predict the risk of HCC.
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Affiliation(s)
- M. Neamatallah
- Department of Medical Biochemistry and Molecular Biology, Mansoura University, Mansoura, Egypt
| | - M. S. Serria
- Department of Medical Biochemistry and Molecular Biology, Mansoura University, Mansoura, Egypt
| | - M. El‐Bendary
- Tropical Medicine and Hepatology Department, Mansoura University, Mansoura, Egypt
| | - A.‐H. El‐Gilany
- Department of Public Health and Preventive Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - A. Alhawarey
- Tropical Medicine and Hepatology Department, Mansoura University, Mansoura, Egypt
| | - S. Abed
- Tropical Medicine and Hepatology Department, Mansoura University, Mansoura, Egypt
| | - Y. A. Setate
- Infection Control Unit, Mansoura Specialized Hospital (MSH), Delta University for Science and Technology, Gamasa, Egypt
| | - O. A. Ammar
- Basic Science Department, Delta University for Science and Technology, Gamasa, Egypt
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Early histopathologic changes in primary biliary cholangitis: does 'minimal change' primary biliary cholangitis exist? A pathologist's view. Eur J Gastroenterol Hepatol 2021; 33:e7-e12. [PMID: 32804848 DOI: 10.1097/meg.0000000000001876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an autoimmune, slowly progressive, cholestatic liver disease characterized by nonsuppurative destructive cholangitis, and interlobular bile duct destruction. Necroinflammatory activities of the hepatic parenchyma and limiting plates of milder form along with late liver fibrosis may develop. Serum liver tests include elevated serum alkaline phosphatase along with a positive antimitochondrial antibody (AMA) in nearly 95% of patients. Liver biopsies are an important confirmatory and staging tool and are additionally very helpful when AMA is negative. More specifically, the earliest changes in liver biopsy suspicious for PBC can be detected, namely loss of the canals of Hering (CoH), as proposed by various authors recently. CoH loss has been described as an early feature of PBC. We focus on early histologic features of PBC, investigating through the literature the possible role of 'minimal change' supporting the clinical diagnosis of PBC, even in the absence of characteristic granulomatous duct destructive lesions.
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CORRELATION OF PREVALENCE OF THE CORONAVIRUS DISEASE 2019 (2019- nCoV) WITH THE POLYMORPHISMS AT rs7975232 (ApaI) AND rs731236 (TaqI) AMONG 26 POPULATIONS. ANADOLU KLINIĞI TIP BILIMLERI DERGISI 2021. [DOI: 10.21673/anadoluklin.987578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Sun S, Xu M, Zhuang P, Chen G, Dong K, Dong R, Zheng S. Effect and mechanism of vitamin D activation disorder on liver fibrosis in biliary atresia. Sci Rep 2021; 11:19883. [PMID: 34615940 PMCID: PMC8494743 DOI: 10.1038/s41598-021-99158-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/26/2021] [Indexed: 12/13/2022] Open
Abstract
To investigate the mechanism of 25 hydroxyvitamin D (25(OH)D) deficiency in children with biliary atresia (BA) and its effect on liver fibrosis. The serum vitamin D and 25(OH)D, and expression of 25 hydroxylase (CYP2R1 and CYP27A1) in the liver of BA patients were detected and compared with those in the control group. We investigated the effect of differential expression of CYP2R1 in hepatocytes on the expression of genes related to liver fibrosis in primary hepatic stellate cells (HSCs) of BA and animal models of cholestasis. The ratio of 25(OH)D/vitamin D in the BA group was significantly lower than that in the control group. The mRNA and protein expression of CYP2R1 and CYP27A1 in liver tissue of the BA group was significantly lower than that in the control group. Exogenous active vitamin D (calcitriol) inhibited the proliferation and migration of primary HSCs isolated from BA patients, and reduced the expression of fibrosis-related genes in vitro. Downregulation of expression of CYP2R1 in hepatocytes increased expression of transforming growth factor (TGF)-β1, collagen (Col)-1α1 and tissue inhibitor of metalloproteinase (TIMP)-1, and decreased the expression of matrix metalloproteinase (MMP)-2 in cocultured primary HSCs of BA. Upregulation of expression of CYP2R1 in mice with bile duct ligation significantly increased the level of 25(OH)D, decreased the expression of TGF-β1, Col-1α1 and TIMP-1, and increased the expression of MMP-2. Children with BA have impaired vitamin D activation due to CYP2R1 deficiency. The dysactivation of vitamin D can promote the proliferation and activation of HSCs and participate in the development of hepatic fibrosis in BA.
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Affiliation(s)
- Song Sun
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Menghua Xu
- The Center of Laboratory Medicine, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Peijun Zhuang
- Anesthesiology Department, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Gong Chen
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Kuiran Dong
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Rui Dong
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
| | - Shan Zheng
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
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Kempinska-Podhorodecka A, Adamowicz M, Chmielarz M, Janik MK, Milkiewicz P, Milkiewicz M. Vitamin-D Receptor-Gene Polymorphisms Affect Quality of Life in Patients with Autoimmune Liver Diseases. Nutrients 2020; 12:E2244. [PMID: 32727130 PMCID: PMC7469002 DOI: 10.3390/nu12082244] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 07/19/2020] [Accepted: 07/23/2020] [Indexed: 02/07/2023] Open
Abstract
Vitamin D deficiency has been associated with depressive symptoms and reduced physical functioning. The aim of the study was to characterize the relationship between polymorphisms of the vitamin D receptor (VDR) gene and the quality of life in patients with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). Three polymorphisms of the VDR gene (TaqI-rs731236, BsmI-rs1544410, and ApaI-rs7975232) were analyzed in patients with AIH (n = 142) and PBC (n = 230) and in healthy individuals (n = 376). Patient quality of life was assessed by validated questionnaires such as Medical Outcomes Study Short-Form 36 (SF-36), State Trait Anxiety Inventory (STAI), Modified Fatigue-Impact Scale (MFIS), Patient-Health Questionnaire 9 (PHQ-9), and PBC-40. The TaqI C and ApaI A alleles are risk alleles in both AIH and PBC, and a significant dominance of the A allele in BsmI was observed in AIH patients. In terms of quality of life, the presence of the CC or CT TaqI genotype was associated with emotional reactions, including the fatigue and the cognitive skills of patients with PBC, whereas in the group of AIH patients, homozygotes CC of TaqI, AA of BsmI, and AA of ApaI had worse physical, social, emotional, and mental function. The genetic variations of VDR gene can influence individual susceptibility to develop chronic autoimmune liver diseases such as AIH and PBC and affect quality of life.
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Affiliation(s)
| | - Monika Adamowicz
- Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland; (M.A.); (M.C.); (M.M.)
| | - Mateusz Chmielarz
- Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland; (M.A.); (M.C.); (M.M.)
| | - Maciej K. Janik
- Liver and Internal Medicine Unit, Medical University of Warsaw, 02-097 Warsaw, Poland; (M.K.J.); (P.M.)
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Medical University of Warsaw, 02-097 Warsaw, Poland; (M.K.J.); (P.M.)
- Translational Medicine Group, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Malgorzata Milkiewicz
- Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland; (M.A.); (M.C.); (M.M.)
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Mostafaee A, Rafiei S, Fazeli Z, Sayad A, Rahimi M, Rajabi S, Khamseh F, Shamshirgaran F, Rajabibazl M. The association analysis between rs1544410 and rs10735810 polymorphisms located at VDR gene and susceptibility to Multiple Sclerosis in Iranian population. GENE REPORTS 2019. [DOI: 10.1016/j.genrep.2019.100538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Khan MA, Dar HA, Baba MA, Shah AH, Singh B, Shiekh NA. Impact of Vitamin D Status in Chronic Liver Disease. J Clin Exp Hepatol 2019; 9:574-580. [PMID: 31695247 PMCID: PMC6823692 DOI: 10.1016/j.jceh.2019.03.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 03/05/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Vitamin D deficiency is extremely common in chronic liver disease (CLD) patients. Up to 93% of these patients have some degree of vitamin D insufficiency. Liver plays an important role in the metabolism and pleiotropic functions of vitamin D. Vitamin D deficiency has been associated with increased mortality, bacterial infections, portal hypertension complications, and fibrosis severity. We aimed to determine the impact of vitamin D level in CLD. METHODS One hundred fifty individuals consisting of 75 cirrhotic patients (cases) and 75 respective attendants (controls) were enrolled between July 2015 and July 2017. A detailed clinical and laboratory evaluation was done along with estimation of vitamin D level. Unpaired t-test and analysis of variance was used to compare difference in the level of continuous variables between different groups. Linear regression analysis was performed to analyze the correlation between vitamin D deficiency and severity of liver disease. RESULTS The age of patients ranged from 18 years to 69 years with mean of 48.85 ± 13.6 years in the case group and 46.57 ± 17.24 years in the control group. Out of 75 CLD patients, vitamin D deficiency (<20 ng/dl) was found in 31 (41.4%) patients, out of which 14(18.7%) suffered from severe vitamin D deficiency (<10 ng/ml). On applying analysis of variance test, there was significant difference in vitamin D level and serum albumin and serum bilirubin (P < 0.05). On linear regression, vitamin D level showed significant negative correlation with Child-Pugh score (r = -0.7379, P < 0.0001) and Model For End-Stage Liver Disease score (r = -0.6671, P < 0.0001). CONCLUSION Our study concluded that CLD is associated with a significantly low level of vitamin D, which was independent to patient's gender, body mass index, residence, and education level. The findings of our study suggest that awareness of serum vitamin D level in patients with CLD is important. Further studies are required to validate the importance of vitamin D levels and impact of vitamin D supplementation on CLD.
