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Furukawa R, Kuwatani M, Jiang JJ, Tanaka Y, Hasebe R, Murakami K, Tanaka K, Hirata N, Ohki I, Takahashi I, Yamasaki T, Shinohara Y, Nozawa S, Hojyo S, Kubota SI, Hashimoto S, Hirano S, Sakamoto N, Murakami M. GGT1 is a SNP eQTL gene involved in STAT3 activation and associated with the development of Post-ERCP pancreatitis. Sci Rep 2024; 14:12224. [PMID: 38806529 PMCID: PMC11133343 DOI: 10.1038/s41598-024-60312-2] [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: 11/25/2023] [Accepted: 04/21/2024] [Indexed: 05/30/2024] Open
Abstract
Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP.
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Affiliation(s)
- Ryutaro Furukawa
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Masaki Kuwatani
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Jing-Jing Jiang
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
- Institute of Preventive Genomic Medicine, School of Life Sciences, Northwest University, Xian, China
| | - Yuki Tanaka
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
- Quantum Immunology Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology (QST), Chiba, Japan
| | - Rie Hasebe
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
- Division of Molecular Neuroimmunology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan
| | - Kaoru Murakami
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
| | - Kumiko Tanaka
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
| | - Noriyuki Hirata
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
| | - Izuru Ohki
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
- Quantum Immunology Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology (QST), Chiba, Japan
| | - Ikuko Takahashi
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
| | - Takeshi Yamasaki
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
- Division of Molecular Neuroimmunology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan
| | - Yuta Shinohara
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
| | - Shunichiro Nozawa
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Shintaro Hojyo
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
- Quantum Immunology Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology (QST), Chiba, Japan
- Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan
| | - Shimpei I Kubota
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
- Quantum Immunology Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology (QST), Chiba, Japan
| | - Shigeru Hashimoto
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan
- Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Masaaki Murakami
- Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan.
- Quantum Immunology Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology (QST), Chiba, Japan.
- Division of Molecular Neuroimmunology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan.
- Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan.
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Yu B, Yu Y, Wang X, Xu C, Xiao Y. A narrative review on the role of genetics in children with acute recurrent pancreatitis and chronic pancreatitis. Pediatr Investig 2023; 7:268-276. [PMID: 38050536 PMCID: PMC10693666 DOI: 10.1002/ped4.12404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 09/27/2023] [Indexed: 12/06/2023] Open
Abstract
The incidence of pancreatitis in children has increased over the past two decades. With advances in molecular biological techniques and clinical research, genetic variations have emerged as a pivotal etiological factor in pediatric pancreatitis. This review aims to summarize recent clinical research advancements in understanding pediatric pancreatitis caused by various gene mutations. As of the year 2020, researchers had identified 12 genes implicated in the pathogenesis of pancreatitis. These genes primarily contributed to the development of pancreatitis through three mechanisms. Pancreatitis resulting from these gene mutations exhibits several distinct characteristics, including early onset, a heightened risk of developing pancreatic duct stones, rapid disease progression, and a significantly increased risk of pancreatic endocrine and exocrine dysfunction, as well as pancreatic cancer in the future. Genetic sequencing is recommended for children with pancreatitis based on six indications. The sequencing not only assists in the clinical diagnosis but also enhances our understanding of the pathophysiology of pancreatitis.
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Affiliation(s)
- Bo Yu
- School of Clinical MedicineShanghai University of Medicine and Health SciencesShanghaiChina
| | - Yi Yu
- Pediatric DepartmentRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Xinqiong Wang
- Pediatric DepartmentRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Pediatric DepartmentRuijin Hospital NorthSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Chundi Xu
- Pediatric DepartmentRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Pediatric DepartmentRuijin Hospital NorthSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Yuan Xiao
- Pediatric DepartmentRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Pediatric DepartmentXin Rui Hospital (Wuxi Branch of Ruijin Hospital)JiangsuChina
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Choi YH, Lim Y, Jang DK, Ahn DW, Ryu JK, Paik WH, Kim YT, Kim JH, Lee SH. Genetic susceptibility to post-endoscopic retrograde cholangiopancreatography pancreatitis identified in propensity score-matched analysis. Korean J Intern Med 2023; 38:854-864. [PMID: 37867141 PMCID: PMC10636551 DOI: 10.3904/kjim.2022.404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/02/2023] [Accepted: 06/16/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND/AIMS A previous history of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a risk factor for PEP, suggesting that there may be a genetic predisposition to PEP. However, nothing is known about this yet. The aim of this study was to identify genetic variations associated with PEP. METHODS A cohort of high-risk PEP patients was queried from December 2016 to January 2019. For each PEP case, two propensity score-matched controls were selected. Whole exome sequencing was performed using blood samples. Genetic variants reported to be related to pancreatitis were identified. To discover genetic variants that predispose to PEP, a logistic regression analysis with clinical adjustment was performed. Gene-wise analyses were also conducted. RESULTS Totals of 25 PEP patients and 50 matched controls were enrolled. Among the genetic variants reported to be associated with pancreatitis, only CASR rs1042636 was identified, and it showed no significant difference between the case and control groups. A total of 54,269 non-synonymous variants from 14,313 genes was identified. Logistic regression analysis of these variants showed that the IRF2BP1 rs60158447 GC genotype was significantly associated with the occurrence of PEP (odds ratio 2.248, FDR q value = 0.005). Gene-wise analyses did not show any significant results. CONCLUSION This study found that the IRF2BP1 gene variant was significantly associated with PEP. This genetic variant is a highly targeted PEP risk factor candidate and can be used for screening high-risk PEP groups before ERCP through future validation. (ClinicalTrials.gov no. NCT02928718).
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Affiliation(s)
- Young Hoon Choi
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul,
Korea
| | - Younggyun Lim
- Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul,
Korea
| | - Dong Kee Jang
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul,
Korea
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang,
Korea
| | - Dong-Won Ahn
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul,
Korea
| | - Ji Kon Ryu
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul,
Korea
| | - Woo Hyun Paik
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul,
Korea
| | - Yong-Tae Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul,
Korea
| | - Ju Han Kim
- Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul,
Korea
| | - Sang Hyub Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul,
Korea
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Abstract
PURPOSE OF REVIEW Not all patients with severe hypertriglyceridemia develop acute pancreatitis. We surveyed recent literature on inter-individual genetic variation in susceptibility to pancreatitis. RECENT FINDINGS Genetic determinants of pancreatitis include: rare Mendelian disorders caused by highly penetrant pathogenic variants in genes involved in trypsinogen activation; uncommon susceptibility variants in genes involved in trypsinogen activation, protein misfolding as well as calcium metabolism and cystic fibrosis, that have variable penetrance and show a range of odds ratios for pancreatitis; and common polymorphisms in many of the same genes that have only a small effect on risk. The role of these genetic variants in modulating pancreatitis risk in hypertriglyceridemia is unclear. However, among genetic determinants of plasma triglycerides, those predisposing to more severe hypertriglyceridemia associated with chylomicronemia appear to have higher pancreatitis risk. SUMMARY Currently, among patients with severe hypertriglyceridemia, the most consistent predictor of pancreatitis risk is the triglyceride level. Furthermore, pancreatitis risk appears to be modulated by a higher genetic burden of factors associated with greater magnitude of triglyceride elevation. The role of common and rare genetic determinants of pancreatitis itself in this metabolic context is unclear.
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Affiliation(s)
- Shyann M T Hang
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
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Shah IA, Prasad H, Banerjee S, Kurien RT, Chowdhury SD, Visweswariah SS. A novel frameshift mutation in TRPV6 is associated with hereditary pancreatitis. Front Genet 2023; 13:1058057. [PMID: 36699452 PMCID: PMC9868559 DOI: 10.3389/fgene.2022.1058057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/23/2022] [Indexed: 01/11/2023] Open
Abstract
Introduction: Hereditary pancreatitis (HP) is a rare debilitating disease with incompletely understood etio-pathophysiology. The reduced penetrance of genes such as PRSS1 associated with hereditary pancreatitis indicates a role for novel inherited factors. Methods: We performed whole-exome sequencing of three affected members of an Indian family (Father, Son, and Daughter) with chronic pancreatitis and compared variants with those seen in the unaffected mother. Results: We identified a novel frameshift mutation in exon 11 of TRPV6 (c.1474_1475delGT; p.V492Tfs*136), a calcium channel, in the patients. Functional characterization of this mutant TRPV6 following heterologous expression revealed that it was defective in calcium uptake. Induction of pancreatitis in mice induced Trpv6 expression, indicating that higher expression levels of the mutant protein and consequent dysregulation of calcium levels in patients with chronic pancreatitis could aggravate the disease. Discussion: We report a novel frameshift mutation in TRPV6 in an Indian family with HP that renders the mutant protein inactive. Our results emphasize the need to expand the list of genes used currently for evaluating patients with hereditary pancreatitis.
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Affiliation(s)
- Idrees A. Shah
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - Hari Prasad
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - Sanghita Banerjee
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - Reuben Thomas Kurien
- Department of Gastroenterology, Christian Medical College Vellore, Vellore, Tamil Nadu, India
| | - Sudipta Dhar Chowdhury
- Department of Gastroenterology, Christian Medical College Vellore, Vellore, Tamil Nadu, India
| | - Sandhya S. Visweswariah
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
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Abstract
Hereditary pancreatitis (HP) is a rare inherited chronic pancreatitis (CP) with strong genetic associations, with estimated prevalence ranging from 0.3 to 0.57 per 100,000 across Europe, North America, and East Asia. Apart from the most well-described genetic variants are PRSS1, SPINK1, and CFTR, many other genes, such as CTRC, CPA1, and CLDN2 and CEL have been found to associate with HP, typically in one of the 3 main mechanisms such as altered trypsin activity, pancreatic ductal cell secretion, and calcium channel regulation. The current mainstay of management for patients with HP comprises genetic testing for eligible individuals and families, alcohol and tobacco cessation avoidance, pain control, and judicious screening for complications, including exocrine and endocrine insufficiency and pancreatic cancer.
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Affiliation(s)
- Yichun Fu
- Henry D. Janowitz Division of Gastroenterology, One Gustave L. Levy Place, Box 1069, New York, NY 10029, USA; Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Aimee L Lucas
- Henry D. Janowitz Division of Gastroenterology, One Gustave L. Levy Place, Box 1069, New York, NY 10029, USA; Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA.
