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Chou WK, Lam S, Kumar B. Clinical and genetic determinants of severe acute pancreatitis: A genetic association study in the UK Biobank. J Gastroenterol Hepatol 2023; 38:1656-1662. [PMID: 37433748 DOI: 10.1111/jgh.16284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 06/01/2023] [Accepted: 06/26/2023] [Indexed: 07/13/2023]
Abstract
BACKGROUND AND AIM The clinical severity of acute pancreatitis is unpredictable, ranging from self-limiting disease to life-threatening inflammation. The determinants of severe acute pancreatitis (SAP) are unclear. We aim to identify clinical variables and single nucleotide polymorphisms (SNP) associated with SAP. METHODS We used UK Biobank data to conduct a case-control clinical and genetic association study. Pancreatitis patients were identified through national hospital and mortality records across the United Kingdom. Clinical covariates and SAP were analyzed for associations. Genotyped data that included 35 SNPs were assessed for independent associations with SAP and SNP to SNP interaction. RESULTS A total of 665 patients with SAP and 3304 non-SAP patients were identified. Male sex and older age increased odds of developing SAP (odds ratio [OR] 1.48; 95% confiden interval [CI] 1.24-1.78, P < 0.0001) and (OR 1.23; 95% CI 1.17-1.29), P < 0.0001), respectively. SAP was associated with diabetes (OR 1.46; 95% CI 1.15-1.86, P = 0.002), chronic kidney disease (OR 1.74; 95% CI 1.26-2.42, P = 0.001), and cardiovascular disease (OR 2.00; 95% CI 1.54-2.61, P = 0.0001). A significant association was established between IL-10 rs3024498 and SAP (OR 1.24; 95% CI 1.09-1.41, P = 0.0014). Epistasis analysis revealed that the odds of SAP was greater by an interaction between TLR 5 rs5744174 and Factor V rs6025 (ORinteraction 7.53; P = 6.64 × 10-5 ). CONCLUSION This study reports clinical risk factors for SAP. We also show evidence for an interaction between rs5744174 and rs6025 as determinants for SAP in addition to rs3024498 independently altering the severity of acute pancreatitis.
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Affiliation(s)
- Wing Kiu Chou
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Stephen Lam
- Norwich Medical School, University of East Anglia, Norwich, UK
- Department of Upper Gastrointestinal Surgery, Norfolk and Norwich University Hospital, Norwich, UK
| | - Bhaskar Kumar
- Norwich Medical School, University of East Anglia, Norwich, UK
- Department of Upper Gastrointestinal Surgery, Norfolk and Norwich University Hospital, Norwich, UK
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Venkatesh K, Glenn H, Delaney A, Andersen CR, Sasson SC. Fire in the belly: A scoping review of the immunopathological mechanisms of acute pancreatitis. Front Immunol 2023; 13:1077414. [PMID: 36713404 PMCID: PMC9874226 DOI: 10.3389/fimmu.2022.1077414] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 12/21/2022] [Indexed: 01/13/2023] Open
Abstract
Introduction Acute pancreatitis (AP) is characterised by an inflammatory response that in its most severe form can cause a systemic dysregulated immune response and progression to acute multi-organ dysfunction. The pathobiology of the disease is unclear and as a result no targeted, disease-modifying therapies exist. We performed a scoping review of data pertaining to the human immunology of AP to summarise the current field and to identify future research opportunities. Methods A scoping review of all clinical studies of AP immunology was performed across multiple databases. Studies were included if they were human studies of AP with an immunological outcome or intervention. Results 205 studies met the inclusion criteria for the review. Severe AP is characterised by significant immune dysregulation compared to the milder form of the disease. Broadly, this immune dysfunction was categorised into: innate immune responses (including profound release of damage-associated molecular patterns and heightened activity of pattern recognition receptors), cytokine profile dysregulation (particularly IL-1, 6, 10 and TNF-α), lymphocyte abnormalities, paradoxical immunosuppression (including HLA-DR suppression and increased co-inhibitory molecule expression), and failure of the intestinal barrier function. Studies including interventions were also included. Several limitations in the existing literature have been identified; consolidation and consistency across studies is required if progress is to be made in our understanding of this disease. Conclusions AP, particularly the more severe spectrum of the disease, is characterised by a multifaceted immune response that drives tissue injury and contributes to the associated morbidity and mortality. Significant work is required to develop our understanding of the immunopathology of this disease if disease-modifying therapies are to be established.
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Affiliation(s)
- Karthik Venkatesh
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
| | - Hannah Glenn
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Anthony Delaney
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Christopher R. Andersen
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Sarah C. Sasson
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW, Australia
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van den Berg FF, Issa Y, Vreijling JP, Lerch MM, Weiss FU, Besselink MG, Baas F, Boermeester MA, van Santvoort HC. Whole-exome Sequencing Identifies SLC52A1 and ZNF106 Variants as Novel Genetic Risk Factors for (Early) Multiple-organ Failure in Acute Pancreatitis. Ann Surg 2022; 275:e781-e788. [PMID: 33427755 DOI: 10.1097/sla.0000000000004312] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVE The aim of this study was to identify genetic variants associated with early multiple organ failure (MOF) in acute pancreatitis. SUMMARY BACKGROUND DATA MOF is a life-threatening complication of acute pancreatitis, and risk factors are largely unknown, especially in early persistent MOF. Genetic risk factors are thought to enhance severity in complex diseases such as acute pancreatitis. METHODS A 2-phase study design was conducted. First, we exome sequenced 9 acute pancreatitis patients with early persistent MOF and 9 case-matched patients with mild edematous pancreatitis (phenotypic extremes) from our initial Dutch cohort of 387 patients. Secondly, 48 candidate variants that were overrepresented in MOF patients and 10 additional variants known from literature were genotyped in a replication cohort of 286 Dutch and German patients. RESULTS Exome sequencing resulted in 161,696 genetic variants, of which the 38,333 non-synonymous variants were selected for downstream analyses. Of these, 153 variants were overrepresented in patients with multiple-organ failure, as compared with patients with mild acute pancreatitis. In total, 58 candidate variants were genotyped in the joined Dutch and German replication cohort. We found the rs12440118 variant of ZNF106 to be overrepresented in patients with MOF (minor allele frequency 20.4% vs 11.6%, Padj=0.026). Additionally, SLC52A1 rs346821 was found to be overrepresented (minor allele frequency 48.0% vs 42.4%, Padj= 0.003) in early MOF. None of the variants known from literature were associated.Conclusions: This study indicates that SLC52A1, a riboflavin plasma membrane transporter, and ZNF106, a zinc finger protein, may be involved in disease progression toward (early) MOF in acute pancreatitis.
