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1
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Mohamed G, Munir M, Rai A, Gaddam S. Pancreatic Cancer: Screening and Early Detection. Gastroenterol Clin North Am 2025; 54:205-221. [PMID: 39880528 DOI: 10.1016/j.gtc.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
Pancreatic cancer, often diagnosed at advanced stages, has poor survival rates. Effective screening aims to detect the disease early, improving outcomes. Current guidelines recommend screening high-risk groups, including those with a family history or genetic predispositions, using methods like endoscopic ultrasound and MRI. The American Gastroenterological Association and other organizations advise annual surveillance for high-risk individuals, typically starting at the age of 50 or 10 years younger than the youngest affected relative. For certain genetic syndromes, such as Peutz-Jeghers syndrome or hereditary pancreatitis, screening may begin as early as the age of 35 to 40 years.
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Affiliation(s)
- Ghada Mohamed
- Department of Internal Medicine, Lahey Hospital & Medical Center, 41 Mall Road, Burlington, MA 01805, USA
| | - Malak Munir
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, ST, Suite 7705, Los Angeles, CA 90048, USA
| | - Amar Rai
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, ST, Suite 7705, Los Angeles, CA 90048, USA
| | - Srinivas Gaddam
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, ST, Suite 7705, Los Angeles, CA 90048, USA.
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2
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Xu F, Yang C, Tang M, Wang M, Cheng Z, Chen D, Chen X, Liu K. The Role of Gut Microbiota and Genetic Susceptibility in the Pathogenesis of Pancreatitis. Gut Liver 2021; 16:686-696. [PMID: 34911043 PMCID: PMC9474482 DOI: 10.5009/gnl210362] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/06/2021] [Accepted: 09/17/2021] [Indexed: 11/22/2022] Open
Abstract
Pancreatitis is one of the most common inflammatory diseases of the pancreas caused by autodigestion induced by excessive premature protease activation. However, recognition of novel pathophysiological mechanisms remains a still challenge. Both genetic and environmental factors contribute to the pathogenesis of pancreatitis, and the gut microbiota is a potential source of an environmental effect. In recent years, several new frontiers in gut microbiota and genetic risk assessment research have emerged and improved the understanding of the disease. These investigations showed that the disease progression of pancreatitis could be regulated by the gut microbiome, either through a translocation influence or in a host immune response manner. Meanwhile, the onset of the disease is also associated with the heritage of a pathogenic mutation, and the disease progression could be modified by genetic risk factors. In this review, we focused on the recent advances in the role of gut microbiota in the pathogenesis of pancreatitis, and the genetic susceptibility in pancreatitis.
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Affiliation(s)
- Fumin Xu
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Chunmei Yang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Mingcheng Tang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Ming Wang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Zhenhao Cheng
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Dongfeng Chen
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiao Chen
- Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Kaijun Liu
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
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Chronic pancreatitis for the clinician. Part 1: Etiology and diagnosis. Interdisciplinary position paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 45:231-248. [PMID: 34157366 DOI: 10.1016/j.gastrohep.2021.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/13/2021] [Accepted: 05/07/2021] [Indexed: 11/24/2022]
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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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5
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Shelton CA, Grubs RE, Umapathy C, Yadav D, Whitcomb DC. Impact of hereditary pancreatitis on patients and their families. J Genet Couns 2020; 29:971-982. [PMID: 32026589 DOI: 10.1002/jgc4.1221] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 01/08/2020] [Accepted: 01/12/2020] [Indexed: 12/15/2022]
Abstract
Hereditary pancreatitis (HP), a highly penetrant (~80%) autosomal dominant disease associated with PRSS1 variants, causes acute pancreatitis in childhood and chronic pancreatitis by early adulthood. Other clinical features include pain, diabetes, and risk of pancreatic cancer. HP kindreds were prospectively recruited from 1995 to 2015. At enrollment, study participants completed medical and family history questionnaires, and provided samples for genotyping. Participants were recontacted between 2015 and 2017 and asked to complete a survey on concerns and experiences related to HP, PRSS1 testing, and genetic counseling. Data were analyzed with descriptive and thematic methods. Thirty-nine affected participants with HP and 21 unaffected family members completed the survey. Among unaffected family members, 'worry' and 'helplessness' were frequently described as the most difficult problem in their family because of HP, particularly with regard to pain. Three participants described the impact of drug addiction on their family. 'School or work limitations' was the leading financial concern, with 65.5% (36/55) rating it as 'moderately' or 'extremely important.' Unexpectedly, only 62% (21/34) of affected PRSS1 carriers believed the chance for a parent to pass HP to his or her children was 50%, whereas 18% (6/34) believed the chance was 100%. The impact of HP on individuals and families varied, which may reflect the highly unpredictable nature of HP severity and outcomes. Based on current and previously reported findings, an overview of important issues for genetic counselors to consider for counseling HP families is included.
