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Famili DT, Mistry A, Gerasimenko O, Gerasimenko J, Tribe RM, Kyrana E, Dhawan A, Goldberg MF, Voermans N, Willis T, Jungbluth H. Pancreatitis in RYR1-related disorders. Neuromuscul Disord 2023; 33:769-775. [PMID: 37783627 DOI: 10.1016/j.nmd.2023.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/15/2023] [Accepted: 09/15/2023] [Indexed: 10/04/2023]
Abstract
Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in a wide range of tissues, non-skeletal muscle manifestations associated with RYR1 mutations have only been rarely reported. Here, we report three patients with a diagnosis of Central Core Disease (CCD), King-Denborough Syndrome (KDS) and Malignant Hyperthermia Susceptibility (MHS), respectively, who in addition to their (putative) RYR1-related disorder also developed symptoms and signs of acute pancreatitis. In two patients, episodes were recurrent, with severe multisystem involvement and sequelae. RyR1-mediated calcium signalling plays an important role in normal pancreatic function but has also been critically implicated in the pathophysiology of acute pancreatitis, particularly in bile acid- and ethanol-induced forms. Findings from relevant animal models indicate that pancreatic damage in these conditions may be ameliorated through administration of the specific RyR1 antagonist dantrolene and other compounds modifying pancreatic metabolism including calcium signalling. These observations suggest that patients with RYR1 gain-of-function variants may be at increased risk of developing acute pancreatitis, a condition which should therefore be considered in the health surveillance of such individuals.
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Affiliation(s)
- Dennis T Famili
- Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, United Kingdom
| | - Arti Mistry
- Department of Women and Children's Health, Faculty of Life Sciences and Medicine (FoLSM), King's College London, London, United Kingdom
| | - Oleg Gerasimenko
- School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | | | - Rachel M Tribe
- Department of Women and Children's Health, Faculty of Life Sciences and Medicine (FoLSM), King's College London, London, United Kingdom
| | - Eirini Kyrana
- Department of Paediatric Hepatology, King's College Hospital, London, United Kingdom
| | - Anil Dhawan
- Department of Paediatric Hepatology, King's College Hospital, London, United Kingdom
| | | | - Nicol Voermans
- Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Tracey Willis
- Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, United Kingdom
| | - Heinz Jungbluth
- Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, United Kingdom; Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine (FoLSM), King's College London, London, United Kingdom.
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A high prevalence of genetic polymorphisms in idiopathic and alcohol-associated chronic pancreatitis patients in Ireland. HPB (Oxford) 2021; 23:231-237. [PMID: 32669225 DOI: 10.1016/j.hpb.2020.06.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/03/2020] [Accepted: 06/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Individual genetic architecture is considered central to susceptibility and progression of disease in chronic pancreatitis. The study aimed to evaluate the presence of common pancreatic gene mutations in a defined cohort of idiopathic and alcohol-induced chronic pancreatitis patients in Ireland. METHODS The study comprised patients with idiopathic and alcohol-induced chronic pancreatitis and historic controls. Variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, cationic trypsinogen (PRSS1) gene and serine protease inhibitor kazal type-1 (SPINK1) gene, were assessed by Taqman© genotyping assay. RESULTS Of n = 126 patients and n = 167 controls, mutations were detected in 23 (20%) and in 10 (6%) respectively (P < 0.001). The majority of mutations found were in the SPINK1 gene variant N34S (13%) which increased disease risk almost six-fold (OR 5.9). Neither CFTR severe mutation (F508del) (P = 0.649) nor mild variant (R117H) (P = 0.327) were over-represented amongst patients compared to control subjects. PRSS1 variants were not detected in either patient or control subjects. CONCLUSION There was a significant prevalence of chronic pancreatitis-associated gene mutations in this well-phenotyped cohort. In patients with alcohol-related or idiopathic chronic pancreatitis, the possibility of genetic mutations in the SPINK 1 gene should be considered as a contributing aetiology factor.