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Affiliation(s)
| | - Hilal A. Dar
- Address for correspondence: Dr Hilal Ahmad Dar, Department of Gastroenterology Sher- i- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, 190011, India. Tel.: +194 2401013x2270, +919419313331(mobile).
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Triantos C, Aggeletopoulou I, Kalafateli M, Spantidea PI, Vourli G, Diamantopoulou G, Tapratzi D, Michalaki M, Manolakopoulos S, Gogos C, Kyriazopoulou V, Mouzaki A, Thomopoulos K. Prognostic significance of vitamin D receptor (VDR) gene polymorphisms in liver cirrhosis. Sci Rep 2018; 8:14065. [PMID: 30218108 PMCID: PMC6138740 DOI: 10.1038/s41598-018-32482-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 09/04/2018] [Indexed: 02/07/2023] Open
Abstract
Several polymorphisms in the vitamin D receptor (VDR) are associated with the occurrence of chronic liver disease. Here, we investigated the association between BsmI, ApaI, TaqI and FokI VDR polymorphisms and the severity of liver cirrhosis in relation to serum cytokine and lipopolysaccharide binding protein (LBP) levels and their role on survival in cirrhotic patients. We found that patients harboring the BB genotype had higher MELD score, and they were mainly at CP stage C; patients harboring the AA genotype had increased LBP, IL-1β and IL-8 levels, and they were mostly at CP stage C; TT genotype carriers had higher MELD score and they were mainly at CP stage C and FF genotype carriers had lower IL-1β levels when compared to Bb/bb, Aa/aa, Tt/tt and Ff/ff genotypes respectively. In the multivariate analysis ApaI, BsmI and TaqI polymorphisms were independently associated with liver cirrhosis severity. In the survival analysis, the independent prognostic factors were CP score, MELD and the FF genotype. Our results indicate that the ApaI, TaqI and BsmI polymorphisms are associated with the severity of liver cirrhosis, through the immunoregulatory process. Survival is related to the FF genotype of FokI polymorphism, imparting a possible protective role in liver cirrhosis.
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Affiliation(s)
- Christos Triantos
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece.
| | | | - Maria Kalafateli
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece
| | - Panagiota I Spantidea
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Georgia Vourli
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece
| | | | - Dimitra Tapratzi
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece
| | - Marina Michalaki
- Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Internal Medicine, University of Patras, Patras, Greece
| | - Spilios Manolakopoulos
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, 11527, Athens, Greece
| | - Charalambos Gogos
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Venetsana Kyriazopoulou
- Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Internal Medicine, University of Patras, Patras, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
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Genetics and epigenetics in the pathogenesis of primary biliary cholangitis. Clin J Gastroenterol 2017; 11:11-18. [PMID: 29159718 DOI: 10.1007/s12328-017-0799-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 11/05/2017] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic, slowly progressive cholestatic autoimmune liver disease predominantly afflicting women. PBC is characterized by the presence of disease-specific antimitochondrial antibodies and the histological destruction of intrahepatic bile ducts, which eventually lead to cirrhosis and hepatic failure. Fortunately, ursodeoxycholic acid therapy has improved the outcome of the vast majority of PBC cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. PBC patients may also have genetically determined risk factors in non-HLA regions. Meanwhile, exposure to environmental factors, such as infectious diseases and harmful chemicals, can produce epigenetic alterations in some individuals and subsequent PBC onset. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies on this disease and its future prospects in terms of epigenetics.
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Kempinska-Podhorodecka A, Milkiewicz M, Jabłonski D, Milkiewicz P, Wunsch E. ApaI polymorphism of vitamin D receptor affects health-related quality of life in patients with primary sclerosing cholangitis. PLoS One 2017; 12:e0176264. [PMID: 28426778 PMCID: PMC5398696 DOI: 10.1371/journal.pone.0176264] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 04/07/2017] [Indexed: 12/12/2022] Open
Abstract
Background Polymorphisms of vitamin D receptor (VDR) contribute to the pathogenesis of multiple autoimmune conditions. Methods We investigated the incidence of VDR polymorphisms (rs1544410-BsmI; rs7975232-ApaI; rs731236-TaqI) in a group of patients with primary sclerosing cholangitis (PSC, n = 275) and in healthy controls (n = 376). Additionally, correlations of the VDR polymorphisms with clinical and biochemical factors of the disease were analysed. Results The genotype and allele distributions of these polymorphisms in PSC patients were similar to those observed in controls. However, the ApaI polymorphism was associated with an impaired health-related quality of life (HRQoL). The generic SF-36 questionnaire showed that the Role-Physical (p = 0.01), Role-Emotional (p = 0.01), Physical Component Summary (p = 0.01) and Mental Component Summary (p = 0.003) scores were significantly affected. Similarly, the disease-specific questionnaires, PBC-40 and PBC-27, demonstrated that carriers of the C allele suffered from more severe Itch (p = 0.03 assessed by PBC-40 and PBC-27), more Fatigue (p = 0.02 assessed by PBC-40 and PBC-27) and Impaired Cognitive Capacity (p = 0.04 and p = 0.03). Correspondingly, individuals who were AA homozygotes (non-carriers of the C allele of ApaI) had higher summary scores for the Physical (p = 0.01) and Mental Components (p = 0.006) measured with SF-36. Moreover, they experienced less itch (p = 0.03) and less Fatigue (p = 0.03) and had better Cognitive Abilities (p = 0.04) as assessed by the PBC-40 and PBC-27 questionnaires. No associations between other VDR polymorphisms and clinical or laboratory findings were made. Conclusion In summary, this study is the first to show that the ApaI polymorphisms in VDR may exert an effect on disease-related symptoms and quality of life in patients with PSC.
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Affiliation(s)
| | - Malgorzata Milkiewicz
- Department of Medical Biology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Dariusz Jabłonski
- Department of General and Endocrine Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery of the Medical University of Warsaw, Warsaw, Poland
| | - Ewa Wunsch
- Translational Medicine Group, Pomeranian Medical University in Szczecin, Szczecin, Poland
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Genetic Contribution to the Pathogenesis of Primary Biliary Cholangitis. J Immunol Res 2017; 2017:3073504. [PMID: 28255561 PMCID: PMC5309396 DOI: 10.1155/2017/3073504] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 01/12/2017] [Indexed: 12/14/2022] Open
Abstract
Formerly termed primary biliary cirrhosis, primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease characterized by the presence of antimitochondrial antibodies. Ursodeoxycholic acid (UDCA) therapy is the most effective and approved treatment for PBC and leads to a favorable outcome in the vast majority of cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. Individuals in different geographic regions of the world may have varying susceptibility alleles that reflect indigenous triggering antigens. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies (GWAS) on this disease.
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Elangovan H, Chahal S, Gunton JE. Vitamin D in liver disease: Current evidence and potential directions. Biochim Biophys Acta Mol Basis Dis 2017; 1863:907-916. [PMID: 28064017 DOI: 10.1016/j.bbadis.2017.01.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 12/06/2016] [Accepted: 01/02/2017] [Indexed: 01/10/2023]
Abstract
Consistent with its multifaceted nature, growing evidence links vitamin D with hepatic disease. In this review, we summarise the roles of vitamin D in different liver pathologies and explore the clinical utility of vitamin D-based treatments in hepatology. We find that the small number of clinical trials coupled with the profound heterogeneity of study protocols limits the strength of evidence needed to ascribe definite clinical value to the hormone in liver disease. Nevertheless, the experimental data is promising and further bench and bedside studies will likely define a clearer role in hepatic therapeutics.
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Affiliation(s)
- Harendran Elangovan
- The Garvan Institute of Medical Research, The University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Sarinder Chahal
- The Garvan Institute of Medical Research, The University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Jenny E Gunton
- The Garvan Institute of Medical Research, The University of New South Wales (UNSW), Sydney, NSW, Australia; The Westmead Institute of Medical Research, The University of Sydney, NSW, Australia.