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Affiliation(s)
- Celeste A Shelton
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.,Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Robin E Grubs
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chandraprakash Umapathy
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Dhiraj Yadav
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - David C Whitcomb
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.,Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
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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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PRSS1 (R122H) mutation in an Indian family with low penetrance is associated with pancreatitis phenotype. Indian J Gastroenterol 2018; 37:67-69. [PMID: 29476405 DOI: 10.1007/s12664-018-0828-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 01/10/2018] [Indexed: 02/04/2023]
Abstract
Mutations in PRSS1 gene namely R122H and N29I cause hereditary pancreatitis. They are autosomal dominant with a high penetrance (80%) reported in North American, North-east Asian, and North European ethnicities. However, the mutations are reportedly absent in Indian, African, and South American ethnicities. We report here for the first time a family from India that is positive for R122H mutation in the PRSS1 gene. The proband is symptomatic with chronic pancreatitis, however, the father although heterozygous for R122H is asymptomatic.
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Dytz MG, Mendes de Melo J, de Castro Santos O, da Silva Santos ID, Rodacki M, Conceição FL, Ortiga-Carvalho TM. Hereditary Pancreatitis Associated With the N29T Mutation of the PRSS1 Gene in a Brazilian Family: A Case-Control Study. Medicine (Baltimore) 2015; 94:e1508. [PMID: 26376395 PMCID: PMC4635809 DOI: 10.1097/md.0000000000001508] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hereditary pancreatitis (HP) is an autosomal-dominant disease with incomplete penetrance manifesting as early-onset chronic relapsing pancreatitis. A mutation in the PRSS1 gene is present in greater than 70% of HP kindreds and leads to a gain-of-function characterized by the increased autocatalytic conversion of trypsinogen to active trypsin, promoting autodigestion and damage to acinar cells. Other genetic defects observed in the pathogenic mechanism of pancreatitis include mutations in the genes encoding SPINK1, CTRC, and CPA1. There are few reports of HP in Latin America, and no families have been investigated in Brazil. A case-control observational study was conducted at Clementino Fraga Filho University Hospital in Brazil. Patients with suspected HP and healthy controls were enrolled in this study, and a detailed questionnaire was administered to patients with HP. PRSS1 and SPINK1 genes were analyzed by DNA sequencing, and a family that fit the HP diagnostic criteria was identified. The neutral polymorphism c.88-352A > G in the SPINK1 gene was found to be prevalent in the individuals studied, but no important alterations were found in this gene. Ten out of 16 individuals in this family carried the N29T mutation in the PRSS1 gene, with 2 clinically unaffected mutation carriers. The median age of HP onset was 6 years. Pancreatic exocrine failure occurred in 6 patients, 5 of whom also had diabetes mellitus. Surgical procedures were performed on 3 affected members, and no cases of pancreatic cancer have been reported thus far. This study identified the first PRSS1 gene mutation in a Brazilian family with HP.
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Affiliation(s)
- Marcio Garrison Dytz
- From the Department of Endocrinology, Clementino Fraga Filho University Hospital (MGD, OdCS, FLC); Laboratory of Translational Endocrinology, Institute of Biophysics Carlos Chagas Filho (MGD, JMdM, IDdSS, TMO-C); and Department of Diabetes and Nutrology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil (MR)
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10
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Familial Pancreatic Cancer: Challenging Diagnostic Approach and Therapeutic Management. J Gastrointest Cancer 2014; 45:256-61. [DOI: 10.1007/s12029-014-9609-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet 2013; 132:1077-130. [PMID: 23820649 PMCID: PMC3778950 DOI: 10.1007/s00439-013-1331-2] [Citation(s) in RCA: 437] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 06/15/2013] [Indexed: 02/06/2023]
Abstract
Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as 'reduced (or incomplete) penetrance'. Reduced penetrance is not uncommon; indeed, there are many known examples of 'disease-causing mutations' that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.
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Affiliation(s)
- David N. Cooper
- Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN UK
| | - Michael Krawczak
- Institute of Medical Informatics and Statistics, Christian-Albrechts University, 24105 Kiel, Germany
| | | | - Chris Tyler-Smith
- The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
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Awano H, Lee T, Yagi M, Masamune A, Kume K, Takeshima Y, Iijima K. Childhood-onset hereditary pancreatitis with mutations in the CT gene and SPINK1 gene. Pediatr Int 2013; 55:646-9. [PMID: 24134754 DOI: 10.1111/ped.12152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2012] [Revised: 12/13/2012] [Accepted: 02/08/2013] [Indexed: 11/28/2022]
Abstract
Hereditary pancreatitis (HP) is an autosomal-dominant gene disorder. The affected genes have been identified as the cationic trypsinogen (CT) gene and the serine protease inhibitor Kazal type 1 (SPINK1) gene. These gene abnormalities alone, however, do not necessarily regulate the onset or severity of pancreatitis, suggesting the involvement of other gene abnormalities and environmental factors. Reported herein is the case of a 9-year-old boy with early-onset HP due to mutations in the CT and SPINK1 genes. The patient had a p.R122H heterozygous mutation in the CT gene and a p.N34S heterozygous mutation in the SPINK1 gene. The father had heterozygous mutation of the SPINK1 gene, and the mother had heterozygous mutation of the CT gene, although neither had a prior history of pancreatitis. In this patient, early onset of HP was attributed to the presence of gene abnormalities in the CT and SPINK1 genes.
