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1.
Leptin brain entry via a tanycytic LepR-EGFR shuttle controls lipid metabolism and pancreas function.
Duquenne, M, Folgueira, C, Bourouh, C, Millet, M, Silva, A, Clasadonte, J, Imbernon, M, Fernandois, D, Martinez-Corral, I, Kusumakshi, S, et al
Nature metabolism. 2021;(8):1071-1090
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Abstract
Metabolic health depends on the brain's ability to control food intake and nutrient use versus storage, processes that require peripheral signals such as the adipocyte-derived hormone, leptin, to cross brain barriers and mobilize regulatory circuits. We have previously shown that hypothalamic tanycytes shuttle leptin into the brain to reach target neurons. Here, using multiple complementary models, we show that tanycytes express functional leptin receptor (LepR), respond to leptin by triggering Ca2+ waves and target protein phosphorylation, and that their transcytotic transport of leptin requires the activation of a LepR-EGFR complex by leptin and EGF sequentially. Selective deletion of LepR in tanycytes blocks leptin entry into the brain, inducing not only increased food intake and lipogenesis but also glucose intolerance through attenuated insulin secretion by pancreatic β-cells, possibly via altered sympathetic nervous tone. Tanycytic LepRb-EGFR-mediated transport of leptin could thus be crucial to the pathophysiology of diabetes in addition to obesity, with therapeutic implications.
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The Close Link of Pancreatic Iron With Glucose Metabolism and With Cardiac Complications in Thalassemia Major: A Large, Multicenter Observational Study.
Pepe, A, Pistoia, L, Gamberini, MR, Cuccia, L, Peluso, A, Messina, G, Spasiano, A, Allò, M, Bisconte, MG, Putti, MC, et al
Diabetes care. 2020;(11):2830-2839
Abstract
OBJECTIVE We systematically explored the link of pancreatic iron with glucose metabolism and with cardiac complications in a cohort of 1,079 patients with thalassemia major (TM) enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project. RESEARCH DESIGN AND METHODS MRI was used to quantify iron overload (T2* technique) and cardiac function (cine images) and to detect macroscopic myocardial fibrosis (late gadolinium enhancement technique). Glucose metabolism was assessed by the oral glucose tolerance test (OGTT). RESULTS Patients with normal glucose metabolism showed significantly higher global pancreas T2* values than patients with impaired fasting glucose, impaired glucose tolerance, and diabetes. A pancreas T2* <13.07 ms predicted an abnormal OGTT. A normal pancreas T2* value showed a 100% negative predictive value for disturbances of glucose metabolism and for cardiac iron. Patients with myocardial fibrosis showed significantly lower pancreas T2* values. Patients with cardiac complications had significantly lower pancreas T2* values. No patient with arrhythmias/heart failure had a normal global pancreas T2*. CONCLUSIONS Pancreatic iron is a powerful predictor not only for glucose metabolism but also for cardiac iron and complications, supporting the close link between pancreatic iron and heart disease and the need to intensify iron chelation therapy to prevent both alterations of glucose metabolism and cardiac iron accumulation.
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Pancreatic Exocrine Insufficiency as a Complication of Gastrointestinal Surgery and the Impact of Pancreatic Enzyme Replacement Therapy.
Chaudhary, A, Domínguez-Muñoz, JE, Layer, P, Lerch, MM
Digestive diseases (Basel, Switzerland). 2020;(1):53-68
Abstract
BACKGROUND Pancreatic exocrine insufficiency (PEI) is characterized by inadequate production, insufficient secretion, and/or inactivation of pancreatic enzymes, resulting in maldigestion. The aim of this review was to analyze the prevalence and pathophysiology of PEI resulting from gastrointestinal (GI) surgery and to examine the use of pancreatic enzyme replacement therapy (PERT) for effectively managing PEI. SUMMARY A targeted PubMed search was conducted for studies examining the prevalence and pathophysiology of PEI in patients following GI surgery and for studies assessing the effects of PERT in these patients. PEI is a common complication following GI surgery that can lead to nutritional deficiencies, which may contribute to morbidity and mortality in patients. Timely treatment of PEI with PERT can prevent malnutrition, increase quality of life, and possibly reduce the associated mortality. Treatment of PEI should aim not only to alleviate symptoms but also to achieve significant improvements in nutritional parameters. Dose optimization of PERT is required for effective management of PEI, in addition to regular assessment of nutritional status, appropriate patient education, and reassessment if symptoms return. Key Messages: Difficulties in detecting PEI following GI surgery can result in undiagnosed and untreated maldigestion, leading to metabolic complications and increased morbidity. Both are preventable by early administration and monitoring for optimal doses of PERT.