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Mousa HS, Carbone M, Malinverno F, Ronca V, Gershwin ME, Invernizzi P. Novel therapeutics for primary biliary cholangitis: Toward a disease-stage-based approach. Autoimmun Rev 2016; 15:870-6. [DOI: 10.1016/j.autrev.2016.07.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 06/01/2016] [Indexed: 12/22/2022]
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Shaker O, Nassar Y, Ayoub S, Elrazki M, Zahra A. Impact of FokI (rs10735810) and BsmI (rs1544410) on Treatment of Chronic HCV Patients With Genotype 4. J Clin Lab Anal 2016; 30:1021-1027. [PMID: 27087054 DOI: 10.1002/jcla.21974] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 12/27/2015] [Accepted: 01/18/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND AIM Chronic infection with hepatitis C virus (HCV) is a huge problem both globally and at the level of the individual patient. Our aim is to detect the influence of vitamin D receptor gene polymorphisms (BsmI and Fok1) and vitamin D level in HCV patients under treatment with interferon. SUBJECT AND METHODS Blood samples were taken from 103 HCV patients all of them are genotype 4. They were divided into responders (n = 63) and nonresponders (n = 40) according to their response to interferon treatment. Also 120 subjects with matched age and sex were enrolled as controls. All subjects were subjected to history taking, general examination, liver function tests, hepatitis markers, HCV quantitation by real-time polymerase chain reaction (PCR), DNA extraction from whole blood, PCR-restriction fragment length polymorphism (RFLP) for genotyping, and quantitation of vitamin D level by ELISA. RESULTS There were significant differences between responders and nonresponders in the mean values of vitamin D (P = 0.001) as well as the prevalence of single nucleotide polymorphism (SNP) BsmI (Bb) (P = 0.02). Meanwhile, no significant differences in Fok1 genotype between responders and nonresponders to interferon therapy of HCV patients in all genotypes [FF, Ff, ff) (P = 0.34, 0.091, and 0.43), respectively. CONCLUSION BsmI and vitamin D level in chronic liver disease patients are predictors of response to combination therapy of HCV.
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Affiliation(s)
- Olfat Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt.
| | - Yasser Nassar
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Shymaa Ayoub
- Department of Biochemistry, Fayoum University, Al Fayoum, Egypt
| | - Maissa Elrazki
- Department of Tropical Medicine, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Amr Zahra
- Department of Biochemistry, Fayoum University, Al Fayoum, Egypt
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Wu M, Yue M, Huang P, Zhang Y, Xie C, Yu R, Li J, Wang J. Vitamin D level and vitamin D receptor genetic variations contribute to HCV infection susceptibility and chronicity in a Chinese population. INFECTION GENETICS AND EVOLUTION 2016; 41:146-152. [PMID: 27063396 DOI: 10.1016/j.meegid.2016.03.032] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 03/26/2016] [Accepted: 03/30/2016] [Indexed: 02/08/2023]
Abstract
Vitamin D and vitamin D receptor (VDR) are involved in multiple immune-mediated disorders including chronic hepatitis C virus (HCV) infection. The aim of this study was to determine the association between plasma vitamin D level, VDR genetic polymorphisms and risk of HCV infection susceptibility and chronicity. Seven single nucleotide polymorphisms (SNPs) in VDR gene were genotyped and plasma 25-hydroxyvitamin D [25(OH)D] levels were measured in a Han Chinese population of 898 HCV persistent infection cases, 558 spontaneous clearance subjects and 1136 uninfected controls with high risk of HCV infection. In this case-control study, the average plasma 25(OH)D level in persistent infection patients was significantly lower than that in spontaneous clearance cases (P=0.039) and controls (P=0.005). Logistic analyses indicated that rs7975232-C, rs2239185-T and rs11574129-T alleles were significantly associated with a decreased risk of HCV infection susceptibility (all PBonferroni<0.05, in additive/dominant models; Ptrend=9.000×10(-4), combined effects in a locus-dosage manner). The protective effects of three favorable alleles were more evident among males, females and subjects aged ≤50years (all P<0.05). Haplotype analyses suggested that compared with the most frequent haplotype Ars7975232Trs731236Crs11574129, CTT was correlated with a reduced risk of HCV infection susceptibility (P=2.200×10(-3)). These findings implied that low vitamin D levels might be associated with an increased risk for HCV infection and chronicity, and favorable VDR variants (rs7975232-C, rs2239185-T and rs11574129-T) might contribute to a decreased susceptibility to HCV infection in a high-risk Chinese population.
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Affiliation(s)
- Mengping Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China
| | - Ming Yue
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, 210029, Nanjing, Jiangsu, China
| | - Peng Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China
| | - Yun Zhang
- Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China
| | - Chaonan Xie
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China
| | - Rongbin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, 210029, Nanjing, Jiangsu, China
| | - Jie Wang
- Department of Basic and Community Nursing, School of Nursing, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China.
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Zhang AP, Yang JH. Advances in understanding pathogenesis of primary biliary cholangitis. Shijie Huaren Xiaohua Zazhi 2016; 24:169-175. [DOI: 10.11569/wcjd.v24.i2.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by chronic and progressive cholestasis. In recent years, the incidence and prevalence of PBC are increasing year by year. However, the etiology and pathogenesis are not fully understood. It is believed that genetic susceptibility, environmental factors, and immunologic tolerance are related with the pathogenesis of PBC. This article reviews the progress in the understanding of the pathogenesis of PBC.
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Gonzalez-Sanchez E, Firrincieli D, Housset C, Chignard N. Nuclear receptors in acute and chronic cholestasis. Dig Dis 2015; 33:357-66. [PMID: 26045270 DOI: 10.1159/000371688] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Nuclear receptors (NRs) form a family of 48 members. NRs control hepatic processes such as bile acid homeostasis, lipid metabolism and mechanisms involved in fibrosis and inflammation. Due to their central role in the regulation of hepatoprotective mechanisms, NRs are promising therapeutic targets in cholestatic disorders. KEY MESSAGES NRs can be classified into five different physiological clusters. NRs from the 'bile acids and xenobiotic metabolism' and from the 'lipid metabolism and energy homeostasis' clusters are strongly expressed in the liver. Furthermore, NRs from these clusters, such as farnesoid X receptor α (FXRα), pregnane X receptor (PXR) and peroxisome proliferator-activated receptors (PPARs), have been associated with the pathogenesis and the progression of cholestasis. The latter observation is also true for vitamin D receptor (VDR), which is barely detectable in the whole liver, but has been linked to cholestatic diseases. Involvement of VDR in cholestasis is ascribed to a strong expression in nonparenchymal liver cells, such as biliary epithelial cells, Kupffer cells and hepatic stellate cells. Likewise, NRs from other physiological clusters with low hepatic expression, such as estrogen receptor α (ERα) or reverse-Erb α/β (REV-ERB α/β), may also control pathophysiological processes in cholestasis. CONCLUSIONS In this review, we will describe the impact of individual NRs on cholestasis. We will then discuss the potential role of these transcription factors as therapeutic targets.
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Affiliation(s)
- Ester Gonzalez-Sanchez
- INSERM UMR_S 938, Centre de Recherche Saint-Antoine, and Sorbonne Universités, UPMC Université Paris 06, Paris, France
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Purohit T, Cappell MS. Primary biliary cirrhosis: Pathophysiology, clinical presentation and therapy. World J Hepatol 2015; 7:926-941. [PMID: 25954476 PMCID: PMC4419097 DOI: 10.4254/wjh.v7.i7.926] [Citation(s) in RCA: 67] [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: 12/08/2014] [Revised: 01/15/2015] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune, slowly progressive, cholestatic, liver disease characterized by a triad of chronic cholestasis, circulating anti-mitochondrial antibodies (AMA), and characteristic liver biopsy findings of nonsuppurative destructive cholangitis and interlobular bile duct destruction. About 10% of PBC patients, however, lack AMA. A variant, called PBC-autoimmune hepatitis (AIH) overlap, is characterized by the above findings of PBC together with findings of elevated serum alanine aminotransferase, elevated serum immunoglobulin G, and circulating anti-smooth muscle antibodies, with liver biopsy demonstrating periportal or periseptal, lymphocytic, piecemeal necrosis. PBC is hypothesized to be related to environmental exposure in genetically vulnerable individuals. It typically occurs in middle-aged females. Prominent clinical features include fatigue, pruritis, jaundice, xanthomas, osteoporosis, and dyslipidemia. The Mayo Risk score is the most widely used and best prognostic system. Ursodeoxycholic acid is the primary therapy. It works partly by reducing the concentration and injury from relatively toxic bile acids. PBC-AIH overlap syndrome is treated with ursodeoxycholic acid and corticosteroids, especially budesonide. Obeticholic acid and fibrate are promising new, but incompletely tested, therapies. Liver transplantation is the definitive therapy for advanced disease, with about 70% 10-year survival after transplantation. Management of pruritis includes local skin care, dermatologist referral, avoiding potential pruritogens, cholestyramine, and possibly opioid antagonists, sertraline, or rifaximin. Management of osteoporosis includes life-style modifications, administration of calcium and vitamin D, and alendronate. Statins are relatively safe to treat the osteopenia associated with PBC. Associated Sjogren’s syndrome is treated by artificial tears, cyclosporine ophthalmic emulsion to stimulate tear production; and saliva substitutes, cholinergic agents, and scrupulous oral and dental care. Complications of cirrhosis from advanced PBC include esophageal varices, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatoma formation.