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Affiliation(s)
- Fons F van den Berg
- Department of Surgery, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Yama Issa
- Department of Surgery, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Jeroen P Vreijling
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Markus M Lerch
- Departments of Clinical Chemistry, Genetics and Pediatrics, Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Frank Ulrich Weiss
- Departments of Clinical Chemistry, Genetics and Pediatrics, Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Marc G Besselink
- Department of Surgery, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Frank Baas
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Marja A Boermeester
- Department of Surgery, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Hjalmar C van Santvoort
- Department of Surgery, University Medical Center, Utrecht, The Netherlands; Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands
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IL-10-1082G>A polymorphism, use of opioids and age affect the course of acute pancreatitis. Eur J Gastroenterol Hepatol 2021; 32:178-185. [PMID: 32804849 DOI: 10.1097/meg.0000000000001875] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE We aimed to determine the association of two of the most important functional polymorphisms of IL-8 and IL-10 with the clinical course and outcome of acute pancreatitis. METHOD Ninety-three patients with acute pancreatitis were genotyped for IL-8-251T>A and IL-10-1082G>A using PCR-RFLP. The severity of the disease was determined based on the Atlanta Classification system. RESULTS In patients treated with opioids, the odds for severe form of acute pancreatitis, its complications, and death were increased. Advanced age was associated with higher odds of organ/multiple organ failure and other systemic complications. Multivariate logistic regression analyses confirmed the observed effect of age and use of opioids, and revealed higher odds for the development of severe form of acute pancreatitis [P = 0.017, odds ratio (OR): 4.324, 95% confidence interval (CI): 1.305-14.323], its complications in general (P = 0.011, OR: 4.936, 95% CI: 1.442-16.897), pancreatic necrosis (P = 0.032, OR: 3.922, 95% CI: 1.122-13.707) and systemic inflammatory response syndrome (P = 0.037, OR: 3.838, 95% CI: 1.085-13.583) in the absence of IL-10-1082G>A variant allele. The effect of IL-8 -251T>A on acute pancreatitis severity or mortality was not detected. CONCLUSION Our study suggests the IL-10 -1082A allele as a protective factor in acute pancreatitis. Opioid analgesics treatment in acute pancreatitis is associated with severity, complications and mortality, while advanced age increases the risk of systemic complications.
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van den Berg FF, Kempeneers MA, van Santvoort HC, Zwinderman AH, Issa Y, Boermeester MA. Meta-analysis and field synopsis of genetic variants associated with the risk and severity of acute pancreatitis. BJS Open 2019; 4:3-15. [PMID: 32011822 PMCID: PMC6996643 DOI: 10.1002/bjs5.50231] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 09/11/2019] [Indexed: 12/17/2022] Open
Abstract
Background Genetic risk factors can provide insight into susceptibility for acute pancreatitis (AP) and disease progression towards (infected) necrotizing pancreatitis and persistent organ failure. The aim of the study was to undertake a systematic review of the genetic evidence for AP. Methods Online databases (MEDLINE, Embase, BIOSIS, Web of Science, Cochrane Library) were searched to 8 February 2018. Studies that reported on genetic associations with AP susceptibility, severity and/or complications were eligible for inclusion. Meta‐analyses were performed of variants that were reported by at least two data sources. Venice criteria and Bayesian false‐discovery probability were applied to assess credibility. Results Ninety‐six studies reporting on 181 variants in 79 genes were identified. In agreement with previous meta‐analyses, credible associations were established for SPINK1 (odds ratio (OR) 2·87, 95 per cent c.i. 1·89 to 4·34), IL1B (OR 1·23, 1·06 to 1·42) and IL6 (OR 1·64, 1·15 to 2·32) and disease risk. In addition, two novel credible single‐nucleotide polymorphisms were identified in Asian populations: ALDH2 (OR 0·48, 0·36 to 0·64) and IL18 (OR 1·47, 1·18 to 1·82). Associations of variants in TNF, GSTP1 and CXCL8 genes with disease severity were identified, but were of low credibility. Conclusion Genetic risk factors in genes related to trypsin activation and innate immunity appear to be associated with susceptibility to and severity of AP.
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Affiliation(s)
- F F van den Berg
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - M A Kempeneers
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - H C van Santvoort
- Department of Surgery, St Antonius Hospital, Nieuwegein, the Netherlands.,Department of Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - A H Zwinderman
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Y Issa
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - M A Boermeester
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
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Garg PK, Singh VP. Organ Failure Due to Systemic Injury in Acute Pancreatitis. Gastroenterology 2019; 156:2008-2023. [PMID: 30768987 PMCID: PMC6486861 DOI: 10.1053/j.gastro.2018.12.041] [Citation(s) in RCA: 336] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/07/2018] [Accepted: 12/29/2018] [Indexed: 02/07/2023]
Abstract
Acute pancreatitis may be associated with both local and systemic complications. Systemic injury manifests in the form of organ failure, which is seen in approximately 20% of all cases of acute pancreatitis and defines "severe acute pancreatitis." Organ failure typically develops early in the course of acute pancreatitis, but also may develop later due to infected pancreatic necrosis-induced sepsis. Organ failure is the most important determinant of outcome in acute pancreatitis. We review here the current understanding of the risk factors, pathophysiology, timing, impact on outcome, and therapy of organ failure in acute pancreatitis. As we discuss the pathophysiology of severe systemic injury, the distinctions between markers and mediators of severity are highlighted based on evidence supporting their causality in organ failure. Emphasis is placed on clinically relevant end points of organ failure and the mechanisms underlying the pathophysiological perturbations, which offer insight into potential therapeutic targets to treat.
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Huber W, Algül H, Lahmer T, Mayr U, Lehmann M, Schmid RM, Faltlhauser A. Pancreatitis cytosorbents (CytoSorb) inflammatory cytokine removal: A Prospective Study (PACIFIC). Medicine (Baltimore) 2019; 98:e13044. [PMID: 30681551 PMCID: PMC6358351 DOI: 10.1097/md.0000000000013044] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) usually has a mild course with a mortality rate below 1%. However, around 10% of patients develop severe AP (SAP) involving extra-pancreatic tissues and other organ systems. The mortality of SAP is around 42%. The outcome of SAP is closely related to the development of systemic inflammation and consecutive organ failures. Most current therapies including fluid resuscitation, antimicrobial therapy, drainage procedures, and endoscopic management of complications are symptomatic rather than causative approaches, except sphincterotomy for gallstone pancreatitis. Regarding the high mortality of SAP and its close association with systemic inflammation, extracorporeal removal of inflammatory mediators is an appealing approach. Several recent studies have demonstrated that the CytoSorb adsorber effectively eliminates inflammatory cytokines, such as IL-1ß, IL-6, IL-8, IL-10, and TNF-alpha. Some of these trials suggested that therapy with CytoSorb might improve outcome, including a reduction in the vasopressor dosage and reversal of shock.Therefore, it is the objective of this study to evaluate the effectiveness of 2 consecutive 24 h-treatments with CytoSorb on hemodynamics in patients with early SAP. METHODS This study includes patients with early SAP (APACHE-II ≥10) and transpulmonary thermodilution hemodynamic monitoring (PiCCO; EV-1000) within a maximum of seven days from the onset of pain. Eligible patients will be treated with 2 consecutive periods of CytoSorb. A 20%-improvement in the vasopressor dependency index (VDI) - which relates is derived from mean arterial pressure (MAP) and catecholamine dosage - is the primary outcome. In addition to this clinical outcome, there are several laboratory (cytokine levels) and translational endpoints (including multiplex-ELISAs of numerous anti- and pro-inflammatory cytokines/chemokines and DNA analyses). Primary outcome analysis will compare the incidence of the primary endpoint in 30 patients from the intervention group to 60 matched controls with advanced hemodynamic monitoring recruited from recent studies in SAP within the same setting and the same centers. DISCUSSION A potential improvement in hemodynamics and/or other outcomes by CytoSorb would provide a new therapeutic option in the early treatment of SAP with a pathophysiological rationale. TRIAL REGISTRATION This study was registered on March 17, 2017 (ClinicalTrials.gov Identifier: NCT03082469). URL: https://clinicaltrials.gov/ct2/show/NCT03082469. VERSION V_PACIFIC_1.0 September 30, 2018.
