RESUMO
BACKGROUND: Recent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression. OBJECTIVE: To explore the faecal and salivary microbiota as potential diagnostic biomarkers. METHODS: We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case-control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case-control study (n=76), in the validation phase. RESULTS: Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19-9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation. CONCLUSION: Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.
Assuntos
Carcinoma Ductal Pancreático , Microbiota , Neoplasias Pancreáticas , Biomarcadores Tumorais , Antígeno CA-19-9 , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Estudos de Casos e Controles , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , RNA Ribossômico 16S/genética , Neoplasias PancreáticasRESUMO
BACKGROUND: The value of serum triglycerides (TGs) related to complications and the severity of acute pancreatitis (AP) has not been clearly defined. Our study aimed to analyze the association of elevated levels of TG with complications and the severity of AP. METHODS: The demographic and clinical data of patients with AP were prospectively analyzed. TG levels were measured in the first 24 h of admission. Patients were divided into two groups: one with TG values of<200 mg/dL and another with TG≥200 mg/dL. Data on the outcomes of AP were collected. RESULTS: From January 2016 to December 2019, 247 cases were included: 200 with TG<200 mg/dL and 47 with TG≥200 mg/dL. Triglyceride levels≥200 mg/dL were associated with respiratory failure (21.3 vs. 10%, p=0.033), renal failure (23.4 vs. 12%, p=0.044), cardiovascular failure (19.1 vs. 7.5%, p=0.025), organ failure (34 vs. 18.5%, p=0.02), persistent organ failure (27.7 vs. 9.5%, p=0.001), multiple organ failure (19.1 vs. 8%, p=0.031), moderately severe and severe AP (68.1 vs. 40.5%, p=0.001), pancreatic necrosis (63.8 vs. 34%, p<0.001), and admission to the intensive care unit (27.7 vs. 9.5%, p=0.003). In the multivariable analysis, a TG level of≥200 mg/dL was independently associated with respiratory, renal, and cardiovascular failure, organ failure, persistent organ failure, multiple organ failure, pancreatic necrosis, severe pancreatitis, and admission to the intensive care unit (p<0.05). CONCLUSIONS: In our cohort, TG≥200 mg/dL was related to local and systemic complications. Early determinations of TG levels in AP could help identify patients at risk of complications.
Assuntos
Pancreatite Necrosante Aguda , Doença Aguda , Humanos , Insuficiência de Múltiplos Órgãos , Estudos Retrospectivos , Índice de Gravidade de Doença , TriglicerídeosRESUMO
Chronic pancreatitis is a chronic fibroinflammatory disease of the pancreas with prevalence around 50 cases per 100,000 inhabitants. It appears to originate from diverse and yet mixed etiological factors. It shows highly variable presenting features, complication types and disease progression rates. Treatment options are as wide as the multiple personalized scenarios the disease might exhibit at a given time point. Some medical societies have developed guidelines for diagnosis and treatment based on scientific evidence. Although these efforts are to be acknowledged, the gathered level of evidence for any topic is usually low and, therefore, recommendations tend to be vague or weak. In the present series of position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on interdisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 1 of this paper series discusses topics on aetiology and diagnosis of chronic pancreatitis. Main clinical features are abdominal pain, exocrine and endocrine insufficiency and symptoms derived from complications. Some patients remain symptom-free. Diagnosis (definitive, probable or uncertain) should be based on objective data obtained from imaging, histology, or functional tests.