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Masri OA, Chalhoub JM, Sharara AI. Role of vitamins in gastrointestinal diseases. World J Gastroenterol 2015; 21:5191-5209. [PMID: 25954093 PMCID: PMC4419060 DOI: 10.3748/wjg.v21.i17.5191] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 02/23/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
A tremendous amount of data from research was published over the past decades concerning the roles of different vitamins in various gastrointestinal diseases. For instance, most vitamins showed an inverse relationship with the risk of colorectal carcinoma as well as other malignancies like gastric and esophageal cancer in observational trials, however interventional trials failed to prove a clear beneficial preventive role. On the other hand, more solid evidence was obtained from high quality studies for a role of certain vitamins in specific entities. Examples for this include the therapeutic role of vitamin E in patients with non-alcoholic steatohepatitis, the additive role of vitamins B12 and D to the standard therapy of chronic hepatitis C virus, the role of vitamin C in reducing the risk of gallstones, the positive outcome with vitamin B12 in patients with aphthous stomatitis, and the beneficial effect of vitamin D and B1 in patients with inflammatory bowel disease. Other potential uses are yet to be elaborated, like those on celiac disease, pancreatic cancer, pancreatitis, cholestasis and other potential fields. Data from several ongoing interventional trials are expected to add to the current knowledge over the coming few years. Given that vitamin supplementation is psychologically accepted by patients as a natural compound with relative safety and low cost, their use should be encouraged in the fields where positive data are available.
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Bogdanos D, Leung PS, Gershwin ME. Liver and the Biliary Tract. Mucosal Immunol 2015. [DOI: 10.1016/b978-0-12-415847-4.00087-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Iruzubieta P, Terán &A, Crespo J, Fábrega E. Vitamin D deficiency in chronic liver disease. World J Hepatol 2014; 6:901-915. [PMID: 25544877 PMCID: PMC4269909 DOI: 10.4254/wjh.v6.i12.901] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 10/14/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023] Open
Abstract
Vitamin D is an important secosteroid hormone with known effect on calcium homeostasis, but recently there is increasing recognition that vitamin D also is involved in cell proliferation and differentiation, has immunomodulatory and anti-inflammatory properties. Vitamin D deficiency has been frequently reported in many causes of chronic liver disease and has been associated with the development and evolution of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) virus infection. The role of vitamin D in the pathogenesis of NAFLD and CHC is not completely known, but it seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its importance in these liver diseases. Published studies provide evidence for routine screening for hypovitaminosis D in patients with liver disease. Further prospectives studies demonstrating the impact of vitamin D replacement in NAFLD and CHC are required.
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Abstract
BACKGROUND Vitamin D is a fat-soluble sterol derivative that is predominantly synthesized in the liver and has multiple functions. The accumulative data showed that the clinical manifestations and prognosis of chronic liver diseases are associated with serum vitamin D levels. DATA SOURCES A PubMed and Google Scholar search using terms: "vitamin D", "25(OH)D", "liver disease", "viral hepatitis", "non-alcoholic fatty liver disease", "liver fibrosis", "cirrhosis", "hepatocellular carcinoma" and "autoimmune liver disease" was performed, and relevant articles published in English between January 2000 and March 2014 were reviewed. Full-text publications relevant to the field were selected and relevant articles from reference lists were also included. RESULTS The insufficiency or deficiency of vitamin D is common in various kinds of chronic liver diseases including viral hepatitis B and C. Serum 25-hydroxyvitamin D and vitamin D receptors are possibly interrelated with the incidence, treatment and prognosis of diseases. Though the evidence of vitamin D supplementation in viral hepatitis and associated liver diseases is still limited, there is great potential to apply this adjuvant therapy to improve the treatments. CONCLUSIONS Although the exact role and mechanisms of vitamin D have not been fully elucidated in chronic liver diseases, it is potentially beneficial in the treatment of chronic liver diseases. Further mechanistic studies are needed to validate its clinical application.
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Affiliation(s)
- En-Qiang Chen
- Center of Infectious Diseases, West China Hospital; and Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China.
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Baghdasaryan A, Chiba P, Trauner M. Clinical application of transcriptional activators of bile salt transporters. Mol Aspects Med 2014; 37:57-76. [PMID: 24333169 PMCID: PMC4045202 DOI: 10.1016/j.mam.2013.12.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 11/21/2013] [Accepted: 12/01/2013] [Indexed: 02/07/2023]
Abstract
Hepatobiliary bile salt (BS) transporters are critical determinants of BS homeostasis controlling intracellular concentrations of BSs and their enterohepatic circulation. Genetic or acquired dysfunction of specific transport systems causes intrahepatic and systemic retention of potentially cytotoxic BSs, which, in high concentrations, may disturb integrity of cell membranes and subcellular organelles resulting in cell death, inflammation and fibrosis. Transcriptional regulation of canalicular BS efflux through bile salt export pump (BSEP), basolateral elimination through organic solute transporters alpha and beta (OSTα/OSTβ) as well as inhibition of hepatocellular BS uptake through basolateral Na(+)-taurocholate cotransporting polypeptide (NTCP) represent critical steps in protection from hepatocellular BS overload and can be targeted therapeutically. In this article, we review the potential clinical implications of the major BS transporters BSEP, OSTα/OSTβ and NTCP in the pathogenesis of hereditary and acquired cholestatic syndromes, provide an overview on transcriptional control of these transporters by the key regulatory nuclear receptors and discuss the potential therapeutic role of novel transcriptional activators of BS transporters in cholestasis.
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Affiliation(s)
- Anna Baghdasaryan
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Peter Chiba
- Institute of Medical Chemistry, Medical University of Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
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Zimmer V, Lammert F. Role of genetics in diagnosis and therapy of acquired liver disease. Mol Aspects Med 2014; 37:15-34. [DOI: 10.1016/j.mam.2013.10.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 10/07/2013] [Accepted: 10/15/2013] [Indexed: 02/08/2023]
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Li YJ, Tang YW, Shi YQ, Han S, Wang JB, Zhou XM, Chen Y, Wu ZD, Han ZY, Han Y, Wu KC, Fan DM. Polymorphisms in the vitamin D receptor gene and risk of primary biliary cirrhosis: a meta-analysis. J Gastroenterol Hepatol 2014; 29:706-15. [PMID: 24224838 DOI: 10.1111/jgh.12443] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/04/2013] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIM Primary biliary cirrhosis (PBC) is a chronic and progressive cholestatic autoimmune liver disease. Although many studies have evaluated the association between many functional polymorphisms in the vitamin D receptor (VDR) gene and PBC risk, debates still exist. Our aim is to evaluate the association between VDR gene polymorphisms, including TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232), and the risk of PBC by a systematic review. METHODS We searched literatures in PubMed, SCOPUS, and EMBASE until July 2013. We calculated pooled odds ratios (OR) and 95% confidence intervals (CIs) using a fixed effects model or a random effects model for the risk to PBC associated with different VDR gene polymorphisms. And the heterogeneity assumption decided the effect model. RESULTS A total of six relevant studies, with 1322 PBC cases and 2264 controls, were included in this meta-analysis. The results indicated that TaqI (rs731236) polymorphism was significantly associated with PBC risk (for T vs t OR = 0.75, 95% CI 0.63, 0.89, Pz = 0.001; TT + Tt vs tt OR = 0.62, 95% CI 0.44, 0.86, Pz = 0.005; OR = 0.74, 95% CI 0.58, 0.94, Pz = 0.016 for recessive model), while ApaI (rs7975232) or BsmI (rs1544410) polymorphism did not. CONCLUSION Based on current evidences from published studies, the cumulative effect of TaqI polymorphism in VDR was significantly associated with PBC. Larger studies with mixed ethnicity subjects and stratified by clinical and sub clinical characteristics are needed to validate our findings.
