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Yu B, Yu Y, Wang X, Xu C, Xiao Y. A narrative review on the role of genetics in children with acute recurrent pancreatitis and chronic pancreatitis. Pediatr Investig 2023; 7:268-276. [PMID: 38050536 PMCID: PMC10693666 DOI: 10.1002/ped4.12404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 09/27/2023] [Indexed: 12/06/2023] Open
Abstract
The incidence of pancreatitis in children has increased over the past two decades. With advances in molecular biological techniques and clinical research, genetic variations have emerged as a pivotal etiological factor in pediatric pancreatitis. This review aims to summarize recent clinical research advancements in understanding pediatric pancreatitis caused by various gene mutations. As of the year 2020, researchers had identified 12 genes implicated in the pathogenesis of pancreatitis. These genes primarily contributed to the development of pancreatitis through three mechanisms. Pancreatitis resulting from these gene mutations exhibits several distinct characteristics, including early onset, a heightened risk of developing pancreatic duct stones, rapid disease progression, and a significantly increased risk of pancreatic endocrine and exocrine dysfunction, as well as pancreatic cancer in the future. Genetic sequencing is recommended for children with pancreatitis based on six indications. The sequencing not only assists in the clinical diagnosis but also enhances our understanding of the pathophysiology of pancreatitis.
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Affiliation(s)
- Bo Yu
- School of Clinical MedicineShanghai University of Medicine and Health SciencesShanghaiChina
| | - Yi Yu
- Pediatric DepartmentRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Xinqiong Wang
- Pediatric DepartmentRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Pediatric DepartmentRuijin Hospital NorthSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Chundi Xu
- Pediatric DepartmentRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Pediatric DepartmentRuijin Hospital NorthSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Yuan Xiao
- Pediatric DepartmentRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Pediatric DepartmentXin Rui Hospital (Wuxi Branch of Ruijin Hospital)JiangsuChina
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2
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Yuzyuk TN, Nelson HA, Johnson LM. Inherited causes of exocrine pancreatic insufficiency in pediatric patients: clinical presentation and laboratory testing. Crit Rev Clin Lab Sci 2023:1-16. [PMID: 36876586 DOI: 10.1080/10408363.2023.2179968] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
Pediatric patients with exocrine pancreatic insufficiency (EPI) have symptoms that include abdominal pain, weight loss or poor weight gain, malnutrition, and steatorrhea. This condition can be present at birth or develop during childhood for certain genetic disorders. Cystic fibrosis (CF) is the most prevalent disorder in which patients are screened for EPI; other disorders also are associated with pancreatic dysfunction, such as hereditary pancreatitis, Pearson syndrome, and Shwachman-Diamond syndrome. Understanding the clinical presentation and proposed pathophysiology of the pancreatic dysfunction of these disorders aids in diagnosis and treatment. Testing pancreatic function is challenging. Directly testing aspirates produced from the pancreas after stimulation is considered the gold standard, but the procedures are not standardized or widely available. Instead, indirect tests are often used in diagnosis and monitoring. Although indirect tests are more widely available and easier to perform, they have inherent limitations due to a lack of sensitivity and/or specificity for EPI.
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Affiliation(s)
- Tatiana N Yuzyuk
- Department of Pathology, University of Utah/ARUP Laboratories, Salt Lake City, UT, USA
| | - Heather A Nelson
- Department of Pathology, University of Utah/ARUP Laboratories, Salt Lake City, UT, USA
| | - Lisa M Johnson
- Department of Laboratories, Seattle Children's Hospital, Seattle, WA, USA
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3
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Kruse J, Mueller R, Aghdassi AA, Lerch MM, Salloch S. Genetic Testing for Rare Diseases: A Systematic Review of Ethical Aspects. Front Genet 2022; 12:701988. [PMID: 35154238 PMCID: PMC8826556 DOI: 10.3389/fgene.2021.701988] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 11/17/2021] [Indexed: 11/29/2022] Open
Abstract
Genetic testing is associated with many ethical challenges on the individual, organizational and macro level of health care systems. The provision of genetic testing for rare diseases in particular requires a full understanding of the complexity and multiplicity of related ethical aspects. This systematic review presents a detailed overview of ethical aspects relevant to genetic testing for rare diseases as discussed in the literature. The electronic databases Pubmed, Science Direct and Web of Science were searched, resulting in 55 relevant publications. From the latter, a total of 93 different ethical aspects were identified. These ethical aspects were structured into three main categories (process of testing, consequences of the test outcome and contextual challenges) and 20 subcategories highlighting the diversity and complexity of ethical aspects relevant to genetic testing for rare diseases. This review can serve as a starting point for the further in-depth investigation of particular ethical issues, the education of healthcare professionals regarding this matter and for informing international policy development on genetic testing for rare diseases.
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Affiliation(s)
- Judith Kruse
- Institute of Ethics and History of Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Regina Mueller
- Institute of Ethics and History of Medicine, Medical Faculty, University Tübingen, Tübingen, Germany
| | - Ali A Aghdassi
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | | | - Sabine Salloch
- Institute of Ethics, History and Philosophy of Medicine, Hannover Medical School, Hannover, Germany
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4
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Panchoo AV, VanNess GH, Rivera-Rivera E, Laborda TJ. Hereditary pancreatitis: An updated review in pediatrics. World J Clin Pediatr 2022; 11:27-37. [PMID: 35096544 PMCID: PMC8771313 DOI: 10.5409/wjcp.v11.i1.27] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/08/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hereditary Pancreatitis (HP) has emerged as a significant cause of acute, acute recurrent and chronic pancreatitis in the pediatric population. Given that it presents similarly to other causes of pancreatitis, a positive family history and/or isolation of a gene mutation are vital in its designation. Inheritance patterns remain complex, but mutations involving the PRSS1, SPINK1, CFTR and CTRC genes are commonly implicated. Since being first described in 1952, dozens of genetic alterations that modify the action of pancreatic enzymes have been identified. Among children, these variants have been isolated in more than 50% of patients with chronic pancreatitis. Recent research has noted that such mutations in PRSS1, SPINK1 and CFTR genes are also associated with a faster progression from acute pancreatitis to chronic pancreatitis. Patients with HP are at increased risk of developing diabetes mellitus, exocrine pancreatic insufficiency, and pancreatic adenocarcinoma. Management follows a multi-disciplinary approach with avoidance of triggers, surveillance of associated conditions, treatment of pancreatic insufficiency and use of endoscopic and surgical interventions for complications. With significant sequela, morbidity and a progressive nature, a thorough understanding of the etiology, pathophysiologic mechanisms, diagnostic evaluation, current management strategies and future research considerations for this evolving disease entity in pediatrics is warranted.
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Affiliation(s)
- Arvind Vasant Panchoo
- Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of San Antonio, San Antonio, TX 78207, United States
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States
| | - Grant H VanNess
- Faculty of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Edgardo Rivera-Rivera
- Department of Pediatric Gastroenterology, Parkview Health, Fort Wayne, IN 46845, United States
| | - Trevor J Laborda
- Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of San Antonio, San Antonio, TX 78207, United States
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States
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Abstract
BACKGROUND Chronic pancreatitis (CP) is defined according to the recently proposed mechanistic definition as a pathological fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental, and/or other risk factors who develop persistent pathological responses to parenchymal injury or stress. METHODS The clinical practice guidelines for CP in Japan were revised in 2021 based on the 2019 Japanese clinical diagnostic criteria for CP, which incorporate the concept of a pathogenic fibro-inflammatory syndrome in the pancreas. In this third edition, clinical questions are reclassified into clinical questions, background questions, and future research questions. RESULTS Based on analysis of newly accumulated evidence, the strength of evidence and recommendations for each clinical question is described in terms of treatment selection, lifestyle guidance, pain control, treatment of exocrine and endocrine insufficiency, and treatment of complications. A flowchart outlining indications, treatment selection, and policies for cases in which treatment is ineffective is provided. For pain control, pharmacological treatment and the indications and timing for endoscopic and surgical treatment have been updated in the revised edition. CONCLUSIONS These updated guidelines provide clinicians with useful information to assist in the diagnosis and treatment of CP.