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Affiliation(s)
- Hiroyuki Awano
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
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Abstract
Pancreatic cancer remains one of the most challenging of all cancers. Genetic risk factors are believed to play a major role, but other than genes coding for blood group, genetic risks for sporadic cases remain elusive. However, several germline mutations have been identified that lead to hereditary pancreatic cancer, familial pancreatic cancer, and increased risk for pancreatic cancer as part of a familial cancer syndrome. The most important genes with variants increasing risk for pancreatic cancer include BRCA1, BRCA2, PALB2, ATM, CDKN2A, APC, MLH1, MSH2, MSH6, PMS2, PRSS1, and STK11. Recognition of members of high-risk families is important for understanding pancreatic cancer biology, for recommending risk reduction strategies and, in some cases, initiating cancer surveillance programs. Because the best methods for surveillance have not been established, the recommendation to refer at-risk patients to centers with ongoing research programs in pancreatic cancer surveillance is supported.
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Mittal K, Kabra M, Juyal R, BK T. De novo deletion in MECP2 in a monozygotic twin pair: a case report. BMC MEDICAL GENETICS 2011; 12:113. [PMID: 21871116 PMCID: PMC3176152 DOI: 10.1186/1471-2350-12-113] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Accepted: 08/27/2011] [Indexed: 11/10/2022]
Abstract
BACKGROUND Rett syndrome (RTT) is a severe, progressive, neurodevelopmental disorder predominantly observed in females that leads to intellectual disability. Mutations and gross rearrangements in MECP2 account for a large proportion of cases with RTT. A limited number of twin pairs with RTT have also been reported in literature. CASE PRESENTATION We investigated 13 year old, monozygotic twin females with RTT and some noticeable differences in development using a combinatorial approach of sequencing and Taqman assay. Monozygosity status of the twins was confirmed by informative microsatellite markers. CONCLUSIONS The twins shared a de novo deletion in exon 3 in the MBD domain of MECP2. To the best of our knowledge, this is only the second report of genetic analysis of a monozygotic twin pair.
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Affiliation(s)
- Kirti Mittal
- Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi 110021, India
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Machin G. Non-identical monozygotic twins, intermediate twin types, zygosity testing, and the non-random nature of monozygotic twinning: A review. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2009; 151C:110-27. [DOI: 10.1002/ajmg.c.30212] [Citation(s) in RCA: 106] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Abstract
Hereditary chronic pancreatitis (HCP) is a very rare form of early-onset chronic pancreatitis. Apart from young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. Diagnostic criteria and treatment of HCP also resemble those of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile-duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, the disease is mild in most patients. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation, disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes--such as the anionic trypsinogen (PRSS2), the serine protease inhibitor Kazal type 1 (SPINK1), and the cystic fibrosis transmembrane conductance regulator (CFTR)--have also been found to be associated with chronic pancreatitis (idiopathic and hereditary). Genetic testing should only be performed in carefully selected patients by direct DNA sequencing, and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications such as pseudocysts and bile-duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. The risk of pancreatic cancer is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.
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17
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Räty S, Piironen A, Babu M, Pelli H, Sand J, Uotila S, Nordback I, Herzig KH. Screening for human cationic trypsinogen (PRSS1) and trypsinogen inhibitor gene (SPINK1) mutations in a Finnish family with hereditary pancreatitis. Scand J Gastroenterol 2007; 42:1000-5. [PMID: 17613931 DOI: 10.1080/00365520701206738] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Mutations in the cationic trypsinogen gene (PRSS1) have been linked with hereditary pancreatitis (HP). A change in R122H in the third exon is one of the mutations most frequently associated with HP. A mutation N34S in the serine protease inhibitor Kazal type 1 gene has also been shown to be linked with HP. The purpose of this study was to report on the incidence of PRSS1 and SPINK1 mutations in a Finnish family with HP and to correlate the findings to the clinical symptoms. MATERIAL AND METHODS The study included 36 individuals from one Finnish family with HP (21 M, 15 F, median age 38 years). All individuals underwent abdominal ultrasound and laboratory tests (glucose, faecal elastase-1 test). Blood samples were taken for mutational analysis of PRSS1 (R122H, N29I and A16V) and SPINK1 (N34S). RESULTS Ten (28%) individuals were affected by mutations: the most frequent mutation was R122H, affecting 8 (22%) individuals; 2 (6%) individuals were affected by the N34S mutation and none by the other tested mutations (N29I and A16V). Four out of eight (50%) R122H-positive individuals had a diagnosis of chronic pancreatitis without other known aetiologies. Four out of five (80%) male individuals with the R122H mutation also had clinical pancreatitis, whereas none of the three mutation-positive females had any signs or symptoms of chronic pancreatitis. The two individuals with the N34S mutation did not have any signs of chronic pancreatitis. CONCLUSIONS In the investigated Finnish pedigree with HP, the PRSS1 mutation R122H is linked with chronic disease. Although the SPINK1 mutation (N34S) was also observed in two individuals, it was not linked with the disease.
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Affiliation(s)
- Sari Räty
- Departments of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland.
