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Wiley MB, Bauer J, Alvarez V, Mehrotra K, Cheng W, Kolics Z, Giarrizzo M, Ingle K, Bialkowska AB, Jung B. Activin A signaling stimulates neutrophil activation and macrophage migration in pancreatitis. Sci Rep 2024; 14:9382. [PMID: 38654064 PMCID: PMC11039671 DOI: 10.1038/s41598-024-60065-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/18/2024] [Indexed: 04/25/2024] Open
Abstract
Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in mice improves outcomes in two murine models of AP. To test the hypothesis that activin is produced early in response to pancreatitis and is maintained throughout disease progression to stimulate immune cells, we first performed digital spatial profiling (DSP) of human chronic pancreatitis (CP) patient tissue. Then, transwell migration assays using RAW264.7 mouse macrophages and qPCR analysis of "neutrophil-like" HL-60 cells were used for functional correlation. Immunofluorescence and western blots on cerulein-induced pancreatitis samples from pancreatic acinar cell-specific Kras knock-in (Ptf1aCreER™; LSL-KrasG12D) and functional WT Ptf1aCreER™ mouse lines mimicking AP and CP to allow for in vivo confirmation. Our data suggest activin promotes neutrophil and macrophage activation both in situ and in vitro, while pancreatic activin production is increased as early as 1 h in response to pancreatitis and is maintained throughout CP in vivo. Taken together, activin is produced early in response to pancreatitis and is maintained throughout disease progression to promote neutrophil and macrophage activation.
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Affiliation(s)
- Mark B Wiley
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Jessica Bauer
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Valentina Alvarez
- Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA
| | - Kunaal Mehrotra
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Wenxuan Cheng
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Zoe Kolics
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Michael Giarrizzo
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, 11794, USA
| | - Komala Ingle
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, 11794, USA
| | - Agnieszka B Bialkowska
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, 11794, USA
| | - Barbara Jung
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
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Akshintala VS, Kanthasamy K, Bhullar FA, Sperna Weiland CJ, Kamal A, Kochar B, Gurakar M, Ngamruengphong S, Kumbhari V, Brewer-Gutierrez OI, Kalloo AN, Khashab MA, van Geenen EJM, Singh VK. Incidence, severity, and mortality of post-ERCP pancreatitis: an updated systematic review and meta-analysis of 145 randomized controlled trials. Gastrointest Endosc 2023; 98:1-6.e12. [PMID: 37004815 DOI: 10.1016/j.gie.2023.03.023] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 03/01/2023] [Accepted: 03/21/2023] [Indexed: 04/04/2023]
Abstract
BACKGROUND AND AIMS The incidence, severity, and mortality of post-ERCP pancreatitis (PEP) largely remain unknown with changing trends in ERCP use, indication, and techniques. We sought to determine the incidence, severity, and mortality of PEP in consecutive and high-risk patients based on a systemic review and meta-analysis of patients in placebo and no-stent arms of randomized control trials (RCTs). METHODS The MEDLINE, Embase, and Cochrane databases were searched from the inception of each database to June 2022 to identify full-text RCTs evaluating PEP prophylaxes. The incidence, severity, and mortality of PEP from the placebo or no-stent arms of RCTs were recorded for consecutive and high-risk patients. A random-effects meta-analysis for a proportions model was used to calculate PEP incidence, severity, and mortality. RESULTS One hundred forty-five RCTs were found with 19,038 patients in the placebo or no-stent arms. The overall cumulative incidence of PEP was 10.2% (95% confidence interval [CI], 9.3-11.3), predominantly among the academic centers conducting such RCTs. The cumulative incidences of severe PEP and mortality were .5% (95% CI, .3-.7) and .2% (95% CI, .08-.3), respectively, across 91 RCTs with 14,441 patients. The cumulative incidences of PEP and severe PEP were 14.1% (95% CI, 11.5-17.2) and .8% (95% CI, .4-1.6), respectively, with a mortality rate of .2% (95% CI, 0-.3) across 35 RCTs with 3733 patients at high risk of PEP. The overall trend for the incidence of PEP among patients randomized to placebo or no-stent arms of RCTs has remained unchanged from 1977 to 2022 (P = .48). CONCLUSIONS The overall incidence of PEP is 10.2% but is 14.1% among high-risk patients based on this systematic review of placebo or no-stent arms of 145 RCTs; this rate has not changed between 1977 and 2022. Severe PEP and mortality from PEP are relatively uncommon.
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Affiliation(s)
- Venkata S Akshintala
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Kavin Kanthasamy
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Furqan A Bhullar
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | | | - Ayesha Kamal
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Bharati Kochar
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Merve Gurakar
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | | | - Vivek Kumbhari
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | | | - Anthony N Kalloo
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Mouen A Khashab
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Erwin-Jan M van Geenen
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Vikesh K Singh
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
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Wiley MB, Mehrotra K, Bauer J, Yazici C, Bialkowska AB, Jung B. Acute Pancreatitis: Current Clinical Approaches, Molecular Pathophysiology, and Potential Therapeutics. Pancreas 2023; 52:e335-e343. [PMID: 38127317 PMCID: PMC11913250 DOI: 10.1097/mpa.0000000000002259] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 06/28/2023] [Indexed: 12/23/2023]
Abstract
OBJECTIVE Severe acute pancreatitis (SAP), pancreatic inflammation leading to multiorgan failure, is associated with high morbidity and mortality. There is a critical need to identify novel therapeutic strategies to improve clinical outcomes for SAP patients. MATERIALS AND METHODS A comprehensive literature review was performed to identify current clinical strategies, known molecular pathophysiology, and potential therapeutic targets for SAP. RESULTS Current clinical approaches focus on determining which patients will likely develop SAP. However, therapeutic options are limited to supportive care and fluid resuscitation. The application of a novel 5-cytokine panel accurately predicting disease outcomes in SAP suggests that molecular approaches will improve impact of future clinical trials in AP. CONCLUSIONS Inflammatory outcomes in acute pancreatitis are driven by several unique molecular signals, which compound to promote both local and systemic inflammation. The identification of master cytokine regulators is critical to developing therapeutics, which reduce inflammation through several mechanisms.
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Affiliation(s)
- Mark B Wiley
- From the Department of Medicine, University of Washington, Seattle, WA
| | - Kunaal Mehrotra
- From the Department of Medicine, University of Washington, Seattle, WA
| | - Jessica Bauer
- From the Department of Medicine, University of Washington, Seattle, WA
| | - Cemal Yazici
- Department of Medicine, University of Illinois Chicago, Chicago, IL
| | - Agnieszka B Bialkowska
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY
| | - Barbara Jung
- From the Department of Medicine, University of Washington, Seattle, WA
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Czaja AJ. Immune Inhibitory Properties and Therapeutic Prospects of Transforming Growth Factor-Beta and Interleukin 10 in Autoimmune Hepatitis. Dig Dis Sci 2022; 67:1163-1186. [PMID: 33835375 DOI: 10.1007/s10620-021-06968-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 03/22/2021] [Indexed: 12/14/2022]
Abstract
Transforming growth factor-beta and interleukin 10 have diverse immune inhibitory properties that have restored homeostatic defense mechanisms in experimental models of autoimmune disease. The goals of this review are to describe the actions of each cytokine, review their investigational use in animal models and patients, and indicate their prospects as interventions in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Transforming growth factor-beta expands the natural and inducible populations of regulatory T cells, limits the proliferation of natural killer cells, suppresses the activation of naïve CD8+ T cells, decreases the production of interferon-gamma, and stimulates fibrotic repair. Interleukin 10 selectively inhibits the CD28 co-stimulatory signal for antigen recognition and impairs antigen-specific activation of uncommitted CD4+ and CD8+ T cells. It also inhibits maturation of dendritic cells, suppresses Th17 cells, supports regulatory T cells, and limits production of diverse pro-inflammatory cytokines. Contradictory immune stimulatory effects have been associated with each cytokine and may relate to the dose and accompanying cytokine milieu. Experimental findings have not translated into successful early clinical trials. The recombinant preparation of each agent in low dosage has been safe in human studies. In conclusion, transforming growth factor-beta and interleukin 10 have powerful immune inhibitory actions of potential therapeutic value in autoimmune hepatitis. The keys to their therapeutic application will be to match their predominant non-redundant function with the pivotal pathogenic mechanism or cytokine deficiency and to avoid contradictory immune stimulatory actions.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA.