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6
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Katabathina VS, Buddha S, Rajebi H, Shah JN, Morani AC, Lubner MG, Dasyam A, Nazarullah A, Menias CO, Prasad SR. Pancreas in Hereditary Syndromes: Cross-sectional Imaging Spectrum. Radiographics 2021; 41:1082-1102. [PMID: 34143711 DOI: 10.1148/rg.2021200164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
A wide spectrum of hereditary syndromes predispose patients to distinct pancreatic abnormalities, including cystic lesions, recurrent pancreatitis, ductal adenocarcinoma, nonductal neoplasms, and parenchymal iron deposition. While pancreatic exocrine insufficiency and recurrent pancreatitis are common manifestations in cystic fibrosis and hereditary pancreatitis, pancreatic cysts are seen in von Hippel-Lindau disease, cystic fibrosis, autosomal dominant polycystic kidney disease, and McCune-Albright syndrome. Ductal adenocarcinoma can be seen in many syndromes, including Peutz-Jeghers syndrome, familial atypical multiple mole melanoma syndrome, Lynch syndrome, hereditary breast and ovarian cancer syndrome, Li-Fraumeni syndrome, and familial pancreatic cancer syndrome. Neuroendocrine tumors are commonly seen in multiple endocrine neoplasia type 1 syndrome and von Hippel-Lindau disease. Pancreatoblastoma is an essential component of Beckwith-Wiedemann syndrome. Primary hemochromatosis is characterized by pancreatic iron deposition. Pancreatic pathologic conditions associated with genetic syndromes exhibit characteristic imaging findings. Imaging plays a pivotal role in early detection of these conditions and can positively affect the clinical outcomes of those at risk for pancreatic malignancies. Awareness of the characteristic imaging features, imaging-based screening protocols, and surveillance guidelines is crucial for radiologists to guide appropriate patient management. ©RSNA, 2021.
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Affiliation(s)
- Venkata S Katabathina
- From the Departments of Radiology (V.S.K., S.B., H.R.) and Pathology (A.N.), University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229; Department of Radiology, Le Bonheur Children's Hospital, Memphis, Tenn (J.N.S.); Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (A.C.M., S.R.P.); Department of Radiology, University of Wisconsin, Madison, Wis (M.G.L.); Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.D.); and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M.)
| | - Suryakala Buddha
- From the Departments of Radiology (V.S.K., S.B., H.R.) and Pathology (A.N.), University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229; Department of Radiology, Le Bonheur Children's Hospital, Memphis, Tenn (J.N.S.); Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (A.C.M., S.R.P.); Department of Radiology, University of Wisconsin, Madison, Wis (M.G.L.); Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.D.); and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M.)
| | - Hamid Rajebi
- From the Departments of Radiology (V.S.K., S.B., H.R.) and Pathology (A.N.), University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229; Department of Radiology, Le Bonheur Children's Hospital, Memphis, Tenn (J.N.S.); Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (A.C.M., S.R.P.); Department of Radiology, University of Wisconsin, Madison, Wis (M.G.L.); Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.D.); and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M.)
| | - Jignesh N Shah
- From the Departments of Radiology (V.S.K., S.B., H.R.) and Pathology (A.N.), University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229; Department of Radiology, Le Bonheur Children's Hospital, Memphis, Tenn (J.N.S.); Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (A.C.M., S.R.P.); Department of Radiology, University of Wisconsin, Madison, Wis (M.G.L.); Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.D.); and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M.)
| | - Ajay C Morani
- From the Departments of Radiology (V.S.K., S.B., H.R.) and Pathology (A.N.), University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229; Department of Radiology, Le Bonheur Children's Hospital, Memphis, Tenn (J.N.S.); Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (A.C.M., S.R.P.); Department of Radiology, University of Wisconsin, Madison, Wis (M.G.L.); Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.D.); and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M.)
| | - Meghan G Lubner
- From the Departments of Radiology (V.S.K., S.B., H.R.) and Pathology (A.N.), University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229; Department of Radiology, Le Bonheur Children's Hospital, Memphis, Tenn (J.N.S.); Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (A.C.M., S.R.P.); Department of Radiology, University of Wisconsin, Madison, Wis (M.G.L.); Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.D.); and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M.)
| | - Anil Dasyam
- From the Departments of Radiology (V.S.K., S.B., H.R.) and Pathology (A.N.), University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229; Department of Radiology, Le Bonheur Children's Hospital, Memphis, Tenn (J.N.S.); Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (A.C.M., S.R.P.); Department of Radiology, University of Wisconsin, Madison, Wis (M.G.L.); Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.D.); and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M.)
| | - Alia Nazarullah
- From the Departments of Radiology (V.S.K., S.B., H.R.) and Pathology (A.N.), University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229; Department of Radiology, Le Bonheur Children's Hospital, Memphis, Tenn (J.N.S.); Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (A.C.M., S.R.P.); Department of Radiology, University of Wisconsin, Madison, Wis (M.G.L.); Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.D.); and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M.)
| | - Christine O Menias
- From the Departments of Radiology (V.S.K., S.B., H.R.) and Pathology (A.N.), University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229; Department of Radiology, Le Bonheur Children's Hospital, Memphis, Tenn (J.N.S.); Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (A.C.M., S.R.P.); Department of Radiology, University of Wisconsin, Madison, Wis (M.G.L.); Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.D.); and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M.)
| | - Srinivasa R Prasad
- From the Departments of Radiology (V.S.K., S.B., H.R.) and Pathology (A.N.), University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229; Department of Radiology, Le Bonheur Children's Hospital, Memphis, Tenn (J.N.S.); Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (A.C.M., S.R.P.); Department of Radiology, University of Wisconsin, Madison, Wis (M.G.L.); Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.D.); and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M.)
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7
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Andersson R, Löhr JM. Swedish national guidelines for chronic pancreatitis. Scand J Gastroenterol 2021; 56:469-483. [PMID: 33617407 DOI: 10.1080/00365521.2021.1881815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/11/2021] [Accepted: 01/20/2021] [Indexed: 02/04/2023]
Abstract
Chronic pancreatitis (CP) should be suspected in the case of recurrent upper abdominal pain of unknown origin and/or clinical signs of exocrine pancreatic insufficiency (EPI). Alcohol is the most common etiological factor associated with CP, others being smoking, male gender, and hereditary forms. CP is often associated with recurrent episodes of acute exacerbations.As of today, there is no accepted clinical definition of CP. However, irreversible morphological changes within the pancreas often occur, including dilatation of the main and branch pancreatic ducts, calcifications in ducts and parenchyma, parenchymal atrophy, and development of pseudocysts, though less so in the early phase of CP.
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8
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Weiss FU, Laemmerhirt F, Lerch MM. Acute Pancreatitis: Genetic Risk and Clinical Implications. J Clin Med 2021; 10:E190. [PMID: 33430357 PMCID: PMC7825757 DOI: 10.3390/jcm10020190] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/23/2020] [Accepted: 01/04/2021] [Indexed: 12/16/2022] Open
Abstract
Acute pancreatitis (AP) is one of the most common gastroenterological indications for emergency admittance and hospitalization. Gallstones, alcohol consumption or the presence of additional initiating factors give rise to a disease with a diverse clinical appearance and a hard-to predict course of progression. One major challenge in the treatment of AP patients is the early identification of patients at risk for the development of systemic complications and organ failure. In addition, 20%-30% of patients with a first episode of AP later experience progress to recurrent or chronic disease. Complex gene-environment interactions have been identified to play a role in the pathogenesis of pancreatitis, but so far no predictive genetic biomarkers could be implemented into the routine clinical care of AP patients. The current review explains common and rare etiologies of acute pancreatitis with emphasis on underlying genetic aberrations and ensuing clinical management.
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Affiliation(s)
- Frank U. Weiss
- Department of Medicine A, University Medicine Greifswald, 17475 Greifswald, Germany; (F.L.); (M.M.L.)
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9
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Genetic Abnormalities in Pancreatitis: An Update on Diagnosis, Clinical Features, and Treatment. Diagnostics (Basel) 2020; 11:diagnostics11010031. [PMID: 33375361 PMCID: PMC7824215 DOI: 10.3390/diagnostics11010031] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/12/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023] Open
Abstract
Several pancreatitis susceptibility genes have been identified to date. A relationship between a mutation in the cationic trypsinogen (protease serine 1, PRSS1) gene and hereditary pancreatitis (HP) was first identified in 1996. Currently, HP has been defined as either two or more individuals within a family exhibiting pancreatitis for two or more generations, or pancreatitis linked to mutation of the PRSS1 gene. In 2000, a mutation in the serine protease inhibitor gene (Kazal type 1: SPINK1) was reported to be related to sporadic pancreatitis of unknown etiology. This paper reviews and summarizes the current published data on the pancreatitis susceptibility genes, mainly PRSS1 and SPINK1 genes, and introduces a diagnostic and therapeutic approach for dealing with patients with these gene mutations. Patients with these genetic predispositions, both children and adults, have often been initially diagnosed with idiopathic acute pancreatitis, in approximately 20-50% of pediatric cases and 28-80% of adult cases. In such patients, where the etiology is unknown, genetic testing, which requires pre-test and post-test genetic counselling, may prove helpful. Patients with chronic pancreatitis (CP) due to SPINK1 gene mutation and HP patients have a potentially high risk of pancreatic exocrine insufficiency, diabetes mellitus, and, of particular importance, pancreatic cancer. Thus, these patients require careful long-term follow-up and management. Specifically, symptomatic CP patients often need endoscopic therapy or surgery, often following a step-up approach beginning with endoscopic therapy and progressing to surgery if necessary, which is similar to the therapeutic approach for patients with CP due to other etiologies. It is important that clinicians are aware of the characteristics of patients with pancreatitis susceptibility genetic abnormalities.