Assuntos
Pancreatite Crônica/diagnóstico , Pancreatite Crônica/etiologia , Diagnóstico Diferencial , Humanos , Cirrose Hepática/diagnóstico , Imageamento por Ressonância Magnética , Medição da Dor/métodos , Testes de Função Pancreática/métodos , Neoplasias Pancreáticas/diagnóstico , Pseudocisto Pancreático/diagnóstico , Pancreatite Crônica/patologia , Fatores de Risco , Sociedades Médicas , Espanha , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
Chronic pancreatitis is associated with impaired quality of life, high incidence of comorbidities, serious complications and mortality. Healthcare costs are exorbitant. Some medical societies have developed guidelines for treatment based on scientific evidence, but the gathered level of evidence for any individual topic is usually low and, therefore, recommendations tend to be vague or weak. In the present position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on multidisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 2 of these paper series discuss topics on treatment and follow-up. The therapeutic approach should include assessment of etiological factors, clinical manifestations and complications. The complexity of these patients advocates for detailed evaluation in multidisciplinary committees where conservative, endoscopic, interventional radiology or surgical options are weighed. Specialized multidisciplinary units of Pancreatology should be constituted. Indications for surgery are refractory pain, local complications, and suspicion of malignancy. Enzyme replacement therapy is indicated if evidence of exocrine insufficiency or after pancreatic surgery. Response should be evaluated by nutritional parameters and assessment of symptoms. A follow-up program should be planned for every patient with chronic pancreatitis.
Assuntos
Pancreatite Crônica , Qualidade de Vida , Seguimentos , Humanos , Pancreatite Crônica/complicações , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/terapia , Sociedades MédicasRESUMO
OBJECTIVES: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI). DESIGN: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis. RESULTS: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55). CONCLUSION: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Obesidade/complicações , Neoplasias Pancreáticas/etiologia , Idoso , Índice de Massa Corporal , Peptídeo C/sangue , Estudos de Casos e Controles , Causalidade , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Escolaridade , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Análise de Mediação , Pessoa de Meia-Idade , Obesidade/genética , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fatores Sexuais , Fumar/efeitos adversosRESUMO
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, mainly due to late diagnosis at advanced tumor stages. In this study, we aimed to identify plasma protein biomarkers for early detection of PDAC. Totally, 135 PDAC patients (early PDAC, Stage I/II, n = 71; advanced PDAC, Stage III/IV, n = 64), 13 benign lesions/chronic pancreatitis patients and 72 healthy individuals, with corresponding plasma samples from a case-control study in Sweden were included. A proximity extension assay was used to detect 92 cancer-related proteins, and an enzyme-linked immunosorbent assay/electrochemiluminescence immunoassay was used to detect CA19-9. Predictive features were selected from these 93 candidate proteins and three covariates in the Swedish participants, and then validated in Spanish participants, including 37 early PDAC patients, 38 advanced PDAC patients, 19 chronic pancreatitis patients and 36 healthy controls. A panel of eight proteins discriminating early PDAC from healthy individuals was identified, and the cross-validated area under the curves (AUCs) were 0.85 (95% confidence interval, 95% CI, 0.78-0.91) and 0.81 (95% CI, 0.70-0.92) in the Swedish and Spanish participants, respectively. Another eight-protein panel was predictive for classifying advanced PDAC from healthy controls in two populations, with cross-validated AUCs of 0.89 (95% CI, 0.83-0.95) and 0.90 (95% CI, 0.83-0.98), respectively. In conclusion, eight protein biomarkers were identified and externally validated, potentially allowing early detection of PDAC patients if validated in additional prospective studies.
Assuntos
Biomarcadores Tumorais/sangue , Proteínas Sanguíneas/análise , Carcinoma Ductal Pancreático/diagnóstico , Detecção Precoce de Câncer/métodos , Neoplasias Pancreáticas/diagnóstico , Idoso , Antígenos CD/sangue , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/sangue , Estudos de Casos e Controles , Moléculas de Adesão Celular/sangue , Feminino , Humanos , Cadeias beta de Integrinas/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Curva ROCRESUMO
BACKGROUND: Chronic pancreatitis (CP) is a complex inflammatory disease with remarkably impaired quality of life and permanent damage of the pancreas. This paper is part of the international consensus guidelines on CP and presents the consensus on factors elevating the risk for CP. METHODS: An international working group with 20 experts on CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 14 statements generated from evidence on four questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available per statement. To determine the level of agreement, the working group voted on the 14 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: Strong consensus and agreement were obtained for the following statements: Alcohol, smoking, and certain genetic alterations are risk factors for CP. Past history, family history, onset of symptoms, and life-style factors including alcohol intake and smoking history should be determined. Alcohol consumption dose-dependently elevates the risk of CP up to 4-fold. Ever smokers, even smoking less than a pack of cigarettes per day, have an increased risk for CP, as compared to never smokers. CONCLUSIONS: Both genetic and environmental factors can markedly elevate the risk for CP. Therefore, health-promoting lifestyle education and in certain cases genetic counselling should be employed to reduce the incidence of CP.