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Lyu Y, Wang B, Cheng Y, Xu Y, Du W. Comparative Efficacy of 9 Major Drugs for Postendoscopic Retrograde Cholangiopancreatography Pancreatitis: A Network Meta-Analysis. Surg Laparosc Endosc Percutan Tech 2019; 29:426-432. [PMID: 31490455 DOI: 10.1097/sle.0000000000000707] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is one of the most common complications after ERCP. The optimal drugs for reducing the risk of PEP are still unclear. This study aimed to compare the efficacy of 9 major drugs used worldwide for the prevention of PEP through a network meta-analysis. METHODS We conducted a systematic search of the literature up to October 2018 on PubMed, Embase, Web of Science, the Cochrane Central Library, and ClinicalTrials.gov. Randomized controlled trials (RCTs) comparing allopurinol, diclofenac, gabexate (GAB), glyceryl trinitrate (GTN), indomethacin, nafamostat, octreotide, somatostatin, and ulinastatin for protection against PEP were included. RESULTS Eighty-six randomized controlled trials involving 25,246 patients were included in this network meta-analysis. Results indicated that diclofenac, GAB, GTN, indomethacin, somatostatin, and ulinastatin were more effective than placebo with odds ratios ranging between 0.48 (95% credible interval, 0.26-0.86) for GAB and 0.61 (0.39-0.94) for somatostatin. However, allopurinol, nafamostat, and octreotide showed similar efficacy as placebo in reducing the risk of PEP. No significant differences were found in the efficacy between diclofenac, GAB, GTN, indomethacin, somatostatin, and ulinastatin. In terms of prognosis, GAB may be the most effective treatment (surface under the cumulative ranking curve=70.6%) and the least effective was octreotide (surface under the cumulative ranking curve=28%). CONCLUSIONS Although our analysis suggests that GAB may be the most effective drug in preventing PEP, the limitations of our study warrants more high-quality head-to-head trials of these clinical drugs in the future.
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Affiliation(s)
- Yunxiao Lyu
- Department of Hepatobiliary Surgery, Dongyang People's Hospital, Dongyang, Zhejiang, China
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Plavsic I, Zitinic I, Tulic V, Poropat G, Marusic M, Hauser G. Early immune response in post endoscopic retrograde cholangiopancreatography pancreatitis as a model for acute pancreatitis. World J Meta-Anal 2019; 7:96-100. [DOI: 10.13105/wjma.v7.i3.96] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/27/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023] Open
Abstract
This opinion review summarizes comparison of clinical presentation and immunology of post-endoscopic pancreatitis and acute pancreatitis (AP) of other etiology. The rationale for this topic was found in studies that mention differences in clinical presentation between these entities, stating that severe form of AP after endoscopic retrograde cholangiopancreatography was more severe than AP of other etiology. Found difference in clinical presentation may have a background in different immunology that needs to be further investigated.
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Affiliation(s)
- Ivana Plavsic
- Department of Anesthesiology and Critical care medicine, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Ivana Zitinic
- Department of Emergency Medicine, Clinical Hospital Centre, Rijeka 51000, Croatia
| | - Vera Tulic
- Department of Anesthesiology and Critical care medicine, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Poropat
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, Medical Faculty Rijeka, University of Rijeka, Rijeka 51000, Croatia
| | - Marinko Marusic
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Sv. Duh, Zagreb, Faculty of Health Studies, University of Rijeka, Rijeka 51000, Croatia
- Medical Faculty Osijek, University of J.J. Stossmayer, Osijek 31000, Croatia
| | - Goran Hauser
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, Faculty of Health Studies, University of Rijeka, Rijeka 51000, Croatia
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Plavsic I, Žitinić I, Mikolasevic I, Poropat G, Hauser G. Endoscopic retrograde cholangiopancreatography-induced and non-endoscopic retrograde cholangiopancreatography-induced acute pancreatitis: Two distinct clinical and immunological entities? World J Gastrointest Endosc 2018; 10:259-266. [PMID: 30364685 PMCID: PMC6198307 DOI: 10.4253/wjge.v10.i10.259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 06/10/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is common gastrointestinal disease of varied aetiology. The most common cause of AP is gallstones, followed by alcohol abuse as an independent risk factor. With the increased need for invasive techniques to treat pancreatic and bile duct pathologies such as endoscopic retrograde cholangiopancreatography (ERCP), AP has emerged as the most frequent complication. While severe AP following ERCP is rare (0.5%), if it does develop it has a greater severity index compared to non-ERCP AP. Development of a mild form of AP after ERCP is not considered a clinically relevant condition. Differences in the clinical presentation and prognosis of the mild and severe forms have been found between non-ERCP AP and post-endoscopic pancreatitis (PEP). It has been proposed that AP and PEP may also have different immunological responses to the initial injury. In this review, we summarise the literature on clinical and inflammatory processes in PEP vs non-ERCP AP.
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Affiliation(s)
- Ivana Plavsic
- Department of Anesthesiology and Critical care medicine, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Ivana Žitinić
- Department of Emergency Medicine, Clinical Hospital Centre, Rijeka 51000, Croatia
| | - Ivana Mikolasevic
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Poropat
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Hauser
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, Faculty of health Studies, University of Rijeka, Rijeka 51000, Croatia
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Lyu Y, Cheng Y, Wang B, Xu Y, Du W. What is impact of nonsteroidal anti-inflammatory drugs in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of randomized controlled trials. BMC Gastroenterol 2018; 18:106. [PMID: 29973142 PMCID: PMC6032784 DOI: 10.1186/s12876-018-0837-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 06/26/2018] [Indexed: 12/16/2022] Open
Abstract
Background Recently, although studies have investigated the role of NSAIDs in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP), selection of the ideal drug, the time and route of its administration for the appropriate population remain controversial. Methods A systematic search was done in sources including PubMed, Embase, Web of Science, the Cochrane Library Central, and ClinicalTrials.gov from from August 1, 1990 to August 1, 2017. Randomized controlled trials comparing the prophylactic use of NSAIDs versus a placebo were included. Statistical analysis was performed using the RevMan 5.3 software to assess the outcomes. Results A total of 21 randomized controlled trials were included in the meta-analysis. Our study showed that NSAIDs significantly reduced the incidence of PEP (RR, 0.61, 95%CI,0.52–0.72; p < 0.00001). The analysis showed that indomethacin administration post-ERCP (RR, 0.47; 95% CI, 0.31–0.70; p = 0.0002) appeared to be more effective in preventing PEP than indomethacin administration pre-ERCP (RR, 0.59; 95% CI, 0.45–0.79; P = 0.0003), but there was no significant difference between the high-risk and average-risk population(p = 0.13). In the diclofenac group, it was noted that administration of diclofenac pre-ERCP (RR, 0.32; 95% CI, 0.16–0.63; p = 0.001) was more effective than that in post-ERCP (RR, 0.65; 95% CI, 0.27–1.599; p = 0.35). The relative risk of PEP was 0.63 (95% CI, 0.27–1.50; p = 0.30) in high-risk patients and 0.41 (95% CI, 0.17–0.98; p = 0.02) in average-risk patients. With regard to the route of administration, PEP decreased significantly only in patients receiving the drug rectally (RR, 0.53; 95% CI, 0.44–0.63; p < 0.00001), but not for those who received intramuscularly (RR, 0.74; 95% CI, 0.47–1.17; p = 0.20), intravenously (RR, 0.97; 95% CI, 0.51–1.83; p = 0.93), and orally (RR = 0.88; 95% CI, 0.55–0.1.43; p = 0.62). Conclusions Rectal administration of NSAIDs (both indomethacin and diclofenac) was effective in preventing PEP in unselected patients. A single dose of indomethacin after ERCP might be effective in preventing PEP in both high-risk and average-risk patients. However, diclofenac administered rectally before ERCP might be protective against PEP in high-risk patients compared to a placebo. However, more high quality head-to-head RCTs are required.