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The Hepatobiliary System: An Overview of Normal Function and Diagnostic Testing in Pregnancy.
Gonzalez-Brown, V, Frey, HA
Clinical obstetrics and gynecology. 2020;(1):122-133
Abstract
Pregnancy is associated with physiological adaptions that affect every organ system. Changes in liver function in pregnancy have important effects on nutrient metabolism, protein synthesis, and the biotransformation of substances in preparation for excretion. A clear understanding of the anatomic and functional changes of the hepatobiliary system is necessary for the diagnosis and evaluation of disease, as well as understanding how these changes predispose women to pregnancy-specific hepatic conditions. In this review, the effect of gestational changes in hepatobiliary function on laboratory tests and the role of diagnostic imaging of the liver and gallbladder in pregnancy will be discussed.
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The assessment of pancreatic exocrine function in patients with inoperable pancreatic cancer: In need of a new gold-standard.
Carnie, LE, Lamarca, A, McNamara, MG, Bibby, N, O'Reilly, DA, Valle, JW
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2020;(4):668-675
Abstract
BACKGROUND Pancreatic exocrine insufficiency is commonplace in patients with pancreatic cancer, adversely impacting on quality of life and survival. Whilst the management of exocrine insufficiency is well established, diagnosis remains challenging in clinical practice. A plethora of diagnostic tests exist. Nevertheless, a lack of consensus remains about the optimal diagnostic method, specifically in patients with pancreatic cancer. Research, to date, has primarily been undertaken in patients with chronic pancreatitis and cystic fibrosis. This manuscript will review the current literature and will examine the evidence around the diagnostic tests available for pancreatic exocrine insufficiency and whether any exists specifically for pancreatic cancer cohorts. FINDINGS Evidence to recommend an individual test for the diagnosis of pancreatic exocrine insufficiency in clinical practice is lacking. Direct testing (by direct sampling of pancreatic secretions) has the highest specificity and sensitivity but is no longer routinely deployed or feasible in practice. Indirect testing, such as faecal elastase, is less accurate with high false-positive rates, but is routinely available in clinical practice. The 13C-mixed triglyceride breath test and the gold-standard 72-h faecal fat test have high specificity for indirect tests, but are not routinely available and cumbersome to undertake. A combination approach including nutritional markers and faecal elastase has more recently been proposed. CONCLUSION Further research is required to identify the most optimal and accurate diagnostic tool to diagnose pancreatic exocrine insufficiency in patients with pancreatic cancer in clinical practice.
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Guidelines on the histopathology of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and the European Pancreatic Club.
Esposito, I, Hruban, RH, Verbeke, C, Terris, B, Zamboni, G, Scarpa, A, Morohoshi, T, Suda, K, Luchini, C, Klimstra, DS, et al
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2020;(4):586-593
Abstract
BACKGROUND Chronic pancreatitis is a complex multifactorial fibro-inflammatory disease. Consensus guidelines are needed for the histopathological evaluation of non-autoimmune chronic pancreatitis (CP). METHODS An international working group with experts on the histopathology of CP evaluated 15 statements generated from evidence on seven key clinically relevant questions. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on the statements for strength of agreement, using a nine-point Likert scale, and Cronbach's alpha reliability coefficients were calculated. RESULTS Strong consensus was obtained for 12 statements relating to all seven key questions including that: the cardinal features of CP are the triad of fibrosis, loss of acinar tissue and duct changes; there are no unique histopathological features that distinguish the different aetiologies of CP; clinical history and laboratory investigations, including genetic testing, are important in establishing the aetiology of CP; there is no reproducible and universally accepted histological grading system for assessing severity of CP, although classification as "mild", "moderate" and "severe" is usually applied; scoring systems for fibrosis are not validated for clinical use; asymptomatic fibrosis is a common finding associated with ageing, and not necessarily evidence of CP; there are no obvious diagnostic macroscopic features of early CP; histopathology is not the gold standard for the diagnosis of CP; and cytology alone is not a reliable method for the diagnosis of CP. CONCLUSIONS Cardinal histopathological features of CP are well-defined and internationally accepted and pathological assessment is relevant for the purpose of differential diagnosis with other pancreatic diseases, especially cancer. However, a reliable diagnosis of CP requires integration of clinical, laboratory and imaging features and cannot be made by histology alone.