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Affiliation(s)
- Wolfgang Huber
- Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar; Technische Universität, München, Ismaninger Straße 22, D-81675 München
| | - Hana Algül
- Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar; Technische Universität, München, Ismaninger Straße 22, D-81675 München
| | - Tobias Lahmer
- Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar; Technische Universität, München, Ismaninger Straße 22, D-81675 München
| | - Ulrich Mayr
- Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar; Technische Universität, München, Ismaninger Straße 22, D-81675 München
| | - Miriam Lehmann
- Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar; Technische Universität, München, Ismaninger Straße 22, D-81675 München
| | - Roland M. Schmid
- Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar; Technische Universität, München, Ismaninger Straße 22, D-81675 München
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Valverde-López F, Wilcox CM, Redondo-Cerezo E. Evaluation and management of acute pancreatitis in Spain. GASTROENTEROLOGIA Y HEPATOLOGIA 2018; 41:618-628. [PMID: 30149943 DOI: 10.1016/j.gastrohep.2018.06.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 06/04/2018] [Accepted: 06/19/2018] [Indexed: 02/06/2023]
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Park JW, Choi JS, Han KJ, Lee SH, Kim EJ, Cho JH. Association of a genetic polymorphism of IL1RN with risk of acute pancreatitis in a Korean ethnic group. Korean J Intern Med 2018; 33:1103-1110. [PMID: 29117667 PMCID: PMC6234396 DOI: 10.3904/kjim.2017.133] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 05/29/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Several epidemiological studies have validated the association of interleukin gene polymorphisms with acute pancreatitis (AP) in different populations. However, there have been few studies in Asian ethnic groups. We aimed to investigate the relationships between inflammatory cytokine polymorphisms and AP as pilot research in a Korean ethnic group. METHODS Patients who had been diagnosed with AP were prospectively enrolled. DNA was extracted from whole blood, and DNA sequencing was subsequently performed. Single-nucleotide polymorphisms (SNPs) of the interleukin 1β (IL1B), interleukin 1 receptor antagonist (IL1RN), and tumor necrosis factor α (TNFA) genes of patients with AP were compared to those of normal controls. RESULTS Between January 2011 and January 2013, a total of 65 subjects were enrolled (40 patients with AP vs. 25 healthy controls). One intronic SNP (IL1RN -1129T>C, rs4251961) was significantly associated with the risk of AP (odds ratio, 0.304; 95% confidence interval, 0.095 to 0.967; p = 0.043). However, in our study, AP was not found to be associated with polymorphisms in the promoter regions of inflammatory cytokine genes, including IL1B (-118C>T, c47+242C>T, +3954C/T, and -598T>C) and TNFA (-1211T>C, -1043C>A, -1037C>T, -488G>A, and -418G>A). CONCLUSION IL1RN -1129T>C (rs4251961) genotypes might be associated with a significant increase of AP risk in a Korean ethnic group.
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Affiliation(s)
- Jin Woo Park
- Division of Gastroenterology, Department of Internal Medicine, International St. Mary’s Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Ja Sung Choi
- Division of Gastroenterology, Department of Internal Medicine, International St. Mary’s Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Ki Joon Han
- Division of Gastroenterology, Department of Internal Medicine, International St. Mary’s Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Sang Heun Lee
- Division of Gastroenterology, Department of Internal Medicine, International St. Mary’s Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Eui Joo Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Jae Hee Cho
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
- Correspondence to Jae Hee Cho, M.D. Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon 21565, Korea Tel: +82-32-460-3778 Fax: +82-32-460-3408 E-mail:
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Jain S, Midha S, Mahapatra SJ, Gupta S, Sharma MK, Nayak B, Jacob TG, Garg PK. Interleukin-6 significantly improves predictive value of systemic inflammatory response syndrome for predicting severe acute pancreatitis. Pancreatology 2018; 18:500-506. [PMID: 29779831 DOI: 10.1016/j.pan.2018.05.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 05/06/2018] [Accepted: 05/08/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Predicting severe acute pancreatitis (AP) is important for triage, prognosis, and designing therapeutic trials. Persistent systemic inflammatory response syndrome (SIRS) predicts severe AP but its diagnostic accuracy is suboptimal. Our objective was to study if cytokine levels could improve the predictive value of clinical variables for the development of severe AP. METHODS Consecutive patients with AP were included in a prospective cohort study at a tertiary care center. Serum levels of IL-6, TNF-α, IL-10, MCP-1, GM-CSF and IL-1β were measured at day 3 of onset of AP. Variables such as age, co-morbidity, etiology, SIRS, and cytokines were modeled to predict severe AP by multivariable regression analysis. Genotyping was done to correlate IL-6, TNF-α and MCP-1 gene polymorphisms with cytokine levels. RESULTS Of 236 patients with AP, 115 patients admitted within 7 days of onset formed the study group. 37 of the 115 (32%) patients developed organ failure. Independent predictors of organ failure were persistent SIRS (OR 34; 95% CI: 7.2-159) and day 3 serum IL-6 of >160 pg/ml (OR 16.1; 95% CI:1.8-142). IL-6 gene (-174 G/C) GG genotype was associated with significantly higher levels of IL-6 compared to CC/CG genotype. Serum IL-6 >160 pg/ml increased the positive predictive value of persistent SIRS from 56% to 85% and specificity from 64% to 95% for predicting OF without compromising its sensitivity and negative predictive value. CONCLUSION Serum IL-6 of >160 ng/ml added significantly to the predictive value of SIRS for severe AP.
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Affiliation(s)
- Saransh Jain
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Shallu Midha
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Soumya Jagannath Mahapatra
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Swatantra Gupta
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Manish Kumar Sharma
- Department of Anatomy, 1st Floor, Teaching Block, All India Institute of Medical Sciences, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Tony George Jacob
- Department of Anatomy, 1st Floor, Teaching Block, All India Institute of Medical Sciences, New Delhi, India
| | - Pramod Kumar Garg
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India.