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Affiliation(s)
- Yunxiao Lyu
- Department of General Surgery, Dongyang people's Hospital, Dongyang, 322100, Zhejiang Province, China.
| | - Yunxiao Cheng
- Department of General Surgery, Dongyang people's Hospital, Dongyang, 322100, Zhejiang Province, China
| | - Bin Wang
- Department of General Surgery, Dongyang people's Hospital, Dongyang, 322100, Zhejiang Province, China
| | - Yueming Xu
- Department of General Surgery, Dongyang people's Hospital, Dongyang, 322100, Zhejiang Province, China
| | - Weibing Du
- Department of General Surgery, Dongyang people's Hospital, Dongyang, 322100, Zhejiang Province, China
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Manohar M, Verma AK, Venkateshaiah SU, Sanders NL, Mishra A. Pathogenic mechanisms of pancreatitis. World J Gastrointest Pharmacol Ther 2017; 8:10-25. [PMID: 28217371 PMCID: PMC5292603 DOI: 10.4292/wjgpt.v8.i1.10] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/23/2016] [Accepted: 08/16/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for pancreatic pathogenesis.
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Mansour-Ghanaei F, Joukar F, Taherzadeh Z, Sokhanvar H, Hasandokht T. Suppository naproxen reduces incidence and severity of post-endoscopic retrograde cholangiopancreatography pancreatitis: Randomized controlled trial. World J Gastroenterol 2016; 22:5114-5121. [PMID: 27275104 PMCID: PMC4886387 DOI: 10.3748/wjg.v22.i21.5114] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 10/27/2015] [Accepted: 01/17/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the efficacy of rectally administered naproxen for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). METHODS This double-blind randomized control trial conducted from January 2013 to April 2014 at the Gastrointestinal and Liver Diseases Research Center in Rasht, Iran. A total of 324 patients were selected from candidates for diagnostic or therapeutic ERCP by using the simple sampling method. Patients received a single dose of Naproxen (500 mg; n = 162) or a placebo (n = 162) per rectum immediately before ERCP. The overall incidence of PEP, incidence of mild to severe PEP, serum amylase levels and adverse effects were measured. The primary outcome measure was the development of pancreatitis onset of pain in the upper abdomen and elevation of the serum amylase level to > 3 × the upper normal limit (60-100 IU/L) within 24 h after ERCP. The severity of PEP was classified according to the duration of therapeutic intervention for PEP: mild, 2-3 d; moderate 4-10 d; and severe, > 10 d and/or necessitated surgical or intensive treatment, or contributed to death. RESULTS PEP occurred in 12% (40/324) of participants, and was significantly more frequent in the placebo group compared to the naproxen group (P < 0.01). Of the participants, 25.9% (84/324) developed hyperamylasemia within 2 h of procedure completion, among whom only 35 cases belonged to the naproxen group (P < 0.01). The incidence of PEP was significantly higher in female sex, in patients receiving pancreatic duct injection, more than 3 times pancreatic duct cannulations, and ERCP duration more than 40 min (Ps < 0.01). There were no statistically significant differences between the groups regarding the procedures or factors that might increase the risk of PEP, sphincterotomy, precut requirement, biliary duct injection and number of pancreatic duct cannulations. In the subgroup of patients with pancreatic duct injection, the rate of pancreatitis in the naproxen group was significantly lower than that in the placebo (6 patients vs 23 patients, P < 0.01, RRR = 12%, AR = 0.3, 95%CI: 0.2-0.6). Naproxen reduced the PEP in patients with ≥ 3 pancreatic cannulations (P < 0.01, RRR = 25%, AR = 0.1, 95%CI: 0.1-0.4) and an ERCP duration > 40 min (P < 0.01, RRR = 20%, AR = 0.9, 95%CI: 0.4-1.2). CONCLUSION Single dose of suppository naproxen administered immediately before ERCP reduces the incidence of PEP.
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Lusczek ER, Colling K, Muratore S, Conwell D, Freeman M, Beilman G. Stereotypical Metabolic Response to Endoscopic Retrograde Cholangiopancreatography Show Alterations in Pancreatic Function Regardless of Post-Procedure Pancreatitis. Clin Transl Gastroenterol 2016; 7:e169. [PMID: 27148850 PMCID: PMC4893679 DOI: 10.1038/ctg.2016.26] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 03/23/2016] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVES: Metabolomics-based diagnosis or prediction of risk may improve patient outcomes and improve understanding of the pathogenesis of acute pancreatitis (AP). Endoscopic retrograde cholangiopancreatography (ERCP) is a risk factor for developing AP. This pilot study examined metabolomes of patients before and after ERCP, hypothesizing that metabolomics could differentiate between patients who did and did not develop post-ERCP pancreatitis, and that biomarkers associated with development of AP could be identified. METHODS: Patients at high risk for developing post-ERCP pancreatitis were prospectively enrolled at the University of Minnesota from October 2012 to February 2014. Urine and serum samples were collected before ERCP, 2 h after ERCP, and daily thereafter if patients were admitted to the hospital with AP. Pancreatitis severity was calculated with Bedside Index for Severity in Acute Pancreatitis (BISAP) and Modified Glasgow scores. Patients who developed AP (n=9) were matched to patients who did not develop AP (n=18) by age and gender. Urine and serum metabolites were profiled with nuclear magnetic resonance spectroscopy. Partial least squares discriminant analysis (PLS-DA) was performed to detect changes in metabolic profiles associated with development of pancreatitis. Metabolic networks were constructed to probe functional relationships among metabolites. RESULTS: Of the 113 enrolled patients, 9 developed mild AP according to BISAP and modified Glasglow scores. PLS-DA showed common differences between pre- and post-ERCP metabolic profiles in urine and serum regardless of AP status, characterized by increases in serum and urine ketones and serum glucose. Pre-ERCP lipase levels were somewhat elevated in those who went on to develop AP, though this did not reach statistical significance. Metabolic networks differed between patients with AP and those without after ERCP; however, metabolomics did not identify specific prognostic or diagnostic markers of ERCP-induced AP. Aspartate and asparagine were identified as well-connected hubs in post-ERCP serum networks of cases and were correlated with aspartate transaminase (AST) and white blood cell count levels. These features were not evident in controls. Serum aspartate was elevated in AP patients relative to those without AP after ERCP (P=0.03). CONCLUSIONS: In this pilot study, ERCP was found to induce global changes in urine and serum metabolomes indicative of alterations in pancreatic function and insulin resistance. This should be taken into consideration in future research on this topic. Post-ERCP serum metabolic networks indicate functional differences surrounding aspartate metabolism between patients with AP and those without. Further study must be done in larger patient populations to test elevated lipase as a prognostic biomarker associated with risk of developing AP and to examine active metabolic mechanisms at work.
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Affiliation(s)
| | - Kristen Colling
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Sydne Muratore
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Darwin Conwell
- Department of Internal Medicine, Ohio State University, Columbus, Ohio, USA
| | - Martin Freeman
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Greg Beilman
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
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Abstract
Alcohol and gallstones are the most common etiologic factors in acute pancreatitis (AP). Recurrent AP can lead to chronic pancreatitis (CP). Although the underlying pathophysiology of the disease is complex, immune cells are critical in the pathogenesis of pancreatitis and determining disease severity. In this review, we discuss the role of innate and adaptive immune cells in both AP and CP, potential immune-based therapeutic targets, and animal models used to understand our knowledge of the disease. The relative difficulty of obtaining human pancreatic tissue during pancreatitis makes animal models necessary. Animal models of pancreatitis have been generated to understand disease pathogenesis, test therapeutic interventions, and investigate immune responses. Although current animal models do not recapitulate all aspects of human disease, until better models can be developed available models are useful in addressing key research questions. Differences between experimental and clinical pancreatitis need consideration, and when therapies are tested, models with established disease ought to be included.