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Takáts A, Berke G, Szentesi A, Farkas G, Izbéki F, Erőss B, Czakó L, Vincze Á, Hegyi P, Sahin-Tóth M, Hegyi E. Common calcium-sensing receptor (CASR) gene variants do not modify risk for chronic pancreatitis in a Hungarian cohort. Pancreatology 2021; 21:1305-1310. [PMID: 34481716 PMCID: PMC8663126 DOI: 10.1016/j.pan.2021.08.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/17/2021] [Accepted: 08/22/2021] [Indexed: 12/11/2022]
Abstract
The calcium-sensing receptor (CASR) is expressed in the pancreas where it might regulate calcium concentrations in pancreatic secretions. Two independent studies reported conflicting results claiming that commonly occurring missense variants of the CASR gene are risk factors for chronic pancreatitis (CP). Here, we attempted to replicate the association between CASR variants and CP. We analyzed 337 patients and 840 controls from the Hungarian National Pancreas Registry either by direct sequencing of exon 7 and the flanking noncoding regions or by TaqMan SNP genotyping assays. We identified two common missense variants, c.2956G>T (p.A986S), and c.2968A>G (p.R990G), three low-frequency variants, c.3031C>G (p.Q1011E), c.2610G>A (p.E870=) and c.∗60T>A, and 8 rare variants including the novel variant c.1895G>A (p.G632D). When allelic or genotype distributions were considered, none of the CASR variants associated with CP. Subgroup analysis of nonalcoholic versus alcoholic patients revealed no disease association either. Our results demonstrate that common CASR variants do not modify the risk for CP and should not be considered as genetic risk factors in the clinical setting.
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Affiliation(s)
- Amanda Takáts
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Gergő Berke
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Andrea Szentesi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; First Department of Medicine, University of Szeged, Szeged, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Gyula Farkas
- Department of Surgery, University of Szeged, Szeged, Hungary
| | - Ferenc Izbéki
- Szent György University Teaching Hospital of Fejér County, Székesfehérvár, Hungary
| | - Bálint Erőss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - László Czakó
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Áron Vincze
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; First Department of Medicine, University of Szeged, Szeged, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Miklós Sahin-Tóth
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Eszter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.
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Ewers M, Canaff L, Weh AE, Masson E, Eiseler K, Chen JM, Rebours V, Bugert P, Michl P, Rosendahl J, Férec C, Goltzman D, Witt H. The three common polymorphisms p.A986S, p.R990G and p.Q1011E in the calcium sensing receptor (CASR) are not associated with chronic pancreatitis. Pancreatology 2021; 21:1299-1304. [PMID: 34446336 DOI: 10.1016/j.pan.2021.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND The calcium sensing receptor (CASR) is a G protein-coupled receptor that is responsible for assessing extracellular Ca2+ levels and thus plays a crucial role in calcium homeostasis. Hypercalcemia is a metabolic risk factor for pancreatitis and rare CASR variants have been described in patients with chronic pancreatitis. At the carboxy-terminal tail of CASR, there is a cluster of three common polymorphisms, p.A986S (rs1801725), p.R990G (rs1042636) and p.Q1011E (rs1801726), which have been associated with chronic pancreatitis in various studies, but with conflicting results. METHODS We examined 542 German and 339 French patients with chronic pancreatitis as well as 1025 German controls for the 3 common CASR polymorphism by melting curve analysis. For comparison, we used genotype data from 583 French controls from a previous study. In addition, we functionally analyzed the three variants by NFAT and SRE luciferase reporter systems as well as Western blotting and verified cell surface expression by ELISA. RESULTS In both cohorts, neither the genotype nor the allele frequencies differed significantly between patients and controls. In both luciferase assays, p.R990G showed a significant leftward shift, indicating an increased responsiveness of the receptor. p.A986S showed a leftward shift in the SRE but not in the NFAT reporter assay, while the responsiveness of p.Q1011E did not differ from the wild-type. These functional studies therefore do not support the contributions of variant CASR to increasing the risk of pancreatitis. CONCLUSIONS The three frequent CASR polymorphisms are unlikely to increase the risk for chronic pancreatitis.
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Affiliation(s)
- Maren Ewers
- Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine (EKFZ), Technical University Munich (TUM), Freising, Germany
| | - Lucie Canaff
- Departments of Medicine and Physiology, McGill University Health Centre, McGill University, Montréal, Québec, Canada
| | - Antonia Em Weh
- Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine (EKFZ), Technical University Munich (TUM), Freising, Germany
| | - Emmanuelle Masson
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; Service de Génétique Médicale et de Biologie de La Reproduction, CHRU Brest, F-29200, Brest, France
| | - Katharina Eiseler
- Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine (EKFZ), Technical University Munich (TUM), Freising, Germany
| | - Jian-Min Chen
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France
| | - Vinciane Rebours
- Department of Gastroenterology and Pancreatology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, Université de Paris, Paris, France
| | - Peter Bugert
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany
| | - Patrick Michl
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Jonas Rosendahl
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Claude Férec
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; Service de Génétique Médicale et de Biologie de La Reproduction, CHRU Brest, F-29200, Brest, France
| | - David Goltzman
- Departments of Medicine and Physiology, McGill University Health Centre, McGill University, Montréal, Québec, Canada
| | - Heiko Witt
- Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine (EKFZ), Technical University Munich (TUM), Freising, Germany.
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Actkins KV, Beasley HK, Faucon AB, Davis LK, Sakwe AM. Calcium-Sensing Receptor Polymorphisms at rs1801725 Are Associated with Increased Risk of Secondary Malignancies. J Pers Med 2021; 11:642. [PMID: 34357109 PMCID: PMC8304025 DOI: 10.3390/jpm11070642] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/07/2021] [Accepted: 07/02/2021] [Indexed: 12/19/2022] Open
Abstract
Dysregulation of systemic calcium homeostasis during malignancy is common in most patients with high-grade tumors. However, it remains unclear whether single nucleotide polymorphisms (SNPs) that alter the sensitivity of the calcium-sensing receptor (CaSR) to circulating calcium are associated with primary and/or secondary neoplasms at specific pathological sites in patients of European and African ancestry. Multivariable logistic regression models were used to analyze the association of CASR SNPs with circulating calcium, parathyroid hormone, vitamin D, and primary and secondary neoplasms. Circulating calcium is associated with an increased risk for breast, prostate, and skin cancers. In patients of European descent, the rs1801725 CASR SNP is associated with bone-related cancer phenotypes, deficiency of humoral immunity, and a higher risk of secondary neoplasms in the lungs and bone. Interestingly, circulating calcium levels are higher in homozygous patients for the inactivating CASR variant at rs1801725 (TT genotype), and this is associated with a higher risk of secondary malignancies. Our data suggest that expression of CaSR variants at rs1801725 is associated with a higher risk of developing secondary neoplastic lesions in the lungs and bone, due in part to cancer-induced hypercalcemia and/or tumor immune suppression. Screening of patients for CASR variants at this locus may lead to improved management of high calcium associated tumor progression.
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Affiliation(s)
- Ky’Era V. Actkins
- Department of Microbiology, Immunology and Physiology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN 37208, USA;
| | - Heather K. Beasley
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN 37208, USA; (H.K.B.); (L.K.D.)
| | - Annika B. Faucon
- Vanderbilt University Medical Center, Vanderbilt Genetics Institute, Nashville, TN 37232, USA;
| | - Lea K. Davis
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN 37208, USA; (H.K.B.); (L.K.D.)
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Amos M. Sakwe
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN 37208, USA; (H.K.B.); (L.K.D.)
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10
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Abstract
Chronic pancreatitis is a clinical entity that results from the progressive inflammation and irreversible fibrosis of the pancreas resulting from the cumulative injury sustained by the pancreas over time. It is an illness with variable presentations that can severely impact quality of life, while its long-term complications such as exocrine pancreatic insufficiency (EPI), diabetes mellitus, and risk of pancreatic cancer can become life threatening. The diagnosis of chronic pancreatitis can be challenging as despite the recent advancements in imaging technology, the radiographic findings do not become prominent until late stages of disease. Thus, the physicians' clinical acumen in obtaining thorough history taking focusing on risk factors, clinical symptoms, in addition to high-quality imaging, often guide to the accurate diagnosis of chronic pancreatitis. Endoscopy also plays a pivotal role in the diagnosis and management of chronic pancreatitis. Endoscopic ultrasound (EUS) is believed to be the most sensitive modality for diagnosing chronic pancreatitis. Despite efforts, however, natural history studies have demonstrated that 61% of individuals with chronic pancreatitis will require at least one endoscopic intervention, while 31% will require a surgical procedure as part of their management strategy. Recent advancements in genomic studies have furthered our understanding of the genetic polymorphisms that are associated with the pathogenesis of chronic pancreatitis. Genetic testing offers the potential to reveal treatable pancreatitis-related disorders, and can inform decision making with regard to radical therapies for persistent or severe disease such as total pancreatectomy with islet autotransplantation (TPIAT). The management of patients suffering from chronic pancreatitis often requires a multi-disciplinary approach, addressing pertinent symptoms as well as the sequelae of chronic inflammation and fibrosis. Abdominal pain is the prevailing symptom and most common complication of chronic pancreatitis, and impairs quality of life. Although heavily dependent on a wide range of analgesia, endoscopic treatment such as endoscopic retrograde cholangiopancreatography (ERCP) and surgical intervention can offer long-lasting relief of symptoms. For EPI, treatment with pancreatic enzyme supplements offers marginal-to-moderate relief. The most feared complication of chronic pancreatitis-the development of pancreatic cancer-has no known prevention measure to date.
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11
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Shyamasunder AH, Pai R, Ramamoorthy H, Sakhti D, Manipadam MT, Kapoor N, Paul TV, Jebasingh F, Thomas N, Abraham DT, Paul MJ, Chacko AG, Prabhu K, Rajaratnam S. Clinical Profile and Mutations Associated with Multiple Endocrine Neoplasia-Type1 (MEN1) and Their First-Degree Relatives at Risk of Developing MEN1: A Prospective Study. Horm Metab Res 2021; 53:245-256. [PMID: 33853118 DOI: 10.1055/a-1402-0183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Multiple Endocrine Neoplasia type-1 (MEN1) is an autosomal dominant disorder with a combined occurrence of tumours of parathyroid glands, pancreatic islets, and anterior pituitary. About 90% of these patients carry mutations in the MEN1 gene, though the spectrum is not well defined in India. Forty clinically suspected cases of MEN1 were enrolled prospectively over six years; 32 patients (23 index-cases and nine affected relatives) with≥2 classical endocrine tumours of MEN1 were considered definite, and eight were categorised as 'MEN1-like'. Details of their clinical presentation, treatment and mutational analysis including MEN1 gene, 3' and 5' untranslated regions (UTR) of MEN1, CDKN1B, and CaSR genes were collated. Asymptomatic first-degree relatives were also screened. Among the 32 definite MEN1 patients, all had primary hyperparathyroidism, 22 (68.7%) had gastroentero-pancreatic neuroendocrine tumours, and 21 (66%) had pituitary adenoma. Of the 23 definite index-cases, 13 (56.5%) carried mutations in the MEN1 gene. Five of nine affected first-degree relatives (55.5%), and four of 10 asymptomatic relatives (40%) also had MEN1 mutations. Seven of 10 MEN1 mutation-negative definite index-cases harboured p.V109G polymorphism in the CDKN1B gene. All eight MEN1-like cases were negative for mutations and large deletions in MEN1, mutations in 3' and 5' UTR of MEN1, CaSR and CDKN1B genes. The study has helped to clearly document the pattern of mutations among Indian MEN1 patients. However, the absence of MEN1 mutation in ~44% of cases and the presence of p.V109G polymorphism in CDKN1B gene raise the question whether such polymorphisms could independently contribute to pathogenesis.