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Diagnosis and Management of Chronic Pancreatitis: A Review.
Singh, VK, Yadav, D, Garg, PK
JAMA. 2019;(24):2422-2434
Abstract
IMPORTANCE Chronic pancreatitis (CP) is a chronic inflammatory and fibrotic disease of the pancreas with a prevalence of 42 to 73 per 100 000 adults in the United States. OBSERVATIONS Both genetic and environmental factors are thought to contribute to the pathogenesis of CP. Environmental factors associated with CP include alcohol abuse (odds ratio [OR], 3.1; 95% CI, 1.87-5.14) for 5 or more drinks per day vs abstainers and light drinkers as well as smoking (OR, 4.59; 95% CI, 2.91-7.25) for more than 35 pack-years in a case-control study involving 971 participants. Between 28% to 80% of patients are classified as having "idiopathic CP." Up to 50% of these individuals have mutations of the trypsin inhibitor gene (SPINK1) or the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 1% of people diagnosed with CP may have hereditary pancreatitis, associated with cationic trypsinogen (PRSS1) gene mutations. Approximately 80% of people with CP present with recurrent or chronic upper abdominal pain. Long-term sequelae include diabetes in 38% to 40% and exocrine insufficiency in 30% to 48%. The diagnosis is based on pancreatic calcifications, ductal dilatation, and atrophy visualized by imaging with computed tomography, magnetic resonance imaging, or both. Endoscopic ultrasound can assist in making the diagnosis in patients with a high index of suspicion such as recurrent episodes of acute pancreatitis when imaging is normal or equivocal. The first line of therapy consists of advice to discontinue use of alcohol and smoking and taking analgesic agents (nonsteroidal anti-inflammatory drugs and weak opioids such as tramadol). A trial of pancreatic enzymes and antioxidants (a combination of multivitamins, selenium, and methionine) can control symptoms in up to 50% of patients. Patients with pancreatic ductal obstruction due to stones, stricture, or both may benefit from ductal drainage via endoscopic retrograde cholangiopancreatography (ERCP) or surgical drainage procedures, such as pancreaticojejunostomy with or without pancreatic head resection, which may provide better pain relief among people who do not respond to endoscopic therapy. CONCLUSIONS AND RELEVANCE Chronic pancreatitis often results in chronic abdominal pain and is most commonly caused by excessive alcohol use, smoking, or genetic mutations. Treatment consists primarily of alcohol and smoking cessation, pain control, replacement of pancreatic insufficiency, or mechanical drainage of obstructed pancreatic ducts for some patients.
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Histologic Analysis of Endoscopic Ultrasound-Guided Through the Needle Microforceps Biopsies Accurately Identifies Mucinous Pancreas Cysts.