Assuntos
Pancreatite Crônica/prevenção & controle , Humanos , Cooperação Internacional , Pancreatite Crônica/etiologia , Pancreatite Crônica/terapia , Fatores de RiscoRESUMO
OBJECTIVE: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. DESIGN: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. RESULTS: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and ≥80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (≥70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. CONCLUSION: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.
Assuntos
Neoplasias Pancreáticas/cirurgia , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia , Sistema de Registros , Programa de SEER , Análise de Sobrevida , Estados Unidos/epidemiologiaRESUMO
Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene-disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case-control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58-0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21-0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19-0.89, and OR = 0.73, 95%CI 0.53-1.00, respectively). Several inflammatory-related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.
Assuntos
Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Estudos de Casos e Controles , Biologia Computacional/métodos , Europa (Continente)/epidemiologia , Feminino , Ontologia Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Razão de Chances , Fatores de RiscoRESUMO
Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Gluâ¯∗â¯48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn's disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1ß, TNFα). The patient's 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient's daughter provides a glimpse of the preclinical phase of the condition.
Assuntos
Linfócitos B/fisiologia , Imunodeficiência de Variável Comum/imunologia , Gastroenteropatias/imunologia , NF-kappa B/genética , Deleção de Sequência/genética , Células Th1/fisiologia , Adolescente , Adulto , Agamaglobulinemia , Células Cultivadas , Imunodeficiência de Variável Comum/genética , Citocinas/metabolismo , Feminino , Gastroenteropatias/genética , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Proteína Adaptadora de Sinalização NOD2/genética , Infecções Respiratórias , Adulto JovemRESUMO
OBJECTIVE: Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk. DESIGN: Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case-control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model. RESULTS: Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17â years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk. CONCLUSIONS: This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association.
Assuntos
Asma/epidemiologia , Carcinoma Ductal Pancreático/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Rinite Alérgica/epidemiologia , Idoso , Estudos de Casos e Controles , Dermatite Alérgica de Contato/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de ProteçãoRESUMO
OBJECTIVE: To provide evidence-based recommendations for the management of exocrine pancreatic insufficiency (EPI) after pancreatic surgery. BACKGROUND: EPI is a common complication after pancreatic surgery but there is certain confusion about its frequency, optimal methods of diagnosis, and when and how to treat these patients. METHODS: Eighteen multidisciplinary reviewers performed a systematic review on 10 predefined questions following the GRADE methodology. Six external expert referees reviewed the retrieved information. Members from Spanish Association of Pancreatology were invited to suggest modifications and voted for the quantification of agreement. RESULTS: These guidelines analyze the definition of EPI after pancreatic surgery, (one question), its frequency after specific techniques and underlying disease (four questions), its clinical consequences (one question), diagnosis (one question), when and how to treat postsurgical EPI (two questions) and its impact on the quality of life (one question). Eleven statements answering those 10 questions were provided: one (9.1%) was rated as a strong recommendation according to GRADE, three (27.3%) as moderate and seven (63.6%) as weak. All statements had strong agreement. CONCLUSIONS: EPI is a frequent but under-recognized complication of pancreatic surgery. These guidelines provide evidence-based recommendations for the definition, diagnosis, and management of EPI after pancreatic surgery.