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13
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Incidence, severity, and mortality of post-ERCP pancreatitis: a systematic review by using randomized, controlled trials. Gastrointest Endosc 2015; 81:143-149.e9. [PMID: 25088919 DOI: 10.1016/j.gie.2014.06.045] [Citation(s) in RCA: 325] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 06/26/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Data regarding the incidence and severity of post-ERCP pancreatitis (PEP) are primarily from nonrandomized studies. OBJECTIVE To determine the incidence, severity, and mortality of PEP from a systematic review of the placebo or no-stent arms of randomized, controlled trials (RCTs). DESIGN MEDLINE, EMBASE, and Cochrane databases were searched to identify RCTs evaluating the efficacy of drugs and/or pancreatic stents to prevent PEP. SETTING Systematic review of patients enrolled in RCTs evaluating agents for PEP prophylaxis. PATIENTS Patients in the placebo or no-stent arms of the RCTs INTERVENTION ERCP. MAIN OUTCOME MEASUREMENTS Incidence, severity, and mortality of PEP. RESULTS There were 108 RCTs with 13,296 patients in the placebo or no-stent arms. Overall, the PEP incidence was 9.7% and the mortality rate was 0.7%. Severity of PEP was reported for 8857 patients: 5.7%, 2.6%, and 0.5% of cases were mild, moderate, and severe, respectively. The incidence of PEP in 2345 high-risk patients was 14.7% and the severity of PEP was mild, moderate, and severe in 8.6%, 3.9%, and 0.8%, respectively, with a 0.2% mortality rate. The incidence of PEP was 13% in North American RCTs compared with 8.4% in European and 9.9% in Asian RCTs. ERCPs conducted before and after 2000 had a PEP incidence of 7.7% and 10%, respectively. LIMITATIONS Difference in PEP risk among patients in the included RCTs. CONCLUSION The incidence of PEP and severe PEP is similar in high-risk patients and the overall cohort. Discrepancies in the incidence of PEP across geographic regions require further study.
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14
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Li J, Yang WJ, Huang LM, Tang CW. Immunomodulatory therapies for acute pancreatitis. World J Gastroenterol 2014; 20:16935-16947. [PMID: 25493006 PMCID: PMC4258562 DOI: 10.3748/wjg.v20.i45.16935] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/24/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
It is currently difficult for conventional treatments of acute pancreatitis (AP), which primarily consist of anti-inflammatory therapies, to prevent the progression of AP or to improve its outcome. This may be because the occurrence and progression of AP, which involves various inflammatory cells and cytokines, includes a series of complex immune events. Considering the complex immune system alterations during the course of AP, it is necessary to monitor the indicators related to immune cells and inflammatory mediators and to develop more individualized interventions for AP patients using immunomodulatory therapy. This review discusses the recent advances in immunomodulatory therapies. It has been suggested that overactive inflammatory responses should be inhibited and excessive immunosuppression should be avoided in the early stages of AP. The optimal duration of anti-inflammatory therapy may be shorter than previously expected (< 24 h), and appropriate immunostimulatory therapies should be administered during the period from the 3rd d to the 14th d in the course of AP. A combination therapy of anti-inflammatory and immune-stimulating drugs would hopefully constitute an alternative to anti-inflammatory drug monotherapy. Additionally, the detection of the genotypes of critical inflammatory mediators may be useful for screening populations of AP patients at high risk of severe infections to enable the administration of early interventions to improve their prognosis.
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15
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Abstract
Post-procedure pancreatitis is the most common complication of endoscopic retrograde cholangio pancreatography (ERCP) and carries a high morbidity and mortality occurring in at least 3%-5% of all procedures. We reviewed the available literature searching for "ERCP" and "pancreatitis" and "post-ERCP pancreatitis". in PubMed and Medline. This review looks at the diagnosis, risk factors, causes and methods of preventing post-procedure pancreatitis. These include the evidence for patient selection, endoscopic techniques and pharmacological prophylaxis of ERCP induced pancreatitis. Selecting the right patient for the procedure by a risk benefits assessment is the best way of avoiding unnecessary ERCPs. Risk is particularly high in young women with sphincter of Oddi dysfunction (SOD). Many of the trials reviewed have rather few numbers of subjects and hence difficult to appraise. Meta-analyses have helped screen for promising modalities of prophylaxis. At present, evidence is emerging that pancreatic stenting of patients with SOD and rectally administered nonsteroidal anti-inflammatory drugs in a large unselected trial reduce the risk of post-procedure pancreatitis. A recent meta-analysis have demonstrated that rectally administered indomethecin, just before or after ERCP is associated with significantly lower rate of pancreatitis compared with placebo [OR = 0.49 (0.34-0.71); P = 0.0002]. Number needed to treat was 20. It is likely that one of these prophylactic measures will begin to be increasingly practised in high risk groups.
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Affiliation(s)
- Lin-Lee Wong
- Lin-Lee Wong, Her-Hsin Tsai, Department of Gastroenterology, Castle Hill Hospital, HEY NHS Trust and Hull York Medical School, Cottingham HU165JQ, United Kingdom
| | - Her-Hsin Tsai
- Lin-Lee Wong, Her-Hsin Tsai, Department of Gastroenterology, Castle Hill Hospital, HEY NHS Trust and Hull York Medical School, Cottingham HU165JQ, United Kingdom
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16
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The effect of indomethacin in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis. Pancreas 2014; 43:338-42. [PMID: 24622061 DOI: 10.1097/mpa.0000000000000086] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) is a severe complication with substantial morbidity and mortality. Indomethacin has been identified to prevent this complication; however, the results using indomethacin have varied. Therefore, we performed a meta-analysis on the efficacy of rectally administered indomethacin in the prevention of post-ERCP pancreatitis (PEP). METHODS A systematic search was performed in November 2012. Randomized, placebo-controlled trials (randomized controlled trials) in adult patients that compared rectally administered indomethacin versus placebo in prevention of PEP were included. Meta-analysis was performed using a fixed-effects model to assess the primary outcome (PEP) and secondary outcomes (mild or moderate to severe PEP) using Review Manager 5.1. RESULTS Four randomized controlled trials met the inclusion criteria (n = 1422). The use of indomethacin near the time of ERCP demonstrated a statistically significant decrease in PEP (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.34-0.71; P < 0.01), mild PEP (OR, 0.52; 95% CI, 0.32-0.86; P = 0.01), and moderate to severe PEP (OR, 0.45; 95% CI, 0.24-0.83; P = 0.01) as compared with placebo. The number needed to treat with indomethacin to prevent 1 episode of pancreatitis is 17 patients. CONCLUSIONS Rectal indomethacin significantly reduced the incidence of PEP. We recommend using indomethacin before or just after the procedure in patients undergoing ERCP.
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17
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Wong LL, Tsai HH. Prevention of post-ERCP pancreatitis. World J Gastrointest Pathophysiol 2014; 5:1-10. [PMID: 24891970 PMCID: PMC4024515 DOI: 10.4291/wjgp.v5.i1.1] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 10/26/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
Post-procedure pancreatitis is the most common complication of endoscopic retrograde cholangio pancreatography (ERCP) and carries a high morbidity and mortality occurring in at least 3%-5% of all procedures. We reviewed the available literature searching for “ERCP” and “pancreatitis” and “post-ERCP pancreatitis”. in PubMed and Medline. This review looks at the diagnosis, risk factors, causes and methods of preventing post-procedure pancreatitis. These include the evidence for patient selection, endoscopic techniques and pharmacological prophylaxis of ERCP induced pancreatitis. Selecting the right patient for the procedure by a risk benefits assessment is the best way of avoiding unnecessary ERCPs. Risk is particularly high in young women with sphincter of Oddi dysfunction (SOD). Many of the trials reviewed have rather few numbers of subjects and hence difficult to appraise. Meta-analyses have helped screen for promising modalities of prophylaxis. At present, evidence is emerging that pancreatic stenting of patients with SOD and rectally administered nonsteroidal anti-inflammatory drugs in a large unselected trial reduce the risk of post-procedure pancreatitis. A recent meta-analysis have demonstrated that rectally administered indomethecin, just before or after ERCP is associated with significantly lower rate of pancreatitis compared with placebo [OR = 0.49 (0.34-0.71); P = 0.0002]. Number needed to treat was 20. It is likely that one of these prophylactic measures will begin to be increasingly practised in high risk groups.