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Interferon-γ Aggravated L-Arginine-Induced Acute Pancreatitis in Sprague-Dawley Rats and Its Possible Mechanism: Trypsinogen Activation and Autophagy Up-regulation. Pancreas 2017; 46:619-625. [PMID: 28375949 DOI: 10.1097/mpa.0000000000000826] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES It has been confirmed that the initiation of acute pancreatitis (AP) involves intracellular trypsinogen activation and local cytokines release during its early stage. The former is related to autophagic disorder, and the latter is resulting from nuclear factor-κB activation. Although great efforts have been exerted, there is still nonspecific treatment currently. Recent data showed that immunomodulatory therapy is always promising. However, the effects of interferon-γ (IFN-γ) on AP are controversial. This study is designed to elucidate the effects of IFN-γ on AP severity and explore its impacts on the major mechanisms of AP. METHODS Sprague-Dawley rats were used to establish AP model by intraperitoneal injection of 20% L-arginine (4 g/kg) twice with an interval of 1 hour. The effects of IFN-γ on the severity of AP, trypsinogen activation peptide, and tumor necrosis factor α, Interleukin-1, Interleukin-6 levels, and autophagy activity were detected. RESULTS Compared with AP rats without IFN-γ administration, AP rats with IFN-γ administration had more severe pathological changes in pancreata, greater levels of trypsinogen activation concomitant with autophagy up-regulation, and higher levels of cytokine release. CONCLUSIONS Interferon-γ aggravated L-arginine-induced AP in Sprague-Dawley rats and led to intracellular trypsinogen activation and inflammatory response. The former may be related to autophagy up-regulation.
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Pădureanu V, Boldeanu MV, Streaţă I, Cucu MG, Siloşi I, Boldeanu L, Bogdan M, Enescu AŞ, Forţofoiu M, Enescu A, Dumitrescu EM, Alexandru D, Şurlin VM, Forţofoiu MC, Petrescu IO, Petrescu F, Ioana M, Ciurea ME, Săftoiu A. Determination of VEGFR-2 (KDR) 604A>G Polymorphism in Pancreatic Disorders. Int J Mol Sci 2017; 18:ijms18020439. [PMID: 28218664 PMCID: PMC5343973 DOI: 10.3390/ijms18020439] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 02/03/2017] [Indexed: 12/15/2022] Open
Abstract
Pancreatic disorders have a high prevalence worldwide. Despite the fact that screening methods became more effective and the knowledge we have nowadays about pancreatic diseases has enhanced, their incidence remains high. Our purpose was to determine whether single nucleotide polymorphism (SNP) of VEGFR-2/KDR (vascular endothelial growth factor receptor 2/kinase insert domain receptor) influences susceptibility to develop pancreatic pathology. Genomic DNA was extracted from blood samples collected from patients diagnosed with acute pancreatitis (n = 110), chronic pancreatitis (n = 25), pancreatic cancer (n = 82) and healthy controls (n = 232). VEGFR-2 (KDR) 604A>G (rs2071559) polymorphism frequency was determined with TaqMan allelic discrimination assays. Statistical assessment was performed by associating genetic polymorphism with clinical and pathological data. In both pancreatic disorders and healthy control groups the polymorphism we studied was in Hardy-Weinberg equilibrium. Association between increased risk for pancreatic disorders and studied polymorphism was statistically significant. KDR 604AG and AG + GG genotypes were more prevalent in acute pancreatitis and pancreatic cancer patients than in controls. These genotypes influence disease development in a low rate. No association was found between chronic pancreatitis and KDR 604AG and AG + GG genotypes. In Romanian cohort, we found an association between the KDR 604A→G polymorphism and acute pancreatitis and pancreatic cancer. Carriers of the -604G variant allele were more frequent among acute pancreatitis and pancreatic cancer than among controls, suggesting that KDR 604G allele may confer an increased risk for these diseases. In the future, more extensive studies on larger groups are necessary, in order to clarify the role of VEGFR2 polymorphisms in pancreatic pathology.
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Affiliation(s)
- Vlad Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Mihail Virgil Boldeanu
- Department of Immunology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
- Medico Science SRL-Stem Cell Bank Unit, 1B Brazda lui Novac Street, 200690 Craiova, Romania.
| | - Ioana Streaţă
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Mihai Gabriel Cucu
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Isabela Siloşi
- Department of Immunology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Lidia Boldeanu
- Medico Science SRL-Stem Cell Bank Unit, 1B Brazda lui Novac Street, 200690 Craiova, Romania.
| | - Maria Bogdan
- Maria Bogdan, Department of Pharmacology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Anca Ştefania Enescu
- Department of Anatomy, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Maria Forţofoiu
- Department of Medico-Surgical Emergencies, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Aurelia Enescu
- Department of Medico-Surgical Emergencies, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Elena Mădălina Dumitrescu
- Faculty of Nursing and Midwifery, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Dragoş Alexandru
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Valeriu Marian Şurlin
- Department of Surgery, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Mircea Cătălin Forţofoiu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Ileana Octavia Petrescu
- Department of Pediatrics, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Florin Petrescu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Mihai Ioana
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Marius Eugen Ciurea
- Department of Plastic Surgery, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
| | - Adrian Săftoiu
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania.
- Visiting Clinical Professor, Gastrointestinal Unit, Copenhagen University Hospital Herlev, 2730 Herlev, Denmark.
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Shafik NM, Abou-Fard GM. Ameliorative Effects of Curcumin on Fibrinogen-Like Protein-2 Gene Expression, Some Oxido-Inflammatory and Apoptotic Markers in a Rat Model of l-Arginine-Induced Acute Pancreatitis. J Biochem Mol Toxicol 2016; 30:302-8. [PMID: 26862043 DOI: 10.1002/jbt.21794] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Revised: 01/08/2016] [Accepted: 01/15/2016] [Indexed: 12/17/2022]
Abstract
The aim of the study was to investigate the ameliorative effects of curcumin on fibrinogen like protein-2 (fgl-2), some oxido-inflammatory and apoptotic markers in rat-induced acute pancreatitis (AP). Seventy-five albino rats were divided into control group, l-arginine (l-Arg)-induced AP group, curcumin pre-treated group before AP induction, curcumin post-treated group after AP induction, and curcumin injected group only. AP group showed severe necrotizing pancreatitis confirmed by histopathological changes and elevations in serum amylase and lipase activities, levels of epithelial neutrophil-activating peptide 78, tissue content of protein carbonyls, levels of tumor necrosis factor α, and caspase-3 as well as myeloperoxidase activity. Significant elevation in pancreatic fgl-2 mRNA expression was detected in AP group. Improvement of all parameters was detected with increase of caspase-3 in both curcumin-treated groups that confirmed curcumin ameliorative effects against AP through induction of apoptosis and inhibition of micro-thrombosis, inflammation, and oxidative stress.