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10
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Müller R, Aghdassi AA, Kruse J, Lerch MM, Simon P, Salloch S. Perceptions of genetic testing in patients with hereditary chronic pancreatitis and their families: a qualitative triangulation. Eur J Hum Genet 2020; 29:29-38. [PMID: 32788661 PMCID: PMC7852527 DOI: 10.1038/s41431-020-00705-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 12/13/2022] Open
Abstract
Hereditary chronic pancreatitis (HCP) is a genetically determined condition characterized by intermittent acute episodes of pancreatitis and long-term impairment of the exocrine and endocrine pancreatic functions. Genetic test results can have substantial psychological and social consequences for the individuals tested and their families. Nevertheless, little is known so far about the subjective experience of individuals genetically tested for HCP. This qualitative study examines the viewpoints of HCP patients and their relatives in order to identify the psychosocial and ethical implications related to genetic testing within families. Semi-structured qualitative individual interviews and a focus group with HCP patients and their family members were conducted. Data were audio-recorded, transcribed verbatim and analysed using qualitative content analysis. A total of 28 individuals were enrolled in the study: 24 individuals (17 patients, 7 relatives) were interviewed in semi-structured one-on-one interviews and 4 individuals (2 patients, 2 life partners) participated in the focus group. Emerging topics covered (1) genetic testing in childhood, (2) genetic testing within the family and (3) family planning. The study reveals that genetic testing for HCP has a wide influence in familial contexts and is accompanied by normative issues, such as autonomy, reproductive decisions and sharing of information within the family. The results raise the awareness of the complexity of family contexts: familial relationships and dynamics can have great influence on the individual decisions related to genetic testing. Increased understanding of these relational contexts can help health professionals, for example, in counselling, to discuss genetic testing better with patients and families.
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Affiliation(s)
- Regina Müller
- Institute of Ethics and History of Medicine, University of Tübingen, Gartenstraße 47, 72074, Tübingen, Germany.
| | - Ali A Aghdassi
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany
| | - Judith Kruse
- Institute of Ethics and History of Medicine, University Medicine Greifswald, Ellernholzstr. 1-2, 17487, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany
| | - Peter Simon
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany
| | - Sabine Salloch
- Institute of History, Ethics and Philosophy of Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
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11
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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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12
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Sánchez Rodríguez E, García García de Paredes A, Albillos A. Current management of acute idiopathic pancreatitis and acute recurrent pancreatitis. Rev Clin Esp 2019. [DOI: 10.1016/j.rceng.2019.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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13
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Sánchez Rodríguez E, García García de Paredes A, Albillos A. Manejo actual de la pancreatitis aguda idiopática y la pancreatitis aguda recurrente. Rev Clin Esp 2019; 219:266-274. [DOI: 10.1016/j.rce.2018.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 12/28/2018] [Indexed: 02/07/2023]
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14
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Weiss FU, Laemmerhirt F, Lerch MM. Etiology and Risk Factors of Acute and Chronic Pancreatitis. Visc Med 2019; 35:73-81. [PMID: 31192240 DOI: 10.1159/000499138] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 02/25/2019] [Indexed: 12/24/2022] Open
Abstract
Based on the recognition of common etiological and genetic risk factors, acute and chronic pancreatitis are increasingly regarded as a continuum of the same disease, with a significant overlap of clinical manifestations and phenotypes but distinct morphological and imaging appearances. Recent population-based and cohort studies have found that tobacco smoke conveys a greater risk than immoderate alcohol consumption for the development of chronic pancreatitis, and hypertriglyceridemia has been identified as a risk factor for acute pancreatitis - even when plasma levels are only mildly elevated. Hereditary pancreatitis, in its autosomal dominant form, is associated with mutations in the cationic trypsinogen gene (PRSS1), whereas a number of germline variations in other genes have been found to represent risk factors for chronic as well as acute pancreatitis. For now, most of these involve the pancreatic digestive protease/antiprotease system. Oftentimes, affected patients are burdened with multiple or accumulating risk factors, and genetic traits when combined with environmental toxins compound the chance of developing the disease. Determining the underlying etiology of pancreatitis is worth the effort since formerly intractable varieties such as autoimmune pancreatitis are now becoming increasingly treatable, and subtype-specific therapeutic modalities may become available.
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Affiliation(s)
- Frank Ulrich Weiss
- Department of Medicine A, Greifswald Medical School, Greifswald, Germany
| | - Felix Laemmerhirt
- Department of Medicine A, Greifswald Medical School, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, Greifswald Medical School, Greifswald, Germany
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15
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Abstract
Individuals with acute recurrent and chronic pancreatitis may have an inherited predisposition to the development of the disease. Pancreatitis in the setting of a significant family history of the disease can be classified as hereditary or familial pancreatitis. In this article, the authors closely examine the specific genes implicated in pancreatitis, investigate the role of genetic testing for diagnosis, and describe the impact of genetic testing results on clinical management.
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Affiliation(s)
- Aws Hasan
- Department of Internal Medicine, Columbia University Medical Center, 630 West 168 Street, New York, NY, 10032, USA
| | - Dagmara I Moscoso
- Division of Digestive and Liver Diseases, Columbia University Medical Center, 630 West 168 Street, New York, NY, 10032, USA
| | - Fay Kastrinos
- Division of Digestive and Liver Diseases, Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, 161 Fort Washington Avenue, Suite 862, New York, NY 10032, USA.
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16
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Qualitative Assessment of the Symptoms and Impact of Pancreatic Exocrine Insufficiency (PEI) to Inform the Development of a Patient-Reported Outcome (PRO) Instrument. PATIENT-PATIENT CENTERED OUTCOMES RESEARCH 2018; 10:615-628. [PMID: 28332032 PMCID: PMC5605612 DOI: 10.1007/s40271-017-0233-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Pancreatic exocrine insufficiency (PEI) affects patients with chronic pancreatitis (CP) and cystic fibrosis (CF) who produce insufficient digestive pancreatic enzymes. Common symptoms include steatorrhoea, diarrhea, and abdominal pain. OBJECTIVE The objective of the study was to develop and test the content validity of a patient-reported outcome (PRO) instrument assessing PEI symptoms and their impact on health-related quality of life. METHODS Instrument development was supported by a literature review, expert physician interviews (n = 10: Germany 4, UK 3, France 3), and exploratory, qualitative, concept-elicitation interviews with patients with CF and CP with PEI (n = 61: UK 29, Germany 18, France 14) and expert physicians (n = 10). Cognitive debriefing of the draft instrument was then performed with patients with PEI (n = 37: UK 24, Germany 8, France 5), and feasibility was assessed with physicians (n = 3). For all interviews, verbatim transcripts were qualitatively analysed using thematic analysis methods and Atlas.ti computerized qualitative software. All themes were data driven rather than a priori. RESULTS Patient interviews elicited symptoms and impacts not reported in the literature. Six symptom concepts emerged: pain, bloating, bowel symptoms, nausea/vomiting, eating problems, and tiredness/fatigue. Six impact domains were also identified. A 45-item instrument was developed in English, French, and German for testing in cognitive debriefing patient interviews. Following cognitive debriefing, 18 items were deleted. CONCLUSION Rigorous qualitative patient research and expert clinical input supported development of a PEI-specific PRO with the potential to aid management and monitoring of unmet needs among patients with PEI. The next step is to perform psychometric evaluation of the resulting instrument.
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17
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The shaping, making and baking of a pancreatologist. Pancreatology 2018; 18:347-353. [PMID: 29699868 DOI: 10.1016/j.pan.2018.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 04/17/2018] [Accepted: 04/19/2018] [Indexed: 12/11/2022]
Abstract
The European Pancreatic Club Lifetime Achievement award is a distinction awarded for research on the pancreas. It comes with the obligation to submit a review article to the society's journal, Pancreatology. Since the research topics of my group have recently been covered in reviews and book chapters I want to use this opportunity to appraise the stations of my clinical and research education, the projects that I pursued and abandoned, the lessons I have learned from them, and the women and men who influenced my training and development as a physician scientist. Some crossed my path, some become collaborators and friends, and some turned into role models and had a lasting impact on my life.