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Affiliation(s)
| | - Rekha Pai
- Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | | | - Dhananjayan Sakhti
- Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | | | - Nitin Kapoor
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| | - Thomas Vizhalil Paul
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| | - Felix Jebasingh
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| | - Nihal Thomas
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| | - Deepak Thomas Abraham
- Department of Endocrine Surgery, Christian Medical College, Vellore, Tamil Nadu, India
| | | | - Ari George Chacko
- Department of Neurosurgery, Christian Medical College, Vellore, Tamil Nadu, India
| | - Krishna Prabhu
- Department of Neurosurgery, Christian Medical College, Vellore, Tamil Nadu, India
| | - Simon Rajaratnam
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
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12
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Yuan S, Giovannucci EL, Larsson SC. Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study. NPJ Genom Med 2021; 6:27. [PMID: 33782414 PMCID: PMC8007637 DOI: 10.1038/s41525-021-00189-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/26/2021] [Indexed: 12/19/2022] Open
Abstract
We conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p < 5 × 10-8 were selected from corresponding genome-wide association studies. Summary-level data for pancreatitis were obtained from the FinnGen consortium and UK Biobank. Univariable and multivariable Mendelian randomization analyses were performed and results from FinnGen and UK Biobank were combined using the fixed-effects meta-analysis method. Genetic predisposition to gallstone disease, type 2 diabetes and smoking initiation was associated with an increased risk of acute pancreatitis. The combined odds ratios (ORs) were 1.74 (95% confidence interval (CI), 1.57, 1.93) for gallstone disease, 1.14 (95% CI, 1.06, 1.21) for type 2 diabetes and 1.56 (95% CI, 1.32, 1.83) for smoking initiation. The association for type 2 diabetes attenuated after adjustment for gallstone disease. Genetic predisposition to gallstone disease and smoking initiation as well as higher genetically predicted serum calcium and triglyceride levels were associated with an increased risk of chronic pancreatitis. The combined ORs of chronic pancreatitis were 1.27 (95% CI, 1.08, 1.50) for gallstone disease, 1.86 (95% CI, 1.43, 2.43) for smoking initiation, 2.20 (95% CI, 1.30, 3.72) for calcium and 1.47 (95% CI, 1.23, 1.76) for triglycerides. This study provides evidence in support that gallstone disease, type 2 diabetes, smoking and elevated calcium and triglyceride levels are causally associated with the risk of acute or chronic pancreatitis.
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Affiliation(s)
- Shuai Yuan
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Edward L Giovannucci
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA.,Department of Nutrition, Harvard T H Chan School of Public Health, Boston, MA, USA
| | - Susanna C Larsson
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. .,Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
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13
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Taha HS, Moustafa EM, Moawed FSM, Hegazy MGA. Curative role of mesenchymal stromal cells in chronic pancreatitis: Modulation of MAPK and TGF-β1/SMAD factors. Int J Immunopathol Pharmacol 2021; 35:20587384211054036. [PMID: 34696610 PMCID: PMC8552371 DOI: 10.1177/20587384211054036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 09/29/2021] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Living organisms respond to physical, chemical, and biological threats with a potent inflammatory response which alters organ cell signaling and leads to dysfunction. We evaluated the therapeutic effect of bone marrow-based mesenchymal stromal cell (BM-MSC) transplanted in rats to preserve tissue integrity and to restore homeostasis and function in the pancreatitis experimental pattern. METHODS This study involved 40 adult male Wister rats. Repeated L-arginine injections caused chronic pancreatitis (CP), leading to the development of pancreatic damage and shifting the intracellular signaling pathways. Rats were then infused with BM-MSC labeled with PKH26 fluorescent linker dye for 12 weeks. RESULTS Cell-surface indicators of BM-MSCs such as CD 90 and CD29 were expressed with the lack of CD34 expression. BM-MSC treatment considerably improved the alterations induced in a series of inflammatory markers, including IL-18, TNF-α, CRP, PGE2, and MCP-1. Furthermore, improvement was found in digestive enzymes and lipid profile with amelioration in myeloperoxidase activity. BM-MSC treatment also regulated the (TGF-/p-38MPAK/SMAD2/3) signaling factors that enhances repair of damaged pancreatic tissue, confirmed by reversed alteration of histopathological examination. CONCLUSION our results further bring to light the promise of cell transplant therapy for chronic pancreatitis.
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Affiliation(s)
- Hager S Taha
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Enas M Moustafa
- Radiation Biology Department, National Center for Radiation Research & Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Fatma SM Moawed
- Health Radiation Research Department, National Center for Radiation Research & Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Marwa GA Hegazy
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
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14
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Genetic Abnormalities in Pancreatitis: An Update on Diagnosis, Clinical Features, and Treatment. Diagnostics (Basel) 2020; 11:diagnostics11010031. [PMID: 33375361 PMCID: PMC7824215 DOI: 10.3390/diagnostics11010031] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/12/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023] Open
Abstract
Several pancreatitis susceptibility genes have been identified to date. A relationship between a mutation in the cationic trypsinogen (protease serine 1, PRSS1) gene and hereditary pancreatitis (HP) was first identified in 1996. Currently, HP has been defined as either two or more individuals within a family exhibiting pancreatitis for two or more generations, or pancreatitis linked to mutation of the PRSS1 gene. In 2000, a mutation in the serine protease inhibitor gene (Kazal type 1: SPINK1) was reported to be related to sporadic pancreatitis of unknown etiology. This paper reviews and summarizes the current published data on the pancreatitis susceptibility genes, mainly PRSS1 and SPINK1 genes, and introduces a diagnostic and therapeutic approach for dealing with patients with these gene mutations. Patients with these genetic predispositions, both children and adults, have often been initially diagnosed with idiopathic acute pancreatitis, in approximately 20-50% of pediatric cases and 28-80% of adult cases. In such patients, where the etiology is unknown, genetic testing, which requires pre-test and post-test genetic counselling, may prove helpful. Patients with chronic pancreatitis (CP) due to SPINK1 gene mutation and HP patients have a potentially high risk of pancreatic exocrine insufficiency, diabetes mellitus, and, of particular importance, pancreatic cancer. Thus, these patients require careful long-term follow-up and management. Specifically, symptomatic CP patients often need endoscopic therapy or surgery, often following a step-up approach beginning with endoscopic therapy and progressing to surgery if necessary, which is similar to the therapeutic approach for patients with CP due to other etiologies. It is important that clinicians are aware of the characteristics of patients with pancreatitis susceptibility genetic abnormalities.
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15
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Moustafa EM, Moawed FSM, Abdel-Hamid GR. Icariin Promote Stem Cells Regeneration and Repair Acinar Cells in L-arginine / Radiation -Inducing Chronic Pancreatitis in Rats. Dose Response 2020; 18:1559325820970810. [PMID: 33192204 PMCID: PMC7607780 DOI: 10.1177/1559325820970810] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/28/2020] [Indexed: 12/11/2022] Open
Abstract
Objective: Chronic Pancreatitis (CP) is a multifactorial disease. It was characterized by severe inflammation and acinar cell destruction. Thus, the present study was initiated to evaluating the ability of bone marrow-based mesenchymal stem cell (MSCs) combined with Icariin to restore and regenerate acinar cells in the pancreas of rats suffering chronic pancreatitis. Methods: Chronic pancreatitis was induced in rats via both L-arginine plus radiation, repeated L-arginine injection (2.5g/Kg body-weight, 1, 4,7,10,13,16,19 days), then, on day 21, rats were exposed to a single dose of gamma-radiation (6 Gy), which exacerbate injury of pancreatic acinar cells. One day after irradiation, rats were treated with either MSCs (1 × 107 /rat, once, tail vein injection) labeled PKH26 fluorescent linker dye and/or Icariin (100 mg/Kg, daily, orally) for 8 weeks. Results: Icariin promotes MSCs proliferation boosting its productivity in vitro. MSCs, and/or icariin treatments has regulated molecular factors TGF-β/PDGF and promoted the regeneration of pancreatic tissues by releasing PDX-1 and MafA involved in the recruitment of stem/progenitor cell in the tissue, and confirmed by histopathological examination. Moreover, a significant decrease in IL-8 and TNF-α cytokines with significant amelioration of myeloperoxidase activity were noted. As well as, reduction in MCP-1 and collagen type-1 levels along with Hedgehog signaling down-regulating expression in such cells, Patched-1, Smoothened, and GLi-1. Conclusion: The potent bioactive therapeutic Icariin combined with MSCs induces a significantly greater improvement, compared to each therapy alone.