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Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am 2007; 36:325-33, ix. [PMID: 17533082 DOI: 10.1016/j.gtc.2007.03.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
An appreciation for the background of disease, not to mention the medical management of individuals, may be significantly affected by testing for mutations and genetic variants associated with pancreatitis. Pretest and posttest counseling are essential for patients and families to benefit fully from genetic testing for a susceptibility to develop pancreatitis. The clinician, often working directly with a qualified genetic counselor, must ensure that patients and families appreciate the benefits and limitations of genetic tests, that results are interpreted accurately, and that patients understand implications of information for both their medical care and personal decisions. This article focuses on the approach to genetic counseling for pancreatitis and implications of recent advances.
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Affiliation(s)
- Erin N Fink
- Department of Medicine, University of Pittsburgh, 1218 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15213, USA
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19
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Rosendahl J, Bödeker H, Mössner J, Teich N. Hereditary chronic pancreatitis. Orphanet J Rare Dis 2007; 2:1. [PMID: 17204147 PMCID: PMC1774562 DOI: 10.1186/1750-1172-2-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2006] [Accepted: 01/04/2007] [Indexed: 12/19/2022] Open
Abstract
Hereditary chronic pancreatitis (HCP) is a very rare form of early onset chronic pancreatitis. With the exception of the young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. As well, diagnostic criteria and treatment of HCP resemble that of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, most patients have a mild disease. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2), the serine protease inhibitor, Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) have been found to be associated with chronic pancreatitis (idiopathic and hereditary) as well. Genetic testing should only be performed in carefully selected patients by direct DNA sequencing and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications, such as pseudocysts, bile duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. Pancreatic cancer risk is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.
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Affiliation(s)
- Jonas Rosendahl
- Medizinische Klinik und Poliklinik II, Universität Leipzig, Germany
| | - Hans Bödeker
- Medizinische Klinik und Poliklinik II, Universität Leipzig, Germany
| | - Joachim Mössner
- Medizinische Klinik und Poliklinik II, Universität Leipzig, Germany
| | - Niels Teich
- Medizinische Klinik und Poliklinik II, Universität Leipzig, Germany
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Abstract
The number of hospitalizations in children with acute and chronic pancreatitis is increasing and accounts for significant morbidity. Acute pancreatitis is a reversible event involving diffuse inflammation of the pancreas with variable involvement of other regional tissues, remote organs, or both, whereas chronic pancreatitis is a process that produces irreversible changes in the pancreatic structure and function. Mutations in the gene encoding cationic trypsinogen have recently been identified to be associated with hereditary pancreatitis. Genetic mutations in the pancreatic secretory trypsin inhibitor and the cystic fibrosis transmembrane conductance regulator have been described to play a role in the development of pancreatitis as well. Mutations in the cytokine target genes relating to regulation of inflammation are likely to be important in determining the severity of pancreatitis. These findings, along with the advances in cell biology, have contributed to a better understanding of the pathophysiology of pancreatic diseases.
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Affiliation(s)
- Leena Kandula
- Department of Pediatrics, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, 2nd Floor DeSoto Bldg., Pittsburgh, PA 15213, USA
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21
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Teich N, Rosendahl J, Tóth M, Mössner J, Sahin-Tóth M. Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis. Hum Mutat 2006; 27:721-30. [PMID: 16791840 PMCID: PMC2793115 DOI: 10.1002/humu.20343] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ten years ago, the groundwork for the discovery of the genetic basis of chronic pancreatitis was laid by linkage analyses of large kindreds with autosomal dominant hereditary chronic pancreatitis. Subsequent candidate gene sequencing of the 7q35 chromosome region revealed a strong association of the c.365G > A (p.R122 H) mutation of the PRSS1 gene encoding cationic trypsinogen with hereditary pancreatitis. In the following years, further mutations of this gene were discovered in patients with hereditary or idiopathic chronic pancreatitis. In vitro the mutations increase autocatalytic conversion of trypsinogen to active trypsin and thus probably cause premature, intrapancreatic trypsinogen activation in vivo. The clinical presentation is highly variable, but most affected mutation carriers have relatively mild disease. In this review, we summarize the current knowledge on trypsinogen mutations and their role in pancreatic diseases.
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Affiliation(s)
- Niels Teich
- Medizinische Klinik und Poliklinik II, Universität Leipzig, Germany.
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22
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Vitone LJ, Greenhalf W, Howes NR, Raraty MGT, Neoptolemos JP. Trypsinogen mutations in pancreatic disorders. Endocrinol Metab Clin North Am 2006; 35:271-87, viii. [PMID: 16632092 DOI: 10.1016/j.ecl.2006.02.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
There are multiple PRSS1 mutations described in hereditary pancreatitis but only a minority of these are clinically relevant. The two most frequent point mutations are in exon 2 (N29I) and exon3 (R122H), found in diverse racial populations. Both mutations result in early onset pancreatitis but the mechanism underlying this phenotype is unclear. The frequency of these mutations in such diverse populations suggests they have spontaneously occurred many times. The origin of the major mutations may be explained by gene conversions, accounting for multiple founders. The implications are discussed in terms of mechanism of action of the mutations and clinical presentation.