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18
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Martín R, Miquel S, Ulmer J, Kechaou N, Langella P, Bermúdez-Humarán LG. Role of commensal and probiotic bacteria in human health: a focus on inflammatory bowel disease. Microb Cell Fact 2013; 12:71. [PMID: 23876056 PMCID: PMC3726476 DOI: 10.1186/1475-2859-12-71] [Citation(s) in RCA: 152] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 07/18/2013] [Indexed: 02/08/2023] Open
Abstract
The human gut is one of the most complex ecosystems, composed of 1013-1014 microorganisms which play an important role in human health. In addition, some food products contain live bacteria which transit through our gastrointestinal tract and could exert beneficial effects on our health (known as probiotic effect). Among the numerous proposed health benefits attributed to commensal and probiotic bacteria, their capacity to interact with the host immune system is now well demonstrated. Currently, the use of recombinant lactic acid bacteria to deliver compounds of health interest is gaining importance as an extension of the probiotic concept. This review summarizes some of the recent findings and perspectives in the study of the crosstalk of both commensal and probiotic bacteria with the human host as well as the latest studies in recombinant commensal and probiotic bacteria. Our aim is to highlight the potential roles of recombinant bacteria in this ecosystem.
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Affiliation(s)
- Rebeca Martín
- INRA, UMR1319 Micalis, Jouy-en-Josas, F-78350, France
- AgroParisTech, UMR Micalis, Jouy-en-Josas, F-78350, France
| | - Sylvie Miquel
- INRA, UMR1319 Micalis, Jouy-en-Josas, F-78350, France
- AgroParisTech, UMR Micalis, Jouy-en-Josas, F-78350, France
| | - Jonathan Ulmer
- INRA, UMR1319 Micalis, Jouy-en-Josas, F-78350, France
- AgroParisTech, UMR Micalis, Jouy-en-Josas, F-78350, France
| | - Noura Kechaou
- INRA, UMR1319 Micalis, Jouy-en-Josas, F-78350, France
- AgroParisTech, UMR Micalis, Jouy-en-Josas, F-78350, France
| | - Philippe Langella
- INRA, UMR1319 Micalis, Jouy-en-Josas, F-78350, France
- AgroParisTech, UMR Micalis, Jouy-en-Josas, F-78350, France
| | - Luis G Bermúdez-Humarán
- INRA, UMR1319 Micalis, Jouy-en-Josas, F-78350, France
- AgroParisTech, UMR Micalis, Jouy-en-Josas, F-78350, France
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19
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Zheng L, Xue J, Jaffee EM, Habtezion A. Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology 2013; 144:1230-40. [PMID: 23622132 PMCID: PMC3641650 DOI: 10.1053/j.gastro.2012.12.042] [Citation(s) in RCA: 252] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 12/12/2012] [Accepted: 12/21/2013] [Indexed: 12/22/2022]
Abstract
Immune cells are important in the pathogenesis of acute pancreatitis and determine disease severity. Results from cytokine-based clinical trials for acute pancreatitis have been disappointing, so strategies that target and alter the behavior of infiltrating immune cells require consideration. Recurrent acute pancreatitis can progress to chronic pancreatitis, which is a well-described risk factor for pancreatic ductal adenocarcinoma (PDA). However, most patients with chronic pancreatitis do not develop PDA, and most patients with PDA do not have a history of pancreatitis. Interestingly, chronic pancreatitis and PDA tissues have similarities in their desmoplasia and inflammatory infiltrates, indicating overlapping inflammatory responses. Further studies are needed to determine the differences and similarities of these responses, improve our understanding of PDA pathogenesis, and develop specific immune-based therapies. Immune cells in PDA produce immunosuppressive signals that allow tumors to evade the immune response. Unlike single therapeutic agent studies that block immunosuppressive mechanisms, studies of combination therapies that include therapeutic vaccines have provided promising results.
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Affiliation(s)
- Lei Zheng
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jing Xue
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Elizabeth M. Jaffee
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Aida Habtezion
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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20
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Is high-dose nafamostat mesilate effective for the prevention of post-ERCP pancreatitis, especially in high-risk patients? Pancreas 2011; 40:1215-9. [PMID: 21775918 DOI: 10.1097/mpa.0b013e31822116d5] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Infusion of the protease inhibitor nafamostat mesilate (20 mg) effectively prevents post-ERCP pancreatitis, but only in low-risk groups. This study was performed to evaluate the use of high-dose nafamostat mesilate (50 mg) for prevention of post-ERCP pancreatitis (PEP), especially in high-risk groups. METHODS A total of 608 patients who underwent ERCP were included; 13 patients were excluded. Patients were divided into 3 groups: controls (group A), infusion with 20 mg of nafamostat mesilate (group B), or infusion with 50 mg of nafamostat mesilate (group C). The incidence of PEP was analyzed. RESULTS The overall incidence of acute pancreatitis was 7.4% (44/595). There was a significant difference in the incidence of PEP with or without nafamostat mesilate (13.0% vs 4.0% and 5.1%, respectively; P < 0.0001). Subgroup analysis showed that in low-risk patients, the rate of PEP was significantly different with nafamostat (11.9% vs 2.7% and 4.0%, respectively; P = 0.007). In high-risk patients, the rate of PEP was not significantly different among treatment groups (14.6% vs 5.9% vs 6.9%, respectively; P = 0.108). CONCLUSIONS Nafamostat mesilate prophylaxis (20 or 50 mg) is effective in preventing post-ERCP pancreatitis. However, the preventive effect of high-dose nafamostat mesilate (50 mg) is not significant in high-risk patients.
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21
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Abstract
IMPORTANCE OF THE FIELD Acute pancreatitis (AP) is a multifactorial disorder not fully understood yet. In particular, the pathogenetic pathways promoting a severe life-threatening course of AP are the subject of ongoing investigations. P-selectin has been shown to play a central role in the complex pathophysiology in AP as well as various other inflammatory conditions. AREAS COVERED IN THIS REVIEW P-selectin function in AP is reviewed with focus on its dual function as a mediator of leukocyte recruitment and cell adhesion, which implies the unique effect of linking both inflammation and coagulation, especially in the progression from mild to severe necrotizing AP. Potential therapeutic aspects are discussed with regard to the clinical situation. WHAT THE READER WILL GAIN A better understanding of the pathogenic role of P-selectin in AP and of the rationale for a therapeutic blockade. TAKE HOME MESSAGE P-selectin is a glycoprotein that mediates the adhesion of activated platelets and leukocytes to the vessel wall in various inflammatory conditions. Both pathophysiological steps are closely linked and play a key role in the course of severe AP. A treatment approach by inhibition of P-selectin could be of distinct interest as a therapeutic option in severe AP.
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Affiliation(s)
- Thilo Hackert
- University of Heidelberg, Department of Surgery, Germany.
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22
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Woods KE, Willingham FF. Endoscopic retrograde cholangiopancreatography associated pancreatitis: A 15-year review. World J Gastrointest Endosc 2010; 2:165-78. [PMID: 21160744 PMCID: PMC2998911 DOI: 10.4253/wjge.v2.i5.165] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Revised: 04/29/2010] [Accepted: 05/06/2010] [Indexed: 02/06/2023] Open
Abstract
The aim of this article is to review the literature regarding post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. We searched for and evaluated all articles describing the diagnosis, epidemiology, pathophysiology, morbidity, mortality and prevention of post-ERCP pancreatitis (PEP) in adult patients using the PubMed database. Search terms included endoscopic retrograde cholangiopancreatography, pancreatitis, ampulla of vater, endoscopic sphincterotomy, balloon dilatation, cholangiography, adverse events, standards and utilization. We limited our review of articles to those published between January 1, 1994 and August 15, 2009 regarding human adults and written in the English language. Publications from the reference sections were reviewed and included if they were salient and fell into the time period of interest. Between the dates queried, seventeen large (> 500 patients) prospective and four large retrospective trials were conducted. PEP occurred in 1%-15% in the prospective trials and in 1%-4% in the retrospective trials. PEP was also reduced with pancreatic duct stent placement and outcomes were improved with endoscopic sphincterotomy compared to balloon sphincter dilation in the setting of choledocholithiasis. Approximately 34 pharmacologic agents have been evaluated for the prevention of PEP over the last fifteen years in 63 trials. Although 22 of 63 trials published during our period of review suggested a reduction in PEP, no pharmacologic therapy has been widely accepted in clinical use in decreasing the development of PEP. In conclusion, PEP is a well-recognized complication of ERCP. Medical treatment for prevention has been disappointing. Proper patient selection and pancreatic duct stenting have been shown to reduce the complication rate in randomized clinical trials.