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O'Brien CM, O'Brien AC, Gleeson L, Conlon K, Feeney J, Malone DE. Imaging of genetically-mediated pancreatitis. Clin Imaging 2020; 65:113-118. [PMID: 32387800 DOI: 10.1016/j.clinimag.2020.04.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/12/2020] [Accepted: 04/07/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVES To review the imaging of patients with Genetically-Mediated Pancreatitis (GMP), identify common imaging findings in this cohort and assess phenotypical characteristics of specific genotypes. MATERIALS AND METHODS Retrospective review of the databases of the Irish National Surgical Centre for Pancreatic Cancer (NSCPC) and Cystic Fibrosis (CF) from November 2010 to January 2018. Retrospective imaging and chart review for the patients with positive genetics for GMP. RESULTS The NSCPC database contained 699 patients; the CF database included 352 patients. Of these 1051, 14 were identified as having GMP (age range: 20-65, M:F ratio of 1:1). 14 of 1051 patients from the database had positive genetics for GMP. 10 had imaging to support a diagnosis of hereditary pancreatitis or familial recurrent pancreatitis (1.3%) and 4 had imaging to support a diagnosis of CF-related pancreatitis. Imaging findings were considered in 3 categories, determined by genotype - PRSS1 hereditary pancreatitis, SPINK 1 autosomal recessive pancreatitis and those for CFTR - cystic fibrosis related pancreatitis. Imaging findings in PRSS1 hereditary pancreatitis patients included: pancreatic atrophy, calcification and main pancreatic duct (MPD) dilatation, referred to as the PRSS1 imaging triad. Patients with the SPINK1 gene mutation had less severe imaging manifestations (pancreatic atrophy 33%, MPD dilatation 33%, pancreatic calcification 33%). CFTR patients with imaging findings had pancreatic atrophy (100%). CONCLUSION GMP should be suspected when the features of 'chronic pancreatitis' are seen in young adults with no history of excess alcohol intake. Genetic testing, endocrinology review and long-term imaging follow-up for pancreatic carcinoma are indicated.
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Affiliation(s)
- Ciara M O'Brien
- St. Vincent's University Hospital, 196 Merrion Rd, Elm Park, Dublin, D04T6F4, Ireland.
| | - Amy C O'Brien
- St. Vincent's University Hospital, 196 Merrion Rd, Elm Park, Dublin, D04T6F4, Ireland.
| | - Laura Gleeson
- St. Vincent's University Hospital, 196 Merrion Rd, Elm Park, Dublin, D04T6F4, Ireland.
| | - Kevin Conlon
- St. Vincent's University Hospital, 196 Merrion Rd, Elm Park, Dublin, D04T6F4, Ireland; Tallaght University Hospital, Tallaght, Dublin D24 NR0A, Ireland.
| | - John Feeney
- Tallaght University Hospital, Tallaght, Dublin D24 NR0A, Ireland.
| | - Dermot E Malone
- St. Vincent's University Hospital, 196 Merrion Rd, Elm Park, Dublin, D04T6F4, Ireland.
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Wang H, Li F, Qu J, Mao T, Chen J, Li M, Lu Z, Fang Y, Shi G, Li B. The mechanism of damage by trace amounts of acetamiprid to the midgut of the silkworm, Bombyx mori. ENVIRONMENTAL TOXICOLOGY 2019; 34:1043-1051. [PMID: 31120183 DOI: 10.1002/tox.22775] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 04/23/2019] [Accepted: 04/30/2019] [Indexed: 06/09/2023]
Abstract
Acetamiprid is widely used for agricultural pest control. However, it remains poorly understood whether the environmental residues of acetamiprid have the potential effects on economic insect. In this study, we evaluated the effects of acetamiprid on silkworm growth and development. The exposure to trace amounts of acetamiprid significantly decreased body weight, viability, and spinning ability. In addition, the activity of trypsin in the midgut was decreased after exposure. DGE and KEGG pathway enrichment analysis revealed that the significantly differentially expressed genes were mainly involved in nutrient metabolism, stress responses, and inflammation pathways. These results, in combination with hematoxylin-eosin staining and transmission electron microscopy, indicated that acetamiprid could cause oxidative damage to midgut, lead to inflammatory responses, and affect the activities of midgut digestive enzymes, thus resulting in abnormal growth and development. Our findings greatly contributed to the evaluation of the effects of acetamiprid residues on other nontarget beneficial insect.