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Affiliation(s)
- Yuan-jun Li
- Department of Student Bridge I of Aerospace Medicine, Fourth Military Medical University, Xi'an, China
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Nobili V, Giorgio V, Liccardo D, Bedogni G, Morino G, Alisi A, Cianfarani S. Vitamin D levels and liver histological alterations in children with nonalcoholic fatty liver disease. Eur J Endocrinol 2014; 170:547-53. [PMID: 24412930 DOI: 10.1530/eje-13-0609] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE To investigate the association between plasma vitamin D (VD) levels and histological liver damage in children with nonalcoholic fatty liver disease (NAFLD). SUBJECTS AND METHODS In this cross-sectional study, carried out in a tertiary care center for obesity, 73 consecutive overweight and obese children with persistently elevated serum aminotransferase levels and diffusely hyperechogenic liver on ultrasonography were selected for liver biopsy. Nonalcoholic steatohepatitis (NASH) and fibrosis were histologically diagnosed using NAFLD Clinical Research Network (CRN) criteria. The plasma levels of 25-OH-VD were measured by HPLC. Bone mineral density (BMD) of lumbar spine was evaluated by dual-energy X-ray absorptiometry. Multiple linear regression analysis was used to evaluate the association between 25-OH-VD levels and the predictors of interest after correction for age, gender, waist circumference, BMI, and other potential confounders. RESULTS The children (64% males) were aged 8-18 years, and their median BMI was 2.45 SDS. Both parathyroid hormone levels and BMD were within the normal range. All cases of fibrosis were detected in children with NASH. On multivariable linear regression with correction for age, gender, and BMI, 25-OH-VD levels were found to be 9 (95% CI 12-6) ng/ml lower in children with NASH than in those without NASH (P<0.001) and 9 (12-6) ng/ml lower in children with stage 1 fibrosis than in those with stage 0 fibrosis and 9 (13-6) ng/ml lower in children with stage 2 than in those with stage 0 fibrosis (P<0.001 for both). CONCLUSION VD levels are inversely associated with NASH and fibrosis in children with NAFLD.
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Affiliation(s)
- Valerio Nobili
- Hepato-Metabolic Disease Unit, Bambino Gesù Children's Hospital - IRCCS, Rome, Italy
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Agmon-Levin N, Theodor E, Segal RM, Shoenfeld Y. Vitamin D in systemic and organ-specific autoimmune diseases. Clin Rev Allergy Immunol 2014; 45:256-66. [PMID: 23238772 DOI: 10.1007/s12016-012-8342-y] [Citation(s) in RCA: 165] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Lately, vitamin D has been linked with metabolic and immunological processes, which established its role as an essential component of human health preservation. Vitamin D has been defined as natural immune modulators, and upon activation of its receptors (VDRs), it regulates calcium metabolism, cellular growth, proliferation and apoptosis, and other immunological functions. Epidemiological data underline a strong correlation between poor vitamin D status and higher risk for chronic inflammatory illnesses of various etiologies, including autoimmune diseases. Epidemiological, genetic, and basic studies indicated a potential role of vitamin D in the pathogenesis of certain systemic and organ-specific autoimmune diseases. These studies demonstrate correlation between low vitamin D and prevalence of diseases. In addition, VDRs' polymorphisms observed in some of these autoimmune diseases may further support a plausible pathogenic link. Notably, for some autoimmune disease, no correlation with vitamin D levels could be confirmed. Thus, in the current review we present the body of evidence regarding the plausible roles of vitamin D and VDR's polymorphism in the pathogenesis of autoimmunity. We summarize the data regarding systemic (i.e., systemic lupus erythematosus, rheumatoid arthritis, etc.) and organ-specific (i.e., multiple sclerosis, diabetes mellitus, primary biliary cirrhosis, etc.) autoimmune diseases, in which low level of vitamin D was found comparing to healthy subjects. In addition, we discuss the correlations between vitamin D levels and clinical manifestations and/or activity of diseases. In this context, we address the rational for vitamin D supplementation in patients suffering from autoimmune diseases. Further studies addressing the mechanisms by which vitamin D affects autoimmunity and the proper supplementation required are needed.
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Affiliation(s)
- Nancy Agmon-Levin
- The Zabludowics Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel Hashomer, 52621, Israel
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Li M, Zheng H, Tian QB, Rui MN, Liu DW. HLA-DR polymorphism and primary biliary cirrhosis: evidence from a meta-analysis. Arch Med Res 2014; 45:270-9. [PMID: 24657596 DOI: 10.1016/j.arcmed.2014.03.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Accepted: 02/26/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS We undertook this study to review and quantitatively analyze the association between human leukocyte antigen (HLA) DR polymorphisms and susceptibility of primary biliary cirrhosis (PBC). METHODS All relevant publications on the association between HLA-DR polymorphisms and PBC were searched through June 2013. Odds ratios (OR) and confidence intervals (CI) for the comparisons between case and control group were calculated. Statistical analysis was performed using Stata 11.0 software. RESULTS Nineteen articles (or 20 studies including the substudies) were identified. For DR*7 allele, the ORs (95% CIs) were 1.530 (1.310, 1.788), 1.757 (1.285, 2.403) and 1.495 (1.211, 1.845) in overall, Asian and European populations, respectively. For DR*8 alleles, the ORs (95% CIs) were 3.158 (1.822, 5.475), 2.803 (2.420, 3.247) and 3.056 (2.573, 3.629) in Asian, American and European subgroups, respectively. The subgroup analysis for DR*11 and DR*13 showed a significant association in Asian and European population. For DR*12 and *15 alleles, the overall ORs (95% CIs) were 0.551 (0.404, 0.753) and 0.721 (0.607, 0.857). However, in subgroup analysis for DR*12 allele, the association was only found in Asian population. In addition, statistical significance exists in American and European populations in the subgroup analysis for DR*15 allele. CONCLUSION Our meta-analysis suggested that HLA-DR *7 and *8 allele polymorphisms contributed to the susceptibility of PBC, whereas DR*11, *12, *13 and *15 allele polymorphisms are protective factors in certain population.
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Affiliation(s)
- Man Li
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Hao Zheng
- Department of Ultrasonography, Hebei Chest Hospital, Shijiazhuang, China
| | - Qing-bao Tian
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Mei-na Rui
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Dian-wu Liu
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China.
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Mo C, Lu Y, Deng Y, Wang J, Xie L, Li T, He Y, Qin X, Li S. Lack of association between vitamin D receptor gene ApaI, BsmI, and TaqI polymorphisms and primary biliary cirrhosis risk: a meta-analysis. Tumour Biol 2014; 35:4913-20. [PMID: 24526415 DOI: 10.1007/s13277-014-1645-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Accepted: 01/12/2014] [Indexed: 12/31/2022] Open
Abstract
Previous studies have reported the association between vitamin D receptor (VDR) polymorphisms and the risk of primary biliary cirrhosis (PBC), although these results remain controversial. The aim of this meta-analysis was to evaluate the association of three polymorphisms in VDR with PBC risk. The relevant studies were identified through an electronic database search carried out in September 2013. The crude odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the association between VDR polymorphisms and PBC risk. Six eligible studies which met our selection criteria were included. Overall, the ApaI, BsmI, and TaqI polymorphisms in the VDR gene were not associated with PBC risk (ApaI A vs a OR = 1.132, 95% CI = 0.870-1.472, p = 0.355; BsmI B vs b OR = 1.148, 95% CI = 0.697-1.891, p = 0.589; TaqI t vs T OR = 1.1432, 95% CI = 0.709-1.841, p = 0.584). Furthermore, in subgroup analysis by ethnicity for the ApaI, BsmI, and TaqI polymorphisms, there were no significant results in either Caucasians or Asians under the allele contrast and recessive and dominant models. This meta-analysis indicated that VDR polymorphisms were not a risk factor for PBC. Larger and more carefully designed studies are needed to verify our results.
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Affiliation(s)
- Cuiju Mo
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
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Firrincieli D, Braescu T, Housset C, Chignard N. Illuminating liver fibrosis with vitamin D. Clin Res Hepatol Gastroenterol 2014; 38:5-8. [PMID: 24238723 DOI: 10.1016/j.clinre.2013.10.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 09/27/2013] [Accepted: 10/10/2013] [Indexed: 02/04/2023]
Abstract
Hepatic fibrosis results from the accumulation of extracellular matrix-producing myofibroblasts in the liver. The mechanisms leading to the activation of hepatic stellate cells (HSCs) into myofibroblasts have been well described. By contrast, few molecular pathways leading to myofibroblast deactivation have been documented. Recently, the vitamin D-VDR axis has been shown to modulate HSC activity through a complex mechanism involving epigenetic modifications induced by the SMAD pathway.
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Affiliation(s)
- D Firrincieli
- Inserm UMR_S 938, CdR Saint-Antoine, 75012 Paris, France; UPMC Univ Paris 06, 75012 Paris, France
| | - T Braescu
- Inserm UMR_S 938, CdR Saint-Antoine, 75012 Paris, France; UPMC Univ Paris 06, 75012 Paris, France
| | - C Housset
- Inserm UMR_S 938, CdR Saint-Antoine, 75012 Paris, France; UPMC Univ Paris 06, 75012 Paris, France; AP-HP, hôpital Saint-Antoine, service d'hépatologie, 75012 Paris, France
| | - N Chignard
- Inserm UMR_S 938, CdR Saint-Antoine, 75012 Paris, France; UPMC Univ Paris 06, 75012 Paris, France.