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Affiliation(s)
- Noha M Shafik
- Department of Medical Biochemistry, Faculty of Medicine Tanta University, Tanta, Egypt.
| | - Ghada M Abou-Fard
- Department of Physiology, Faculty of Medicine Tanta University, Tanta, Egypt
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Shen Y, Deng X, Xu N, Li Y, Miao B, Cui N. Relationship between the degree of severe acute pancreatitis and patient immunity. Surg Today 2014; 45:1009-17. [PMID: 25410475 DOI: 10.1007/s00595-014-1083-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 08/12/2014] [Indexed: 12/21/2022]
Abstract
PURPOSE To investigate the relationship between the APACHE II score and the immunity of patients with severe acute pancreatitis. METHODS Clinical data were collected from 88 patients with acute pancreatitis, divided into four groups according to the severity of the disease. C-reactive protein (CRP), tumor necrosis factor-α, interleukin-6, interleukin-10, interleukin-4 and endotoxin (ET) in serum were measured on admission and then on days 3, 5, and 7. RESULTS The incidence of local complications and multiple organ dysfunction syndrome increased with a higher APACHE II score. The CRP levels were increased significantly on day 3 in all four groups, but remained high only in the extremely severe group. In the mild and moderate groups, the pro-/anti-inflammatory cytokines peaked on day 3 and then decreased slowly. In the severe and extremely severe groups, the proinflammatory cytokines levels peaked on days 3 and 5, and then decreased rapidly. The antiinflammatory cytokines increased progressively on days 3, 5 and 7. The ET levels peaked significantly and then decreased slowly in the mild, moderate and severe groups, but remained high in the extremely severe group. CONCLUSIONS An APACHE II score of 16 or higher is predictive of more local and systemic complications, excessive immune response, and premature immunosuppression.
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Affiliation(s)
- Yinfeng Shen
- Department of Surgery, Hubei Hospital of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
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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: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 03/13/2014] [Accepted: 10/16/2014] [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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Determination of iNOS-2087A>G Polymorphism in Acute Pancreatitis Patients. CURRENT HEALTH SCIENCES JOURNAL 2014; 40:249-52. [PMID: 26793321 PMCID: PMC4709709 DOI: 10.12865/chsj.40.04.03] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Accepted: 10/15/2014] [Indexed: 12/22/2022]
Abstract
PURPOSE To determine whether single nucleotide polymorphism (SNP) of inducible nitric oxide synthase (iNOS) is involved in susceptibility for acute pancreatitis. MATERIAL AND METHODS Genomic DNA was extracted from blood samples collected from cases of acute pancreatitis (n=110) and normal population controls frequency matched for age and sex (n=232). iNOS - 2087A>G polymorphism was genotyped using TaqMan allelic discrimination assays. The association of the genetic polymorphism with clinical and pathological data of the patients was evaluated. RESULTS We have found no significant statistical association between this polymorphism and an increased risk of developing acute pancreatitis. CONCLUSION In Romanian population, the risk of developing acute pancreatitis is not increased by the presence of iNOS-2087A>G polymorphism.
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Liu Y, Dan G, Wu L, Chen G, Wu A, Zeng P, Xu W. Functional effect of polymorphisms in the promoter of TNFAIP3 (A20) in acute pancreatitis in the Han Chinese population. PLoS One 2014; 9:e103104. [PMID: 25050625 PMCID: PMC4106899 DOI: 10.1371/journal.pone.0103104] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 06/25/2014] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND The zinc finger protein A20 is an important negative regulator of inflammation; polymorphisms in the corresponding gene, TNFAIP3, have been reported to be associated with several inflammation diseases. However, only a few studies have focused on the relationship between TNFAIP3 polymorphisms and acute pancreatitis (AP). METHODS We enrolled 201 healthy controls and 190 acute pancreatitis patients (including 47 systemic inflammatory response syndrome patients) for this study and used DNA sequencing to investigate polymorphisms in the TNFAIP3 promoter. The functional effects of these variants on transcriptional activity, A20 expression, NF-κB activity, and TNF-α and IL-1β levels, after in vitro lipopolysaccharide stimulation, were assessed. RESULTS Two SNPs (rs59693083 and rs5029924) in the TNFAIP3 promoter were selected based on bioinformatic analysis. Neither of these SNPs was associated with susceptibility to AP; however, acute pancreatitis patients who possessed the T allele of rs5029924 were more likely to experience systemic inflammatory response syndrome. Moreover, rs5029924 was found to affect TNFAIP3 promoter activity. After lipopolysaccharide stimulation, the expression of A20 protein significantly decreased, while the activity of NF-κB and the production of TNF-α and IL-1β significantly increased in whole blood leukocytes from subjects with the T allele. CONCLUSION The rs5029924 polymorphism in the TNFAIP3 promoter may alter the risk of systemic inflammatory response syndrome in acute pancreatitis patients by influencing the expression of A20 protein.
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Affiliation(s)
- Yugang Liu
- Center of Laboratory Medicine, Chengdu Military General Hospital, Chengdu, P.R. China
| | - Gang Dan
- Center of Laboratory Medicine, Chengdu Military General Hospital, Chengdu, P.R. China
| | - Lijuan Wu
- Center of Laboratory Medicine, Chengdu Military General Hospital, Chengdu, P.R. China
- * E-mail:
| | - Guangyu Chen
- Department of General Surgery, Chengdu Military General Hospital, Chengdu, P.R. China
| | - Ailin Wu
- Center of Laboratory Medicine, Chengdu Military General Hospital, Chengdu, P.R. China
| | - Ping Zeng
- Center of Laboratory Medicine, Chengdu Military General Hospital, Chengdu, P.R. China
| | - Wanqing Xu
- Center of Laboratory Medicine, Chengdu Military General Hospital, Chengdu, P.R. China
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Abstract
OBJECTIVES The anti-inflammatory effects of O-1602 and cannabidiol (CBD), the ligands of G protein-coupled receptor 55 (GPR55), on experimental acute pancreatitis (AP) were investigated. METHODS Acute pancreatitis was induced in C57BL mice by intraperitoneal injection of 50 μg/kg cerulein hourly, with a total of 6 times. Drugs (O-1602, 10 mg/kg, or CBD, 0.5 mg/kg) were given by intraperitoneal injection 2 times at 30 minutes before the first injection and immediately before the fifth cerulein injection. At 3 hours after the last injection, the blood, the lungs, and the pancreas were harvested for the pancreatic enzyme activity, myeloperoxidase activity, and pro-inflammatory cytokines measurement; and the expressions of GPR55 mRNA and protein in the pancreas were detected. RESULTS Cannabidiol or O-1602 treatment significantly improved the pathological changes of mice with AP and decreased the enzyme activities, IL-6 and tumor necrosis factor α; levels, and the myeloperoxidase activities in plasma and in the organ tissues. G protein-coupled receptor 55 mRNA and protein expressed in the pancreatic tissue, and the expressions were decreased in the mice with AP, and either CBD or O-1602 attenuated these changes to a certain extent. CONCLUSION Cannabidiol and O-1602 showed anti-inflammatory effects in mice with AP and improved the expression of GPR55 in the pancreatic tissue as well.