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Affiliation(s)
- Louis J Vitone
- Division of Surgery and Oncology, The University of Liverpool, 5th Floor UCD Building, Daulby Street, Liverpool, L69 3GA, United Kingdom
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Khalid A, Finkelstein S, Thompson B, Kelly L, Hanck C, Godfrey TE, Whitcomb DC. A 93 year old man with the PRSS1 R122H mutation, low SPINK1 expression, and no pancreatitis: insights into phenotypic non-penetrance. Gut 2006; 55:728-31. [PMID: 16354799 PMCID: PMC1856140 DOI: 10.1136/gut.2005.067959] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND The cationic trypsinogen (PRSS1) R122H mutation causes autosomal dominant hereditary pancreatitis (HP) with multiple attacks of acute pancreatitis, but the penetrance, frequency, and severity of attacks are highly variable. HP twins study suggests that modifier genes influence severity but not penetrance. AIM To investigate potential trypsin associated factors in subjects with the PRSS1 R122H mutation and phenotypic non-penetrance. METHODS Two subjects from HP families (including a 93 year old subject with PRSS1 R122H without pancreatitis), one with chronic pancreatitis and one with a normal pancreas, were studied. Relative expression of: (a) the PRSS1 R122 and H122 alleles; and (b) the PRSS1 and SPINK1 genes in pancreatitis were determined using complementary methods. RESULTS PRSS1 wild-type (R122) and mutant (H122) allele expression was equivalent in multiple (> 3) samples from the phenotypically affected and non-penetrant subjects with R122H genotypes using allele specific quantitative reverse transcription-polymerase chain reaction (RT-PCR) and intron spanning nested RT-PCR followed by cDNA sequencing. Compared with PRSS1 mRNA levels, SPINK1 mRNA levels were low in normal appearing tissue but markedly increased in samples with chronic inflammation, independent of PRSS1 genotype. CONCLUSION Attacks of acute pancreatitis in HP subjects appear to be independent of the relative expression of the mutant PRSS1 H122 allele or SPINK1 gene expression. The marked increase in SPINK1 gene expression with inflammation is consistent with its regulation as an acute phase protein.
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Affiliation(s)
- A Khalid
- Division of Gastroenterology, Hepatology, and Nutrition, M2, C-wing, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
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24
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Abstract
The discovery of PRSS 1 mutations in hereditary pancreatitis and analysis of how the genotype affects the presentation and progression of hereditary pancreatitis has led to a better understanding of the pathophysiology of the disease. Patients with hereditary pancreatitis present with symptoms at an early age and have a significant lifetime risk for the development of endocrine and exocrine insufficiency, albeit at a later stage than patients with either idiopathic or alcoholic chronic pancreatitis. There are distinct phenotypic differences between hereditary pancreatitis and with other types of pancreatitis. As many as 80% of patients with symptomatic hereditary pancreatitis have an underlying causative PRSS1 mutation; there are, however, few significant phenotypic differences between these PRSS1 mutations. TheR122H mutation is the most common PRSS1 mutation observed, and patients with the R122H mutation present earlier. This, however, does not necessarily translate into a more aggressive disease with respect to complications of chronic pancreatitis. Indeed, the age of presentation of symptoms may be a poor surrogate for predicting outcome, as inherited disorders of trypsinogen may cause subclinical attacks of pancreatitis, which ultimately lead to pancreatic destruction and dysfunction. All patients, irrespective of whether they carry a PRSS1 mutation, are at significant risk of developing pancreatic ductal adenocarcinoma. The risk appears to be insignificant below the age of 40 years, but it increases incrementally thereafter. Significantly, the risk of pancreatic cancer is not related to PRSS1 mutation type and does not appear to be related to the mode of inheritance. The role of SPINK1 mutations in modifying the expression of PRSS1mutations is unclear but appears to be of clinical importance. It is unlikely that they act as causative mutations per se, at least in the Western form of the disease. Additionally, they do not appear to have an impact on the penetrance of PRSS1 gene mutations in hereditary pancreatitis.
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Affiliation(s)
- Nathan Howes
- Department of Surgery and Oncology, University of Liverpool, 5th Floor, University Clinical Department Building, Daulby Street, Liverpool, L69 3GA, United Kingdom
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25
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Sharma A, Sharma VK, Horn-Saban S, Lancet D, Ramachandran S, Brahmachari SK. Assessing natural variations in gene expression in humans by comparing with monozygotic twins using microarrays. Physiol Genomics 2005; 21:117-23. [PMID: 15644424 DOI: 10.1152/physiolgenomics.00228.2003] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Quantitative variation in gene expression in humans is the outcome of various factors, including differences in genetic background, gender, age, and environment. However, the extent of the influence of these factors on gene expression is not clear. We attempted to address this issue by carrying out gene expression profiling in blood leukocytes with 13 individuals (including 5 pairs of monozygotic twins) on 10,000 genes using HG-U95Av2 oligonucleotide microarrays. The proportion of differentially expressed genes between monozygotic twins was low (up to 1.76%). Most of the variations belonged to the least variable category. These genes, exhibiting "random variations," did not show clear preference to any functional class, although "signaling and communication" and "immune and related functions" generally topped the list. The extent of variation in gene expression increased in comparisons between unrelated individuals (up to 14.13%). Most of the genes (89%) exhibiting random variations in twins also varied in expression in unrelated individuals. As with twins, signaling and communication topped the list, and substantial variations were observed in all three categories: least variable, moderately variable, and most variable. An important outcome of this study was that the housekeeping genes were nearly insensitive to random variations but appeared to be more susceptible to genetic differences. However, the highly expressed housekeeping genes exhibited low variation and appeared to be insensitive to all known factors. Gene expression profiling in monozygotic twins can provide useful data for the assessment of natural variation in gene expression in humans.