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Smyk DS, Orfanidou T, Invernizzi P, Bogdanos DP, Lenzi M. Vitamin D in autoimmune liver disease. Clin Res Hepatol Gastroenterol 2013; 37:535-45. [PMID: 23845396 DOI: 10.1016/j.clinre.2013.05.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 04/27/2013] [Accepted: 05/28/2013] [Indexed: 02/04/2023]
Abstract
The development of autoimmune disease is based on the interaction of genetic susceptibility and environmental causes. Environmental factors include infectious and non-infectious agents, with some of these factors being implicated in several autoimmune diseases. Vitamin D is now believed to play a role in the development (or prevention) of several autoimmune diseases, based on its immunomodulatory properties. As well, the increasing incidence of autoimmune disease as one moves away from the equator, may be due to the lack of sunlight, which is crucial for the maintenance of normal vitamin D levels. A deficiency in vitamin D levels or vitamin D receptors is commonly indicated in autoimmune diseases, with multiple sclerosis (MS) being one of the best-studied and well-known examples. However, the role of vitamin D in other autoimmune diseases is not well defined, including autoimmune liver diseases such as primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis. This review will examine the role of vitamin D as an immunomodulator, followed by a comparison of vitamin D in MS versus autoimmune liver disease. From this comparison, it will become clear that vitamin D likely plays a role in the development of autoimmune liver disease, but this area requires further investigation.
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Affiliation(s)
- Daniel S Smyk
- Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London Medical School at King's College London Hospital, Denmark Hill Campus, London, SE5 9RS, UK.
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Han YP, Kong M, Zheng S, Ren Y, Zhu L, Shi H, Duan Z. Vitamin D in liver diseases: from mechanisms to clinical trials. J Gastroenterol Hepatol 2013; 28 Suppl 1:49-55. [PMID: 23855296 DOI: 10.1111/jgh.12016] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/03/2012] [Indexed: 02/06/2023]
Abstract
Traditionally regarded as a typical vitamin regulating calcium and phosphorus homeostasis, vitamin D is now discovered as a highly versatile molecule with emerging roles in immunity, cancer, infectious diseases, fibrosis, fatty liver diseases, and alcoholic liver diseases. A large body of clinical evidence has demonstrated the prevalence and risks of vitamin D deficiency in various chronic diseases. Biologically active vitamin D, 1,25-dihydroxylvitamin D3, is synthesized in two distinct systems. In addition to the classic two-step hydroxylation in the liver and kidneys, 1,25-dihydroxylvitamin D3 can also be produced locally by immune cells in response to infection. The bioactive vitamin D generated in these two pools apparently functions differently: while the former facilitates calcium adsorption and homeostasis, the latter confers immune regulation. The immune regulatory functions of vitamin D are demonstrated by induction of antimicrobial peptides, suppression of innate immune response, induction of Th2 cytokines, and stimulation of T-regulatory T cells. Vitamin D deficiency or insufficiency is overwhelmingly associated with viral hepatitis, cirrhosis, and fatty liver diseases. Recent clinical trials have shown that vitamin D supplements significantly enhance the efficacy of interferon plus ribavirin therapy through sustained virological response. A recent study showed that 25-dihydroxyvitamin D rather than 1,25-dihydroxyvitamin D could directly suppress hepatitis C virus assembly. Moreover, clinical evidence has shown that vitamin D deficiency is associated with alcoholic and non-alcoholic fatty liver diseases. In this review, we highlight some recent advances in vitamin D researches and clinical trails.
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Affiliation(s)
- Yuan-Ping Han
- The Center for Growth, Metabolism and Aging Research, College of Life Sciences, Sichuan University, Chengdu, Sichuan, China.
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Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S, Bode JG, Bolleyn J, Borner C, Böttger J, Braeuning A, Budinsky RA, Burkhardt B, Cameron NR, Camussi G, Cho CS, Choi YJ, Craig Rowlands J, Dahmen U, Damm G, Dirsch O, Donato MT, Dong J, Dooley S, Drasdo D, Eakins R, Ferreira KS, Fonsato V, Fraczek J, Gebhardt R, Gibson A, Glanemann M, Goldring CEP, Gómez-Lechón MJ, Groothuis GMM, Gustavsson L, Guyot C, Hallifax D, Hammad S, Hayward A, Häussinger D, Hellerbrand C, Hewitt P, Hoehme S, Holzhütter HG, Houston JB, Hrach J, Ito K, Jaeschke H, Keitel V, Kelm JM, Kevin Park B, Kordes C, Kullak-Ublick GA, LeCluyse EL, Lu P, Luebke-Wheeler J, Lutz A, Maltman DJ, Matz-Soja M, McMullen P, Merfort I, Messner S, Meyer C, Mwinyi J, Naisbitt DJ, Nussler AK, Olinga P, Pampaloni F, Pi J, Pluta L, Przyborski SA, Ramachandran A, Rogiers V, Rowe C, Schelcher C, Schmich K, Schwarz M, Singh B, Stelzer EHK, Stieger B, Stöber R, Sugiyama Y, Tetta C, Thasler WE, Vanhaecke T, Vinken M, Weiss TS, Widera A, Woods CG, Xu JJ, Yarborough KM, Hengstler JG. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol 2013; 87:1315-530. [PMID: 23974980 PMCID: PMC3753504 DOI: 10.1007/s00204-013-1078-5] [Citation(s) in RCA: 1074] [Impact Index Per Article: 89.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 05/06/2013] [Indexed: 12/15/2022]
Abstract
This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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Affiliation(s)
- Patricio Godoy
- Leibniz Research Centre for Working Environment and Human Factors (IFADO), 44139 Dortmund, Germany
| | | | - Ute Albrecht
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Melvin E. Andersen
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Nariman Ansari
- Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany
| | - Sudin Bhattacharya
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Johannes Georg Bode
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Jennifer Bolleyn
- Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Christoph Borner
- Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany
| | - Jan Böttger
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany
| | - Albert Braeuning
- Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany
| | - Robert A. Budinsky
- Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI USA
| | - Britta Burkhardt
- BG Trauma Center, Siegfried Weller Institut, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Neil R. Cameron
- Department of Chemistry, Durham University, Durham, DH1 3LE UK
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, 10126 Turin, Italy
| | - Chong-Su Cho
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 151-921 Korea
| | - Yun-Jaie Choi
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 151-921 Korea
| | - J. Craig Rowlands
- Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI USA
| | - Uta Dahmen
- Experimental Transplantation Surgery, Department of General Visceral, and Vascular Surgery, Friedrich-Schiller-University Jena, 07745 Jena, Germany
| | - Georg Damm
- Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Olaf Dirsch
- Institute of Pathology, Friedrich-Schiller-University Jena, 07745 Jena, Germany
| | - María Teresa Donato
- Unidad de Hepatología Experimental, IIS Hospital La Fe Avda Campanar 21, 46009 Valencia, Spain
- CIBERehd, Fondo de Investigaciones Sanitarias, Barcelona, Spain
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Jian Dong
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Steven Dooley
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Dirk Drasdo
- Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, 04107 Leipzig, Germany
- INRIA (French National Institute for Research in Computer Science and Control), Domaine de Voluceau-Rocquencourt, B.P. 105, 78153 Le Chesnay Cedex, France
- UPMC University of Paris 06, CNRS UMR 7598, Laboratoire Jacques-Louis Lions, 4, pl. Jussieu, 75252 Paris cedex 05, France
| | - Rowena Eakins
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Karine Sá Ferreira
- Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany
- GRK 1104 From Cells to Organs, Molecular Mechanisms of Organogenesis, Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Valentina Fonsato
- Department of Medical Sciences, University of Torino, 10126 Turin, Italy
| | - Joanna Fraczek
- Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Rolf Gebhardt
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany
| | - Andrew Gibson
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Matthias Glanemann
- Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Chris E. P. Goldring
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - María José Gómez-Lechón
- Unidad de Hepatología Experimental, IIS Hospital La Fe Avda Campanar 21, 46009 Valencia, Spain
- CIBERehd, Fondo de Investigaciones Sanitarias, Barcelona, Spain
| | - Geny M. M. Groothuis
- Department of Pharmacy, Pharmacokinetics Toxicology and Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Lena Gustavsson
- Department of Laboratory Medicine (Malmö), Center for Molecular Pathology, Lund University, Jan Waldenströms gata 59, 205 02 Malmö, Sweden
| | - Christelle Guyot
- Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland
| | - David Hallifax
- Centre for Applied Pharmacokinetic Research (CAPKR), School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT UK
| | - Seddik Hammad
- Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Adam Hayward
- Biological and Biomedical Sciences, Durham University, Durham, DH13LE UK
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Claus Hellerbrand
- Department of Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany
| | | | - Stefan Hoehme
- Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, 04107 Leipzig, Germany
| | - Hermann-Georg Holzhütter
- Institut für Biochemie Abteilung Mathematische Systembiochemie, Universitätsmedizin Berlin (Charité), Charitéplatz 1, 10117 Berlin, Germany
| | - J. Brian Houston
- Centre for Applied Pharmacokinetic Research (CAPKR), School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT UK
| | | | - Kiyomi Ito
- Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585 Japan
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 USA
| | - Verena Keitel
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | | | - B. Kevin Park
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Claus Kordes
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Gerd A. Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland
| | - Edward L. LeCluyse
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Peng Lu
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | | | - Anna Lutz
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg, Germany