Assuntos
Medicina Baseada em Evidências , Insuficiência Pancreática Exócrina/terapia , Pancreatopatias/cirurgia , Complicações Pós-Operatórias/terapia , Guias de Prática Clínica como Assunto , Humanos , EspanhaRESUMO
Chronic diarrhoea is a common presenting symptom in both primary care medicine and in specialized gastroenterology clinics. It is estimated that >5% of the population has chronic diarrhoea and nearly 40% of these patients are older than 60 years. Clinicians often need to select the best diagnostic approach to these patients and choose between the multiple diagnostic tests available. In 2014 the Catalan Society of Gastroenterology formed a working group with the main objective of creating diagnostic algorithms based on clinical practice and to evaluate diagnostic tests and the scientific evidence available for their use. The GRADE system was used to classify scientific evidence and strength of recommendations. The consensus document contains 28 recommendations and 6 diagnostic algorithms. The document also describes criteria for referral from primary to specialized care.
Assuntos
Diarreia , Algoritmos , Antidiarreicos/uso terapêutico , Doença Crônica , Colite/complicações , Colite/diagnóstico , Técnicas de Diagnóstico do Sistema Digestório , Diarreia/classificação , Diarreia/diagnóstico , Diarreia/etiologia , Diarreia/terapia , Dieta , Açúcares da Dieta/efeitos adversos , Gerenciamento Clínico , Insuficiência Pancreática Exócrina/complicações , Insuficiência Pancreática Exócrina/diagnóstico , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/diagnóstico , Gastroenteropatias/diagnóstico , Microbioma Gastrointestinal , Motilidade Gastrointestinal , Humanos , Síndromes de Malabsorção/complicações , Síndromes de Malabsorção/diagnósticoRESUMO
OBJECTIVE: Pancreatic acinar cell maturation is dependent on the activity of the pancreas transcription factor 1 (PTF1) complex. Induction of pancreatitis leads to MAP kinase activation and transient suppression of the acinar differentiation programme. We investigated the role of MAP kinase-interacting kinase 1 (Mnk1) in mouse exocrine pancreas development and in the response to secretagogue-induced pancreatitis. DESIGN: Mnk1 expression was analysed using immunohistochemistry, RT-qPCR and western blotting. Ptf1a binding to Mnk1 was assessed by chromatin immunoprecipitation and qPCR. Acute pancreatitis was induced in wild type and Mnk1(-/-) mice by 7â h intraperitoneal injections of caerulein. In vitro amylase secretion and trypsinogen activation were assessed using freshly isolated acinar cells. In vivo secretion was quantified by secretin-stimulated MRI. RESULTS: Mnk1 is expressed at the highest levels in pancreatic acinar cells and is a direct PTF1 target. Mnk1 is activated upon induction of pancreatitis and is indispensable for eIF4E phosphorylation. The pancreas of Mnk1(-/-) mice is histologically normal. Digestive enzyme content is significantly increased and c-Myc and Ccnd1 levels are reduced in Mnk1(-/-) mice. Upon induction of acute pancreatitis, Mnk1(-/-) mice show impaired eIF4E phosphorylation, activation of c-Myc and downregulation of zymogen content. Acinar cells show defective relocalisation of digestive enzymes, polarity defects and impaired secretory response in vitro and in vivo. CONCLUSIONS: Mnk1 is a novel pancreatic acinar cell-specific stress response kinase that regulates digestive enzyme abundance and eIF4E phosphorylation. It is required for the physiological secretory response of acinar cells and for the homeostatic response to caerulein administration during acute pancreatitis.