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Affiliation(s)
- Anu Sharma
- Functional Genomics Unit, G. N. Ramachandran Knowledge Center for Genome Informatics, Institute of Genomics and Integrative Biology, Delhi, India
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26
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Howes N, Greenhalf W, Stocken DD, Neoptolemos JP. Cationic trypsinogen mutations and pancreatitis. Gastroenterol Clin North Am 2004; 33:767-87. [PMID: 15528017 DOI: 10.1016/j.gtc.2004.07.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The discovery of PRSS1 mutations in hereditary pancreatitis and analysis of how the genotype affects the presentation and progression of hereditary pancreatitis has led to a better understanding of the pathophysiology of the disease. Patients with hereditary pancreatitis present with symptoms at an early age and have a significant lifetime risk for the development of endocrine and exocrine insufficiency, albeit at a later stage than patients with either idiopathic or alcoholic chronic pancreatitis. There are distinct phenotypic differences between hereditary pancreatitis and with other types of pancreatitis. As many as 80% of patients with symptomatic hereditary pancreatitis have an underlying causative PRSS1 mutation; there are, however, few significant phenotypic differences between these PRSS1 mutations. The R122H mutation is the most common PRSS1 mutation observed, and patients with the R122H mutation present earlier. This, however, does not necessarily translate into a more aggressive disease with respect to complications of chronic pancreatitis. Indeed, the age of presentation of symptoms may be a poor surrogate for predicting outcome, as inherited disorders of trypsinogen may cause subclinical attacks of pancreatitis, which ultimately lead to pancreatic destruction and dysfunction. All patients, irrespective of whether they carry a PRSS1 mutation, are at significant risk of developing pancreatic ductal adenocarcinoma. The risk appears to be insignificant below the age of 40 years, but it increases incrementally thereafter. Significantly, the risk of pancreatic cancer is not related to PRSS1 mutation type and does not appear to be related to the mode of inheritance. The role of SPINK1 mutations in modifying the expression of PRSS1 mutations is unclear but appears to be of clinical importance. It is unlikely that they act as causative mutations per se, at least in the Western form of the disease. Additionally, they do not appear to have an impact on the penetrance of PRSS1 gene mutations in hereditary pancreatitis.
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Affiliation(s)
- Nathan Howes
- Department of Surgery, Liverpool University, 5th Floor, University Clinical Department Building, Daulby Street, Liverpool, L69 3GA, United Kingdom
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27
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Affiliation(s)
- D C Whitcomb
- GI Administration, Mezzanine level, C-Wing, UPMC Presbyterian, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
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28
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Howes N, Lerch MM, Greenhalf W, Stocken DD, Ellis I, Simon P, Truninger K, Ammann R, Cavallini G, Charnley RM, Uomo G, Delhaye M, Spicak J, Drumm B, Jansen J, Mountford R, Whitcomb DC, Neoptolemos JP. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004; 2:252-61. [PMID: 15017610 DOI: 10.1016/s1542-3565(04)00013-8] [Citation(s) in RCA: 369] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hereditary pancreatitis is an autosomal dominant disease that is mostly caused by cationic trypsinogen (PRSS1) gene mutations. The aim was to determine phenotype-genotype correlations of families in Europe. METHODS Analysis of data obtained by the European Registry of Hereditary Pancreatitis and Pancreatic Cancer was undertaken using multilevel proportional hazards modelling. RESULTS There were 112 families in 14 countries (418 affected individuals): 58 (52%) families carried the R122H, 24 (21%) the N29I, and 5 (4%) the A16V mutation, 2 had rare mutations, and 21 (19%) had no PRSS1 mutation. The median (95% confidence interval [CI]) time to first symptoms for R122H was 10 (8, 12) years of age, 14 (11, 18) years for N29I, and 14.5 (10, 21) years for mutation negative patients (P = 0.032). The cumulative risk (95% CI) at 50 years of age for exocrine failure was 37.2% (28.5%, 45.8%), 47.6% (37.1%, 58.1%) for endocrine failure, and 17.5% (12.2%, 22.7%) for pancreatic resection for pain. Time to resection was significantly reduced for females (P < 0.001) and those with the N29I mutation (P = 0.014). The cumulative risk (95% CI) of pancreatic cancer was 44.0% (8.0%, 80.0%) at 70 years from symptom onset with a standardized incidence ratio of 67% (50%, 82%). CONCLUSIONS Symptoms in hereditary pancreatitis start in younger patients and endpoints take longer to be reached compared with other forms of chronic pancreatitis but the cumulative levels of exocrine and endocrine failure are much higher. There is an increasingly high risk of pancreatic cancer after the age of 50 years unrelated to the genotype.
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Affiliation(s)
- Nathan Howes
- Department of Surgery, University of Liverpool, United Kingdom
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29
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Abstract
Genetic changes associated with some forms of chronic pancreatitis have been recently defined. There are three genes that play a role, each with a variety of genotypes and different pathologic mechanisms and clinical correlations. Selection of the appropriate diagnostic tests requires integration of the clinical and family history and the interpretation of results has a significant impact on genetic counseling for the patient and family. The relative significance of some variant alleles is still under investigation as they are common in the population and show low penetrance. Knowledge of the pathophysiology of each abnormal allele could lead the way towards more specific therapeutic options in the future.