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Affiliation(s)
| | - Fatma S M Moawed
- Department of Health Radiation Research, National Center for Radiation Research & Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
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16
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Soytürk M, Bengi G, Oğuz D, Kalkan İH, Yalnız M, Tahtacı M, Demir K, Kasap E, Oruç N, Ünal NG, Sezgin O, Özdoğan O, Altıntaş E, Yaraş S, Parlak E, Köksal AŞ, Saruç M, Ünal H, Ünsal B, Günay S, Duman D, Yurçi A, Kacar S, Filik L. Turkish Gastroenterology Association, Pancreas Study Group, Chronic Pancreatitis Committee Consensus Report. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2020; 31:S1-S41. [PMID: 33210608 PMCID: PMC7752168 DOI: 10.5152/tjg.2020.220920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 09/28/2020] [Indexed: 11/22/2022]
Affiliation(s)
- Müjde Soytürk
- Department of Gastroenterology, Dokuz Eylül University School of Medicine, İzmir, Turkey
| | - Göksel Bengi
- Department of Gastroenterology, Dokuz Eylül University School of Medicine, İzmir, Turkey
| | - Dilek Oğuz
- Department of Gastroenterology, Kırıkkale University School of Medicine, Kırıkkale, Turkey
| | - İsmail Hakkı Kalkan
- Department of Gastroenterology, TOBB University of Economics and Technology School of Medicine, Ankara, Turkey
| | - Mehmet Yalnız
- Department of Gastroenterology, Fırat University School of Medicine, Elazığ, Turkey
| | - Mustafa Tahtacı
- Department of Gastroenterology, Yıldırım Beyazıt University School of Medicine, Ankara, Turkey
| | - Kadir Demir
- Department of Gastroenterology, İstanbul University School of Medicine, İstanbul, Turkey
| | - Elmas Kasap
- Department of Gastroenterology, Celal Bayar University School of Medicine, Manisa, Turkey
| | - Nevin Oruç
- Department of Gastroenterology, Ege University School of Medicine, İzmir, Turkey
| | - Nalan Gülşen Ünal
- Department of Gastroenterology, Ege University School of Medicine, İzmir, Turkey
| | - Orhan Sezgin
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Osman Özdoğan
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Engin Altıntaş
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Serkan Yaraş
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Erkan Parlak
- Department of Gastroenterology, Hacettepe University School of Medicine, Ankara, Turkey
| | - Aydın Şeref Köksal
- Department of Gastroenterology, Sakarya University School of Medicine, Sakarya, Turkey
| | - Murat Saruç
- Department of Gastroenterology, Acibadem University School of Medicine, İstanbul, Turkey
| | - Hakan Ünal
- Department of Gastroenterology, Acibadem University School of Medicine, İstanbul, Turkey
| | - Belkıs Ünsal
- Health Sciences University, Katip Çelebi Training and Research Hospital, İzmir, Turkey
| | - Süleyman Günay
- Health Sciences University, Katip Çelebi Training and Research Hospital, İzmir, Turkey
| | - Deniz Duman
- Department of Gastroenterology, Marmara University School of Medicine, İstanbul, Turkey
| | - Alper Yurçi
- Department of Gastroenterology, Erciyes University School of Medicine, Kayseri, Turkey
| | - Sabite Kacar
- Health Sciences University, Ankara State Hospital, Ankara, Turkey
| | - Levent Filik
- Health Sciences University, Ankara Training and Research Hospital, Ankara, Turkey
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17
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Takahashi T, Miao Y, Kang F, Dolai S, Gaisano HY. Susceptibility Factors and Cellular Mechanisms Underlying Alcoholic Pancreatitis. Alcohol Clin Exp Res 2020; 44:777-789. [PMID: 32056245 DOI: 10.1111/acer.14304] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 02/03/2020] [Indexed: 12/16/2022]
Abstract
Alcohol is a major cause of acute and chronic pancreatitis. There have been some recent advances in the understanding of the mechanisms underlying alcoholic pancreatitis, which include perturbation in mitochondrial function and autophagy and ectopic exocytosis, with some of these cellular events involving membrane fusion soluble N-ethylmaleimide-sensitive factor receptor protein receptor proteins. Although new insights have been unraveled recently, the precise mechanisms remain complex, and their finer details have yet to be established. The overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also the stellate cells and duct cells. Why only some are more susceptible to pancreatitis and with increased severity, while others are not, would suggest that there may be undefined protective factors or mechanisms that enhance recovery and regeneration after injury. Furthermore, there are confounding influences of lifestyle factors such as smoking and diet, and genetic background. Whereas alcohol and smoking cessation and a generally healthy lifestyle are intuitively the advice given to these patients afflicted with alcoholic pancreatitis in order to reduce disease recurrence and progression, there is as yet no specific treatment. A more complete understanding of the pathogenesis of pancreatitis from which novel therapeutic targets could be identified will have a great impact, particularly with the stubbornly high fatality (>30%) of severe pancreatitis. This review focuses on the susceptibility factors and underlying cellular mechanisms of alcohol injury on the exocrine pancreas.
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Affiliation(s)
- Toshimasa Takahashi
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Yifan Miao
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Fei Kang
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Subhankar Dolai
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Herbert Y Gaisano
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
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18
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Cinacalcet sustainedly prevents pancreatitis in a child with a compound heterozygous SPINK1/AP2S1 mutation. Pancreatology 2019; 19:801-804. [PMID: 31391146 DOI: 10.1016/j.pan.2019.07.045] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 07/24/2019] [Accepted: 07/29/2019] [Indexed: 12/11/2022]
Abstract
Familial hypocalciuric hypercalcemia is an autosomal dominant genetic disorder characterized by hypercalcemia associated with inappropriate hypocalciuria and normal parathyroid hormone levels. Acute recurrent pancreatitis (ARP) is rare in children. Predisposing factors include hypercalcemia and mutations in the serine protease inhibitor Kazal-type 1 (SPINK1) gene. The disease carries a heavy morbidity and preventive treatment options are scant. Here, we report a child with a novel genetic/metabolic form of ARP associated with compound heterozygous SPINK1/AP2S1 (adaptor protein-2 σ1-subunit) mutations, recurrence of which was completely abrogated for 6 years by cinacalcet treatment.
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19
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van der Vorst EPC, Peters LJF, Müller M, Gencer S, Yan Y, Weber C, Döring Y. G-Protein Coupled Receptor Targeting on Myeloid Cells in Atherosclerosis. Front Pharmacol 2019; 10:531. [PMID: 31191301 PMCID: PMC6540917 DOI: 10.3389/fphar.2019.00531] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 04/29/2019] [Indexed: 12/11/2022] Open
Abstract
Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVDs), is a lipid-driven, inflammatory disease of the large arteries. Gold standard therapy with statins and the more recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have improved health conditions among CVD patients by lowering low density lipoprotein (LDL) cholesterol. Nevertheless, a substantial part of these patients is still suffering and it seems that 'just' lipid lowering is insufficient. The results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) have now proven that inflammation is a key driver of atherosclerosis and that targeting inflammation improves CVD outcomes. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways have to be promoted. The inflammatory processes in atherosclerosis are facilitated by a network of immune cells and their subsequent responses. Cell networking is orchestrated by various (inflammatory) mediators which interact, bind and induce signaling. Over the last years, G-protein coupled receptors (GPCRs) emerged as important players in recognizing these mediators, because of their diverse functions in steady state but also and specifically during chronic inflammatory processes - such as atherosclerosis. In this review, we will therefore highlight a selection of these receptors or receptor sub-families mainly expressed on myeloid cells and their role in atherosclerosis. More specifically, we will focus on chemokine receptors, both classical and atypical, formyl-peptide receptors, the chemerin receptor 23 and the calcium-sensing receptor. When information is available, we will also describe the consequences of their targeting which may hold promising options for future treatment of CVD.
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Affiliation(s)
- Emiel P. C. van der Vorst
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
- Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, Netherlands
- Institute for Molecular Cardiovascular Research/Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany
- Munich Heart Alliance, German Centre for Cardiovascular Research, Munich, Germany
| | - Linsey J. F. Peters
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Madeleine Müller
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Selin Gencer
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Yi Yan
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Christian Weber
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
- Munich Heart Alliance, German Centre for Cardiovascular Research, Munich, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Yvonne Döring
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
- Munich Heart Alliance, German Centre for Cardiovascular Research, Munich, Germany
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20
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Mayerle J, Sendler M, Hegyi E, Beyer G, Lerch MM, Sahin-Tóth M. Genetics, Cell Biology, and Pathophysiology of Pancreatitis. Gastroenterology 2019; 156:1951-1968.e1. [PMID: 30660731 PMCID: PMC6903413 DOI: 10.1053/j.gastro.2018.11.081] [Citation(s) in RCA: 227] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/14/2018] [Accepted: 11/16/2018] [Indexed: 02/07/2023]
Abstract
Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.
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Affiliation(s)
- Julia Mayerle
- Medical Department II, University Hospital, LMU, Munich, Germany,Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Eszter Hegyi
- Institute for Translational Medicine, University of Pécs, Hungary
| | - Georg Beyer
- Medical Department II, University Hospital, LMU, Munich, Germany
| | - Markus M. Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Miklós Sahin-Tóth
- Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118
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21
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Lowe ME, Goodman MT, Coté GA, Glesby MJ, Haupt M, Schork NJ, Singh VK, Andersen DK, Pandol SJ, Uc A, Whitcomb DC. Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis: Summary of the Working Group on Drug Development and Trials in Recurrent Acute Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 2019; 47:1193-1199. [PMID: 30325857 PMCID: PMC6195328 DOI: 10.1097/mpa.0000000000001164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recurrent acute pancreatitis (RAP) is a complex clinical syndrome with significant morbidity, unpredictable outcomes, and limited treatment options. The National Institute of Diabetes and Digestive and Kidney Disease sponsored a workshop on July 25, 2018, in Pittsburgh, Pennsylvania, to address research gaps impeding development of effective therapies for pancreatitis. The RAP working group identified challenges to clinical progress using existing definitions, risk assessment, diagnostic and severity criteria, disease trajectories, outcomes, and research methods. Recurrent acute pancreatitis includes all the risk of acute pancreatitis and often progresses to chronic pancreatitis with variable complications of chronic pain, exocrine insufficiency, diabetes, and pancreatic cancer. However, the great variability among individuals with RAP requires better precision in defining the risks, individual episodes, as well as their frequency, pathogenic pathways, and specific outcome measures for each of the systems affected by pancreatic inflammation. Because of disease complexity, few patients are similar enough for traditional studies and methods to conduct clinical trials with small sample sizes are required. The need for genetic testing, biomarker development, and better imaging methods was highlighted. Adaptive and N-of-one study designs, better endpoints, and outcome measures including patient-reported outcomes should considered early in developing future therapeutic trial design and include all stakeholders.