Assuntos
Células Acinares/enzimologia , Pâncreas Exócrino/metabolismo , Pancreatite/metabolismo , Pancreatite/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Células Acinares/citologia , Amilases/metabolismo , Animais , Diferenciação Celular , Ceruletídeo , Colangiopancreatografia por Ressonância Magnética , Regulação para Baixo , Ativação Enzimática , Fator de Iniciação 4E em Eucariotos/metabolismo , Marcação de Genes , Resposta ao Choque Térmico/fisiologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Pancreatite/induzido quimicamente , Fosforilação , Fatores de Transcrição/metabolismo , Tripsinogênio/metabolismoRESUMO
The incidence of acute pancreatitis (AP) is increasing. AP is one of the gastrointestinal diseases that most frequently requires hospital admission in affected individuals. In the last few years, considerable scientific evidence has led to substantial changes in the medical and surgical treatment of this disease. New knowledge of the physiopathology of AP indicates that its severity is influenced by its systemic effects (organ failure), especially if the disease is persistent, and also by local complications (fluid collections or necrosis), especially if these become infected. Treatment should be personalized and depends on the patient's clinical status, the location of the necrosis, and disease stage.
Assuntos
Pancreatite/terapia , Doença Aguda , Analgesia/métodos , Colangiopancreatografia Retrógrada Endoscópica , Colelitíase/complicações , Gerenciamento Clínico , Drenagem , Insuficiência Pancreática Exócrina/etiologia , Humanos , Hipertensão Intra-Abdominal/etiologia , Hipertensão Intra-Abdominal/prevenção & controle , Insuficiência de Múltiplos Órgãos/etiologia , Necrose , Apoio Nutricional , Pseudocisto Pancreático/etiologia , Pancreatite/complicações , Pancreatite/diagnóstico por imagem , Pancreatite/fisiopatologia , Prognóstico , Fatores de Risco , Trombofilia/tratamento farmacológico , Trombofilia/etiologiaRESUMO
Chronic pancreatitis lesions usually embrace both intraduct papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC). Patients at genetically-determined high risk of PDAC often harbor IPMN and/or chronic pancreatitis, suggesting IPMN, chronic pancreatitis and PDAC may share pathogenetic mechanisms. Chronic autoimmune pancreatitis (AIP) may also herald PDAC. Concurrent IPMN and AIP have been reported in few patients. Here we describe two patients with IPMN who developed type-1 AIP fulfilling the Honolulu and Boston diagnostic criteria. AIP diffusively affected the whole pancreas, as well as peripancreatic lymph nodes and the gallbladder. Previous pancreatic resection of focal IPMN did not show features of AIP. One of the patients carried a CFTR class-I mutation. Of notice, serum IgG4 levels gradually decreased to normal values after IPMN excision. Common risk factors to IPMN and AIP may facilitate its coincidental generation.
Assuntos
Adenocarcinoma Papilar/complicações , Doenças Autoimunes/etiologia , Cistadenocarcinoma Mucinoso/etiologia , Neoplasias Pancreáticas/complicações , Pancreatite Crônica/etiologia , Idoso , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Imunoglobulina G/análise , Masculino , Fatores de RiscoRESUMO
Chronic pancreatitis (CP) is a relatively uncommon, complex and highly heterogeneous disease. There is no clear pattern applicable to the initial stages of CP, which hampers its early diagnosis. Some of the complications of CP, especially chronic pain, can be difficult to manage. There is wide variation in the diagnosis and treatment of CP and its complications among centers and health professionals. The Spanish Pancreatic Club has developed a consensus document on the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. A list of questions was drawn up. Each question was reviewed by two experts. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. The first part of the consensus document focusses on the diagnosis of CP and its complications.
Assuntos
Pancreatite Crônica/diagnóstico , HumanosRESUMO
Chronic pancreatitis (CP) is a complex disease with a wide spectrum of clinical manifestations ranging from asymptomatic disease to disabling forms or serious complications. The management of CP frequently differs among geographical areas and even among centers. These differences are due to the scarcity of high-quality studies and clinical practice guidelines that focus on the diagnosis and treatment of this disease. The aim of the Spanish Pancreatic Club was to create evidence-based recommendations for the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. These experts were selected on the basis of their clinical and research experience in CP. A list of questions was drawn up and each question was then reviewed by two panelists. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. Levels of evidence were based on the classification of the Oxford Centre for Evidence-Based Medicine. In the second part of the consensus process, recommendations were established for the management of pain, pseudocysts, biliary and duodenal stenosis, pancreatic fistula and ascites, left portal hypertension, diabetes mellitus, exocrine pancreatic insufficiency, and nutritional support in CP.
