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Pediatrics in Review Feb 2021Cystic fibrosis (CF) is one of the most commonly diagnosed genetic disorders. Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine... (Review)
Review
Cystic fibrosis (CF) is one of the most commonly diagnosed genetic disorders. Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific interdisciplinary care centers. Future improvements in health and quality of life for individuals with CF are likely with the recent development of mutation-specific modulator therapies. In this review, we will cover the current understanding of the disease manifestations, diagnosis, and management as well as common complications seen in individuals with CF.
Topics: Bone Density; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Infant; Infant, Newborn; Liver Diseases; Lung; Lung Transplantation; Male; Respiratory Tract Infections; Trypsinogen; Vitamins
PubMed: 33526571
DOI: 10.1542/pir.2019-0212 -
Nature Reviews. Gastroenterology &... Aug 2019The incidence of acute pancreatitis continues to increase worldwide, and it is one of the most common gastrointestinal causes for hospital admission in the USA. In the... (Review)
Review
The incidence of acute pancreatitis continues to increase worldwide, and it is one of the most common gastrointestinal causes for hospital admission in the USA. In the past decade, substantial advancements have been made in our understanding of the pathophysiological mechanisms of acute pancreatitis. Studies have elucidated mechanisms of calcium-mediated acinar cell injury and death and the importance of store-operated calcium entry channels and mitochondrial permeability transition pores. The cytoprotective role of the unfolded protein response and autophagy in preventing sustained endoplasmic reticulum stress, apoptosis and necrosis has also been characterized, as has the central role of unsaturated fatty acids in causing pancreatic organ failure. Characterization of these pathways has led to the identification of potential molecular targets for future therapeutic trials. At the patient level, two classification systems have been developed to classify the severity of acute pancreatitis into prognostically meaningful groups, and several landmark clinical trials have informed management strategies in areas of nutritional support and interventions for infected pancreatic necrosis that have resulted in important changes to acute pancreatitis management paradigms. In this Review, we provide a summary of recent advances in acute pancreatitis with a special emphasis on pathophysiological mechanisms and clinical management of the disorder.
Topics: Acute Disease; Animals; Calcium Signaling; Disease Management; Disease Models, Animal; Endoplasmic Reticulum Stress; Humans; Mutation; Nutritional Support; Pancreatitis; Severity of Illness Index; Terminology as Topic; Trypsinogen
PubMed: 31138897
DOI: 10.1038/s41575-019-0158-2 -
JAMA Dec 2019Chronic 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. (Review)
Review
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.
Topics: Abdominal Pain; Alcoholism; Diagnostic Imaging; Genetic Predisposition to Disease; Humans; Pain Management; Pancreas; Pancreatitis, Chronic; Prognosis; Risk Factors; Smoking
PubMed: 31860051
DOI: 10.1001/jama.2019.19411 -
World Journal of Gastroenterology May 2023Acute pancreatitis (AP) is an inflammatory disease of the pancreas, which can progress to severe AP, with a high risk of death. It is one of the most complicated and... (Review)
Review
Acute pancreatitis (AP) is an inflammatory disease of the pancreas, which can progress to severe AP, with a high risk of death. It is one of the most complicated and clinically challenging of all disorders affecting the abdomen. The main causes of AP are gallstone migration and alcohol abuse. Other causes are uncommon, controversial and insufficiently explained. The disease is primarily characterized by inappropriate activation of trypsinogen, infiltration of inflammatory cells, and destruction of secretory cells. According to the revised Atlanta classification, severity of the disease is categorized into three levels: Mild, moderately severe and severe, depending upon organ failure and local as well as systemic complications. Various methods have been used for predicting the severity of AP and its outcome, such as clinical evaluation, imaging evaluation and testing of various biochemical markers. However, AP is a very complex disease and despite the fact that there are of several clinical, biochemical and imaging criteria for assessment of severity of AP, it is not an easy task to predict its subsequent course. Therefore, there are existing controversies regarding diagnostic and therapeutic modalities, their effectiveness and complications in the treatment of AP. The main reason being the fact, that the pathophysiologic mechanisms of AP have not been fully elucidated and need to be studied further. In this editorial article, we discuss the efficacy of the existing diagnostic and therapeutic modalities, complications and treatment failure in the management of AP.