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18
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Martinelli P, Real FX. Animal Modeling of Pancreatitis-to-Cancer Progression. PANCREATIC CANCER 2018:313-347. [DOI: 10.1007/978-1-4939-7193-0_66] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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19
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Jalaly NY, Moran RA, Fargahi F, Khashab MA, Kamal A, Lennon AM, Walsh C, Makary MA, Whitcomb DC, Yadav D, Cebotaru L, Singh VK. An Evaluation of Factors Associated With Pathogenic PRSS1, SPINK1, CTFR, and/or CTRC Genetic Variants in Patients With Idiopathic Pancreatitis. Am J Gastroenterol 2017; 112:1320-1329. [PMID: 28440306 DOI: 10.1038/ajg.2017.106] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 03/01/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVES We evaluated factors associated with pathogenic genetic variants in patients with idiopathic pancreatitis. METHODS Genetic testing (PRSS1, CFTR, SPINK1, and CTRC) was performed in all eligible patients with idiopathic pancreatitis between 2010 to 2015. Patients were classified into the following groups based on a review of medical records: (1) acute recurrent idiopathic pancreatitis (ARIP) with or without underlying chronic pancreatitis; (2) idiopathic chronic pancreatitis (ICP) without a history of ARP; (3) an unexplained first episode of acute pancreatitis (AP)<35 years of age; and (4) family history of pancreatitis. Logistic regression analysis was used to determine the factors associated with pathogenic genetic variants. RESULTS Among 197 ARIP and/or ICP patients evaluated from 2010 to 2015, 134 underwent genetic testing. A total of 88 pathogenic genetic variants were found in 64 (47.8%) patients. Pathogenic genetic variants were identified in 58, 63, and 27% of patients with ARIP, an unexplained first episode of AP <35 years of age, and ICP without ARP, respectively. ARIP (OR: 18.12; 95% CI: 2.16-151.87; P=0.008) and an unexplained first episode of AP<35 years of age (OR: 2.46; 95% CI: 1.18-5.15; P=0.017), but not ICP, were independently associated with pathogenic genetic variants in the adjusted analysis. CONCLUSIONS Pathogenic genetic variants are most likely to be identified in patients with ARIP and an unexplained first episode of AP<35 years of age. Genetic testing in these patient populations may delineate an etiology and prevent unnecessary diagnostic testing and procedures.
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Affiliation(s)
- Niloofar Y Jalaly
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Robert A Moran
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Pancreatitis Center, Division of Pancreaticobiliary Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Farshid Fargahi
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mouen A Khashab
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ayesha Kamal
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Anne Marie Lennon
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Christi Walsh
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Martin A Makary
- Pancreatitis Center, Division of Pancreaticobiliary Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - David C Whitcomb
- Cell Biology &Molecular Physiology, and Human Genetics, University of Pittsburgh/UPMC, Pittsburgh, Pennsylvania, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh/UPMC, Pittsburgh, Pennsylvania, USA
| | - Liudmila Cebotaru
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Vikesh K Singh
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Pancreatitis Center, Division of Pancreaticobiliary Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Gorelick FS, Lerch MM. Do Animal Models of Acute Pancreatitis Reproduce Human Disease? Cell Mol Gastroenterol Hepatol 2017; 4:251-262. [PMID: 28752114 PMCID: PMC5518169 DOI: 10.1016/j.jcmgh.2017.05.007] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 05/26/2017] [Indexed: 12/10/2022]
Abstract
Acute pancreatitis is currently the most common cause of hospital admission among all nonmalignant gastrointestinal diseases. To understand the pathophysiology of the disease and as a potential step toward developing targeted therapies, attempts to induce the disease experimentally began more than 100 years ago. Recent decades have seen progress in developing new experimental pancreatitis models as well as elucidating many underlying cell biological and pathophysiological disease mechanisms. Some models have been developed to reflect specific causes of acute pancreatitis in human beings. However, the paucity of data relating to the molecular mechanisms of human disease, the likelihood that multiple genetic and environmental factors affect the risk of disease development and its severity, and the limited information regarding the natural history of disease in human beings make it difficult to evaluate the value of disease models. Here, we provide an overview of key models and discuss our views on their strengths for characterizing cell biological disease mechanisms or for identifying potential therapeutic targets. We also acknowledge their limitations.
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Affiliation(s)
- Fred S. Gorelick
- Yale University Medical School and Veterans Affairs Medical Center, West Haven, Connecticut
- Correspondence Address correspondence to: Fred S. Gorelick, MD, VA Connecticut Healthcare System/Yale University Medical School, 950 Campbell Avenue, West Haven, Connecticut 06516. fax: (203) 937-3852.VA Connecticut Healthcare System/Yale University Medical School950 Campbell AvenueWest HavenConnecticut 06516
| | - Markus M. Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
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21
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Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 2016; 45:1365-1375. [PMID: 27748719 PMCID: PMC5117429 DOI: 10.1097/mpa.0000000000000713] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities in chronic pancreatitis (CP) and its sequelae. This conference marked the 20th year anniversary of the discovery of the cationic trypsinogen (PRSS1) gene mutation for hereditary pancreatitis. The event was held on July 27, 2016, and structured into 4 sessions: (1) pathophysiology, (2) exocrine complications, (3) endocrine complications, and (4) pain. The current state of knowledge was reviewed; many knowledge gaps and research needs were identified that require further investigation. Common themes included the need to design better tools to diagnose CP and its sequelae early and reliably, identify predisposing risk factors for disease progression, develop standardized protocols to distinguish type 3c diabetes mellitus from other types of diabetes, and design effective therapeutic strategies through novel cell culture technologies, animal models mimicking human disease, and pain management tools. Gene therapy and cystic fibrosis conductance regulator potentiators as possible treatments of CP were discussed. Importantly, the need for CP end points and intermediate targets for future drug trials was emphasized.
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22
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Abstract
OBJECTIVES Causes of acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) are sometimes difficult to determine in children. In such patients, genetic analysis may prove helpful. The present study analyzed mutations of cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), chymotrypsin C (CTRC), and carboxypeptidase A1 (CPA1) and investigated the clinical features of children with these mutations. METHODS Genetic analyses of mutations in these 4 genes were conducted in 128 patients with ARP or CP. Characteristics of the patients showing mutations were investigated using medical records. RESULTS Fifty of the 128 (39.1%) subjects had at least 1 mutation (median age at onset, 7.6 years). Abdominal pain was the presenting symptom of pancreatitis in 48 of the 50 patients (96%). Fifteen of those 50 patients (30.0%) had a family history of pancreatitis. Gene mutations were present in PRSS1 in 26 patients, SPINK1 in 23, CTRC in 3, and CPA1 in 5. In the 31 patients with mutations in SPINK1, CTRC, or CPA1, 16 (51.6%) had homozygous or heterozygous mutations with other mutations. Three patients underwent surgery and another 4 patients underwent endoscopy to manage ARP or CP. Although 3 of the 7 patients complained of mild abdominal pain, none of those 7 patients experienced any obvious episode of ARP after treatment. CONCLUSIONS In pediatric patients with idiopathic ARP and CP, genetic analysis is useful for identifying the cause of pancreatitis. Early endoscopic or surgical treatment prevents ARP by extending the interval between episodes of pancreatitis in this population.
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23
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Abstract
Hereditary pancreatitis (HP) is a rare cause of acute, recurrent acute, and chronic pancreatitis. It may present similarly to other causes of acute and chronic pancreatitis, and often there has been a protracted evaluation prior to the diagnosis of HP. Since it was first described in 1952, multiple genetic defects that affect the action of digestive enzymes in the pancreas have been implicated. The most common mutations involve the PRSS1, CFTR, SPINK1, and CTRC genes. New mutations in these genes and previously unrecognized mutations in other genes are being discovered due to the increasing use of next-generation genomic sequencing. While the inheritance pathways of these genetic mutations may be variable and complex, sometimes involving coinheritance of other mutations, the clinical presentation of patients tends to be similar. Interactions with environmental triggers often play a role. Patients tend to present at an early age (prior to the second decade of life) and have a significantly increased risk for the development of pancreatic adenocarcinoma. Patients with HP may develop sequelae of chronic pancreatitis such as strictures and fluid collections as well as exocrine and endocrine insufficiency. Management of patients with HP involves avoidance of environmental triggers, surveillance for pancreatic adenocarcinoma, medical therapy for endocrine and exocrine insufficiency, pain management, and endoscopic or surgical treatment for complications. Care for affected patients should be individualized, with an emphasis on early diagnosis and multidisciplinary involvement to develop a comprehensive treatment strategy.
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Affiliation(s)
- Kara L Raphael
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Field F Willingham
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
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24
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Malla SR, Kärrman Mårdh C, Günther A, Mahajan UM, Sendler M, D'Haese J, Weiss FU, Lerch MM, Hansen MB, Mayerle J. Effect of oral administration of AZD8309, a CXCR2 antagonist, on the severity of experimental pancreatitis. Pancreatology 2016; 16:761-9. [PMID: 27450968 DOI: 10.1016/j.pan.2016.07.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/18/2016] [Accepted: 07/06/2016] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Acute pancreatitis is a common gastrointestinal disorder burdened with a high mortality. Two pathophysiological events during experimental pancreatitis are thought to determine the clinical course: premature digestive protease activation and tissue infiltration by inflammatory cells. We have investigated the effect of AZD8309, a potent and orally bioavailable antagonist of the chemokine receptor CXCR2, which has been proposed to regulate the transmigration of neutrophils. METHODS Male C57BL6 mice (25-30 g) received gavage feeding of AZD8309 (50 mg/kg/BW) or mannitol (controls) twice daily starting 3 h prior to pancreatitis induction. Mild pancreatitis was induced by i.p. caerulein administration (50 μg/kg BW), severe pancreatitis by intraductal taurocholate (2%). Pancreas, lung, and serum was harvested up to 48 h after pancreatitis induction and used for histopathology, amylase, lipase, cathepsin B, trypsin, and elastase activity measurements, myeloperoxidase (MPO) content and cytokine concentrations. RESULTS Oral administration of AZD8309 significantly reduced MPO in the pancreas and lungs (8 h & 24 h) and reduced intrapancreatic trypsin and elastase activity (8 h) in caerulein-pancreatitis. In taurocholate-pancreatitis AZD8309 reduced cathepsin B activity and MPO. Serum cytokine levels were reduced by AZD8309 as well as histopathological damage. CONCLUSION The CXCR2 antagonist AZD8309 reduced the transmigration of neutrophils as well as intrapancreatic protease activation in experimental pancreatitis. This effect was sufficient to reduce the overall severity of the disease. CXCR2 may therefore be a viable therapeutic target and AZD8309 a suitable agent for the treatment of acute pancreatitis.