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Affiliation(s)
- John P Tazelaar
- Division of Molecular Diagnostics, University of Pitsburgh Medical Center, PA 15213, USA
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30
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Beranek H, Teich N, Witt H, Schulz HU, Mössner J, Keim V. Analysis of tumour necrosis factor alpha and interleukin 10 promotor variants in patients with chronic pancreatitis. Eur J Gastroenterol Hepatol 2003; 15:1223-7. [PMID: 14560157 DOI: 10.1097/00042737-200311000-00012] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE Cationic trypsinogen gene mutations are strong risk factors of hereditary pancreatitis. However, 20% of subjects with a trypsinogen mutation never get pancreatitis and the cause of this incomplete penetrance is unknown. We investigated the influence of interleukin 10 (IL10) and tumour necrosis factor alpha (TNFalpha) promotor variants on the manifestation of chronic pancreatitis of different underlying causes and in pancreatic cancer. METHODS A total of 335 German patients with chronic pancreatitis were investigated. In 157 patients the disease was related to alcohol abuse; the other cases were of non-alcoholic origin. In the latter group, the serine protease inhibitor, Kazal type 1 (SPINK1) mutation N34S was found in 72 patients and the trypsinogen mutations N29I or R122H were present in 60 patients; in the remaining 46 patients no mutation was found. In addition, we studied 208 patients with pancreatic cancer. As controls, 116 healthy blood donors and 25 healthy carriers of the trypsinogen mutations N29I or R122H were investigated. After DNA extraction from blood leucocytes, genotyping for the cytokine polymorphisms was performed by induced heteroduplex generators and/or direct DNA sequencing of the IL10 and TNFalpha promotor regions. RESULTS The frequencies of the promotor polymorphisms of IL10-627A, IL10-1117A, TNF-238A and TNF-308A in patients with alcoholic chronic pancreatitis, idiopathic pancreatitis, SPINK1-N34S-associated chronic pancreatitis and pancreatic cancer did not differ significantly from the control group. The variant TNF-238A was two to four times more frequent in index patients with trypsinogen mutations than in all other groups. The analysis of the allelic frequencies of whole families with trypsinogen mutations revealed that all subjects with the TNF-238A variant suffered from chronic pancreatitis, whereas all intrafamilial controls with wild-type TNF were unaffected. CONCLUSIONS TNFalpha and IL10 promotor variants are not associated with a manifestation of chronic pancreatitis or pancreatic cancer. The variant TNF-238A, however, might be a relevant risk factor for disease manifestation in families with hereditary pancreatitis.
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Affiliation(s)
- Helen Beranek
- Medizinische Klinik und Poliklinik II, Universität Leipzig, Leipzig, Kinderklinik, Charité Berlin, Berlin, Germany
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31
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Abstract
After routine investigations, including a thorough history, routine laboratory study, and noninvasive imaging with transcutaneous ultrasonogram, 10% to 25% of cases of acute pancreatitis have no readily identifiable cause and are termed idiopathic. But modern medicine has made notable advances in uncovering various causes of acute pancreatitis, and several new diagnostic tools that allow clinicians to less invasively approach the patient without sacrificing the diagnostic yield have been introduced. By being knowledgeable of these new changes and by their proper use in a proper circumstances, clinicians will be able to find the cause more accurately and earlier. This better management will not only improve the well-being of the patients but also reduce the number of "true" idiopathic acute pancreatitis to a minimum.
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Affiliation(s)
- Hyun Jun Kim
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
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32
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33
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Abstract
A number of genetic mutations have recently been identified that appear to be important in the development of pancreatitis. Point mutations in the cationic trypsinogen gene are capable of initiating pancreatitis. These mutations also provide important insights into the pathophysiology of acute pancreatitis and into potential connections between acute and chronic pancreatitis. Mutations in the genes encoding for the pancreatic secretory trypsin inhibitor and the cystic fibrosis transmembrane conductance regulator more likely work in concert with other genes and environmental factors in affecting disease susceptibility. Although the subject so far has received only a limited amount of study, genetic polymorphisms in a wide range of genes relating to pancreatic function and to regulation of inflammation are likely to play major roles in determining each individual's susceptibility to developing pancreatitis, and its severity if it does develop.
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Affiliation(s)
- James H Grendell
- Division of Gastroenterology, Hepatology, and Nutrition, Winthrop University Hospital, 222 Station Plaza North, Suite 429, Mineola, NY 11501, USA.
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34
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Abstract
Hereditary pancreatitis is an autosomal dominant condition, which results in recurrent attacks of acute pancreatitis, progressing to chronic pancreatitis often at a young age. The majority of patients with hereditary pancreatitis express one of two mutations (R122H or N29I) in the cationic trypsinogen gene (PRSS1 gene). It has been hypothesised that one of these mutations, the R122H mutation causes pancreatitis by altering a trypsin recognition site so preventing deactivation of trypsin within the pancreas and prolonging its action, resulting in autodigestion. Families with these two mutations have been identified in many countries and there are also other rarer mutations, which have also been linked to hereditary pancreatitis.