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Affiliation(s)
- Hui Wang
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Fanchi Li
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu, People's Republic of China
- Sericulture Institute of Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Jianwei Qu
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Tingting Mao
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Jian Chen
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Mengxue Li
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Zhengting Lu
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Yilong Fang
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Guofang Shi
- Huzhou Academy of Agricultural Sciences, Huzhou, Zhejiang, China
| | - Bing Li
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu, People's Republic of China
- Sericulture Institute of Soochow University, Suzhou, Jiangsu, People's Republic of China
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Gasiorowska A, Talar-Wojnarowska R, Czupryniak L, Smolarz B, Romanowicz-Makowska H, Kulig A, Malecka-Panas E. The prevalence of cationic trypsinogen (PRSS1) and serine protease inhibitor, Kazal type 1 (SPINK1) gene mutations in Polish patients with alcoholic and idiopathic chronic pancreatitis. Dig Dis Sci 2011; 56:894-901. [PMID: 20676769 PMCID: PMC3041903 DOI: 10.1007/s10620-010-1349-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Accepted: 07/12/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND The main cause of chronic pancreatitis (CP) is excessive alcohol consumption. On the other hand, only 5-10% of heavy drinkers develop chronic pancreatitis. We have only limited information regarding the pathogenic mechanism by which alcohol leads to the disease. Mutations of the PRSS1 and SPINK 1 have been mostly implicated in hereditary and idiopathic CP, but their presence in other types of this disease have also been reported. AIMS The aim of the study was to determine the frequency of PRSS1 and SPINK1 mutations in patients with chronic alcoholic (ACP) and idiopathic pancreatitis (ICP) as well as to investigate their relation to the clinical course of the disease. METHODS The study included 33 ACP and 14 ICP patients as well 46 healthy subjects. The diagnosis of CP was based on clinical data, ultrasound, and computed tomography. After isolation of DNA from peripheral blood two trypsinogen mutations were detected N29I and R122H by allelo-specific amplification polymerase chain reaction (ASA-PCR) and by the PCR-restriction fragment length polymorphism (RFLP). Beside this N34S mutation of SPINK1 was analyzed by PCR restriction fragment length polymorphism (PCR-RFLP). RESULTS PRSS1 mutations have been detected in 11 (33%) patients with ACP. The frequency of the PRSS1 mutations was higher in patients with ACP than in controls (4.3%) (p < 0.001). The frequency of PRSS1 mutation was present in 21.4% of ICP patients, which was significantly higher (p < 0.05) than in controls. Overall, six (18%) SPINK1 mutations in ACP group have been detected. Among 14 patients with ICP, in four (28.6%) of them SPINK1 has been detected. The same mutations have also been found in three (6.5%) control subjects. The frequency of the N34S mutation was higher in patients with ICP than in the controls (p < 0.05), but the frequency of N34S mutation did not differ between ACP and the control group. No relations have been detected between PRSS1 and SPINK1 mutations presence and clinical course and complications of CP. CONCLUSIONS Those preliminary data suggest the high prevalence of SPINK1 and PRSS1 mutations in the Polish population, generally, as well as in CP patients. It may be speculated that those mutations contribute to the development of chronic pancreatitis, especially in patients with alcohol overindulgence.
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Affiliation(s)
- Anita Gasiorowska
- Department of Digestive Tract Diseases, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland
| | - Renata Talar-Wojnarowska
- Department of Digestive Tract Diseases, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland
| | - Leszek Czupryniak
- Diabetology and Metabolic Diseases, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland
| | - Beata Smolarz
- Laboratory of Molecular Genetics, Institute of Polish Mother’s Memorial Hospital, Rzgowska 281/289, 93-338 Lodz, Poland
| | - Hanna Romanowicz-Makowska
- Laboratory of Molecular Genetics, Institute of Polish Mother’s Memorial Hospital, Rzgowska 281/289, 93-338 Lodz, Poland
| | - Andrzej Kulig
- Laboratory of Molecular Genetics, Institute of Polish Mother’s Memorial Hospital, Rzgowska 281/289, 93-338 Lodz, Poland
| | - Ewa Malecka-Panas
- Department of Digestive Tract Diseases, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland
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Kim MP, Evans DB, Vu TM, Fleming JB. The recognition and surgical management of heritable lesions of the pancreas. Surg Oncol Clin N Am 2009; 18:99-119, ix. [PMID: 19056044 DOI: 10.1016/j.soc.2008.09.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Our knowledge regarding the inherited factors that lead to the development of lesions within the pancreas is clearly incomplete. This article addresses clinical issues in patients at moderate-to-high risk for pancreatic malignancy, with special emphasis on the recognition and diagnosis of known genetic syndromes. Using the current available information, the authors attempt to equip the practicing surgeon with critical information to increase clinical suspicion for heritable syndromes and inform specific surgical management. Additionally, this article is meant to encourage the practicing surgeon to participate in the genetic testing/screening, cancer surveillance, and prevention activities of patients who have heritable cancer syndromes and associated pancreatic lesions that require surgery.