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Affiliation(s)
- Mark E. Lowe
- Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO
| | - Marc T. Goodman
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Gregory A. Coté
- Department of Medicine, Medical University of South Carolina, Charleston, SC
| | | | - Mark Haupt
- ARIEL Precision Medicine, Pittsburgh, PA
| | - Nicholas J. Schork
- Department of Quantitative Medicine, The Transcriptional Genomics Research Institute, Phoenix, AZ
| | - Vikesh K. Singh
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD
| | - Stephen J. Pandol
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Aliye Uc
- Division of Gastroenterology, Hepatology, Pancreatology and Nutrition, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA
| | - David C. Whitcomb
- Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
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22
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Zhang X, Jin T, Shi N, Yao L, Yang X, Han C, Wen L, Du D, Szatmary P, Mukherjee R, Liu T, Xia Q, Criddle DN, Huang W, Chvanov M, Sutton R. Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine. Front Physiol 2019; 9:1922. [PMID: 30697165 PMCID: PMC6341295 DOI: 10.3389/fphys.2018.01922] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 12/20/2018] [Indexed: 02/05/2023] Open
Abstract
Pancreatic acinar cells require high rates of amino acid uptake for digestive enzyme synthesis, but excessive concentrations can trigger acute pancreatitis (AP) by mechanisms that are not well understood. We have used three basic natural amino acids L-arginine, L-ornithine, and L-histidine to determine mechanisms of amino acid-induced pancreatic injury and whether these are common to all three amino acids. Caffeine markedly inhibited necrotic cell death pathway activation in isolated pancreatic acinar cells induced by L-arginine, but not L-ornithine, whereas caffeine accelerated L-histidine-induced cell death. Both necroptosis inhibitors of RIPK1 and RIPK3 and a necroptosis activator/apoptosis inhibitor z-VAD increased cell death caused by L-histidine, but not L-arginine or L-ornithine. Cyclophilin D knock-out (Ppif-/-) significantly attenuated cell death induced by L-histidine, but not L-arginine, or L-ornithine. Allosteric modulators of calcium-sensing receptor (CaSR) and G-protein coupled receptor class C group 6 member A (GPRC6A) had inhibitory effects on cell death induced by L-arginine but not L-ornithine or L-histidine. We developed a novel amino acid-induced AP murine model with high doses of L-histidine and confirmed AP severity was significantly reduced in Ppif-/- vs. wild type mice. In L-arginine-induced AP neither Ppif-/-, caffeine, or allosteric modulators of CaSR or GPRC6A reduced pancreatic damage, even though CaSR inhibition with NPS-2143 significantly reduced pancreatic and systemic injury in caerulein-induced AP. These findings demonstrate marked differences in the mechanisms of pancreatic injury induced by different basic amino acids and suggest the lack of effect of treatments on L-arginine-induced AP may be due to conversion to L-ornithine in the urea cycle.
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Affiliation(s)
- Xiaoying Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
- Liverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Tao Jin
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
- Liverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Na Shi
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Linbo Yao
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Xinmin Yang
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Chenxia Han
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Li Wen
- Liverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Dan Du
- West China-Washington Mitochondria and Metabolism Centre, West China Hospital of Sichuan University, Chengdu, China
| | - Peter Szatmary
- Liverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Rajarshi Mukherjee
- Liverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Tingting Liu
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Qing Xia
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
| | - David N. Criddle
- Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
| | - Wei Huang
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Michael Chvanov
- Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
| | - Robert Sutton
- Liverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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Abstract
PURPOSE OF REVIEW Genetic mutations are the primary cause for acute recurrent (ARP) and chronic pancreatitis in children. Further, our medical approach for many diseases is changing from a one-drug therapy to more individualized therapeutic strategies. In respect to the therapeutic management of ARP/chronic pancreatitis, this entails an understanding of the individual, mainly genetic, risk factors that led to pancreatitis disease. RECENT FINDINGS New pancreatitis-associated genes are continuously emerging from increasingly large genetic cohort studies. Furthermore, newer research findings demonstrate that multiple genetic and nongenetic factors are required to increase the individual risk for developing ARP/chronic pancreatitis. Last, there is new exciting development towards targeted pancreatitis therapy in the future. SUMMARY This review introduces the current concept of ARP/chronic pancreatitis as a complex disease caused by multiple genetic and nongenetic factors. This warrants careful evaluation of these patients and ideally consultation of a pancreas expert to help understand individual genetic risk profiles and to provide more effective patient consultation.
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Abstract
Recurrent acute pancreatitis (RAP) is a clinically significant problem globally. The etiology remains unclear in approximately 10% to 15% of patients despite a thorough workup. Data on natural history and efficacy of treatments are limited. We aimed to establish criteria for diagnosis, evaluate the causative factors, and arrive at a consensus on the appropriate workup and management of patients with RAP. The organizing committee was formed, and a set of questions was developed based on the current evidence, controversies, and topics that needed further research. After a vetting process, these topics were assigned to a group of experts from around the world with special interest in RAP. Data were presented as part of a workshop on RAP organized as a part of the annual meeting of the America Pancreatic Association. Pretest and Posttest questions were administered, and the responses were tabulated by the current Grades of Recommendation Assessment, Development and Evaluation system. The consensus guidelines were established in the format of a diagnostic algorithm. Several deficiencies were identified with respect to data on etiology, treatment efficacies, and areas that need immediate research.
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Xiao Y, Yuan W, Yu B, Guo Y, Xu X, Wang X, Yu Y, Yu Y, Gong B, Xu C. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. J Pediatr 2017; 191:158-163.e3. [PMID: 29173301 DOI: 10.1016/j.jpeds.2017.08.063] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 06/24/2017] [Accepted: 08/23/2017] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To identify causal mutations in certain genes in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). STUDY DESIGN After patients were enrolled (CP, 55; ARP, 14) and their clinical characteristics were investigated, we performed next-generation sequencing to detect nucleotide variations among the following 10 genes: cationic trypsinogen protease serine 1 (PRSS1), serine protease inhibitor, Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator gene (CFTR), chymotrypsin C (CTRC), calcium-sensing receptor (CASR), cathepsin B (CTSB), keratin 8 (KRT8), CLAUDIN 2 (CLDN2), carboxypeptidase A1 (CPA1), and ATPase type 8B member 1 (ATP8B1). Mutations were searched against online databases to obtain information on the cause of the diseases. Certain novel mutations were analyzed using the SIFT2 and Polyphen-2 to predict the effect on protein function. RESULTS There were 45 patients with CP and 10 patients with ARP who harbored 1 or more mutations in these genes; 45 patients had at least 1 mutation related to pancreatitis. Mutations were observed in the PRSS1, SPINK1, and CFTR genes in 17 patients, the CASR gene in 5 patients, and the CTSB, CTRC, and KRT8 genes in 1 patient. Mutations were not found in the CLDN, CPA1, or ATP8B1 genes. We found that mutations in SPINK1 may increase the risk of pancreatic duct stones (OR, 11.07; P = .003). The patients with CFTR mutations had a higher level of serum amylase (316.0 U/L vs 92.5 U/L; P = .026). CONCLUSION Mutations, especially those in PRSS1, SPINK1, and CFTR, accounted for the major etiologies in Chinese children with CP or ARP. Children presenting mutations in the SPINK1 gene may have a higher risk of developing pancreatic duct stones.
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Affiliation(s)
- Yuan Xiao
- Pediatric Department, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Wentao Yuan
- Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center and Shanghai Industrial Technology Institute (SITI), Shanghai, China
| | - Bo Yu
- School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Yan Guo
- Pediatric Department, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Xu Xu
- Pediatric Department, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Xinqiong Wang
- Pediatric Department, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yi Yu
- Pediatric Department, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yi Yu
- Pediatric Department, Ruijin Hospital North, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Biao Gong
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Chundi Xu
- Pediatric Department, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China; Pediatric Department, Ruijin Hospital North, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
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26
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Chymotrypsinogen C Genetic Variants, Including c.180TT, Are Strongly Associated With Chronic Pancreatitis in Pediatric Patients. J Pediatr Gastroenterol Nutr 2017; 65:652-657. [PMID: 28968289 DOI: 10.1097/mpg.0000000000001767] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Genetic studies in adults/adolescent patients with chronic pancreatitis (CP) identified chymotrypsinogen C (CTRC) genetic variants but their association with CP risk has been difficult to replicate. To evaluate the risk of CP associated with CTRC variants in CP pediatric patients-control study. METHODS The distribution of CTRC variants in CP pediatric cohort (n = 136, median age at CP onset 8 years) with no history of alcohol/smoking abuse was compared with controls (n = 401, median age 45). RESULTS We showed that p.Arg254Trp (4.6%) and p.Lys247_Arg254del (5.3%) heterozygous mutations are frequent and significantly associated with CP risk in pediatric patients (odds ratio [OR] = 19.1; 95% CI 2.8-160; P = 0.001 and OR = 5.5; 95% CI 1.6-19.4; P = 0.001, respectively). For the first time, we demonstrated that the c.180TT genotype of common p.Gly60Gly variant is strong, an independent CP risk factor (OR = 23; 95% CI 7.7-70; P < 0.001) with effect size comparable to p.Arg254Trp mutation. The other novel observation is that common c.493+51C>A variant, both CA and AA genotype, is significantly underrepresented in CP compared with controls (15% vs 35%; OR = 0.33; 95% CI 0.19-0.59; P < 0.001 and 2.8% vs 11%; OR = 0.24; 95% CI 0.06-0.85; P = 0.027, respectively). CONCLUSIONS Our study provides evidence that CTRC variants, including c.180TT (p.Gly60Gly) are strong CP risk factors. The c.493+51C>A variant may play a protective role against CP development.
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Abstract
OBJECTIVES This research was applied to case-control studies of the association between pancreatitis and SPINK1 gene to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. METHODS MEDLINE and Embase were searched to identify longitudinal studies evaluating pancreatitis and SPINK1. Odds ratios (ORs) and 95% confidence interval (CI) were pooled using random-effect models and calculated using Carlin method. Publication bias was assessed using Egger et al's approach (A famous statistic method by Egger et al). Sensitivity, heterogeneity, and trim and fill analyses were conducted. RESULTS Based on the results, we found that (1) the results support for the association between pancreatitis and SPINK1, when analyzed totally and by subdivision (total [OR, 7.771; 95% CI, 5.232-11.543; P < 0.000]; European [OR,6.400; 95% CI, 4.346-9.426; P < 0.000]; Asian [OR, 11.823; 95% CI, 4.612-30.310; P < 0.000]; American [OR, 3.777; 95% CI, 1.596-8.939; P = 0.002]; mixed: [OR, 13.566; 95% CI, 2.322-79.252, P = 0.004]); (2) no evidence indicates that this association is accounted for by any one study, and no evidence indicates any publication bias exists. CONCLUSIONS The results indicated that SPINK1 gene, particularly the N34S mutation, has a genetic association with the development of pancreatitis.