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Affiliation(s)
- Kevin E Woods
- Kevin E Woods, Department of Medicine, Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
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23
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Senol A, Saritas U, Demirkan H. Efficacy of intramuscular diclofenac and fluid replacement in prevention of post-ERCP pancreatitis. World J Gastroenterol 2009; 15:3999-4004. [PMID: 19705494 PMCID: PMC2731949 DOI: 10.3748/wjg.15.3999] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [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 assess the efficacy of intramuscular diclofenac and fluid replacement for prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.
METHODS: A prospective, placebo-controlled study was conducted in 80 patients who underwent ERCP. Patients were randomized to receive parenteral diclofenac at a loading dose of 75 mg followed by the infusion of 5-10 mL/kg per hour isotonic saline over 4 h after the procedure, or the infusion of 500 mL isotonic saline as placebo. Patients were evaluated clinically, and serum amylase levels were measured 4, 8 and 24 h after the procedure.
RESULTS: The two groups were matched for age, sex, underlying disease, ERCP findings, and type of treatment. The overall incidence of pancreatitis was 7.5% in the diclofenac group and 17.5% in the placebo group (12.5% in total). There were no significant differences in the incidence of pancreatitis and other variables between the two groups. In the subgroup analysis, the frequency of pancreatitis in the patients without sphincter of Oddi dysfunction (SOD) was significantly lower in the diclofenac group than in the control group (P = 0.047).
CONCLUSION: Intramuscular diclofenac and fluid replacement lowered the rate of pancreatitis in patients without SOD.
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24
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Zheng MH, Meng MB, Gu DN, Zhang L, Wu AM, Jiang Q, Chen YP. Effectiveness and tolerability of NSAIDs in the prophylaxis of pancreatitis after endoscopic retrograde cholangiopancreatography: A systematic review and meta-analysis. CURRENT THERAPEUTIC RESEARCH 2009; 70:323-334. [PMID: 24683241 PMCID: PMC3967274 DOI: 10.1016/j.curtheres.2009.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/29/2009] [Indexed: 02/05/2023]
Abstract
BACKGROUND Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography (ERCP). The beneficial effects of pharmaco-logic treatment of acute pancreatitis are unclear. Although the prophylactic use of NSAIDs for the reduction of the risk for pancreatic injury after ERCP has been assessed, the beneficial effects of NSAIDs on pancreatic injury are still being debated. OBJECTIVE The aim of this study was to determine the effectiveness and tolerability of NSAIDs in the prophylaxis of post-ERCP pancreatitis (PEP). METHODS MEDLINE (January 1966-January 2009), EMBASE (January 1966-January 2009), and the Cochrane Central Register of Controlled Trials (Issue 1, 2009) were searched using the key terms: pancreatitis, post-ERCP pancreatitis, nonsteroidal anti-inflammatory drugs, indomethacin, and diclofenac. The methods recommended by the Cochrane Collaboration and the Quality of Reporting Meta-Analyses guideline were used to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) of NSAIDs in the prevention of PEP. RESULTS Four multinational RCTs were included in the meta-analysis (969 patients). The pooled odds ratio for NSAIDs for mild PEP was 0.69 (95% CI, 0.40-1.17; P = NS); moderate to severe PEP, 0.22 (95% CI, 0.05-1.01; P = 0.05); PEP (pooled), 0.44 (95% CI, 0.21-0.93; P = 0.03); in high-risk patients, 0.49 (95% CI, 0.17-1.39; P = NS); and in low-risk patients, 0.29 (95% CI, 0.12-0.71; P = 0.006). No evidence of publication bias was found. CONCLUSION Based on the findings from the present systematic review of 4 RCTs, NSAIDs were effective and well tolerated in the prevention of PEP, especially in low-risk patients.
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Affiliation(s)
- Ming-Hua Zheng
- Department of Infection and Liver Diseases, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
| | - Mao-Bin Meng
- Division of Thoracic Oncology, Cancer Center, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Dian-Na Gu
- Department of Infection and Liver Diseases, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
| | - Lei Zhang
- Department of Infection and Liver Diseases, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
| | - Ai-Min Wu
- Information Service Department, Library of Wenzhou Medical College, Wenzhou, China
| | - Qian Jiang
- Department of Clinical Pharmacy, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Yong-Ping Chen
- Department of Infection and Liver Diseases, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
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Zhang Y, Chen QB, Gao ZY, Xie WF. Meta-analysis: octreotide prevents post-ERCP pancreatitis, but only at sufficient doses. Aliment Pharmacol Ther 2009; 29:1155-64. [PMID: 19302265 DOI: 10.1111/j.1365-2036.2009.03991.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Effects of octreotide on post-endoscopic retrograde cholangiopancreatography pancreatitis have been studied in many clinical trials. These trials have yielded inconclusive results. Results of more recent studies using larger doses, however, seem to be more optimistic. AIM To examine effects of octreotide at different doses on PEP. METHODS A comprehensive search of relevant databases, including Medline, Embase, the Cochrane Controlled Trials Register, the Cochrane Library and Science Citation Index yielded 18 randomized controlled trials (RCTs). Trials were divided into two groups according to the total dosage of octreotide: <0.5 mg (OCT1), > or =0.5 mg (OCT2). The rate of PEP was analysed using a fixed effect model. RESULTS At doses of > or =0.5 mg, octreotide reduced the rate of PEP. In the OCT2 group, analysis revealed a statistically significant difference on PEP between the octreotide group and the controls (3.4% vs. 7.5%, pooled OR = 0.45; 95% CI: 0.28-0.73; P = 0.001, NNT = 25). In the OCT1 group, the rate of PEP was similar between patients receiving octreotide and the controls (7.2% vs. 6.0%, pooled OR = 1.23; 95% CI: 0.80-1.91; P = 0.35). CONCLUSION Octreotide is effective in preventing PEP, but only at sufficient doses (> or =0.5 mg).
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Affiliation(s)
- Y Zhang
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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Nøjgaard C, Hornum M, Elkjaer M, Hjalmarsson C, Heyries L, Hauge T, Bakkevold K, Andersen PK, Matzen P. Does glyceryl nitrate prevent post-ERCP pancreatitis? A prospective, randomized, double-blind, placebo-controlled multicenter trial. Gastrointest Endosc 2009; 69:e31-7. [PMID: 19410035 DOI: 10.1016/j.gie.2008.11.042] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2008] [Accepted: 11/20/2008] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Acute pancreatitis is the most dreaded complication of ERCP. Two studies have shown a significant effect of glyceryl nitrate (GN) in preventing post-ERCP pancreatitis (PEP). We wanted to evaluate this promising effect in a larger study with a realistically precalculated incidence of PEP. DESIGN/PATIENTS A randomized, double-blind, placebo-controlled multicenter study including patients from 14 European centers was performed. A total of 820 patients were entered; 806 were randomized. INTERVENTION The active drug was transdermal GN (Discotrine/Minitran, 3M Pharma) 15 mg/24 hours; placebo (PL) was an identical-looking patch applied before ERCP. A total of 401 patients received GN; 405 received PL. RESULTS Forty-seven patients had PEP (5.8%), 18 (4.5%) in the GN group and 29 (7.1%) in the PL group. The relative risk reduction of PEP in the GN group of 36% (95% CI, 11%-65%) compared with the PL group was not statistically significant (P = .11). Thirteen had mild pancreatitis (4 in the GN group, 9 in the PL group), 26 had moderate pancreatitis (9 in the GN group, 17 in the PL group), and 8 had severe pancreatitis (5 in the GN group, 3 in the PL group). Headache (P < .001) and hypotension (P = .006) were more common in the GN group. Significant variables predictive of PEP were not having biliary stones extracted; hypotension after ERCP; morphine, propofol, glucagon, and general anesthesia during the procedure; or no sufentanil during the procedure. CONCLUSIONS The trial showed no statistically significant preventive effect of GN on PEP. Because of a considerable risk of a type II error, an effect of GN may have been overlooked. (ClinicalTrials.gov ID: NCT00121901.).