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Affiliation(s)
| | | | - Annett Günther
- Department of Medicine A, University Medicine, Greifswald, Germany
| | - Ujjwal M Mahajan
- Department of Medicine A, University Medicine, Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine, Greifswald, Germany
| | - Jan D'Haese
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Germany
| | | | - Markus M Lerch
- Department of Medicine A, University Medicine, Greifswald, Germany
| | - Mark Berner Hansen
- AstraZeneca R&D Mölndal, Innovative and Global Medicines, Mölndal, Sweden
| | - Julia Mayerle
- Department of Medicine A, University Medicine, Greifswald, Germany.
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25
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Lerch MM, Mayerle J, Mahajan U, Sendler M, Weiss FU, Aghdassi A, Moskwa P, Simon P. Development of Pancreatic Cancer: Targets for Early Detection and Treatment. Dig Dis 2016; 34:525-31. [PMID: 27332960 DOI: 10.1159/000445233] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death worldwide and compared to other malignancies its share in cancer mortality is expected to rise further. This is due to a lack of sensitive diagnostic tools that would permit earlier detection in a potentially curable stage and the very slow progress in finding effective drug treatments for pancreatic cancer. KEY MESSAGES Aside from genetic predispositions and environmental agents, chronic pancreatitis is by far the greatest risk factor for PDAC. It also shares several etiological factors with pancreatic cancer and represents its most challenging differential diagnosis. Biomarkers that can distinguish between chronic pancreatitis and PDAC may therefore be suitable for the latter's early detection. Moreover, targeting the natural history of chronic pancreatitis would be one approach to prevent PDAC. Targeting tumor-cell signaling directly by interfering with receptor tyrosine kinases has shown some efficacy, although the results in clinical trials were less encouraging than for other cancers. Other compounds developed have targeted the formation of extracellular matrix around the tumor, the proteolytic activity in the tumor environment, histone deacetylases, hedgehog signaling and heat shock proteins, but none has yet found its way into routine patient care. Attempts to individualize treatment according to the tumor's somatic mutation profile are novel but so far impractical. CONCLUSIONS Progress in the treatment of pancreatic cancer has been exceedingly slow and mostly dependent on improved pharmaceutical preparations or combinations of established chemotherapeutic agents. The promise of major breakthroughs implied in targeting tumor signal transduction events has so far not materialized.
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Affiliation(s)
- Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
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Ito T, Ishiguro H, Ohara H, Kamisawa T, Sakagami J, Sata N, Takeyama Y, Hirota M, Miyakawa H, Igarashi H, Lee L, Fujiyama T, Hijioka M, Ueda K, Tachibana Y, Sogame Y, Yasuda H, Kato R, Kataoka K, Shiratori K, Sugiyama M, Okazaki K, Kawa S, Tando Y, Kinoshita Y, Watanabe M, Shimosegawa T. Evidence-based clinical practice guidelines for chronic pancreatitis 2015. J Gastroenterol 2016; 51:85-92. [PMID: 26725837 DOI: 10.1007/s00535-015-1149-x] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 11/18/2015] [Indexed: 02/07/2023]
Abstract
Chronic pancreatitis is considered to be an irreversible progressive chronic inflammatory disease. The etiology and pathology of chronic pancreatitis are complex; therefore, it is important to correctly understand the stage and pathology and provide appropriate treatment accordingly. The newly revised Clinical Practice Guidelines of Chronic Pancreatitis 2015 consist of four chapters, i.e., diagnosis, staging, treatment, and prognosis, and includes a total of 65 clinical questions. These guidelines have aimed at providing certain directions and clinically practical contents for the management of chronic pancreatitis, preferentially adopting clinically useful articles. These revised guidelines also refer to early chronic pancreatitis based on the Criteria for the Diagnosis of Chronic Pancreatitis 2009. They include such items as health insurance coverage of high-titer lipase preparations and extracorporeal shock wave lithotripsy, new antidiabetic drugs, and the definition of and treatment approach to pancreatic pseudocyst. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the publication of the first edition.
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Affiliation(s)
- Tetsuhide Ito
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan.
| | - Hiroshi Ishiguro
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Hirotaka Ohara
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Terumi Kamisawa
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Junichi Sakagami
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Naohiro Sata
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Yoshifumi Takeyama
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Morihisa Hirota
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Hiroyuki Miyakawa
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Hisato Igarashi
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Lingaku Lee
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Takashi Fujiyama
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Masayuki Hijioka
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Keijiro Ueda
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Yuichi Tachibana
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Yoshio Sogame
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Hiroaki Yasuda
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Ryusuke Kato
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Keisho Kataoka
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Keiko Shiratori
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Masanori Sugiyama
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Kazuichi Okazaki
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Shigeyuki Kawa
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Yusuke Tando
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Yoshikazu Kinoshita
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Mamoru Watanabe
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for chronic pancreatitis", The Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13. Ginza, Chuo, Tokyo, 104-0061, Japan
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Abstract
A 13-year-old boy with a strong family history of hereditary pancreatitis was found to have a PRSS1 mutation after being tested at age 5 years during his first documented incident of pancreatitis. Since then, a multidisciplinary team has been treating him for the diagnosis of hereditary pancreatitis. His pain episodes increased in severity over the past several months such that the pain began to severely interfere with his daily life. After extensive discussion, a total pancreatectomy with auto islet cell transplant was performed. He is now pain free and does not require any insulin. This leads us to the questions of what is hereditary pancreatitis and how is it diagnosed? What are the management and follow-up strategies needed for these patients? This article addresses these questions and informs the reader about this diagnosis and the importance of having a high index of clinical suspicion.
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Genetic susceptibility factors for alcohol-induced chronic pancreatitis. Pancreatology 2015; 15:S23-31. [PMID: 26149858 DOI: 10.1016/j.pan.2015.05.476] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 04/10/2015] [Accepted: 05/27/2015] [Indexed: 12/11/2022]
Abstract
Chronic pancreatitis is a progressive inflammatory disease of the pancreas and frequently associated with immoderate alcohol consumption. Since only a small proportion of alcoholics eventually develop chronic pancreatitis genetic susceptibility factors have long been suspected to contribute to the pathogenesis of the disease. Smaller studies in ethnically defined populations have found that not only polymorphism in proteins involved in the metabolism of ethanol, such as Alcohol Dehydrogenase and Aldehyde Dehydrogenase, can confer a risk for developing chronic pancreatitis but also mutations that had previously been reported in association with idiopathic pancreatitis, such as SPINK1 mutations. In a much broader approach employing genome wide search strategies the NAPS study found that polymorphisms in the Trypsin locus (PRSS1 rs10273639), and the Claudin 2 locus (CLDN2-RIPPLY1-MORC4 locus rs7057398 and rs12688220) confer an increased risk of developing alcohol-induced pancreatitis. These results from North America have now been confirmed by a European consortium. In another genome wide approach polymorphisms in the genes encoding Fucosyltransferase 2 (FUT2) non-secretor status and blood group B were not only found in association with higher serum lipase levels in healthy volunteers but also to more than double the risk for developing alcohol-associated chronic pancreatitis. These novel genetic associations will allow to investigate the pathophysiological and biochemical basis of alcohol-induced chronic pancreatitis on a cellular level and in much more detail than previously possible.