Assuntos
Pancreatite Crônica/terapia , Árvores de Decisões , Humanos , Apoio NutricionalRESUMO
OBJECTIVES: During pancreatitis, specific transcriptional programmes govern functional regeneration after injury. The objective of this study was to analyse the dynamic regulation of pancreatic genes and the role of transcriptional regulators during recovery from pancreatitis. DESIGN: Wild-type and genetically modified mice (Hnf1α(-/-) and Ptf1a(+/-)) were used. After caerulein or L-arginine induced pancreatitis, blood or pancreata were processed for enzymatic assays, ELISA, histology, immunohistochemistry, western blotting and quantitative reverse transcriptase-PCR. Nr5a2 promoter reporter and chromatin immunoprecipitation assays for Hnf1α were also performed. RESULTS: After caerulein pancreatic injury, expression of acinar and endocrine genes rapidly decreased, but eventually recovered, depicting distinct cell-type-specific patterns. Pdx1 and Hnf1α mRNAs underwent marked downregulation, matching endocrine/exocrine gene expression profiles. Ptf1a, Pdx1 and Hnf1α protein levels were also reduced and recovered gradually. These changes were associated with transient impairment of exocrine and endocrine function, including abnormal glucose tolerance. On l-arginine pancreatitis, changes in Ptf1a, Pdx1 and Hnf1α gene and protein expression were recapitulated. Reduced Hnf1α and Ptf1a levels after pancreatitis coincided with increased acinar cell proliferation, both in Hnf1α(-/-) and Ptf1a(+/-) mice. Moreover, Hnf1α(-/-) mice had reduced Ptf1a protein as well as transcripts for Ptf1a and digestive enzymes. Dispersed acini from Hnf1α(-/-) mice showed suboptimal secretory responses to caerulein. Bioinformatics analysis did not support a role for Hnf1α as a direct regulator of digestive enzyme genes. Instead, it was found that Hnf1α binds to, and regulates, the promoter of Nr5a2, coding an orphan nuclear receptor that regulates acinar gene expression. CONCLUSIONS: Dynamic changes in gene expression occur on pancreatitis induction, determining altered exocrine and endocrine function. This analysis uncovers roles for Hnf1α in the regulation of acinar cell determination and function. This effect may be mediated, in part, through direct regulation of Nr5a2.
Assuntos
Células Acinares/metabolismo , Regulação da Expressão Gênica , Fator 1-alfa Nuclear de Hepatócito/genética , Homeostase/genética , Pancreatite/genética , RNA Mensageiro/genética , Células Acinares/patologia , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Fator 1-alfa Nuclear de Hepatócito/biossíntese , Imuno-Histoquímica , Imunoprecipitação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pancreatite/metabolismo , Pancreatite/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Bariatric surgery (BS) is currently the most effective treatment for severe obesity, requiring ongoing multidisciplinary follow-up to ensure proper progress and nutrition post-procedure. Despite its favourable safety profile, it is not exempt from complications, one of which being exocrine pancreatic insufficiency (EPI). The underlying pathophysiological mechanisms of EPI after BS are multifactorial, including poorly synchronized pancreatic enzyme secretion with the passage of nutrients (pancreaticocibal or postcibal asynchrony), insufficient pancreatic stimulation and bacterial overgrowth. We conducted a short literature review of the topic through a case of a patient who underwent BS in our centre and subsequently developed EPI and severe malnutrition. EPI initially was attributed to the surgery, but after a comprehensive evaluation, an unexpected cause was revealed.