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Affiliation(s)
- Camilla Nøjgaard
- Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark
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Sherman S, Cheng CL, Costamagna G, Binmoeller KF, Puespoek A, Aithal GP, Kozarek RA, Chen YK, Van Steenbergen W, Tenner S, Freeman M, Monroe P, Geffner M, Deviere J. Efficacy of recombinant human interleukin-10 in prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis in subjects with increased risk. Pancreas 2009; 38:267-274. [PMID: 19214137 DOI: 10.1097/mpa.0b013e31819777d5] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Pancreatitis is the most common major complication of endoscopic retrograde cholangiopancreatography (ERCP). Inflammatory cytokines are released during acute pancreatitis. Interleukin-10 (IL-10) is a potent inhibitor of cytokines and has been shown to attenuate pancreatitis in animal models and pilot human studies. This study aimed to determine whether prophylactic IL-10 administration reduces the frequency and/or severity of post-ERCP pancreatitis in high-risk patients. METHODS A randomized, multicenter, double-blind, placebo-controlled study was conducted. Patients received IL-10 at a dose of either 8 or 20 microg/kg or placebo as a single intravenous injection 15 to 30 minutes before ERCP. Standardized criteria were used to diagnose and grade the severity of postprocedure pancreatitis. RESULTS A total of 305 of the planned total enrollment of 948 patients were randomized. There was a 15%, 22%, and 14% incidence of post-ERCP pancreatitis in the IL-10 (8 microg/kg), IL-10 (20 microg/kg), and placebo treatment groups, respectively (P = 0.83 for IL-10 8 microg/kg vs placebo and 0.14 for IL-10 20 microg/kg vs placebo). Due to apparent lack of efficacy, the study was terminated at an interim analysis. CONCLUSIONS : There was no apparent benefit of IL-10 treatment when compared with placebo in reducing the incidence of post-ERCP acute pancreatitis in subjects with increased risk.
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Affiliation(s)
- Stuart Sherman
- Division of Gastroenterology/Hepatology, Indiana University Medical Center, Indianapolis, IN 46202, USA.
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Choi CW, Kang DH, Kim GH, Eum JS, Lee SM, Song GA, Kim DU, Kim ID, Cho M. Nafamostat mesylate in the prevention of post-ERCP pancreatitis and risk factors for post-ERCP pancreatitis. Gastrointest Endosc 2009; 69:e11-e18. [PMID: 19327467 DOI: 10.1016/j.gie.2008.10.046] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2008] [Accepted: 10/22/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND Pancreatitis is a major complication of ERCP. OBJECTIVE To determine whether nafamostat mesylate prophylaxis decreases the incidence of post-ERCP pancreatitis (PEP). DESIGN A single-center, randomized, double-blinded, controlled trial. SETTING A large tertiary-referral center. PATIENTS From January 2005 to December 2007, a total of 704 patients who underwent ERCP were analyzed. INTERVENTION Patients received continuous infusion of 500 mL of 5% dextrose solution with 20 mg of nafamostat mesylate (354 patients) or without 20 mg of nafamostat mesylate (350 patients). Serum amylase and lipase levels were checked before ERCP, 4 and 24 hours after ERCP, and when clinically indicated. MAIN OUTCOME MEASUREMENTS The incidence of PEP and risk factors associated with the development of PEP. RESULTS The incidence of acute pancreatitis was 5.4%. There was a significant difference in the incidence of PEP between the nafamostat mesylate and control groups (3.3% vs 7.4%, respectively; P = .018). Univariate analysis identified history of acute pancreatitis (P < .001), difficult cannulation (P = .023), periampullary diverticulum (P = .004), age younger than 40 years (P = .009), and >/=5 pancreatic-duct contrast injections (odds ratio [OR] 2.736, P = .012) as statistically significant risk factors. LIMITATIONS A single-center study. CONCLUSIONS Nafamostat mesylate prophylaxis is partially effective in preventing post-ERCP pancreatitis. Independent risk factors for PEP are a history of acute pancreatitis and multiple pancreatic-duct contrast injections.
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Affiliation(s)
- Cheol Woong Choi
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
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Sherman S, Alazmi WM, Lehman GA, Geenen JE, Chuttani R, Kozarek RA, Welch WD, Souza S, Pribble J. Evaluation of recombinant platelet-activating factor acetylhydrolase for reducing the incidence and severity of post-ERCP acute pancreatitis. Gastrointest Endosc 2009; 69:462-472. [PMID: 19231487 DOI: 10.1016/j.gie.2008.07.040] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2006] [Accepted: 07/22/2008] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatitis is the most common major complication of diagnostic and therapeutic ERCP. Platelet-activating factor (PAF) has been implicated in the pathophysiologic events associated with acute pancreatitis. Animal and human studies suggested that recombinant PAF acetylhydrolase (rPAF-AH) might ameliorate the severity of acute pancreatitis. OBJECTIVE Our purpose was to determine whether prophylactic rPAF-AH administration reduces the frequency or severity of post-ERCP pancreatitis in high-risk patients. DESIGN Randomized, multicenter, double-blind, placebo-controlled study. INTERVENTIONS Patients received rPAF-AH at a dose of either 1 or 5 mg/kg or placebo. Patients were administered a single intravenous infusion over 10 minutes of study drug or placebo <1 hour before ERCP. MAIN OUTCOME MEASUREMENTS Standardized criteria were used to diagnose and grade the severity of post-ERCP pancreatitis. Adverse events were prospectively recorded. RESULTS A total of 600 patients were enrolled. There were no statistically significant differences among the treatment groups with respect to patient demographics, ERCP indications, and patient and procedure risk factors for post-ERCP pancreatitis with the following exceptions: the rPAF-AH 5 mg/kg group had significantly fewer patients younger than 40 years old and scheduled to undergo a therapeutic ERCP involving the pancreatic sphincter or duct. Post-ERCP pancreatitis occurred in 17.5%, 15.9%, and 19.6% of patients receiving rPAF-AH (1 mg/kg), rPAF-AH (5 mg/kg), and placebo, respectively (P = .59 for rPAF-AH 1 mg/kg vs placebo and P = .337 for rPAF-AH 5 mg/kg vs placebo). There was no statistically significant difference between the groups with regard to the severity of pancreatitis, frequency of amylase/lipase elevation more than 3 times normal, or abdominal pain. CONCLUSIONS There was no apparent benefit of rPAF-AH treatment compared with placebo in reducing the incidence of post-ERCP pancreatitis in subjects at increased risk.
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Affiliation(s)
- Stuart Sherman
- Indiana University Medical Center, Indianapolis, Indiana, USA
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Khoshbaten M, Khorram H, Madad L, Ehsani Ardakani MJ, Farzin H, Zali MR. Role of diclofenac in reducing post-endoscopic retrograde cholangiopancreatography pancreatitis. J Gastroenterol Hepatol 2008; 23:e11-6. [PMID: 17683501 DOI: 10.1111/j.1440-1746.2007.05096.x] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Acute pancreatitis following endoscopic retrograde cholangiography presents a unique opportunity for prophylaxis and early modification of the disease process because the initial triggering event is temporally well defined and takes place in the hospital. We report a prospective, single-center, randomized, double-blind controlled trial to determine if rectal diclofenac reduces the incidence of pancreatitis following cholangiopancreatography. METHODS Entry to the trial was restricted to patients who underwent endoscopic retrograde pancreatography. Immediately after endoscopy, patients were given a suppository containing either 100 mg diclofenac or placebo. Estimation of serum amylase level and clinical evaluation were performed in all patients. RESULTS One hundred patients entered the trial, and 50 received rectal diclofenac. Fifteen patients developed pancreatitis (15%), of whom two received rectal diclofenac and 13 received placebo (P < 0.01). CONCLUSIONS This trial shows that rectal diclofenac given immediately after endoscopic retrograde cholangiopancreatography can reduce the incidence of acute pancreatitis.
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Abstract
The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against Post Endoscopic retrograde cholangiopancreatography Pancreatitis (PEP). The protease inhibitor Gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL) is a nitrogen oxide (NO) donor, which relaxes the sphincter of Oddi. Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted. Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials. The non-steroidal anti-inflammatory drugs (NSAID) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP. Interleukin 10 (IL-10) is a cytokine with anti-inflammatory properties but two trials testing IL-10 as prophylaxis to PEP have returned conflicting results. Antibodies against tumor necrosis factor-alpha (TNF-α) have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics beta-lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted.