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Affiliation(s)
- Michael P Kim
- Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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Clinical and radiological outcome of patients suffering from chronic pancreatitis associated with gene mutations. Pancreas 2008; 37:371-6. [PMID: 18953248 DOI: 10.1097/mpa.0b013e31817f52a1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen gene (PRSS1), and serine protease inhibitor kazal type 1 (SPINK1) gene mutations have been associated with chronic pancreatitis (CP). The aim of this study was to compare clinical and radiological findings in sporadic CP with (CPgm) and without (CPwt) gene mutations. METHODS Data from patients observed between 2001 and 2006 were collected. All patients were tested for 25 CFTR gene mutations, for R122H and N29I on the PRSS1 gene, and for N34S mutation on the SPINK1 gene. RESULTS We found 34 (17.2%) of 198 patients with CPgm, 23 (11.6%) of them on the CFTR gene, 11 (5.6%) on the SPINK1, and none on the PRSS1 gene. The age at clinical onset was younger in CPgm (36.2 +/- 17.2 years) than in CPwt (44 +/- 12.6 years; P = 0.005). There were more heavy drinkers among CPwt (33%) than among CPgm (9%; P = 0.003), and the same applied to smokers (69% vs 33%, respectively; P < 0.0001). In CPgm group, the onset of pancreatic calcifications was observed more frequently in drinkers and/or smokers. Exocrine and endocrine insufficiency occurred less frequently and later in CPgm than in CPwt patients. CONCLUSIONS Clinical and radiological outcome differ in CPgm compared with CPwt. Alcohol, even in small quantities, and cigarette smoking influence the onset of pancreatic calcifications.
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Luo X, Wu ZX, Liu QC, Chen ZD. Clinical and hereditary characteristics of hereditary pancreatitis: an analysis of 13 cases. Shijie Huaren Xiaohua Zazhi 2008; 16:2188-2190. [DOI: 10.11569/wcjd.v16.i19.2188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the clinical manifestations and genetic characterisitcs of hereditary pancreatitis (HP).
METHODS: We retrospectively reviewed the clinical data of 13 HP patients (10 from 3 families, and 3 sporadic cases).
RESULTS: The ages of the 10 patients from 3 families ranged from 8 to 48 years old (7 cases less than 20 years old and 3 cases more than 20 years old), and the mutation of protease serine 1 (PRSS1) gene occurred frequently. The clinical manifestations were various and recurrent abdominal pain was an important sign. Dominant heredity was the genetic character, and HP occurred earlier in the next generation. The 3 sporadic cases were all above 25 years old.
CONCLUSION: HP has various clinical manifestations and genetic anticipation characteristic.
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Novel mutation and polymorphism of PRSS1 gene in the Chinese patients with hereditary pancreatitis and chronic pancreatitis. Chin Med J (Engl) 2008. [DOI: 10.1097/00029330-200801020-00003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Pho-Iam T, Thongnoppakhun W, Yenchitsomanus PT, Limwongse C. A Thai family with hereditary pancreatitis and increased cancer risk due to a mutation in PRSS1 gene. World J Gastroenterol 2005; 11:1634-8. [PMID: 15786540 PMCID: PMC4305944 DOI: 10.3748/wjg.v11.i11.1634] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate mutation of serine protease 1–cationic trypsinogen (CT, PRSS1) gene in members of a Thai family with hereditary pancreatitis and pancreatic cancer.
METHODS: Polymerase chain reaction and direct sequencing were performed to analyze the PRSS1 gene in two members of the family affected by pancreatitis. Allele specific amplification (ASA) method was then developed to detect the mutation of the PRSS1 gene in all available members of the family and normal control subjects.
RESULTS: A cytosine (C) to thymine (T) mutation at position 2441 (g.2441C>T) of the PRSS1 gene, which results in a substitution of arginine by cysteine at position 116 (R116C) of CT, was identified by direct sequencing in both clinically affected members of the family but was not found in the unaffected member. This mutation, which might be arising from deamination of methylated cytosine in CpG dinucleotide of codon 116 (CGT>TGT), was also detected by the ASA method in the two affected members and a proband’s brother but was not observed in unaffected members and 54 normal control subjects.