Topics: Humans; Pancreatitis; Acute Disease; Pancreas; Diagnostic Imaging; Biomarkers; Severity of Illness Index
PubMed: 37274068
DOI: 10.3748/wjg.v29.i18.2747 -
Gastroenterology May 2023Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising drug targets, but few have been causally linked with AP. Our objective was to identify blood proteins linked with AP by combining genome-wide association meta-analysis and proteome-wide Mendelian randomization (MR) studies.
METHODS
We performed a genome-wide association meta-analysis totalling 10,630 patients with AP and 844,679 controls and a series of inverse-variance weighted MR analyses using cis-acting variants on 4719 blood proteins from the deCODE study (N = 35,559) and 4979 blood proteins from the Fenland study (N = 10,708).
RESULTS
The meta-analysis identified genome-wide significant variants (P <5 × 10) at 5 loci (ABCG5/8, TWIST2, SPINK1, PRSS2 and MORC4). The proteome-wide MR analyses identified 68 unique blood proteins that may causally be associated with AP, including 29 proteins validated in both data sets. Functional annotation of these proteins confirmed expression of many proteins in metabolic tissues responsible for digestion and energy metabolism, such as the esophagus, adipose tissue, and liver as well as acinar cells of the pancreas. Genetic colocalization and investigations into the druggable genome also identified potential drug targets for AP.
CONCLUSIONS
This large genome-wide association study meta-analysis for AP identified new variants linked with AP as well as several blood proteins that may be causally associated with AP. This study provides new information on the genetic architecture of this disease and identified pathways related to AP, which may be further explored as possible therapeutic targets for AP.
Topics: Humans; Proteome; Mendelian Randomization Analysis; Genome-Wide Association Study; Acute Disease; Pancreatitis; Blood Proteins; Polymorphism, Single Nucleotide; Trypsin; Trypsinogen; Trypsin Inhibitor, Kazal Pancreatic; Nuclear Proteins
PubMed: 36736436
DOI: 10.1053/j.gastro.2023.01.028 -
Analytical Biochemistry Jul 2022Trypsin has been identified as a pancreatic protease comprising three isoenzymes, trypsin-1, -2, and -3. However, the gene for trypsinogen-3, PRSS3, also gives rise to...
Trypsin has been identified as a pancreatic protease comprising three isoenzymes, trypsin-1, -2, and -3. However, the gene for trypsinogen-3, PRSS3, also gives rise to additional variants, trypsinogen-4A and B, which differ from trypsinogen-3 only with respect to the leader-peptide part, and when activated are identical to trypsin-3. The unique overlapping leader peptides of trypsinogen-4A and B allowed us to develop a specific sandwich-type immunofluorometric assay that detects both these isoforms, but not trypsinogen-3 or activated trypsinogen-4. We measured the concentrations of trypsinogen-4 in various cell line lysates and bile of primary sclerosing cholangitis patients. Lysates of cell lines MDA-MB-231 and PC-3, and astrocytes contained trypsinogen-4, while the conditioned media from these cells did not, suggesting that trypsinogen-4, lacking a classical signal sequence, is not secreted from the cells. Interestingly, 5.7% of the 212 bile samples analyzed contained measurable (>2.4 μg/l) trypsinogen-4. In conclusion, we have established a specific assay for trypsinogen-4 and demonstrated that trypsinogen-4 can be found in biological samples. However, the clinical utility of the assay remains to be established.