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Yang Z, Qi X, Wu Q, Li A, Xu P, Fan D. Lack of association between TNF-α gene promoter polymorphisms and pancreatitis: a meta-analysis. Gene 2012; 503:229-34. [PMID: 22579868 DOI: 10.1016/j.gene.2012.04.057] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Accepted: 04/18/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Tumor necrosis factor alpha (TNF-α) is a major proinflammatory cytokine involved in the etiology of pancreatitis. The association between pancreatitis and the -308G>A and -238G>A polymorphisms in TNF-α gene has been analyzed in several studies, but results have been inconsistent. The purpose of this study was to integrate previous findings and explore whether these polymorphisms are associated with susceptibility and severity to pancreatitis. METHODS A meta-analysis was performed by searching PubMed, Cochrane Library, and ScienceDirect databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS Our meta-analysis of a total of 1569 pancreatitis cases and 1330 control subjects from twelve published case-control studies for the -308G>A polymorphism (OR 0.98; 95% CI 0.83-1.17), and of 480 cases and 302 controls from four studies for the -238G>A polymorphism (OR 0.92; 95% CI 0.58-1.47) did not show any significant associations of susceptibility to pancreatitis with the variant GA+AA genotypes compared with the GG genotype. An association between severity of acute pancreatitis and -308G>A polymorphism was not found either (OR 0.93; 95% CI 0.69-1.24). CONCLUSION Polymorphisms in two sites of TNF-α gene promoter do not alter the risk of pancreatitis.
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Affiliation(s)
- Zhiping Yang
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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20
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Clinical observation of immunity in patients with secondary infection from severe acute pancreatitis. Inflamm Res 2012; 61:743-8. [PMID: 22466614 DOI: 10.1007/s00011-012-0467-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Revised: 03/06/2012] [Accepted: 03/12/2012] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES To observe immune system changes in patients with secondary infection from severe acute pancreatitis (SAP). METHODS Seventy-nine patients were recruited. The percentages of CD4+, CD8+, natural killer (NK), HLA-DR+ cells and B lymphocytes, and the CD4+/CD8+ ratio, were determined. In addition, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-4 (IL-4) serum levels were determined on days 1, 7, 14, and 28. RESULTS Fifteen patients had a secondary infection. The immune response of the infected group was quite different from the non-infected group, with a higher percentage of CD4+ and HLA-DR+ cells on days 1, 7, 14 and 28, a higher percentage of CD8+ and NK cells on days 14 and 28, a reduced CD4+/CD8+ ratio, and a reduction in B lymphocytes. The cytokine levels in the infected group were different from the non-infected group, with a rise in TNF-α and IL-6 through the first 2 weeks, but dropping at 1 month. IL-10 and IL-4 increased initially, but then dropped over the next 3 weeks. CONCLUSIONS An early excessive immune response followed by a subsequent immune deficiency is closely related to secondary SAP infection.
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Bishehsari F, Sharma A, Stello K, Toth C, O’Connell MR, Evans AC, LaRusch J, Muddana V, Papachristou GI, Whitcomb DC. TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis. Pancreatology 2012; 12:113-8. [PMID: 22487520 PMCID: PMC4350817 DOI: 10.1016/j.pan.2012.02.014] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Revised: 02/20/2012] [Accepted: 02/20/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Acute pancreatitis (AP) is a complex inflammatory syndrome with unpredictable progression to systemic inflammation and multi-organ dysfunction syndrome (MODS). Tumor necrosis factor alpha (TNF-α) is a cytokine that may link inflammation to the systemic inflammatory response syndrome (SIRS), which usually precedes MODS. Small genetic cohort studies of the TNFA promoter in AP produced ambiguous results. We performed a comprehensive evaluation of TNFA promoter variants to assess both susceptibility to AP and risk of progression to MODS. METHODS We prospectively ascertained 401 controls and 211 patients with AP that were assessed for persistent SIRS (>48 h) and MODS. MODS was defined as failure of ≥2 organ systems (cardiovascular, pulmonary, and/or renal) persisting more than 48 h. Subjects were genotyped by DNA sequencing and analyzed for SNPs at -1031 C/T (rs1799964), -863 A/C (rs1800630), -857 C/T (rs1799724), -308 A/G (rs1800629), and -238 A/G (rs361525). RESULTS Twenty-three of 211 AP patients (11%) developed MODS. TNFA promoter variants were not associated with susceptibility to AP, but progression to MODS was associated with the minor allele at -1031C (56.5% vs. 32.4% P = 0.022, OR: 2.7; 95%CI: 1.12-6.51) and -863A (43.5% vs. 21.8% P = 0.022, OR: 2.76; 95%CI: 1.12-6.74). CONCLUSION TNFA promoter variants do not alter susceptibility to AP, but rather the TNF-α expression-enhancing -1031C and -863A alleles significantly increased the risk of AP progression to MODS. These data, within the context of previous studies, clarify the risk of specific genetic variants in TNFA and therefore the role of TNF-α in the overall AP syndrome.
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Affiliation(s)
- Faraz Bishehsari
- Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA USA 15213
| | - Arun Sharma
- Universtity of Pittsburgh School of Medicine, Pittsburgh, PA USA 15213
| | - Kimberly Stello
- Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA USA 15213
| | - Chad Toth
- Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA USA 15213
| | - Michael Richard O’Connell
- Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA USA 15213
| | - Anna C Evans
- Universtity of Pittsburgh School of Medicine, Pittsburgh, PA USA 15213
| | - Jessica LaRusch
- Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA USA 15213
| | - Venkata Muddana
- Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA USA 15213
| | - Georgios I Papachristou
- Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA USA 15213,VA Pittsburgh Health Care System, Pittsburgh, PA
| | - David C Whitcomb
- Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA USA 15213,Department of Cell Biology & Physiology, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA USA 15213,Department of Human Genetics, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA USA 15213
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Shen Y, Cui N, Miao B, Zhao E. Immune dysregulation in patients with severe acute pancreatitis. Inflammation 2011; 34:36-42. [PMID: 20405190 DOI: 10.1007/s10753-010-9205-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
To investigate patients with severe acute pancreatitis (SAP) by dynamic levels of pro-/anti-inflammatory cytokines and endotoxin (ET) in plasma and the relationship between immunity and infection, organ dysfunction. Seventy-two patients with SAP were recruited. The ET, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-4 (IL-4) were determined on admission and days 3, 7, and 14. For comparison, patients were analyzed through infection group versus non-infection group, multiple organ dysfunction syndrome (MODS) group versus non-MODS group. There were sixteen patients with secondary infection, twenty-two with MODS, and nine deaths. The infection group had higher levels of ET than the non-infection group on days 3 and 7. The dynamic cytokine levels of patients in the MODS group were unanimous with those outcomes in the infection group. The levels of cytokines in the infection group were different from the non-infection group, with more levels of TNF-α, IL-6 on days 3 and 7 and less on days 14, and more levels of IL-10, IL-4 on days 7 and 14. The levels of TNF-α, IL-6 in the MODS group were different from the non-MODS group, with more levels on days 3 and 7, and less levels on days 14. Immune dysregulation may play an important role in infection and organ dysfunction for patients with SAP.