| | - Daniel J. Maltman
- Reinnervate Limited, NETPark Incubator, Thomas Wright Way, Sedgefield, TS21 3FD UK
| | - Madlen Matz-Soja
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany
| | - Patrick McMullen
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg, Germany
| | | | - Christoph Meyer
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jessica Mwinyi
- Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland
| | - Dean J. Naisbitt
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Andreas K. Nussler
- BG Trauma Center, Siegfried Weller Institut, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Peter Olinga
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
| | - Francesco Pampaloni
- Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany
| | - Jingbo Pi
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Linda Pluta
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Stefan A. Przyborski
- Reinnervate Limited, NETPark Incubator, Thomas Wright Way, Sedgefield, TS21 3FD UK
- Biological and Biomedical Sciences, Durham University, Durham, DH13LE UK
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 USA
| | - Vera Rogiers
- Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Cliff Rowe
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Celine Schelcher
- Department of Surgery, Liver Regeneration, Core Facility, Human in Vitro Models of the Liver, Ludwig Maximilians University of Munich, Munich, Germany
| | - Kathrin Schmich
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg, Germany
| | - Michael Schwarz
- Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany
| | - Bijay Singh
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 151-921 Korea
| | - Ernst H. K. Stelzer
- Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany
| | - Bruno Stieger
- Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland
| | - Regina Stöber
- Leibniz Research Centre for Working Environment and Human Factors (IFADO), 44139 Dortmund, Germany
| | - Yuichi Sugiyama
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama Biopharmaceutical R&D Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan
| | - Ciro Tetta
- Fresenius Medical Care, Bad Homburg, Germany
| | - Wolfgang E. Thasler
- Department of Surgery, Ludwig-Maximilians-University of Munich Hospital Grosshadern, Munich, Germany
| | - Tamara Vanhaecke
- Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Mathieu Vinken
- Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Thomas S. Weiss
- Department of Pediatrics and Juvenile Medicine, University of Regensburg Hospital, Regensburg, Germany
| | - Agata Widera
- Leibniz Research Centre for Working Environment and Human Factors (IFADO), 44139 Dortmund, Germany
| | - Courtney G. Woods
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | | | | | - Jan G. Hengstler
- Leibniz Research Centre for Working Environment and Human Factors (IFADO), 44139 Dortmund, Germany
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Zhu M, Xu LM. Relationship between vitamin D and chronic liver diseases. Shijie Huaren Xiaohua Zazhi 2013; 21:1714-1719. [DOI: 10.11569/wcjd.v21.i18.1714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Vitamin D is a fat-soluble vitamin with multiple biological effects that is predominantly synthetized in the liver. Various kinds of chronic liver diseases are associated with vitamin D deficiency, and vitamin D supplementation may influence treatment outcome. This article summarizes the role of vitamin D in the pathogenesis and treatment of chronic liver diseases to provide new insight into the treatment of these diseases.
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Abstract
Cholestatic liver diseases encompass a wide spectrum of disorders with different causes, resulting in impaired bile flow and accumulation of bile acids and other potentially hepatotoxic cholephils. The understanding of the molecular mechanisms of bile formation and cholestasis has recently improved significantly through new insights into nuclear receptor (patho)biology. Nuclear receptors are ligand-activated transcription factors, which act as central players in the regulation of genes responsible for elimination and detoxification of biliary constituents accumulating in cholestasis. They also control other pathophysiologic processes such as inflammation, fibrogenesis, and carcinogenesis involved in the pathogenesis and disease progression of cholestasis liver diseases.
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Affiliation(s)
- Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Anna Baghdasaryan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Corresponding author. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Vienna, Austria.
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Ding N, Yu RT, Subramaniam N, Sherman MH, Wilson C, Rao R, Leblanc M, Coulter S, He M, Scott C, Lau SL, Atkins AR, Barish GD, Gunton JE, Liddle C, Downes M, Evans RM. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 2013; 153:601-13. [PMID: 23622244 PMCID: PMC3673534 DOI: 10.1016/j.cell.2013.03.028] [Citation(s) in RCA: 499] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Revised: 01/14/2013] [Accepted: 03/11/2013] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is a reversible wound-healing response involving TGFβ1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFβ1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFβ1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFβ1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis.
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Affiliation(s)
- Ning Ding
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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The role of vitamin d in primary biliary cirrhosis: possible genetic and cell signaling mechanisms. Gastroenterol Res Pract 2013; 2013:602321. [PMID: 23589715 PMCID: PMC3622384 DOI: 10.1155/2013/602321] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 11/08/2012] [Accepted: 11/12/2012] [Indexed: 02/08/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is an immune-mediated chronic inflammatory disease of the liver of unknown etiology. Vitamin D deficiency is highly prevalent in patients with PBC, and many studies have demonstrated the significant effect of calcitriol on liver cell physiology. Vitamin D has antiproliferative and antifibrotic effects on liver fibrosis. Genetic studies have provided an opportunity to determine which proteins link vitamin D to PBC pathology (e.g., the major histocompatibility complex class II molecules, the vitamin D receptor, toll-like receptors, apolipoprotein E, Nramp1, and cytotoxic T lymphocyte antigen-4). Vitamin D also exerts its effect on PBC through cell signaling mechanisms, that is, matrix metalloproteinases, prostaglandins, reactive oxygen species, and the transforming growth factor betas. In conclusion, vitamin D may have a beneficial role in the treatment of PBC. The best form of vitamin D for use in the PBC is calcitriol because it is the active form of vitamin D3 metabolite, and its receptors are present in the sinusoidal endothelial cells, Kupffer cells, and stellate cells of normal livers, as well as in the biliary cell line.
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The associated ion between the VDR gene polymorphisms and susceptibility to hepatocellular carcinoma and the clinicopathological features in subjects infected with HBV. BIOMED RESEARCH INTERNATIONAL 2013; 2013:953974. [PMID: 23586065 PMCID: PMC3618929 DOI: 10.1155/2013/953974] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2012] [Revised: 01/11/2013] [Accepted: 01/28/2013] [Indexed: 02/06/2023]
Abstract
Aim. To evaluate the possible association between the vitamin D receptor (VDR), single-nucleotide polymorphisms (SNPs), and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Method. 968 chronic HBV infection patients were enrolled, of which 436 patients were diagnosed HCC patients, and 532 were non-HCC patients. The clinicopathological characteristics of HCC were evaluated. The genotypes of VDR gene at FokI, BsmI, ApaI, and TaqI were determined. Results. The genotype frequencies of VDR FokI C>T polymorphism were significantly different between HCC and non-HCC groups. HCC patients had a higher prevalence of FokI TT genotype than non-HCC subjects. With FokI CC as reference, the TT carriage had a significantly higher risk for development of HCC after adjustments with age, sex, HBV infection time, α-fetoprotein, smoking status, and alcohol intake. In addition, we also found that the TT genotype carriage of FokI polymorphisms were associated with advanced tumor stage, presence of cirrhosis, and lymph node metastasis. The SNP at BsmI, ApaI, and TaqI did not show positive association with the risk and clinicopathological features of HCC. Conclusion. The FokI C>T polymorphisms may be used as a molecular marker to predict the risk and to evaluate the disease severity of HCC in those infected with HBV.
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Stokes CS, Volmer DA, Grünhage F, Lammert F. Vitamin D in chronic liver disease. Liver Int 2013; 33:338-52. [PMID: 23402606 DOI: 10.1111/liv.12106] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 12/18/2012] [Indexed: 02/13/2023]
Abstract
UNLABELLED Chronic liver disease (CLD) and several related extrahepatic manifestations such as hepatic osteodystrophy are associated with deficiency of vitamin D, which has therefore been suggested as therapeutic target. Vitamin D undergoes hepatic 25-hydroxylation, rendering the liver critical to the metabolic activation of this vitamin. Vitamin D deficiency is highly prevalent in CLD patients, and vitamin D levels are inversely related to the severity of CLD. Declining levels of carrier proteins such as albumin and vitamin D-binding protein might also be critical in CLD. Intervention studies report improvements of CLD following supplementation, and benefits to health outcomes in particular with respect to hepatitis C virus infection have recently been documented. CONTENT We discuss vitamin D sources, functions and metabolism with a focus on the inherent complications of analytical measurements, such as the interference of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D C-3 epimers. Global discrepancies in the definition of optimal serum 25-hydroxyvitamin D levels are covered, and the prevalence of vitamin D deficiency in CLD is reviewed. We also address the functional mechanisms underlying this deficiency, and refer to associations between genetic variation in vitamin D metabolism and CLD. Lastly, we consider the health implications of a vitamin D deficiency in CLD and consider therapeutic options. SUMMARY Herein, we focus on the epidemiological and functional relationships between vitamin D deficiency and CLD, followed by a discussion of the potential implications for therapeutic interventions.