Topics: Bile; Humans; Immunoassay; Isoenzymes; Trypsin; Trypsinogen
PubMed: 35417678
DOI: 10.1016/j.ab.2022.114681 -
Genes Apr 2020Discovery of the cystic fibrosis transmembrane conductance regulator ( gene was the long-awaited scientific advance that dramatically improved the diagnosis and... (Review)
Review
Discovery of the cystic fibrosis transmembrane conductance regulator ( gene was the long-awaited scientific advance that dramatically improved the diagnosis and treatment of cystic fibrosis (CF). The combination of a first-tier biomarker, immunoreactive trypsinogen (IRT), and, if high, DNA analysis for CF-causing variants, has enabled regions where CF is prevalent to screen neonates and achieve diagnoses within 1-2 weeks of birth when most patients are asymptomatic. In addition, IRT/DNA () screening protocols simultaneously contribute important genetic data to determine genotype, prognosticate, and plan preventive therapies such as CFTR modulator selection. As the genomics era proceeds with affordable biotechnologies, the potential added value of whole genome sequencing will probably enhance personalized, precision care that can begin during infancy. Issues remain, however, about the optimal size of panels in genetically diverse regions and how best to deal with incidental findings. Because prospects for a primary DNA screening test are on the horizon, the debate about detecting heterozygote carriers will likely intensify, especially as we learn more about this relatively common genotype. Perhaps, at that time, concerns about CF heterozygote carrier detection will subside, and it will become recognized as beneficial. We share new perspectives on that issue in this article.
Topics: Algorithms; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Association Studies; Genetic Counseling; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Infant, Newborn; Neonatal Screening
PubMed: 32276344
DOI: 10.3390/genes11040401 -
Pediatric Annals Nov 2019Exocrine pancreatic insufficiency in children can lead to lifelong complications related to malnutrition and poor growth. The clinical presentation can be subtle in the... (Review)
Review
Exocrine pancreatic insufficiency in children can lead to lifelong complications related to malnutrition and poor growth. The clinical presentation can be subtle in the early stages of insufficiency as the large functional capacity of the pancreas is gradually lost. The pediatrician plays a crucial role in the early identification of these children to ensure a timely referral so that a diagnosis can be made and therapy initiated. Early nutritional therapy allows for prevention and correction of deficiencies, which leads to improved outcomes and survival. When insufficiency is suspected, the workup should start with an indirect test of exocrine pancreatic function, such as fecal elastase, to establish the diagnosis. Once a diagnosis is established, further testing to delineate the etiology should be pursued, with cystic fibrosis being high on the differential list and assessed for with a sweat test. Assessment of anthropometry at every visit is key, as is monitoring of laboratory parameters and physical examination findings that are suggestive of malabsorption and malnutrition. The mainstay of management is administration of exogenous pancreatic enzymes to facilitate digestion and absorption. [Pediatr Ann. 2019;48(11):e441-e447.].
Topics: Acyl-CoA Dehydrogenase, Long-Chain; Anus, Imperforate; Child; Child Nutrition Disorders; Chymotrypsin; Congenital Bone Marrow Failure Syndromes; Cystic Fibrosis; Dietary Fats; Ectodermal Dysplasia; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Feces; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Lipid Metabolism, Inborn Errors; Mitochondrial Diseases; Muscular Diseases; Nose; Nutrition Assessment; Pancreas; Pancreatic Diseases; Pancreatic Elastase; Pancreatic Function Tests; Pancreatitis, Chronic; Shwachman-Diamond Syndrome; Steatorrhea; Trypsinogen
PubMed: 31710363
DOI: 10.3928/19382359-20191018-01 -
Expert Opinion on Biological Therapy Dec 2021: Trypsinogen and chymotrypsinogen have been used clinically in tissue repair due to their ability to resolve inflammatory symptoms. Recently, novel evidence has...
: Trypsinogen and chymotrypsinogen have been used clinically in tissue repair due to their ability to resolve inflammatory symptoms. Recently, novel evidence has supported the anti-tumourigenic potential of a mixture of trypsinogen and chymotrypsinogen.: First, we analyze the structure of these proteases and the effects of pancreatic proteinases on tissue repair, inflammation and the immune system. Second, we summarize studies that provided evidence of the effects of pancreatic (pro)enzymes on tumor cells both and and some successful clinical applications of pancreatic (pro)enzymes. Finally, we study pancreatic (pro)enzymes potential molecular targets, such as the proteinase-activated receptors (PARs).: This novel therapy has been shown to have effective antitumor effects. Treatment with these (pro) enzymes sensitizes Cancer Stem Cells (CSCs) which may allow chemotherapy and radiotherapy to be more effective, which could positively affect the recovery of cancer patients.
Topics: Chymotrypsin; Chymotrypsinogen; Humans; Neoplasms; Trypsin; Trypsinogen
PubMed: 33896307
DOI: 10.1080/14712598.2021.1922666