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Therapeutic step-up strategy for management of hereditary pancreatitis in children. J Pediatr Surg 2015; 50:511-4. [PMID: 25840052 DOI: 10.1016/j.jpedsurg.2014.05.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Revised: 05/06/2014] [Accepted: 05/07/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND/PURPOSE Various different regimes exist for the treatment of hereditary pancreatitis in childhood. Here, we propose a therapeutic pathway with emphasis on endoscopic and surgical procedures. METHODS From 2006 to 2013, 12 patients with a diagnosis of hereditary pancreatitis were prospectively included in a therapeutic step-up schema. The treatment outcome was evaluated and correlated to aetiological factors and pathoanatomic findings. RESULTS After diagnostic work-up (laboratory data, ultrasound examination, magnetic resonance cholangiopancreatography and genetic testing), all 12 patients underwent early endoscopic retrograde cholangiopancreatography (ERCP), which was successfully performed in ten children. Obstructive pancreatitis was found in eight children, and required sphincterotomy, dilation and stenting for 12 months. In two children with unsuccessful ERCP, open surgical drainage procedures were performed. After a mean follow-up of 32 months all children are free of recurrence of pancreatitis without any impairment of everyday activities. CONCLUSIONS For children with hereditary pancreatitis, a therapeutic step plan with early ERCP and open surgical drainage procedures in case of impossible or insufficient endoscopic treatment prevents recurring pancreatitis and offers a normal quality of life without any major complications.
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30
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Weiss FU, Schurmann C, Guenther A, Ernst F, Teumer A, Mayerle J, Simon P, Völzke H, Radke D, Greinacher A, Kuehn JP, Zenker M, Völker U, Homuth G, Lerch MM. Fucosyltransferase 2 (FUT2) non-secretor status and blood group B are associated with elevated serum lipase activity in asymptomatic subjects, and an increased risk for chronic pancreatitis: a genetic association study. Gut 2015; 64:646-56. [PMID: 25028398 DOI: 10.1136/gutjnl-2014-306930] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Serum lipase activities above the threefold upper reference limit indicate acute pancreatitis. We investigated whether high lipase activity-within the reference range and in the absence of pancreatitis-are associated with genetic single nucleotide polymorphisms (SNP), and whether these identified SNPs are also associated with clinical pancreatitis. METHODS Genome-wide association studies (GWAS) on phenotypes 'serum lipase activity' and 'high serum lipase activity' were conducted including 3966 German volunteers from the population-based Study-of-Health-in-Pomerania (SHIP). Lead SNPs associated on a genome-wide significance level were replicated in two cohorts, 1444 blood donors and 1042 pancreatitis patients. RESULTS Initial discovery GWAS detected SNPs within or near genes encoding the ABO blood group specifying transferases A/B (ABO), Fucosyltransferase-2 (FUT2), and Chymotrypsinogen-B2 (CTRB2), to be significantly associated with lipase activity levels in asymptomatic subjects. Replication analyses in blood donors confirmed the association of FUT-2 non-secretor status (OR=1.49; p=0.012) and ABO blood-type-B (OR=2.48; p=7.29×10(-8)) with high lipase activity levels. In pancreatitis patients, significant associations were found for FUT-2 non-secretor status (OR=1.53; p=8.56×10(-4)) and ABO-B (OR=1.69, p=1.0×10(-4)) with chronic pancreatitis, but not with acute pancreatitis. Conversely, carriers of blood group O were less frequently affected by chronic pancreatitis (OR=0.62; p=1.22×10(-05)) and less likely to have high lipase activity levels (OR=0.59; p=8.14×10(-05)). CONCLUSIONS These are the first results indicating that ABO blood type-B as well as FUT2 non-secretor status are common population-wide risk factors for developing chronic pancreatitis. They also imply that, even within the reference range, elevated lipase activities may indicate subclinical pancreatic injury in asymptomatic subjects.
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Affiliation(s)
- Frank Ulrich Weiss
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Claudia Schurmann
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany The Charles Bronfman Institute for Personalized Medicine, Genetics of Obesity & Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Annett Guenther
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Florian Ernst
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Alexander Teumer
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Julia Mayerle
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Peter Simon
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Dörte Radke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Andreas Greinacher
- Department of Transfusion Medicine, Institute of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Jens-Peter Kuehn
- Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
| | - Martin Zenker
- Institute of Human Genetics, Otto-von-Guericke-Universität Magdeburg, University Hospital Magdeburg, Germany
| | - Uwe Völker
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Georg Homuth
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
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31
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Takács T, Czakó L, Dubravcsik Z, Farkas G, Hegyi P, Hritz I, Kelemen D, Lásztity N, Morvay Z, Oláh A, Pap Á, Párniczky A, Patai Á, Sahin-Tóth M, Szentkereszti Z, Szmola R, Tiszlavicz L, Szücs Á. [Chronic pancreatitis. Evidence based management guidelines of the Hungarian Pancreatic Study Group]. Orv Hetil 2015; 156:262-288. [PMID: 25661971 DOI: 10.1556/oh.2015.30060] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Chronic pancreatitis is an inflammatory disease associated with structural and functional damage of the pancreas. In most cases pain, maldigestion and weight loss are the leading symptoms, which significantly worsen the quality of life. Correct diagnosis and differential diagnosis of chronic pancreatitis and treatment of these patients requires up-to-date and evidence based treatment guidelines. The Hungarian Pancreatic Study Group proposed to prepare an evidence based guideline based on the available international guidelines and evidence. The preparatory and consultation task force appointed by the Hungarian Pancreatic Study Group translated and complemented and/or modified the international guidelines if it was necessary. 123 relevant clinical questions in 11 topics were defined. Evidence was classified according to the UpToDate® grading system. The draft of the guidelines were presented and discussed at the consensus meeting in September 12, 2014. All clinical questions were accepted with total or strong agreement. The present guideline is the first evidence based guideline for chronic pancreatitis in Hungary. This guideline provides very important and helpful data for tuition, everyday practice and proper financing of chronic pancreatitis. Therefore, the authors believe that these guidelines will widely become a basic reference in Hungary.
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Affiliation(s)
- Tamás Takács
- Szegedi Tudományegyetem, Általános Orvostudományi Kar, Szent-Györgyi Albert Klinikai Központ I. Belgyógyászati Klinika Szeged
| | - László Czakó
- Szegedi Tudományegyetem, Általános Orvostudományi Kar, Szent-Györgyi Albert Klinikai Központ I. Belgyógyászati Klinika Szeged
| | | | - Gyula Farkas
- Szegedi Tudományegyetem, Általános Orvostudományi Kar, Szent-Györgyi Albert Klinikai Központ Sebészeti Klinika Szeged
| | - Péter Hegyi
- Szegedi Tudományegyetem, Általános Orvostudományi Kar, Szent-Györgyi Albert Klinikai Központ I. Belgyógyászati Klinika Szeged MTA-SZTE Lendület Gasztroenterológiai Multidiszciplináris Kutatócsoport Szeged
| | - István Hritz
- Szegedi Tudományegyetem, Általános Orvostudományi Kar, Szent-Györgyi Albert Klinikai Központ I. Belgyógyászati Klinika Szeged Bács-Kiskun Megyei Kórház Gasztroenterológia Kecskemét
| | - Dezső Kelemen
- Pécsi Tudományegyetem, Általános Orvostudományi Kar Klinikai Központ, Sebészeti Klinika Pécs
| | | | - Zita Morvay
- Szegedi Tudományegyetem, Általános Orvostudományi Kar, Szent-Györgyi Albert Klinikai Központ Radiológiai Klinika Szeged
| | - Attila Oláh
- Petz Aladár Megyei Oktató Kórház Sebészeti Osztály Győr
| | - Ákos Pap
- Péterfy Sándor utcai Kórház-Rendelőintézet Budapest
| | | | - Árpád Patai
- Semmelweis Egyetem, Általános Orvostudományi Kar II. Belgyógyászati Klinika Budapest
| | - Miklós Sahin-Tóth
- Boston University Henry M. Goldman School of Dental Medicine Department of Molecular and Cell Biology Boston Massachusetts USA
| | - Zsolt Szentkereszti
- Debreceni Egyetem, Általános Orvostudományi Kar, Orvos- és Egészségtudományi Centrum Sebészeti Klinika Debrecen
| | - Richárd Szmola
- Országos Onkológiai Intézet Intervenciós Gasztroenterológiai Részleg Budapest
| | - László Tiszlavicz
- Szegedi Tudományegyetem, Általános Orvostudományi Kar, Szent-Györgyi Albert Klinikai Központ Pathologiai Intézet Szeged
| | - Ákos Szücs
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Sebészeti Klinika Budapest
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ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015; 110:223-62; quiz 263. [PMID: 25645574 PMCID: PMC4695986 DOI: 10.1038/ajg.2014.435] [Citation(s) in RCA: 1082] [Impact Index Per Article: 108.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023]
Abstract
This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.