CONCLUSION: Autosomal dominant pancreatitis with increased cancer risk in the studied Thai family is most likely due to missense (R116C) mutation in the PRSS1 gene.
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Affiliation(s)
- Theeraphong Pho-Iam
- Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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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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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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Otsuki M, Nishimori I, Hayakawa T, Hirota M, Ogawa M, Shimosegawa T. Hereditary pancreatitis: clinical characteristics and diagnostic criteria in Japan. Pancreas 2004; 28:200-6. [PMID: 15028953 DOI: 10.1097/00006676-200403000-00012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND/AIM Hereditary pancreatitis (HP) is the strongest known risk factor for pancreatic cancer. The aim of the present study is to establish diagnostic criteria for HP to predict and identify high-risk groups for pancreatic cancer. METHOD We collected clinical data for 210 patients with recurrent acute or chronic pancreatitis, and examined mutations of the cationic trypsinogen (CT) gene in 57 patients with a family history of pancreatitis or with early-onset idiopathic recurrent acute or chronic pancreatitis (40 years of age or younger). DNA was extracted from peripheral blood leukocytes, and exons 2 and 3 of the CT gene were individually amplified by polymerase chain reaction (PCR) and sequenced. RESULTS Of these 57 patients in whom mutations of the CT gene were examined, the R122H (20 patients) and N29I (5 patients) mutations in the CT gene were observed in 25 patients (43.9%). From the analysis of clinical records and the CT gene of these patients, we proposed the following adaptations to the diagnostic criteria for HP: (1) at least one of the affected members in a family has no known etiological factors, (2) we deleted the definition of "different generation", but included the upper limit of the age of onset of pancreatitis in the case of siblings (at least 1 of the patients in a family <40 years of age). According to these criteria, all patients with the CT gene mutations in the present study could be classified as having HP, with the exception of 2 sporadic cases with the R122H and N29I mutations, respectively. Based on these findings, we revised the criteria for the diagnosis of HP; (1) recurrent acute or chronic pancreatitis with R122H or N29I mutation of the CT gene, or (2) recurrent acute or chronic pancreatitis with a family history of 2 or more affected patients, irrespective of generation, with at least 1 of the patients having no known etiological factors, and in case of siblings only, the onset of the disease in at least 1 of the patients is under age 40 years. CONCLUSION The revised criteria in the present study are appropriate and of clinical usefulness to diagnose patients with HP even in cases without the genetic testing. However, if and when more genes are detected, it will be important to reexamine the mutation-negative patients now classified as HP based on our proposed criteria.
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Affiliation(s)
- J Martínez Sempere
- Sección de Aparato Digestivo, Hospital General Universitario de Alicante, Alicante, España.
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15
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Cavestro GM, Frulloni L, Neri TM, Seghini P, Nouvenne A, Zanetti A, Bovo P, Di Mario F, Okolicsanyi L, Cavallini G. Association of HLA-DRB1*0401 allele with chronic pancreatitis. Pancreas 2003; 26:388-391. [PMID: 12717273 DOI: 10.1097/00006676-200305000-00013] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
INTRODUCTION Chronic pancreatitis (CP) is characterized by irreversible morphologic and functional alterations of the pancreas, clinically presenting with upper abdominal pain as well as exocrine and endocrine insufficiencies. According to a more recent hypothesis, the pathogenesis may involve genetic and immunologic factors. AIM To investigate the major histocompatibility complex (MHC) genes as a genetic background of chronic pancreatitis. METHODOLOGY Allelic polymorphisms were investigated in the genes of the MHC region (HLA B, DRB, DQB) with PCR-based methodologies (PCR-SSP) in 56 patients with CP (44 males and 12 females) and 183 normal controls (78 males and 105 females) of the same ethnic group. All patients and controls gave their informed consent. RESULTS Among HLA-DRB1 genes, DRB1*04 was significantly higher in CP patients than in controls (26.78% versus 8.1%; pc < 0.003; OR = 4.1; CI = 1.85-9.06). DRB1*04 allele specificities in the DRB1*04-positive patients demonstrated significantly higher frequencies of DRB1*0401 allele (14.3% versus 1.1%; p = 0.00017; OR = 15.08; CI = 3.1-73.36). Neither HLA-B nor HLA-DQB1 associations with the disease were found. CONCLUSIONS This study supports a role of HLA-DRB1*0401 as a susceptibility factor for patients with CP. HLA DRB1*0401 contains the 70QKRAA74 amino acid sequence, which is also expressed by several human pathogens, including Epstein-Barr virus. T cells may be triggered in the pancreatic tissue upon exposure to foreign peptides similar enough to cross-react and to break immunologic tolerance.