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Affiliation(s)
- Caroline S Stokes
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
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Barchetta I, Carotti S, Labbadia G, Gentilucci UV, Muda AO, Angelico F, Silecchia G, Leonetti F, Fraioli A, Picardi A, Morini S, Cavallo MG. Liver vitamin D receptor, CYP2R1, and CYP27A1 expression: relationship with liver histology and vitamin D3 levels in patients with nonalcoholic steatohepatitis or hepatitis C virus. Hepatology 2012; 56:2180-7. [PMID: 22753133 DOI: 10.1002/hep.25930] [Citation(s) in RCA: 169] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 06/03/2012] [Indexed: 12/14/2022]
Abstract
UNLABELLED Evidence suggests an association between low serum 25-hydroxy-vitamin D(3) [25(OH)D(3) ] levels and the presence and prognosis of liver disease. Vitamin D receptor (VDR) has been widely detected in the liver, but its expression in the course of liver disease has never been investigated. We evaluated the hepatic expression of VDR along with that of vitamin D 25-hydroxylases in patients with nonalcoholic steatohepatitis (NASH) or chronic hepatitis C (CHC) and its relationship with hepatic histological features and serum 25(OH)D(3) levels. We evaluated 61 patients (25 NASH and 36 CHC) who had undergone liver biopsy for clinical purposes and 20 subjects without liver disease. Serum 25(OH)D(3) was measured via colorimetric assay. Expression of VDR, CYP2R1, and CYP27A1 was evaluated via immunohistochemistry in hepatocytes, cholangiocytes, and liver inflammatory cells. Parenchymal and inflammatory cells from liver biopsies of patients with NASH and CHC expressed VDR, CYP2R1, and CYP27A1. In NASH patients, VDR expression on cholangiocytes was inversely correlated with steatosis severity (P < 0.02), lobular inflammation (P < 0.01), and nonalcoholic fatty liver disease score (P < 0.03). Moreover, expression of CYP2R1 in hepatocytes correlated strongly with VDR positivity on liver inflammatory cells. In CHC subjects, fibrosis stage was associated with low hepatic CYP27A1 expression, whereas portal inflammation was significantly higher in patients with VDR-negative inflammatory cells (P < 0.009) and low VDR expression in hepatocytes (P < 0.03). CONCLUSION VDR is widely expressed in the liver and inflammatory cells of chronic liver disease patients and its expression is negatively associated with the severity of liver histology in both NASH and CHC patients. These data suggest that vitamin D/VDR system may play a role in the progression of metabolic and viral chronic liver damage. (HEPATOLOGY 2012;56:2180-2187).
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Affiliation(s)
- Ilaria Barchetta
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
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Yang L, Ma J, Zhang X, Fan Y, Wang L. Protective role of the vitamin D receptor. Cell Immunol 2012; 279:160-6. [PMID: 23246677 DOI: 10.1016/j.cellimm.2012.10.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Revised: 09/16/2012] [Accepted: 10/17/2012] [Indexed: 02/06/2023]
Abstract
Vitamin D receptor (VDR) is found in most tissues, not just those participating in the classic actions of vitamin D such as bone, gut, and kidney. The nonclassic actions are therefore potential targets for the active metabolite of vitamin D, 1,25(OH)₂D₃. This review is intended to highlight the actions of VDR in role of protection. Medline is searched for articles describing actions of VDR on secondary hyperparathyroidism, diabetic nephropathy, hypertension and atherosclerosis. VDR exerts its protective activities through the following mechanisms: inhibition of renin-angiotensin system (RAS); regulation of proliferation and differentiation; reduction of proteinuria; anti-inflammation and anti-fibrosis. The nonclassic actions of VDR provide a number of potential new clinical applications for 1,25(OH)₂D₃ and its analogs. We believe 1,25(OH)₂D₃/VDR can be of particular value in the prevention of kidney-related diseases.
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Affiliation(s)
- Lina Yang
- Department of Nephrology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China
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Kitson MT, Roberts SK. D-livering the message: the importance of vitamin D status in chronic liver disease. J Hepatol 2012; 57:897-909. [PMID: 22634121 DOI: 10.1016/j.jhep.2012.04.033] [Citation(s) in RCA: 159] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Revised: 03/29/2012] [Accepted: 04/01/2012] [Indexed: 02/06/2023]
Abstract
Vitamin D is synthesized predominantly in the liver and functions as an important secosteroid hormone with pleiotropic effects. While its key regulatory role in calcium and bone homeostasis is well established, recently there is increasing recognition that vitamin D also regulates cell proliferation and differentiation, and has immunomodulatory, anti-inflammatory and anti-fibrotic properties. These non-skeletal effects are relevant in the pathogenesis and treatment of many causes of chronic liver disease. Vitamin D deficiency is frequently present in chronic liver disease and may predict non-response to antiviral therapy in chronic hepatitis C. Small studies suggest that vitamin D supplementation improves sustained viral response rates, while 1α-hydroxylase polymorphisms and vitamin D-binding protein are also implicated in therapeutic outcomes. Vitamin D deficiency also closely relates to the severity of non-alcoholic fatty liver disease (NAFLD) and is implicated in the pathogenesis of insulin resistance, a key factor in the development of NAFLD. In preclinical studies, phototherapy and vitamin D supplementation ameliorate NAFLD histopathology, while vitamin D is a powerful anti-fibrotic against thioacetamide liver injury. In liver transplant recipients severe vitamin D deficiency predicts, and vitamin D supplementation prevents, acute cellular rejection. The role of vitamin D in the activation and regulation of both innate and adaptive immune systems may explain its importance in the above liver diseases. Further prospective studies are therefore warranted to investigate the therapeutic impact of vitamin D supplementation in chronic liver disease.
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Affiliation(s)
- Matthew T Kitson
- Department of Gastroenterology, The Alfred, Melbourne, Australia
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50
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Invernizzi P, Alessio MG, Smyk DS, Lleo A, Sonzogni A, Fabris L, Candusso M, Bogdanos DP, Iorio R, Torre G. Autoimmune hepatitis type 2 associated with an unexpected and transient presence of primary biliary cirrhosis-specific antimitochondrial antibodies: a case study and review of the literature. BMC Gastroenterol 2012; 12:92. [PMID: 22816667 PMCID: PMC3464927 DOI: 10.1186/1471-230x-12-92] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 07/20/2012] [Indexed: 12/14/2022] Open
Abstract
Background Unlike other autoimmune liver diseases, primary biliary cirrhosis (PBC) has never been reported in early childhood, while type 2 autoimmune hepatitis (AIH) is eminently a paediatric disease. Case presentation We describe a case of type 2 AIH with serological positivity for PBC-specific anti-mitochondrial antibodies (AMA) in a 3-year old girl. We found this observation intriguing as AMA and indeed an overlap with PBC are virtually absent in Type 2 AIH, a pediatric form of AIH which is distinct precisely because it is characterized by pathognomonic anti-liver kidney microsomal type 1 (LKM-1) showing a remarkable antigen-specificity directed against cytochrome P4502D6. We also review the literature in relation to AMA positivity in paediatric age and adolescence. In our case, the presence of AIH-2-specific anti-LKM-1 and PBC-specific AMA was confirmed by indirect immunofluorescence (IIF), and immunoblotting and ELISA based on recombinant mitochondrial antigens. The clinical, laboratory and histological features of the child are given in detail. Interestingly the mother was AMA positive without other features of PBC. The child was successfully treated with immunosuppression and five years after the original diagnosis is on a low dose of prednisolone and azathioprine, with no signs of relapse. Anti-LKM-1 antibodies are still present in low titres. AMA were detectable for the first 4 years after the diagnosis and disappeared later. Conclusion This is the first case report in the literature of AIH type 2 with an unexpected PBC-specific AMA positivity in a young child. Response to immunosuppressive treatment was satisfactory and similar to that described in AIH. A review of published reports on AMA positivity in paediatric age shows that the antibody may arise in the context of immunodeficiency and is variably associated with liver damage.
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Affiliation(s)
- Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano(MI), Italy.
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