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Affiliation(s)
- YinFeng Shen
- National Medical Center of Biliopancreatic Diseases, Nankai Hospital, Nankai Clinical School, Tianjin Medical University, Tianjin, People's Republic of China
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Cussigh A, Falleti E, Fabris C, Bitetto D, Cmet S, Fontanini E, Bignulin S, Fornasiere E, Fumolo E, Minisini R, Pirisi M, Toniutto P. Interleukin 6 promoter polymorphisms influence the outcome of chronic hepatitis C. Immunogenetics 2010; 63:33-41. [PMID: 21072509 DOI: 10.1007/s00251-010-0491-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2010] [Accepted: 10/25/2010] [Indexed: 02/07/2023]
Abstract
Host genetic variation may affect the outcome of chronic viral hepatitides, favoring viral clearance and/or modulating the inflammatory response to persistent infection. Our aims were to assess whether interleukin 6 (IL-6) promoter polymorphisms are associated with chronic hepatitis C virus (HCV) infection and to clarify the role of IL-6 haplotypes in facilitating progressive disease. The study included 424 Italian patients (233 males, median age 53 years) affected by HCV chronic infection. IL6 -1363, -597, -572, -174, and +2954 polymorphic loci were assayed by means of restriction fragment length polymorphism. Three hundred forty-four healthy Italian blood donors (245 males, median age 50 years) served as controls. Comparing patients and controls analysis of molecular variance was highly significant (p < 0.0001); at a locus by locus approach, the frequencies of minor alleles in the -1363 (p < 0.02), -597 (p < 0.02), and -174 (p < 0.01) polymorphisms were confirmed to be less represented in patients than in controls. Carrying the wild-type G allele at the -597 and -174 loci identified an unfavorable haplotype; carrying the minor allele in one/both loci identified an indifferent/favorable haplotype. Male patients carrying two unfavorable haplotypes had the highest adjusted mean ± standard error Ishak staging score (3.56 ± 0.19), while females carrying one or no unfavorable haplotypes had the lowest (2.69 ± 0.21); the remaining patients had an intermediate value (3.12 ± 0.13, p < 0.01). In conclusion, IL-6 promoter polymorphisms influence the development of chronic HCV infection. With the permissive effect of male gender, haplotypes represented by the wild-type allele for -597 and -174 loci appear to favor a worse evolution of the disease.
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Falleti E, Fabris C, Vandelli C, Colletta C, Cussigh A, Smirne C, Fontanini E, Cmet S, Minisini R, Bitetto D, Toniutto P, Pirisi M. Genetic polymorphisms of interleukin-6 modulate fibrosis progression in mild chronic hepatitis C. Hum Immunol 2010; 71:999-1004. [PMID: 20655350 DOI: 10.1016/j.humimm.2010.06.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Revised: 06/02/2010] [Accepted: 06/04/2010] [Indexed: 12/11/2022]
Abstract
Genetic polymorphisms of interleukin-6 (IL-6) (-1363G>T, -597G>A, -572G>C, -174G>C, +2954G>C) may affect the outcomes of several diseases. This study was aimed to verify the role of these polymorphisms on the disease progression of patients with hepatitis C virus (HCV) infection and persistently normal transaminases (PNALT). A total of 121 PNALT patients did not receive any antiviral treatment but underwent periodic clinical monitoring, including repeat biopsies, for a median of 120 months. IL6-1363G>T, -597G>A, -572G>C, -174G>C, +2954G>C polymorphisms were related to histologic fibrosis progression. Among patients whose grading and staging scores increased at the end of the follow-up ≥2 Ishak points (N = 60 and N = 26, respectively), IL-6 -174G>C genotype frequencies were GG 37/66, GC 21/45, CC 2/10 (p = 0.041) and GG 18/66, GC 8/45, CC 0/10 (p = 0.040), respectively. The following frequencies were observed for the 572G>C polymorphism: GG 50/105, GC 10/16, CC 0/0, and GG 19/105, GC 7/16, CC 0/0, respectively. Grading progression was independently associated with carriage of the G allele in -174G>C polymorphism (oddd ratio = 5.07%, 95% confidence interval = 0.959-26.8, p = 0.023). Staging progression was independently associated with carriage of the C allele in -572G>C polymorphism (odd ratio = 4.60%, 95% confidence interval 1.42-14.8, p = 0.012). IL-6 polymorphisms influence histologic progression of HCV in patients with PNALT.
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Affiliation(s)
- Edmondo Falleti
- Medical Liver Transplant Unit, University of Udine, Undine, Italy
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Lopez-Font I, Gea-Sorlí S, de-Madaria E, Gutiérrez LM, Pérez-Mateo M, Closa D. Pancreatic and pulmonary mast cells activation during experimental acute pancreatitis. World J Gastroenterol 2010; 16:3411-7. [PMID: 20632444 PMCID: PMC2904888 DOI: 10.3748/wjg.v16.i27.3411] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the activation of pancreatic and pulmonary mast cells and the effect of mast cell inhibition on the activation of peritoneal and alveolar macrophages during acute pancreatitis.
METHODS: Pancreatitis was induced by intraductal infusion of 5% sodium taurodeoxycholate in rats. The mast cell inhibitor cromolyn was administered intraperitoneally (i.p.) 30 min before pancreatitis induction. The pancreatic and pulmonary tissue damage was evaluated histologically and mast cells and their state of activation were evaluated. Peritoneal and alveolar macrophages were obtained and the expression of tumor necrosis factor α was determined. Myeloperoxidase activity was measured to evaluate the effect of mast cell inhibition on the progression of the inflammatory process. Finally, the effect of plasma on cultured mast cells or macrophages was evaluated in vitro.
RESULTS: The mast cell stabilizer significantly reduced inflammation in the pancreas and lung and the activation of alveolar macrophages but had no effect on peritoneal macrophages. Mast cell degranulation was observed in the pancreas during pancreatitis but no changes were observed in the lung. Plasma from rats with pancreatitis could activate alveolar macrophages but did not induce degranulation of mast cells in vitro.
CONCLUSION: Pancreatic mast cells play an important role in triggering the local and systemic inflammatory response in the early stages of acute pancreatitis. In contrast, lung mast cells are not directly involved in the inflammatory response related to pancreatic damage.
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Abstract
Acute pancreatitis and chronic pancreatitis are complex inflammatory disorders of the pancreas with unpredictable severity, complications, and clinical courses. Growing evidence for genetic risk and modifying factors, plus strong evidence that only a minority of patients with these disorders are heavy alcohol drinkers, has revolutionized our concept of these diseases. Once considered a self-inflicted injury, pancreatitis is now recognized as a complex inflammatory condition like inflammatory bowel disease. Genetic linkage and candidate gene studies have identified six pancreas-targeting factors that are associated with changes in susceptibility to acute and/or chronic pancreatitis, including cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2), serine protease inhibitor Kazal 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsinogen C (CTRC) and calcium-sensing receptor (CASR). Patients with mutations in these genes are at increased risk of pancreatitis caused by a variety of stresses including hyperlipidemia and hypercalcemia. Multiple studies are reporting new polymorphisms, as well as complex gene x gene and gene x environmental interactions.