Patients with hereditary pancreatitis present in the same way as those with sporadic pancreatitis but at an earlier age. It is common for patients to remain undiagnosed for many years, particularly if they present with non-specific symptoms. Hereditary pancreatitis should always be considered in patients who present with recurrent pancreatitis with a family history of pancreatic disease. If patients with the 2 common mutations are compared, those with the R122H mutation are more likely to present at a younger age and are more likely to require surgical intervention than those with N29I. Hereditary pancreatitis carries a 40% lifetime risk of pancreatic cancer with those patients aged between 50 to 70 being most at risk in whom screening tests may become important.
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35
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Abstract
The recognition that variations in the DNA sequence of key genes predispose individuals to acute pancreatitis, chronic pancreatitis, and pancreatic cancer represents one of the greatest breakthroughs in pancreas research. This review highlights recent progress in understanding mutations in the cationic trypsinogen gene, the pancreatic secretory trypsin inhibitor gene, and the cystic fibrosis transmembrane conductance regulator gene with respect to pancreatitis. It also notes progress in the use of microarray technology, classification of chronic pancreatitis, and predisposition to pancreatic cancer.
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36
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Applebaum-Shapiro SE, Finch R, Pfützer RH, Hepp LA, Gates L, Amann S, Martin S, Ulrich CD, Whitcomb DC. Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study. Pancreatology 2002; 1:439-43. [PMID: 12120221 DOI: 10.1159/000055844] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hereditary pancreatitis (HP) was defined on a clinical basis alone until the first cationic trypsinogen gene (PRSS1) mutation was discovered through the initial phase of the current Pittsburgh Midwest Multi-Center Pancreatic Study Group (MMPSG) HP study in 1996, making genetic testing available. AIM To evaluate the regional distribution of HP in the United States, and to compare the study's gene mutation database with the pedigree databases to determine whether family history alone predicts the likelihood of detecting mutations in the cationic trypsinogen gene. METHODS Probands of families with HP, familial pancreatitis and idiopathic chronic pancreatitis were recruited through referrals from MMPSG collaborating centers, other physicians and self-referral of patients who had learned of the study through the World Wide Web (www.pancreas.org). Pedigrees were constructed, detailed questionnaires were completed and a blood sample was drawn for each proband and participating family members. The birthplace and current location of each patient was recorded, DNA was analyzed for known mutations and the pattern of phenotype inheritance was determined from analysis of each pedigree. RESULTS A total of 717 individuals were ascertained; 368 (51%) had clinical pancreatitis confirmed and the rest were primarily unaffected family members used for linkage studies. Forty-six clinically unaffected individuals were silent mutation carriers (11% of mutation-positive individuals). HP was most common in Minnesota, New York and the central mid-Atlantic states plus Kentucky and Ohio. One hundred and fifteen of 150 kindreds fulfilled the strict definition of an HP family, and 60 (52%) had PRSS1 mutations. Of the families with a detected mutation, 11% did not fulfill the clinical definition of an HP kindred. CONCLUSIONS The distribution of HP within the United States shows major regional differences. The etiology of HP can be identified in a small majority of HP families through genetic testing. However, family history alone is not a good predictor of finding a mutation in the cationic trypsinogen (PRSS1) gene.
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Affiliation(s)
- S E Applebaum-Shapiro
- Department of Medicine, University of Pittsburgh, Center for Genomic Sciences, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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37
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Whitcomb DC. Hereditary pancreatitis: a model for understanding the genetic basis of acute and chronic pancreatitis. Pancreatology 2002; 1:565-70. [PMID: 12120237 DOI: 10.1159/000055864] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Progress in understanding pancreatic diseases has been limited by a number of factors. Primary problems include the absence of good animal models, and difficulty in understanding the origin of pancreatic disease since the disease is usually manifest by the progressive destruction of the gland itself. Beginning in 1995, our laboratory, with the support of the Midwest Multicenter Pancreatic Study Group, began investigating the genetic basis of hereditary pancreatitis. Utilization of information becoming available through the human genome project allowed us to map and identify the hereditary pancreatitis gene as cationic trypsinogen (PRSS1). Molecular modeling, and subsequent experimental evidence, has solved key elements of the mysteries surrounding the origin of acute pancreatitis and the progression of acute pancreatitis to chronic pancreatitis. The availability of new genetic information and genomic tools should produce a revolution in our understanding of pancreatic diseases.
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Affiliation(s)
- D C Whitcomb
- Departments of Medicine, Cell Biology and Physiology, and Human Genetics, University of Pittsburgh, VA Pittsburgh Health Care System, Pittsburgh, Pa., USA.
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38
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Abstract
Advances in molecular genetics have provided the powerful tools necessary to identify the key molecules and mechanisms that underly the disease process. Continued work in this area promises to reveal new insights as new disease genes are discovered. This article focuses on the insights into the cause of acute and chronic pancreatitis gained by investigation of the HP genes, the diagnosis of the known mutations, the fascinating observation of nonpenetrance, and a look at future directions.
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Affiliation(s)
- D C Whitcomb
- Department of Medicine, University of Pittsburgh, Pennsylvania, USA.
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