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Ravi Kanth VV, Nageshwar Reddy D. Genetics of acute and chronic pancreatitis: An update. World J Gastrointest Pathophysiol 2014; 5:427-437. [PMID: 25400986 PMCID: PMC4231507 DOI: 10.4291/wjgp.v5.i4.427] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 10/01/2014] [Accepted: 10/14/2014] [Indexed: 02/06/2023] Open
Abstract
Progress made in identifying the genetic susceptibility underlying acute and chronic pancreatitis has benefitted the clinicians in understanding the pathogenesis of the disease in a better way. The identification of mutations in cationic trypsinogen gene (PRSS1 gene; functional gain mutations) and serine protease inhibitor kazal type 1 (SPINK1 gene; functional loss mutations) and other potential susceptibility factors in genes that play an important role in the pancreatic secretory functions or response to inflammation during pancreatic injury has changed the current concepts and understanding of a complex multifactorial disease like pancreatitis. An individual's susceptibility to the disease is governed by genetic factors in combination with environmental factors. Candidate gene and genetic linkage studies have identified polymorphisms in cationic trypsinogen (PRSS1), SPINK1, cystic fibrosis trans-membrane conductance regulator (CFTR), Chymotrypsinogen C (CTRC), Cathepsin B (CTSB) and calcium sensing receptor (CASR). Individuals with polymorphisms in the mentioned genes and other as yet identified genes are at an enhanced risk for the disease. Recently, polymorphisms in genes other than those involved in "intra-pancreatic trypsin regulatory mechanism" namely Claudin-2 (CLDN2) and Carboxypeptidase A1 (CPA1) gene have also been identified for their association with pancreatitis. With ever growing number of studies trying to identify the genetic susceptibility in the form of single nucleotide polymorphisms, this review is an attempt to compile the available information on the topic.
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Mastoraki A, Tzortzopoulou A, Tsela S, Danias N, Sakorafas G, Smyrniotis V, Arkadopoulos N. Hereditary pancreatitis: dilemmas in differential diagnosis and therapeutic approach. J Gastrointest Cancer 2014; 45:22-6. [PMID: 24242859 DOI: 10.1007/s12029-013-9559-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Hereditary pancreatitis (HP) is a rare, heterogeneous familial disease and should be suspected in any patient who has suffered at least two attacks of acute pancreatitis for which there is no underlying cause and unexplained chronic pancreatitis with a family history in a first- or second-degree relative. Genetic factors have been implied in cases of familial chronic pancreatitis. The most common PRSS1 mutations worldwide are the R122H and N29I variants. CLINICAL FEATURES HP usually appears with an acute, a recurrent acute, and a chronic phase, referring to the inflammation of the pancreas and the symptoms' onset and duration. The clinical features of acute pancreatitis begin in childhood and last less than 6 months. HP carries a 50-70-fold increased risk of pancreatic cancer within 7-30 years of disease onset. HP diagnosis is defined by the presence of a detected cationic trypsinogen gene mutation (with or without clinical or radiological manifestations of chronic pancreatitis) or when the patient's family satisfies the requirements of the EUROPAC. TREATMENT With regard to the therapeutic approach, pancreatic enzyme replacement therapy and analgesics are offered to control pain. In addition, endoscopic and surgical intersections are reserved for all relevant complications. Unfortunately, surgical removal of affected pancreatic tissue does not necessarily guarantee the patient's long-term survival. Furthermore, the prognostic factors and the efficacy of extended resection remain controversial.
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Affiliation(s)
- Aikaterini Mastoraki
- 4th Department of Surgery, ATTIKON University Hospital, Athens University Medical School, 1 Rimini str., Chaidari, 124 62, Athens, Greece,
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35
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Kwak BO, Lee MJ, Park HW, Kim KS, Chung S. A case of recurrent acute pancreatitis in an obese child. Nutrition 2014; 30:1213-6. [DOI: 10.1016/j.nut.2014.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 03/10/2014] [Accepted: 04/01/2014] [Indexed: 10/25/2022]
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36
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Kamisawa T, Chari ST, Lerch MM, Kim MH, Gress TM, Shimosegawa T. Republished: recent advances in autoimmune pancreatitis: type 1 and type 2. Postgrad Med J 2014; 90:18-25. [PMID: 24336310 DOI: 10.1136/postgradmedj-2012-304224rep] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.
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Affiliation(s)
- Terumi Kamisawa
- Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, , Tokyo, Japan
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37
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Shelton CA, Whitcomb DC. Genetics and treatment options for recurrent acute and chronic pancreatitis. ACTA ACUST UNITED AC 2014; 12:359-71. [PMID: 24954874 DOI: 10.1007/s11938-014-0022-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OPINION STATEMENT Worldwide research efforts demonstrate a major role of gene-environment interactions for the risk, development, and progression of most pancreatic diseases, including recurrent acute and chronic pancreatitis. New findings of pancreas disease-associated risk variants have been reported in the CPA1, GGT1, CLDN2, MMP1, MTHFR, and other genes. These risk genes and their regulatory regions must be added to the known pathogenic variants in the PRSS1, SPINK1, CFTR, CTRC, CASR, UBR1, SBDS, CEL, and CTSB genes. This new knowledge promises to improve disease management and prevention through personalized medicine. At the same time, however, knowledge of an increasing number of pathogenic variants, and their complicated effects when present in combination, results in increasing difficulty in interpretation and development of recommendations. Direct-to-consumer marketing of genetic testing results also adds complexity to disease management paradigms, especially without interpretation and, in many cases, proven accuracy. While improvements in the ability to rapidly and accurately interpret complex genetic tests are clearly needed, some results, such as pathogenic CFTR variants, including a new class of bicarbonate-defective mutations, and PRSS1 variants have immediate implications that direct management. In addition, discovery of pancreatitis-associated genetic variants in patients with glucose intolerance may suggest underlying type 3c diabetes, which also has implications for treatment and disease management.
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Affiliation(s)
- Celeste A Shelton
- Department of Human Genetics, University of Pittsburgh, Crabtree Hall 130 De Soto Street, Pittsburgh, PA, 15261, USA,
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38
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Haemorrhagic pseudocyst of the pancreatic tail causing acute abdominal pain in a 12-year-old girl. ANNALS OF PEDIATRIC SURGERY 2014. [DOI: 10.1097/01.xps.0000434486.86253.78] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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39
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Sarner M. History of the International Association of Pancreatology 1984-2008: a personal perspective by Martin Sarner. Pancreatology 2014; 14:2-5. [PMID: 24555970 DOI: 10.1016/j.pan.2014.01.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Martin Sarner
- 41A Mackennal Street, St. John's Wood, London NW8 7DH, UK.
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40
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Kamisawa T, Chari ST, Lerch MM, Kim MH, Gress TM, Shimosegawa T. Recent advances in autoimmune pancreatitis: type 1 and type 2. Gut 2013; 62:1373-80. [PMID: 23749606 DOI: 10.1136/gutjnl-2012-304224] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.
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Affiliation(s)
- Terumi Kamisawa
- Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
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41
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Abstract
Chronic pancreatitis is a common disorder associated with significant morbidity and mortality. Interdisciplinary consensus guidelines have recently updated the definitions and diagnostic criteria for chronic pancreatitis and provide a critical assessment of therapeutic procedures. Diagnostic imaging relies on endoscopic ultrasound (EUS) as the most sensitive technique, whereas computed tomography (CT) and magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) remain a frequent preoperative requirement. Endoscopic retrograde cholangiopancreatography (ERCP) is now used mostly as a therapeutic procedure except for the differential diagnosis of autoimmune pancreatitis. Complications of chronic pancreatitis, such as pseudocysts, duct stricture and intractable pain can be treated with endoscopic interventions as well as open surgery. In the treatment of pseudocysts endoscopic drainage procedures now prevail while pain treatment has greater long-term effectiveness following surgical procedures. Currently, endocopic as well as surgical treatment of chronic pancreatitis require an ever increasing degree of technical and medical expertise and are provided increasingly more often by interdisciplinary centres. Surgical treatment is superior to interventional therapy regarding the outcome of pain control and duodenum-preserving pancreatic head resection is presently the surgical procedure of choice.
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Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology 2013; 144:1180-93. [PMID: 23622127 DOI: 10.1053/j.gastro.2012.12.043] [Citation(s) in RCA: 313] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 12/06/2012] [Accepted: 12/13/2012] [Indexed: 12/16/2022]
Abstract
Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer. In vitro models can be used to study early stage, short-term processes that involve acinar cell responses. Rodent models reproducibly develop mild or severe disease. One of the most commonly used pancreatitis models is created by administration of supraphysiologic concentrations of caerulein, an ortholog of cholecystokinin. Induction of chronic pancreatitis with factors thought to have a role in human disease, such as combinations of lipopolysaccharide and chronic ethanol feeding, might be relevant to human disease. Models of autoimmune chronic pancreatitis have also been developed. Most models, particularly of chronic pancreatitis, require further characterization to determine which features of human disease they include.
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Affiliation(s)
- Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, Greifswald, Germany.