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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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Teich N, Bauer N, Mössner J, Keim V. Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants. Am J Gastroenterol 2002; 97:341-6. [PMID: 11866271 DOI: 10.1111/j.1572-0241.2002.05467.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Mutations of the cationic trypsinogen (CT) and the serine protease inhibitor, Kazal type 1 (SPINK 1) are associated with chronic pancreatitis. After mutational screening of a cohort of patients with nonalcoholic chronic pancreatitis, we report three novel variants of the trypsinogen molecule and the clinical characteristics of the carriers. METHODS The coding region of the exon 2 and 3 of the CT gene of 523 patients with chronic nonalcoholic pancreatitis (108 patients with suspected hereditary pancreatitis (HP) and 415 patients with "idio pathic" pancreatitis [IP]) and 82 controls was analyzed after polymerase chain reaction amplification. Clinical characteristics were obtained by questioning the patients and their relatives and physicians. HP was suspected when two members of a family had chronic pancreatitis. A restriction digestion was used to analyze the N34S mutation SPINK1. RESULTS The mutation R122H of the cationic trypsinogen was found in 21 index patients, N291 in six index patients, and A16V and D22G in one index patient, all from HP families. The N34S mutation of SPINK1 was found in two index patients with a family history of HP. In three patients, the novel point mutations L104P, R116C, and C139F of the cationic trypsinogen were found. A clear autosomally dominant inheritance of chronic pancreatitis was not present in these families. In 75 index patients from HP families (69.4%), no mutation could be found. The SPINK 1-mutation N34S was detected in only one patient carrying a CT mutation, and was found in 68 (16.4%) of patients with IP. CONCLUSIONS The R122H and N291 mutations of CT are the most common disease-associated mutations in HP; the N34S mutation of SPINK I is the most frequent genetic risk factor associated with IP. The CT gene carries several variations that could be associated with chronic pancreatitis. To avoid overestimating the pathogenetic impact of novel trypsinogen variants, a detailed clinical characterization of all patients with early onset chronic pancreatitis is mandatory.
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Affiliation(s)
- Niels Teich
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Leipzig, Germany
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Keim V, Bauer N, Teich N, Simon P, Lerch MM, Mössner J. Clinical characterization of patients with hereditary pancreatitis and mutations in the cationic trypsinogen gene. Am J Med 2001; 111:622-6. [PMID: 11755505 DOI: 10.1016/s0002-9343(01)00958-5] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE We determined the clinical manifestations of hereditary pancreatitis in nearly 30 families. PATIENTS AND METHODS The two trypsinogen mutations N29I and R122H were identified in a group of 550 patients with chronic pancreatitis of unclear origin. The following criteria were used to characterize the severity of chronic pancreatitis (one point each): calcifications, cysts, dilation of the pancreatic duct, diabetes, hospital treatment, and operation. Stages were defined as stage 0 (no points), stage 1 (one to two points), stage 2 (three to four points), and stage 3 (more than four points). Smoking and drinking habits were also recorded. RESULTS Six families with the N29I mutation (25 subjects with the mutation) and 21 families with the R122H mutation (76 subjects with the mutation) were identified. The median ages for the onset of disease were 11 years in N29I and 10 years in R122H patients. The severity of chronic pancreatitis and symptoms were similar for both mutations. About 26% (n = 26) of the 101 subjects carrying a mutation were asymptomatic, and 42% (n = 42) had mild disease (stage 1). Twenty-nine percent (n = 29) had moderate disease (stage 2), and only 4% (n = 4) had severe disease (stage 3). CONCLUSIONS Symptoms of patients with the N29I or R122H trypsinogen mutation were generally similar. The majority of subjects with trypsinogen mutations had mild disease or was asymptomatic.