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Affiliation(s)
- David C Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
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Chiu D, Niu L, Mu F, Peng X, Zhou L, Li H, Li R, Ni J, Jiang N, Hu Y, Hao Z, Xu K. The experimental study for efficacy and safety of pancreatic cryosurgery. Cryobiology 2010; 60:281-6. [PMID: 20152824 DOI: 10.1016/j.cryobiol.2010.01.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Revised: 01/27/2010] [Accepted: 01/29/2010] [Indexed: 12/17/2022]
Abstract
OBJECTIVE This study was designed to basic information concerning the efficacy and safety of cryosurgery for pancreatic cancer. Fifteen healthy pigs were used to perform biochemical analysis and histological assessment. METHODS Following anesthesia and laparotomy, an argon-helium cryoprobe was inserted into the pancreas. The introduction of argon gas induced a rapid decrease in temperature to -160 degrees C (Group I, 5 pigs) or -110 degrees C (Group II, 5 pigs), respectively, resulting in ice-ball formation of 15-20mm diameter after 5 min. Following freezing, helium gas was circulated in the probe tip to increase the temperature to 10-20 degrees C over 3 min to thaw. The freeze/thaw cycle was then repeated. Group III (3 pigs) had a cryoprobe inserted, but without freezing, and Group IV (2 pigs) included untreated or normal control animals. Levels of serum amylase (AMY), IL-6 and C-RP were measured prior to freezing and for 7 days following the procedure. All pigs were euthanized 7 days post-treatment and pancreases were examined histologically. RESULTS Neither hyperaemia, edema or hemorrhage were observed in the un-frozen parts of the pancreas. Histological assessment revealed a significant level of necrosis in the central and lateral regions of the tissue frozen within the ice-ball. All cellular ultrastructure was destroyed and only observable as a few of remaining nuclei with broken crests and degranulated mitochondria and rough endoplasmic reticulum. There was a significant increase of serum AMY levels for a brief period in both "deep frozen" and the "shallow frozen" groups. However, the AMY also increased in two pigs in the "normal control" group and one pig from the "inserted cryoprobe without freeze" control group. All experimental pigs appeared healthy until the sacrifice time. CONCLUSION Cryosurgery is a safe and effective ablative procedure for pancreatic tissue resulting in minimal complications.
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Affiliation(s)
- David Chiu
- Fuda Cancer Hospital at Guangzhou, China; The GIBH Affiliated Fuda Hospital, Chinese Academy of Sciences, China
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Xue CH, Gao ZJ, Li QP, Xu YP, Zhou CS, Yao J, Fu BQ. Efficacy of celecoxib in the treatment of severe acute pancreatitis in rats. Shijie Huaren Xiaohua Zazhi 2009; 17:3197-3202. [DOI: 10.11569/wcjd.v17.i31.3197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy of celecoxib in the treatment of severe acute pancreatitis (SAP) in rats and explore potential mechanisms involved.
METHODS: A total of 135 Sprague-Dawley rats were used in this study, of which 75 were randomly and equally divided into three groups (SAP model control group, low-dose and high-dose celecoxib treatment groups) to investigate the survival rate, and 60 were randomly and equally divided into four groups (sham operation group, SAP model control group and low-dose and high-dose celecoxib treatment groups) to detect pancreatic histopathological changes, serum tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels, and pancreatic expression of cyclooxygenase-2 (COX-2). SAP was induced in rats by retrograde injection of sodium taurocholate into the biliopancreatic duct. The histopathological changes in the pancreas of rats were evaluated using a semi-quantitative scoring method. The changes in serum TNF-α, IL-1β and IL-6 levels at different time points were measured by enzyme-linked immunosorbent assay (ELISA). The expression of COX-2 mRNA in the pancreas was detected by reverse transcription-polymerase chain reaction (RT-PCR).
RESULTS: Celecoxib ameliorated pancreatic pathological damage in SAP rats. High-dose celecoxib could significantly mitigate edema at 24 hours (2.28 ± 0.30 vs 2.73 ± 0.22, P < 0.05), acinar necrosis at 12 and 24 hours (2.03 ± 0.15 vs 2.48 ± 0.24 and 2.09 ± 0.10 vs 2.65 ± 0.25, respectively; both P < 0.05), and inflammatory cell infiltration at 12 and 24 hours (1.80 ± 0.22 vs 2.51 ± 0.17 and 1.57 ± 0.26 vs 2.20 ± 0.22, respectively; both P < 0.05). The levels of serum TNF-α, IL-1β and IL-6 in SAP rats were significantly higher than those in normal control mice at all time points. After celecoxib treatment, the levels of serum TNF-α, IL-1β and IL-6 significantly decreased in SAP rats, especially prominent in the high-dose group (P < 0.05). Celecoxib treatment could also improve the survival rate of SAP rats (16% vs 52%, P < 0.05).
CONCLUSION: Celecoxib can ameliorate pathological damage in the pancreas of SAP rats possibly by inhibiting the production of serum TNF-α, IL-1β and IL-6 and the expression of COX-2 in the pancreas.
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Effect of baicalin on inflammatory mediator levels and microcirculation disturbance in rats with severe acute pancreatitis. Pancreas 2009; 38:732-8. [PMID: 19657312 DOI: 10.1097/mpa.0b013e3181ad9735] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES To investigate the effect of bacailin on inflammatory mediators and microcirculation disturbance in severe acute pancreatitis (SAP) rats and explore its therapeutic mechanism. METHODS The rats were randomly divided into SAP group, baicalin-treated group and sham operated group. At 3, 6, and 12 hours after operation, we examined the mortality rate of rats, ascites volume, and pancreatic pathological changes in each group and determined the contents of inflammatory mediators in blood as well as the changes in blood viscosity. RESULTS Compared with SAP group, treatment with baicalin is able to improve the pathological damage of the pancreas, reduce the contents of multiple inflammatory mediators in blood, decrease the amount of ascitic fluid, and reduce the mortality rates of SAP rats. The low-shear whole blood viscosity in baicalin-treated group (at 3 hours) as well as the high-shear and low-shear whole blood viscosity in baicalin-treated group (at 12 hours) were significantly lower than that in SAP group. CONCLUSIONS Baicalin has good prospects in the treatment for SAP because it can exert therapeutic effects on this disease through inhibiting the production of inflammatory mediators, decreasing blood viscosity, improving microcirculation, and mitigating the pathological damage of the pancreas.
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Abstract
Acute pancreatitis (AP), especially acute necrotizing pancreatitis, is a common clinical disorder presenting as an acute abdomen. As AP is often complicated with systemic inflammatory response syndrome and multiple organ failure, the overall mortality rate in AP patients is high. At present, the research on the pathogenesis of AP has attracted wide attention though it has not been fully clarified yet. Of many theories to explain the pathogenesis of AP, "the theory of self-digestion of the pancreas" is the dominant hypothesis. In recent years, concerns have also been raised over "the theory of inflammatory mediators", "the theory of intestinal bacterial translocation", "the theory of apoptosis" and "the theory of calcium overload of pancreatic acinar cells". In addition, extensive research on the relationship between hyperlipidemia, especially high triglycerides (TG), and AP has also been conducted. In this article, we will review the recent advances in the pathogenesis of AP.
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