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28
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Abstract
Chronic pancreatitis is defined as a pathological fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathological responses to parenchymal injury or stress. Potential causes can include toxic factors (such as alcohol or smoking), metabolic abnormalities, idiopathic mechanisms, genetics, autoimmune responses and obstructive mechanisms. The pathophysiology of chronic pancreatitis is fairly complex and includes acinar cell injury, acinar stress responses, duct dysfunction, persistent or altered inflammation, and/or neuro-immune crosstalk, but these mechanisms are not completely understood. Chronic pancreatitis is characterized by ongoing inflammation of the pancreas that results in progressive loss of the endocrine and exocrine compartment owing to atrophy and/or replacement with fibrotic tissue. Functional consequences include recurrent or constant abdominal pain, diabetes mellitus (endocrine insufficiency) and maldigestion (exocrine insufficiency). Diagnosing early-stage chronic pancreatitis is challenging as changes are subtle, ill-defined and overlap those of other disorders. Later stages are characterized by variable fibrosis and calcification of the pancreatic parenchyma; dilatation, distortion and stricturing of the pancreatic ducts; pseudocysts; intrapancreatic bile duct stricturing; narrowing of the duodenum; and superior mesenteric, portal and/or splenic vein thrombosis. Treatment options comprise medical, radiological, endoscopic and surgical interventions, but evidence-based approaches are limited. This Primer highlights the major progress that has been made in understanding the pathophysiology, presentation, prevalence and management of chronic pancreatitis and its complications.
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29
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Di Leo M, Bianco M, Zuppardo RA, Guslandi M, Calabrese F, Mannucci A, Neri TM, Testoni PA, Leandro G, Cavestro GM. Meta-analysis of the impact of SPINK1 p.N34S gene variation in Caucasic patients with chronic pancreatitis. An update. Dig Liver Dis 2017; 49:847-853. [PMID: 28546062 DOI: 10.1016/j.dld.2017.04.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 04/24/2017] [Accepted: 04/26/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND SPINK1 p.N34S gene variation is one of the endogenous factors which seem to be associated with chronic pancreatitis (CP). However, in literature there is no clear agreement regarding its contribution in different ethnicity and CP etiologies. AIM To investigate the role of SPINK1 p.N34S gene variation in CP patients with European origin by means of meta-analysis. METHODS Literature search was conducted and case-control studies evaluating Caucasian population, published between May 2007 and May 2015, were included. We also included Caucasian selected studies analyzed in previous meta-analysis. We carried out meta-analysis including all selected studies. After that, we performed two additional meta-analyses considering the incidence of SPINK1 p.N34S gene variation in alcoholic or in idiopathic CP patients vs control group. RESULTS Twenty-five studies were included and the total number of subjects was 8800 (2981 cases and 5819 controls). The presence of p.N34S variation increased nine times the overall CP risk in population of European origin [OR 9.695 (CI 95% 7.931-11.851)]. Also, the contribution of SPINK1 in idiopathic pancreatitis [OR 13.640 (CI 95% 8.858-21.002)] was found to be higher than in alcoholic CP [5.283 (CI 95% 3.449-8.092)]. CONCLUSION The association between SPINK1 p.N34S gene variation and CP is confirmed. Also, we confirmed that the idiopathic etiology needs a better definition by means of genetic analysis.
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Affiliation(s)
- Milena Di Leo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Margherita Bianco
- Gastroenterology Unit 1, Gastroenterological Hospital 'S. De Bellis' IRCCS, Castellana Grotte, BA, Italy
| | - Raffaella Alessia Zuppardo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mario Guslandi
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Federica Calabrese
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessandro Mannucci
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Tauro Maria Neri
- Unit of Medical Genetics, Laboratory of Molecular Genetics, Diagnostic Department, University Hospital of Parma, Parma, Italy
| | - Pier Alberto Testoni
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Gioacchino Leandro
- Gastroenterology Unit 1, Gastroenterological Hospital 'S. De Bellis' IRCCS, Castellana Grotte, BA, Italy; Institute for Digestive and Liver Health, University College, London, UK
| | - Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
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30
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Abstract
On May 16, 2015 at the invitation of the American Gastroenterological Association Institute Council E.P.D. presented a state-of-the-art lecture at Digestive Disease Week 2015. The aims were to discuss a selection of landmark papers in chronic pancreatitis (CP) that influence modern management and to conclude by suggesting some future directions. This is based on that presentation. We will specifically review the following: duct anatomy and pancreas divisum, description of chronic relapsing pancreatitis and its differentiation from recurrent acute pancreatitis and established CP (ECP), natural histories and gene discoveries of alcoholic, idiopathic and hereditary pancreatitis, development of pancreatic cancer in CP, exocrine pancreatic insufficiency and calculation of dose and delivery of enzymes, endoscopic ultrasonography, and autoimmune pancreatitis. With some exceptions, we exclude basic science and surgery.
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Affiliation(s)
- Eugene P DiMagno
- From the *Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Medical School, Mayo Clinic, Rochester, MN; and †Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan School of Medicine, Ann Arbor, MI
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31
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Pallagi P, Hegyi P, Rakonczay Z. The Physiology and Pathophysiology of Pancreatic Ductal Secretion: The Background for Clinicians. Pancreas 2015; 44:1211-1233. [PMID: 26465950 DOI: 10.1097/mpa.0000000000000421] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The human exocrine pancreas consists of 2 main cell types: acinar and ductal cells. These exocrine cells interact closely to contribute to the secretion of pancreatic juice. The most important ion in terms of the pancreatic ductal secretion is HCO3. In fact, duct cells produce an alkaline fluid that may contain up to 140 mM NaHCO3, which is essential for normal digestion. This article provides an overview of the basics of pancreatic ductal physiology and pathophysiology. In the first part of the article, we discuss the ductal electrolyte and fluid transporters and their regulation. The central role of cystic fibrosis transmembrane conductance regulator (CFTR) is highlighted, which is much more than just a Cl channel. We also review the role of pancreatic ducts in severe debilitating diseases such as cystic fibrosis (caused by various genetic defects of cftr), pancreatitis, and diabetes mellitus. Stimulation of ductal secretion in cystic fibrosis and pancreatitis may have beneficial effects in their treatment.
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Affiliation(s)
- Petra Pallagi
- From the *First Department of Medicine, University of Szeged; and †Hungarian Academy of Sciences-University of Szeged Translational Gastroenterology Research Group, Szeged, Hungary
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32
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Whitcomb DC, Shelton CA, Brand RE. Genetics and Genetic Testing in Pancreatic Cancer. Gastroenterology 2015; 149:1252-1264.e4. [PMID: 26255042 DOI: 10.1053/j.gastro.2015.07.057] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 07/28/2015] [Accepted: 07/31/2015] [Indexed: 12/14/2022]
Abstract
Genetic testing of germline DNA is used in patients suspected of being at risk of pancreatic ductal adenocarcinoma (PDAC) to better define the individual's risk and to determine the mechanism of risk. A high genetic risk increases the pretest probability that a biomarker of early cancer is a true positive and warrants further investigation. The highest PDAC risk is generally associated with a hereditary predisposition. However, the majority of PDAC results from complex, progressive gene-environment interactions that currently fall outside the traditional risk models. Over many years, the combination of inflammation, exposure to DNA-damaging toxins, and failed DNA repair promote the accumulation of somatic mutations in pancreatic cells; PDAC risk is further increased by already present oncogenic germline mutations. Predictive models and new technologies are needed to classify patients into more accurate and mechanistic PDAC risk categories that can be linked to improved surveillance and preventative strategies.
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Affiliation(s)
- David C Whitcomb
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Human Genetics, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Cell Biology and Molecular Physiology, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Pittsburgh Cancer Institute, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
| | - Celeste A Shelton
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Randall E Brand
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Pittsburgh Cancer Institute, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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33
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Overrepresentation of Rare CASR Coding Variants in a Sample of Young French Patients With Idiopathic Chronic Pancreatitis. Pancreas 2015; 44:996-8. [PMID: 26166472 DOI: 10.1097/mpa.0000000000000361] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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34
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Abstract
PURPOSE OF REVIEW Variations in extracellular calcium level have a large impact on kidney function. Most of the effects seen are attributed to the calcium-sensing receptor (CaSR), a widely expressed G-protein-coupled cell surface protein with an important function in bone mineral homeostasis. The purpose of this review is to recapitulate the novel functional aspects of CaSR. RECENT FINDINGS Results from mouse models demonstrate important functions for CaSR in various tissues. In the kidney, the main role of CaSR is the regulation of calcium reabsorption in the thick ascending limb, independently of its role on parathyroid hormone secretion. CaSR modulates claudin 14, the gatekeeper of paracellular ion transport in the thick ascending limb that is associated with urinary calcium excretion. One intracellular signaling pathway by which CaSR alters tight junction permeability is the calcineurin-NFAT1c-microRNA-claudin14 axis. SUMMARY The main function of CaSR in the kidney is the regulation of calcium excretion in the thick ascending limb, independently of parathyroid hormone. CaSR modulates paracellular cation transport by altering expression of the tight junction protein claudin 14. Still more work is needed to fully understand all functions of CaSR in the kidney. Alternative pathways of calcium 'sensing' in the kidney need to be investigated.
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Affiliation(s)
- Hakan R Toka
- aDivision of Nephrology, Beth Israel Deaconess Medical Center bDivision of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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35
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Muniraj T, Aslanian HR, Farrell J, Jamidar PA. Chronic pancreatitis, a comprehensive review and update. Part I: epidemiology, etiology, risk factors, genetics, pathophysiology, and clinical features. Dis Mon 2015; 60:530-50. [PMID: 25510320 DOI: 10.1016/j.disamonth.2014.11.002] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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36
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Tomaiuolo AC, Sofia VM, Surace C, Majo F, Genovese S, Petrocchi S, Grotta S, Alghisi F, Lucidi V, Angioni A. Relationship between CFTR and CTRC variants and the clinical phenotype in late-onset cystic fibrosis disease with chronic pancreatitis. J Mol Diagn 2015; 17:171-8. [PMID: 25636364 DOI: 10.1016/j.jmoldx.2014.11.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 10/06/2014] [Accepted: 11/26/2014] [Indexed: 01/29/2023] Open
Abstract
Cystic fibrosis (CF), the most common autosomal recessive disease in whites, is caused by mutations in the CF transmembrane conductance regulator (CFTR). So far, >1900 mutations have been described, most of which are nonsense, missense, and frameshift, and can lead to severe phenotypes, reducing the level of function of the CFTR protein. Synonymous variations are usually considered silent without pathogenic effects. However, synonymous mutations exhibiting exon skipping as a consequence of aberrant splicing of pre-mRNA differ. Herein, we describe the effect of the aberrant splicing of the c.273G>C (G91G) synonymous variation found in a 9-year-old white (ΔF508) patient affected by CF and pancreatitis associated with a variant in chymotrypsin C (CTRC). Magnetic resonance imaging showed an atrophic pancreatic gland with substitution of the pancreatic parenchyma with three cysts. Genetic examination revealed compound heterozygosity for the c.1521_1523delCTT (ΔF508) pathogenic variant and the c.273G>C (G91G) variant in CFTR. Sweat test results confirmed the diagnosis of CF. We have thus identified a synonymous variation (G91G) causing the skipping of exon 3 in a CF patient carrying the ΔF508 mutation. However, the clinical phenotype with pancreatic symptoms encouraged us to investigate a panel of pancreas-related genes, which resulted in finding a known sequence variation inside CTRC. We further discuss the role of these variants and their possible interactions in determining the current phenotype.