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Affiliation(s)
- V Keim
- German Registry of Hereditary Pancreatitis at the Medizinische Klinik und Poliklinik II, Universität Leipzig, Leipzig, Germany
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Applebaum-Shapiro SE, Peters JA, O'Connell JA, Aston CE, Whitcomb DC. Motivations and concerns of patients with access to genetic testing for hereditary pancreatitis. Am J Gastroenterol 2001; 96:1610-7. [PMID: 11374708 DOI: 10.1111/j.1572-0241.2001.03787.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Direct DNA testing is now available for hereditary pancreatitis (HP). This study aimed to identify the factors that motivated individuals to participate in research and to determine how research participants used their genetic test results. METHODS A survey was mailed to 247 participants (110 male, 137 female) who were > or =18 yr of age and living in the US. Data analysis was primarily a description of frequency distribution of the responses. RESULTS Ninety-one of 247 participants (37%) completed the survey. Of the 55 female and 36 male respondents, 60% were 31-55 yr old, and a total of 54% tested positive for HP. The most common reason for participating in research was "to help a relative/family member" (61%), and genetic testing was pursued because of "the disturbance of seeing affected relatives" (48%) and "the desire to help future generations" (33%). Perceived risk of developing HP in the future was the least important motivating factor in seeking genetic testing. Sixty-two percent of respondents had received their genetic test results. All but one chose to share their results with at least one person: most often with family members (96%) and physicians (62%), and least often with insurance companies (4%). The most common influential factor in withholding information was "the fear of insurance discrimination" (23%). CONCLUSIONS The major motivations to participate in the HP genetic research study were to obtain genetic testing and to help current family members and future generations. The major concern was insurance discrimination. Participants clearly appreciate the availability of genetic testing for HP. These results suggest that a mechanism to disclose results to research participants should be considered, and effective ways to protect at-risk individuals from insurance discrimination must remain a genetics health care priority.
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Abstract
Hereditary pancreatitis (HP) is clinically indistinguishable from pancreatitis with other causes. Patients with HP have an increased chance of developing pancreatitis. Mutations in the cationic trypsinogen gene appear to cause most HP, although there is evidence for mild genetic heterogeneity with defects in other genes. Trypsin stabilization and protection from autolysis appear to play a central role in the pathogenesis of pancreatitis. The role of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) as well as the pancreatic secretory trypsin inhibitor (PSTI) in patients with pancreatitis is intriguing but as yet incompletely understood. Genetic testing may help to identify and manage patients with HP. Healthcare professionals should understand the elements necessary for obtaining informed consent for patients undergoing these tests, the limits in interpreting test results, and the psychosocial issues that may arise from genetic testing.
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Affiliation(s)
- R K Rolston
- Division of Molecular Diagnostics, University of Pittsburgh Medical Center, S701 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15213, USA
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Hassan Z, Mohan V, McDermott MF, Ali L, Ogunkolade WB, Aganna E, Cassell PG, Deepa R, Khan AK, Hitman GA. Pancreatitis in fibrocalculous pancreatic diabetes mellitus is not associated with common mutations in the trypsinogen gene. Diabetes Metab Res Rev 2000; 16:454-57. [PMID: 11114105 DOI: 10.1002/1520-7560(2000)9999:9999<::aid-dmrr155>3.0.co;2-k] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND A distinct type of pancreatitis associated with diabetes, termed fibrocalculous pancreatic diabetes (FCPD), has been reported in tropical developing countries including Bangladesh. The molecular basis for autosomal dominant hereditary pancreatitis (HP) has recently been attributed to mutations in exons 2 and 3 of the trypsinogen gene. We have investigated the hypothesis that mutations in the aforementioned exons of this gene might also predispose to FCPD. METHODS Seventy Bangladeshi and 50 South Indian unrelated FCPD patients and seven South Indian families with FCPD probands were studied. Pancreatic calcification was confirmed by abdominal X-ray, ultrasound and/or ERCP. Established mutations of exons 2 and 3 of the trypsinogen gene were studied in these subjects by PCR-RFLP analysis and DNA sequencing. RESULTS The mutations found in hereditary pancreatitis were not observed in this collection of FCPD subjects, and complete DNA sequencing of exons 2 and 3 of the fourth cationic trypsinogen gene also excluded any new mutations. CONCLUSIONS These results indicate that chronic pancreatitis of FCPD is unlikely to be caused by common mutations in the trypsinogen gene.
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Affiliation(s)
- Z Hassan
- Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Whitechapel, London E1 1BB, UK
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