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Mayerle J, Hoffmeister A, Werner J, Witt H, Lerch MM, Mössner J. Chronic pancreatitis--definition, etiology, investigation and treatment. DEUTSCHES ARZTEBLATT INTERNATIONAL 2013; 110:387-93. [PMID: 23826027 DOI: 10.3238/arztebl.2013.0387] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 04/04/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND Chronic pancreatitis has an annual incidence of 23 per 100 000 population in Germany, where it accounts for about 10 000 hospital admissions per year. The disease shortens the life expectancy of its sufferers by an average of 23%. It most commonly affects men aged 20 to 40. METHODS A systematic search for pertinent literature retrieved 19 569 publications, 485 of which were considered in the creation of this guideline, including 67 randomized controlled trials (RCTs). A consensus conference reached agreement on a total of 156 definitions and recommendations. RESULTS The identification of genetic risk factors for pancreatitis is now well established. The diagnosis is made mainly with ultrasonography of the pancreas; if the findings are uncertain, further studies can be performed, including endosonography and endosonographically assisted fine-needle puncture for the examination of small foci of disease. Computed tomography and MRI/magnetic resonance cholangiopancreatography are supplementary diagnostic methods. Endoscopic retrograde cholangiopancreatography is now used almost exclusively for treatment, rather than for diagnosis. 30% to 60% of patients develop complications of chronic pancreatitis, including pseudocysts, bile-duct stenosis, or medically intractable pain, which can be treated with an endoscopic or surgical intervention. Patients with steatorrhea, a pathological pancreatic function test, or clinical evidence of malabsorption should be given pancreatin supplementation. The head of the pancreas should be resected if it contains an inflammatory pseudotumor. CONCLUSION The management of patients with chronic pancreatitis requires close interdisciplinary collaboration, as it can be treated medically and endoscopically as well as surgically.
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Affiliation(s)
- Julia Mayerle
- University Medicine Greifswald, Department of Internal Medicine A
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Abstract
Hereditary pancreatitis shares a majority of clinical and morphologic features with chronic alcoholic pancreatitis, but may present at an earlier age. The term hereditary pancreatitis has primarily been associated with mutations in the serine protease 1 gene (PRSS1) which encodes for cationic trypsinogen. PRSS1 mutations account for approximately 68-81% of hereditary pancreatitis. Mutations in other genes, primarily serine protease inhibitor Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) are also associated with hereditary pancreatitis. While chronic alcoholic pancreatitis may develop in the fourth or fifth decades, patients with hereditary pancreatitis may develop symptoms in the first or second decades of life. Hereditary pancreatitis is diagnosed either by detecting a causative gene mutation or by the presence of chronic pancreatitis in two first-degree or three second-degree relatives, in two or more generations, without precipitating factors and with a negative workup for known causes. Patients with hereditary pancreatitis may have recurrent acute pancreatitis and may develop pancreatic exocrine and endocrine insufficiency. Hereditary pancreatitis may involve premature trypsinogen activation or decreased control of trypsin. Recurrent inflammation can lead to acute pancreatitis and subsequently to chronic pancreatitis with parenchymal calcification. There is a markedly increased risk of pancreatic carcinoma compared with the general population. Patients are often referred for evaluation of pancreatitis, biliary or pancreatic ductal dilatation, jaundice, biliary obstruction, pancreatic duct stone or stricture, pancreatic pseudocysts, and for evaluation for malignancy. Medical treatment includes pancreatic enzyme supplementation, nutritional supplementation, diabetes management, and palliation of pain. Patients should avoid tobacco use and alcohol exposure. Hereditary pancreatitis is reviewed and recommendations for genetic testing are discussed.
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Affiliation(s)
- Milan R. Patel
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Amanda L. Eppolito
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Field F. Willingham
- Director of Endoscopy, Assistant Professor of Medicine, Division of Digestive Diseases, Department of Medicine, 1365 Clifton Road, NE, Atlanta, GA 30322, USA
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Lerch MM, Halangk W, Mayerle J. Preventing pancreatitis by protecting the mitochondrial permeability transition pore. Gastroenterology 2013; 144:265-269. [PMID: 23260493 DOI: 10.1053/j.gastro.2012.12.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Markus M Lerch
- Department of Medicine A, Greifswald University Medicine, Greifswald, Germany.
| | - Walter Halangk
- Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Julia Mayerle
- Department of Medicine A, Greifswald University Medicine, Greifswald, Germany
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Graziani R, Frulloni L, Cicero C, Manfredi R, Ambrosetti MC, Mautone S, Pozzi Mucelli R. Bull's-eye pattern of pancreatic-duct stones on multidetector computed tomography and gene-mutation-associated pancreatitis (GMAP). Radiol Med 2012; 117:1275-86. [PMID: 23090249 DOI: 10.1007/s11547-012-0888-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Accepted: 01/13/2012] [Indexed: 01/28/2023]
Abstract
PURPOSE This study prospectively assessed whether the presence of a bull's-eye pattern of pancreatic-duct stones on multidetector computed tomography (MDCT) correlated with gene-mutation-associated pancreatitis (GMAP) and whether other signs suggestive of GMAP can be detected with MDCT. MATERIALS AND METHODS Forty-seven patients with chronic calcific pancreatitis underwent genetic testing for CFTR, SPINK1 and PRSS1 mutations and an MDCT scan of the abdomen. Qualitative analysis assessed the presence or absence of pancreatic-duct stones with bull's-eye appearance. Quantitative analysis included the number and maximum diameter of stones and the diameter of the main pancreatic duct. RESULTS Fifteen of 47 patients (32%) were positive for gene mutations (GMAP patients). The bull's-eye pattern was found in 10/15 patients (67%) with GMAP and in 4/32 (12%) patients with chronic pancreatitis not associated with GMAP (NGMAP; p<0.0001). The mean diameter of duct stones was 15 mm in patients with GMAP and 10 mm in patients with NGMAP (p<0.04). CONCLUSIONS The presence of duct stones with a bull's-eye pattern correlates with GMAP. Duct stones with diameter ≥15 mm are another sign suggestive of GMAP.
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Affiliation(s)
- R Graziani
- Istituto di Radiologia, Università di Verona, P.le L.A. Scuro 10, 37134, Verona, Italy.
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Perez-Johnston R, Sainani NI, Sahani DV. Imaging of Chronic Pancreatitis (Including Groove and Autoimmune Pancreatitis). Radiol Clin North Am 2012; 50:447-66. [DOI: 10.1016/j.rcl.2012.03.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Abstract
With novel genetic technologies available, there is a paradigm shift in the way that risk assessments, diagnoses,and therapies for genetic susceptibility syndromes are addressed. Hereditary pancreatitis is among these conditions, for which genetic counseling and next generation sequencing, help families better understand, cope with and live healthier lives. Identifying a genetic etiology to a condition formally believed to be solely environmentally induced can alter the path for treatment for many patients. This finding introduces the concept of gene-environment interactions in human disease and the relationship between genetic predisposition and exposure risk in disease development. The genetic counseling process is complex with medical explanations, psychosocial issues relating to coping with diagnosis, potential future health problems, recurrence risks and family planning. These sometimes difficult conversations can be facilitated by a genetic counselor as a member of the multidisciplinary team. This chapter addresses the intricate medical and psychosocial issues that can arise in the setting of treating patients with hereditary pancreatitis.
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Affiliation(s)
- Sheila Solomon
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213
| | - David C Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213
- Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, PA, 15213
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, 15213
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Mayerle J, Dummer A, Sendler M, Malla SR, van den Brandt C, Teller S, Aghdassi A, Nitsche C, Lerch MM. Differential roles of inflammatory cells in pancreatitis. J Gastroenterol Hepatol 2012; 27 Suppl 2:47-51. [PMID: 22320916 DOI: 10.1111/j.1440-1746.2011.07011.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The incidence of acute pancreatitis per 100,000 of population ranges from 5 to 80. Patients suffering from hemorrhagic-necrotizing pancreatitis die in 10-24% of cases. 80% of all cases of acute pancreatitis are etiologically linked to gallstone disease immoderate alcohol consumption. As of today no specific causal treatment for acute pancreatitis exists. Elevated C-reactive protein levels above 130,mg/L can also predict a severe course of acute pancreatitis. The essential medical treatment for acute pancreatitis is the correction of hypovolemia. Prophylactic antibiotics should be restricted to patients with necrotizing pancreatitis, infected necrosis or other infectious complications. However, as premature intracellular protease activation is known to be the primary event in acute pancreatitis. Severe acute pancreatitis is characterized by an early inflammatory immune response syndrome (SIRS) and a subsequent compensatory anti-inflammatory response syndrome (CARS) contributing to severity as much as protease activation does. CARS suppresses the immune system and facilitates nosocomial infections including infected pancreatic necrosis, one of the most feared complications of the disease. A number of attempts have been made to suppress the early systemic inflammatory response but even if these mechanisms have been found to be beneficial in animal models they failed in daily clinical practice.
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Affiliation(s)
- Julia Mayerle
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
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Aghdassi AA, Mayerle J, Christochowitz S, Weiss FU, Sendler M, Lerch MM. Animal models for investigating chronic pancreatitis. FIBROGENESIS & TISSUE REPAIR 2011; 4:26. [PMID: 22133269 PMCID: PMC3274456 DOI: 10.1186/1755-1536-4-26] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 12/01/2011] [Indexed: 02/06/2023]
Abstract
Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed.
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Affiliation(s)
- Alexander A Aghdassi
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
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