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Affiliation(s)
- Anna C Tomaiuolo
- Cytogenetics and Molecular Genetics Units, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Valentina M Sofia
- Cytogenetics and Molecular Genetics Units, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
| | - Cecilia Surace
- Cytogenetics and Molecular Genetics Units, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Fabio Majo
- Cystic Fibrosis Units, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Silvia Genovese
- Cytogenetics and Molecular Genetics Units, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Stefano Petrocchi
- Cytogenetics and Molecular Genetics Units, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Simona Grotta
- Cytogenetics and Molecular Genetics Units, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Federico Alghisi
- Cystic Fibrosis Units, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Vincenzina Lucidi
- Cystic Fibrosis Units, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Adriano Angioni
- Cytogenetics and Molecular Genetics Units, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
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The Common Chymotrypsinogen C (CTRC) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population. Clin Transl Gastroenterol 2015; 6:e68. [PMID: 25569187 PMCID: PMC4418406 DOI: 10.1038/ctg.2014.13] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 09/30/2014] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES: Recurrent acute pancreatitis (RAP) is a complex inflammatory disorder that may progress to fibrosis and other irreversible features recognized as chronic pancreatitis (CP). Chymotrypsinogen C (CTRC) protects the pancreas by degrading prematurely activated trypsinogen. Rare mutations are associated with CP in Europe and Asia. We evaluated the occurrence of CTRC variants in subjects with RAP, CP, and controls from the North American Pancreatitis Study II cohort. METHODS: CP (n=694), RAP (n=448), and controls (n=1017) of European ancestry were evaluated. Subgroup analysis included CFTR and SPINK1 variants, alcohol, and smoking. RESULTS: We identified previously reported rare pathogenic CTRC A73T, R254W, and K247_R254del variants, intronic variants, and G60G (c.180 C>T; rs497078). Compared with controls (minor allele frequency (MAF)=10.8%), c.180T was associated with CP (MAF=16.8%, P<0.00001) but not RAP (MAF=11.9% P=NS). Trend test indicated co-dominant risk for CP (CT odds ratio (OR)=1.36, 95% confidence interval (CI)=1.13–1.64, P=0.0014; TT OR=3.98, 95% CI=2.10–7.56, P<0.0001). The T allele was significantly more frequent with concurrent pathogenic CFTR variants and/or SPINK1 N34S (combined 22.9% vs. 16.1%, OR 1.92, 95% C.I. 1.26–2.94, P=0.0023) and with alcoholic vs. non-alcoholic CP etiologies (20.8% vs. 12.4%, OR=1.9, 95% CI=1.30–2.79, P=0.0009). Alcohol and smoking generally occurred together, but the frequency of CTRC c.180 T in CP, but not RAP, was higher among never drinkers–ever smokers (22.2%) than ever drinker–never smokers (10.8%), suggesting that smoking rather than alcohol may be the driving factor in this association. CONCLUSIONS: The common CTRC variant c.180T acts as disease modifier that promotes progression from RAP to CP, especially in patients with CFTR or SPINK1 variants, alcohol, or smoking.
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Ravi Kanth VV, Nageshwar Reddy D. Genetics of acute and chronic pancreatitis: An update. World J Gastrointest Pathophysiol 2014; 5:427-437. [PMID: 25400986 PMCID: PMC4231507 DOI: 10.4291/wjgp.v5.i4.427] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 10/01/2014] [Accepted: 10/14/2014] [Indexed: 02/06/2023] Open
Abstract
Progress made in identifying the genetic susceptibility underlying acute and chronic pancreatitis has benefitted the clinicians in understanding the pathogenesis of the disease in a better way. The identification of mutations in cationic trypsinogen gene (PRSS1 gene; functional gain mutations) and serine protease inhibitor kazal type 1 (SPINK1 gene; functional loss mutations) and other potential susceptibility factors in genes that play an important role in the pancreatic secretory functions or response to inflammation during pancreatic injury has changed the current concepts and understanding of a complex multifactorial disease like pancreatitis. An individual's susceptibility to the disease is governed by genetic factors in combination with environmental factors. Candidate gene and genetic linkage studies have identified polymorphisms in cationic trypsinogen (PRSS1), SPINK1, cystic fibrosis trans-membrane conductance regulator (CFTR), Chymotrypsinogen C (CTRC), Cathepsin B (CTSB) and calcium sensing receptor (CASR). Individuals with polymorphisms in the mentioned genes and other as yet identified genes are at an enhanced risk for the disease. Recently, polymorphisms in genes other than those involved in "intra-pancreatic trypsin regulatory mechanism" namely Claudin-2 (CLDN2) and Carboxypeptidase A1 (CPA1) gene have also been identified for their association with pancreatitis. With ever growing number of studies trying to identify the genetic susceptibility in the form of single nucleotide polymorphisms, this review is an attempt to compile the available information on the topic.
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American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines. Pancreas 2014; 43:1143-62. [PMID: 25333398 PMCID: PMC5434978 DOI: 10.1097/mpa.0000000000000237] [Citation(s) in RCA: 281] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The diagnosis of chronic pancreatitis remains challenging in early stages of the disease. This report defines the diagnostic criteria useful in the assessment of patients with suspected and established chronic pancreatitis. All current diagnostic procedures are reviewed, and evidence-based statements are provided about their utility and limitations. Diagnostic criteria for chronic pancreatitis are classified as definitive, probable, or insufficient evidence. A diagnostic (STEP-wise; survey, tomography, endoscopy, and pancreas function testing) algorithm is proposed that proceeds from a noninvasive to a more invasive approach. This algorithm maximizes specificity (low false-positive rate) in subjects with chronic abdominal pain and equivocal imaging changes. Furthermore, a nomenclature is suggested to further characterize patients with established chronic pancreatitis based on TIGAR-O (toxic, idiopathic, genetic, autoimmune, recurrent, and obstructive) etiology, gland morphology (Cambridge criteria), and physiologic state (exocrine, endocrine function) for uniformity across future multicenter research collaborations. This guideline will serve as a baseline manuscript that will be modified as new evidence becomes available and our knowledge of chronic pancreatitis improves.
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Leach K, Sexton PM, Christopoulos A, Conigrave AD. Engendering biased signalling from the calcium-sensing receptor for the pharmacotherapy of diverse disorders. Br J Pharmacol 2014; 171:1142-55. [PMID: 24111791 DOI: 10.1111/bph.12420] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 08/22/2013] [Accepted: 08/26/2013] [Indexed: 12/14/2022] Open
Abstract
The human calcium-sensing receptor (CaSR) is widely expressed in the body, where its activity is regulated by multiple orthosteric and endogenous allosteric ligands. Each ligand stabilizes a unique subset of conformational states, which enables the CaSR to couple to distinct intracellular signalling pathways depending on the extracellular milieu in which it is bathed. Differential signalling arising from distinct receptor conformations favoured by each ligand is referred to as biased signalling. The outcome of CaSR activation also depends on the cell type in which it is expressed. Thus, the same ligand may activate diverse pathways in distinct cell types. Given that the CaSR is implicated in numerous physiological and pathophysiological processes, it is an ideal target for biased ligands that could be rationally designed to selectively regulate desired signalling pathways in preferred cell types.
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Affiliation(s)
- K Leach
- Pharmaceutical Sciences, Monash University, Melbourne, Vic., Australia
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XIE RUI, TANG BO, YONG XIN, LUO GANG, YANG SHIMING. Roles of the calcium sensing receptor in digestive physiology and pathophysiology (Review). Int J Oncol 2014; 45:1355-62. [DOI: 10.3892/ijo.2014.2560] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 04/30/2014] [Indexed: 11/06/2022] Open
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Abstract
PURPOSE OF REVIEW Acute pancreatitis, recurrent acute pancreatitis (RAP) and chronic pancreatitis are interrelated and progressive inflammatory disorders of the pancreas with highly variable and complex susceptibility, severity and outcomes. The role of genetics in acute pancreatitis, RAP and progression to chronic pancreatitis within a new framework is needed. RECENT FINDINGS The first genome-wide association study in the pancreas has been published with genome-wide significance linked with noncoding variants at the PRSS1-PRSS2 locus on chromosome seven and the CLDN2 locus on the X chromosome. A new personalized medicine paradigm is being considered to facilitate organization of genetic and other susceptibility risk compared with the risk of disease progression or resolution and risk of complications. SUMMARY A new framework for organizing multiple, complex data sets is emerging. The role of genetics in the context of other variables is important in understanding susceptibility to RAP and in the modification of disease severity and progression to chronic pancreatitis. Questions of when to order testing, what to order and how to use the data in real time remains an area for future research and development.
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Whitcomb DC, Lowry LW. Genetic risk factors for pancreatic disorders. Gastroenterology 2013; 144:1292-302. [PMID: 23622139 PMCID: PMC3684061 DOI: 10.1053/j.gastro.2013.01.069] [Citation(s) in RCA: 201] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 01/15/2013] [Accepted: 01/17/2013] [Indexed: 02/06/2023]
Abstract
A combination of genetic, environmental, and metabolic factors contribute to the development and recurrence of acute and chronic pancreatitis; information on all of these is required to manage patients effectively. For example, variants that affect regulation of the protease, serine (PRSS)1-PRSS2, and claudin (CLDN)2 loci, rather than their coding sequences, interact with other genetic and environmental factors to affect disease development. New strategies are needed to use these data and determine their contribution to pathogenesis, because these variants differ from previously studied, rare variants in exons (coding regions) of genes such as PRSS1, SPINK1, cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin (CTR)C, and calcium-sensing receptor (CASR). Learning how various genetic factors affect pancreatic cells and systems could lead to etiology-based therapies rather than treatment of symptoms.