Yang, D, Trindade, AJ, Yachimski, P, Benias, P, Nieto, J, Manvar, A, Ho, S, Esnakula, A, Gamboa, A, Sethi, A, et al
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019;(8):1587-1596
Abstract
BACKGROUND & AIMS It is a challenge to accurately assess pancreatic cystic lesions (PCLs) and determine their risk. We compared the yield of tissue acquired with endoscopic ultrasound (EUS)-guided microforceps (through the needle tissue biopsy [TTNB]) with that of samples collected by EUS-guided fine-needle-aspiration (EUS-FNA), and the accuracy of analyses of each sample type in the diagnosis of mucinous PCLs. METHODS We performed a prospective open-label study of 114 consecutive adults (56.1% women; mean age, 64.2 y) undergoing EUS-FNA evaluation of PCLs (mean size, 35 mm) at 7 centers, from June 20, 2016, through August 31, 2018. Samples were collected from each cyst by FNA and microforceps; samples collected by FNA were analyzed by cytology and samples collected by TTNB were analyzed by histology. Acquisition yield was defined as the percentage of specimens collected that were adequate for cytologic or histologic analysis. Diagnoses of mucinous cysts were made based on identification of pancreatic mucinous epithelium by cytology analysis of FNA samples or histologic analysis of TTNB samples. Surgical specimens were used as the reference standard when available. RESULTS The EUS-guided microforceps were successfully inserted into 97.4% (111 of 114) of PCLs. Tissue acquisition yield was significantly higher with TTNB (95 of 114; 83.3%) than FNA (43 of 114; 37.7%) (P < .001). Sixty-one PCLs were determined to be mucinous based on TTNB analysis (53.5%) vs 11 with FNA analysis (9.6%) (P < .001). Among PCLs categorized as equivocal, based on the level of carcinoembryonic antigen, TTNB analysis found 50% (41 of 82) to be mucinous and FNA analysis found 8.5% (7 of 82) to be mucinous (P < .001). Findings from analyses of samples collected by TTNB were 100% concordant with findings from histologic analysis of surgical specimens (14 of 14), whereas only 3 of 14 findings from analysis of samples collected by FNA were in agreement with findings from surgical specimens (21.4%) (P < .001). Four of 5 mucinous PCLs with advanced neoplasia (80%) were detected with TTNB compared with none with FNA (P = .04). Self-limited intracystic bleeding occurred in 7 patients (6.1%), and acute pancreatitis in 6 patients (5.3%). CONCLUSIONS In a multicenter prospective study of patients undergoing EUS-FNA for evaluation of PCLs, we found TTNB collection of tissues for histologic analysis to be safe and feasible, with an acquisition yield of 83.3%. Histologic analysis of samples collected by TTNB identified a larger proportion of mucinous PCLs compared with cytologic analysis of samples collected by FNA-even among samples categorized as equivocal, based on the level of carcinoembryonic antigen. More samples collected by TTNB than FNA were found to have advanced neoplasia. Clinicaltrials.gov no: NCT02979509.
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Aquaporins Involvement in Pancreas Physiology and in Pancreatic Diseases.
Arsenijevic, T, Perret, J, Van Laethem, JL, Delporte, C
International journal of molecular sciences. 2019;(20)
Abstract
Aquaporins are a family of transmembrane proteins permeable to water. In mammals, they are subdivided into classical aquaporins that are permeable to water; aquaglyceroporins that are permeable to water, glycerol and urea; peroxiporins that facilitate the diffusion of H2O2 through cell membranes; and so called unorthodox aquaporins. Aquaporins ensure important physiological functions in both exocrine and endocrine pancreas. Indeed, they are involved in pancreatic fluid secretion and insulin secretion. Modification of aquaporin expression and/or subcellular localization may be involved in the pathogenesis of pancreatic insufficiencies, diabetes and pancreatic cancer. Aquaporins may represent useful drug targets for the treatment of pathophysiological conditions affecting pancreatic function, and/or diagnostic/predictive biomarker for pancreatic cancer. This review summarizes the current knowledge related to the involvement of aquaporins in the pancreas physiology and physiopathology.
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Heterotaxy syndrome with agenesis of dorsal pancreas and diabetes mellitus: case report and review of the literature.
Riguetto, CM, Pelichek, S, Moura Neto, A
Archives of endocrinology and metabolism. 2019;(4):445-448
Abstract
Heterotaxy syndrome (HS) is a rare congenital condition with multifactorial heritance, characterized by an abnormal arrangement of thoraco-abdominal organs and vessels. Patients present with multiple cardiac, gastrointestinal, hepatosplenic, pancreatic, renal, neurological and skeletal disorders without any pathognomonic alteration. Despite the described increased risk of diabetes mellitus (DM) in patients with altered pancreatic anatomy, just one case was reported in Korea regarding the association of HS and DM in a 13-year-old girl. Our report refers to a 40-year-old female Brazilian patient with a history of DM and HS with polysplenia and agenesis of dorsal pancreas without cardiac abnormalities. She presented a worsening glycemic control associated with weight gain and signs of insulin resistance. After a proper clinical management of insulin and oral medications, our patient developed an improvement in glycemic control. Although it is a rare disease, HS with polysplenia and pancreatic disorders can be associated with an increased risk of DM. This case highlights the importance of investigating DM in patients with HS, especially those with pancreatic anatomical disorders, for proper clinical management of this rare condition.