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Affiliation(s)
- David C Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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Bai HX, Giefer M, Patel M, Orabi AI, Husain SZ. The association of primary hyperparathyroidism with pancreatitis. J Clin Gastroenterol 2012; 46:656-61. [PMID: 22874807 PMCID: PMC4428665 DOI: 10.1097/mcg.0b013e31825c446c] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The association between primary hyperparathyroidism (PHPT) and acute or chronic pancreatitis is controversial. For this reason, we conducted a review of the literature over the past 30 years to explore the relationship between these 2 disorders. Ten retrospective studies each with >50 patients diagnosed with PHPT were identified. With the notable exception of 2 studies, the rate of pancreatitis among patients with PHPT was higher than that reported in general among hospitalized patients without PHPT. A higher serum calcium level may contribute to pancreatitis in these cases, along with additional genetic or environmental insults. Hypercalcemia may predispose the pancreatic acinar cell to abnormal, sustained calcium levels, lead to premature pancreatic protease activation, and pancreatitis. Although there was only short-term follow-up, most reports cited that definitive treatment of PHPT by parathyroidectomy led to the resolution of pancreatitis attacks. The published cohorts of patients with PHPT and pancreatitis are subject to bias, because serum calcium screening was not universally performed among all control nonpancreatitis patients to evaluate for PHPT. However, the pooled clinical and experimental data suggest an association between PHPT and pancreatitis and implicate hypercalcemia. For clinicians, it is important to recognize pancreatitis in patients with PHPT and, conversely, to consider PHPT by checking serum calcium levels in patients, who present with an unexplained pancreatitis.
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Affiliation(s)
- Harrison X. Bai
- Departments of Pediatrics, Yale University School of Medicine, New Haven, CT
| | | | - Mohini Patel
- Departments of Pediatrics, Yale University School of Medicine, New Haven, CT
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The role of the calcium-sensing receptor in human disease. Clin Biochem 2012; 45:943-53. [PMID: 22503956 DOI: 10.1016/j.clinbiochem.2012.03.034] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Revised: 03/22/2012] [Accepted: 03/27/2012] [Indexed: 01/18/2023]
Abstract
Following the discovery of the calcium-sensing receptor (CaSR) in 1993, its pivotal role in disorders of calcium homeostasis such as Familial Hypocalciuric Hypercalcemia (FHH) was quickly demonstrated. Since then, it has become clear that the CaSR has immense functional versatility largely through its ability to activate many different signaling pathways in a ligand- and tissue-specific manner. This allows the receptor to play diverse and crucial roles in human physiology and pathophysiology, both in calcium homeostasis and in tissues and biological processes unrelated to calcium balance. This review covers current knowledge of the role of the CaSR in disorders of calcium homeostasis (FHH, neonatal severe hyperparathyroidism, autosomal dominant hypocalcemia, primary and secondary hyperparathyroidism, hypercalcemia of malignancy) as well as unrelated diseases such as breast and colorectal cancer (where the receptor appears to play a tumor suppressor role), Alzheimer's disease, pancreatitis, diabetes mellitus, hypertension and bone and gastrointestinal disorders. In addition, it examines the use or potential use of CaSR agonists or antagonists (calcimimetics and calcilytics) and other drugs mediated through the CaSR, in the management of disorders as diverse as hyperparathyroidism, osteoporosis and gastrointestinal disease.
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Abstract
PURPOSE OF REVIEW Chronic pancreatitis is a syndrome characterized by chronic inflammation of the pancreas, with variable pain, calcifications, necrosis, fatty replacement, fibrosis and scarring and other complications. Disease susceptibility, severity, progression and pain patterns vary widely and do not necessarily parallel one another. Much of the variability in susceptibility to recurrent acute and chronic pancreatitis is now clearly shown to be related to genetic differences between patients. This review highlights recent advances and future directions in genetic research. RECENT FINDINGS The strongest risk factors are associated with genetic variations in PRSS1, SPINK1, CFTR, and to a lesser extent, CTRC and CASR. The latest research suggest that a single factor rarely causes pancreatitis, and the majority of patients with recurrent acute and chronic pancreatitis have multiple variants in a gene, or epistatic interactions between multiple genes, coupled with environmental stressors. SUMMARY Pancreatic diseases have a strong genetic component. Rather than a classic Mendelian disorder, recurrent acute and chronic pancreatitis represents truly complex diseases with the interaction and synergism of multiple genetic and environmental factors. The future will require new predictive models to guide prevention and therapy.
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Affiliation(s)
- Jessica LaRusch
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - David C. Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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da Costa MZG, Guarita DR, Ono-Nita SK, Paranaguá-Vezozzo DC, Felga GEG, Pedroso MRA, de Souza MMT, Nasser PD, Ferreira CDS, Carrilho FJ. Genetic risk for alcoholic chronic pancreatitis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2011; 8:2747-57. [PMID: 21845156 PMCID: PMC3155327 DOI: 10.3390/ijerph8072747] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 06/20/2011] [Indexed: 12/14/2022]
Abstract
In recent years many studies have examined the genetic predisposition to pancreatic diseases. Pancreatic disease of an alcoholic etiology was determined to be a multi-factorial disease, where environmental factors interact with the genetic profile of the individual. In this review we discuss the main results from studies examining the frequency of genetic mutations in alcoholic chronic pancreatitis.
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Abstract
We review important new clinical observations in pancreas divisum (PD) made since 2007. PD is common and has the same prevalence in the general population and idiopathic pancreatitis (IP). Up to 53% of patients with PD and IP have underlying idiopathic chronic pancreatitis (CP), and in rigorous prospective clinical follow-up and/or natural history studies, many with idiopathic recurrent acute pancreatitis (IRAP) have idiopathic CP. According to retrospective studies, PD does not modify the natural course of nonalcoholic or alcoholic CP. CFTR and/or SPINK1 gene mutations associate with IP (idiopathic CP and IRAP) independently of the presence of PD. More than one third of patients with pancreatitis or presumed pancreaticobiliary pain respond to placebo. Authors of uncontrolled studies report a significant symptomatic response to surgery and endotherapy in patients with IP and PD, but the response remains unproven and is largely limited to those with IRAP and not idiopathic CP or chronic pain.
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Affiliation(s)
- Matthew J DiMagno
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, 1150 West Medical Center Drive, Room 6520 MSRB I, Ann Arbor, MI 48109-0682, USA.
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Coté GA, Yadav D, Slivka A, Hawes RH, Anderson MA, Burton FR, Brand RE, Banks PA, Lewis MD, Disario JA, Gardner TB, Gelrud A, Amann ST, Baillie J, Money ME, O'Connell M, Whitcomb DC, Sherman S. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2011. [PMID: 21029787 DOI: 10.1016/j.cgh.2010.10.01] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Alcohol has been implicated in the development of chronic pancreatitis (CP) in 60%-90% of patients, although percentages in the United States are unknown. We investigated the epidemiology of alcohol-related CP at tertiary US referral centers. METHODS We studied data from CP patients (n = 539) and controls (n = 695) enrolled in the North American Pancreatitis Study-2 from 2000 to 2006 at 20 US referral centers. CP was defined by definitive evidence from imaging or histologic analyses. Subjects and physicians each completed a study questionnaire. Using physician-assigned diagnoses, patients were assigned to an etiology group: alcohol (with/without other diagnoses), nonalcohol (any etiology of CP from other than alcohol), or idiopathic (no etiology identified). RESULTS The distribution of patients among etiology groups was: alcohol (44.5%), nonalcohol (26.9%), and idiopathic (28.6%). Physicians identified alcohol as the etiology more frequently in men (59.4% men vs 28.1% women), but nonalcohol (18% men vs 36.7% women) and idiopathic etiologies (22.6% men vs 35.2% women) more often in women (P < .01 for all comparisons). Nonalcohol etiologies were equally divided among obstructive, genetic, and other causes. Compared with controls, patients with idiopathic CP were more likely to have ever smoked (58.6% vs 49.7%, P < .05) or have a history of chronic renal disease or failure (5.2% vs 1.2%, P < .01). In multivariate analyses, smoking (ever, current, and amount) was independently associated with idiopathic CP. CONCLUSIONS The frequency of alcohol-related CP at tertiary US referral centers is lower than expected. Idiopathic CP and nonalcohol etiologies represent a large subgroup, particularly among women. Smoking is an independent risk factor for idiopathic CP.
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Affiliation(s)
- Gregory A Coté
- Department of Medicine, Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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50
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Coté GA, Yadav D, Slivka A, Hawes RH, Anderson MA, Burton FR, Brand RE, Banks PA, Lewis MD, Disario JA, Gardner TB, Gelrud A, Amann ST, Baillie J, Money ME, O'Connell M, Whitcomb DC, Sherman S, North American Pancreatitis Study Group. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2011; 9:266-73; quiz e27. [PMID: 21029787 PMCID: PMC3043170 DOI: 10.1016/j.cgh.2010.10.015] [Citation(s) in RCA: 208] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Revised: 09/13/2010] [Accepted: 10/01/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Alcohol has been implicated in the development of chronic pancreatitis (CP) in 60%-90% of patients, although percentages in the United States are unknown. We investigated the epidemiology of alcohol-related CP at tertiary US referral centers. METHODS We studied data from CP patients (n = 539) and controls (n = 695) enrolled in the North American Pancreatitis Study-2 from 2000 to 2006 at 20 US referral centers. CP was defined by definitive evidence from imaging or histologic analyses. Subjects and physicians each completed a study questionnaire. Using physician-assigned diagnoses, patients were assigned to an etiology group: alcohol (with/without other diagnoses), nonalcohol (any etiology of CP from other than alcohol), or idiopathic (no etiology identified). RESULTS The distribution of patients among etiology groups was: alcohol (44.5%), nonalcohol (26.9%), and idiopathic (28.6%). Physicians identified alcohol as the etiology more frequently in men (59.4% men vs 28.1% women), but nonalcohol (18% men vs 36.7% women) and idiopathic etiologies (22.6% men vs 35.2% women) more often in women (P < .01 for all comparisons). Nonalcohol etiologies were equally divided among obstructive, genetic, and other causes. Compared with controls, patients with idiopathic CP were more likely to have ever smoked (58.6% vs 49.7%, P < .05) or have a history of chronic renal disease or failure (5.2% vs 1.2%, P < .01). In multivariate analyses, smoking (ever, current, and amount) was independently associated with idiopathic CP. CONCLUSIONS The frequency of alcohol-related CP at tertiary US referral centers is lower than expected. Idiopathic CP and nonalcohol etiologies represent a large subgroup, particularly among women. Smoking is an independent risk factor for idiopathic CP.
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Affiliation(s)
- Gregory A Coté
- Department of Medicine, Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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