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Romagnuolo J, Hilsden R, Sandha GS, Cole M, Bass S, May G, Love J, Bain VG, McKaigney J, Fedorak RN. Allopurinol to prevent pancreatitis after endoscopic retrograde cholangiopancreatography: a randomized placebo-controlled trial. Clin Gastroenterol Hepatol 2008; 6:465-71; quiz 371. [PMID: 18304883 DOI: 10.1016/j.cgh.2007.12.032] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Endoscopic retrograde cholangiopancreatography (ERCP) is associated with a risk of pancreatitis (PEP). Animal studies suggest that (single-dose) allopurinol (xanthine oxidase inhibitor with high oral bioavailability and long-lasting active metabolites) may reduce this risk; human study results are conflicting. The aim of this study was to determine if allopurinol decreases the rate of PEP. METHODS Patients referred for ERCP to 9 endoscopists at 2 tertiary centers were randomized to receive either allopurinol 300 mg or identical placebo orally 60 minutes before ERCP, stratified according to high-risk ERCP (manometry or pancreatic therapy). The primary outcome (PEP) was adjudicated blindly; pancreatitis was defined according to the Cotton consensus, and evaluated at 48 hours and 30 days. Secondary outcomes included severe PEP, length of stay, and mortality (nil). The trial was terminated after the blinded (midpoint) interim analysis, as recommended by the independent data and safety monitoring committee. RESULTS We randomized 586 subjects, 293 to each arm. The crude PEP rates were 5.5% (allopurinol) and 4.1% (placebo), (P = .44; difference = 1.4%; 95% confidence interval, -2.1% to 4.8%). The Mantel-Haenszel combined risk ratio for PEP with allopurinol, considering stratification, was 1.37 (95% confidence interval, 0.65-2.86). Subgroup analyses suggested nonsignificant trends toward possible benefit in the high-risk group, and possible harm for the remaining subjects. Logistic regression found pancreatic therapy, pancreatic injection, and prior PEP to be the only independent predictors of PEP. CONCLUSIONS Allopurinol does not appear to reduce the overall risk of PEP; however, its potential benefit in the high-risk group (but potential harm for non-high-risk patients) means further study is required.
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Affiliation(s)
- Joseph Romagnuolo
- Digestive Disease Center, Department of Medicine, Medical University of South Carolina, South Carolina 29425, USA.
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Risks of Endoscopic Retrograde Cholangiopancreatography and Sphincterotomy. TECHNIQUES IN GASTROINTESTINAL ENDOSCOPY 2008. [DOI: 10.1016/j.tgie.2007.08.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Cheon YK, Cho KB, Watkins JL, McHenry L, Fogel EL, Sherman S, Schmidt S, Lazzell-Pannell L, Lehman GA. Efficacy of diclofenac in the prevention of post-ERCP pancreatitis in predominantly high-risk patients: a randomized double-blind prospective trial. Gastrointest Endosc 2007; 66:1126-32. [PMID: 18061712 DOI: 10.1016/j.gie.2007.04.012] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Accepted: 04/09/2007] [Indexed: 02/08/2023]
Abstract
BACKGROUND Pancreatitis is one of the major complications of ERCP and endoscopic sphincterotomy. It has been shown that nonsteriodal anti-inflammatory drugs are potent inhibitors of phospholipase A(2), activity which is increased in pancreatitis. A previous study showed reduction of post-ERCP pancreatitis with administration of rectal diclofenac. OBJECTIVE The aim of this study was to determine whether prophylactic oral diclofenac will reduce the incidence and the severity of ERCP-induced pancreatitis, especially in high-risk patients. DESIGN Single-center, randomized, double-blinded, prospective study. SETTING Indiana University Medical Center. PATIENTS A total of 207 evaluable patients were randomized to receive either diclofenac 50 mg or placebo by mouth 30 to 90 minutes before and 4 to 6 hours after ERCP. RESULTS The groups were similar with regard to patient demographics and to patient and procedure risk factors for post-ERCP pancreatitis. The overall incidence of post-ERCP pancreatitis was 16.4%. It occurred in 17 of 102 patients in the control group (16.7%) and in 17 of 105 patients in diclofenac group (16.2%). The pancreatitis was graded mild in 9.8%, moderate in 5.9%, and severe 1.0% of the control group, and mild in 10.5%, moderate in 4.8%, and severe in 1.0% of the diclofenac group. In high-risk patients, the incidence of post-ERCP pancreatitis was 17.3%. It occurred in 18.0% (16/89) in the control group and in 17.8% (16/90) in the diclofenac group. There was no significant difference between the groups in the frequency or severity of post-ERCP pancreatitis in overall and high-risk patients; however, the power of the study was less than 45%. CONCLUSIONS Prophylactic orally administered diclofenac was not observed to affect the frequency or severity of post-ERCP pancreatitis in high-risk patients.
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Affiliation(s)
- Young Koog Cheon
- Indiana University Medical Center; Indianapolis, Indiana 46202, USA
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Lieb JG, Draganov PV. Early successes and late failures in the prevention of post endoscopic retrograde cholangiopancreatography. World J Gastroenterol 2007; 13:3567-74. [PMID: 17659706 PMCID: PMC4146795 DOI: 10.3748/wjg.v13.i26.3567] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). The only way to prevent this complication is to avoid an ERCP all together. Because of the risks involved, a careful consideration should be given to the indication for ERCP and the potential risk/benefit ratio of the test. Once a decision to perform an ERCP is made, the procedure should be carried out with meticulous care by an experienced endoscopist, and with a minimum of pancreatic duct opacification. Several pharmacologic agents have been tested, but to date the most important method of reducing post ERCP pancreatitis is the placement of pancreatic stent. Pancreatic stents should be placed in all patients at high risk of this complication such as those undergoing pancreatic sphincterotomy, pancreatic duct manipulation and intervention, and patients with suspected sphincter of Oddi dysfunction. Pancreatic stents should be also considered in patients requiring precut sphincterotomy to gain biliary access.
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Affiliation(s)
- John G Lieb
- Division of Gastroenterology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610- 0214, USA
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Rudin D, Kiss A, Wetz RV, Sottile VM. Somatostatin and gabexate for post-endoscopic retrograde cholangiopancreatography pancreatitis prevention: meta-analysis of randomized placebo-controlled trials. J Gastroenterol Hepatol 2007; 22:977-83. [PMID: 17559376 DOI: 10.1111/j.1440-1746.2007.04928.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM Prior studies have suggested the efficacy of somatostatin and gabexate in post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis prevention. We examined this notion in our study. METHODS An extensive literature search led to the inclusion of seven homogeneous high-quality studies (Jadad score >or=4), involving 3,130 patients. The studies were grouped according to the drug's length of administration: given as an infusion for 12 h (groups SOM1 and GAB1 for somatostatin and gabexate, respectively); given as an infusion for less then 12 h (groups SOM2 and GAB2 for somatostatin and gabexate, respectively); and given as a bolus (group SOM3 for somatostatin, none identified for gabexate). Separate meta-analyses investigating post-procedural pancreatitis and hyperamylasemia rates were conducted in a random effects model. RESULTS Pancreatitis analyses yielded significant risk differences for the SOM1, SOM3 and GAB1 groups. The resulting values were 7.7% (95% confidence intervals [CI][3.4 to 12.0], P < 0.0001), 8.2% (95% CI [4.4 to 12.0], P < 0.0001) and 5.2% (95% CI [1.1 to 9.4], P = 0.01), respectively. No statistically significant risk differences were observed for the SOM2 and GAB2 groups: -2.3% (95% CI [-5.2 to 0.5], P = 0.11) and -1.1% (95% CI [-3.8 to 1.6], P = 0.41), respectively. Hyperamylasemia analyses yielded significant risk differences for the SOM1 and SOM3 groups (P = 0.017 and 0.001, respectively), although not for the SOM2, GAB1 and GAB2 groups (P = 0.44, 0.49 and 0.47, respectively). CONCLUSIONS Somatostatin administered as a bolus seems to be an efficacious measure of post-ERCP pancreatitis prevention, reducing pancreatitis and hyperamylasemia rates, and being applicable to clinical practice. Further study is required before its introduction into routine care.
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Affiliation(s)
- Dan Rudin
- Department of Internal Medicine, Staten Island University Hospital, 475 Seaview Avenue Staten Island, NY 10305, USA.
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37
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Cooper ST, Slivka A. Incidence, risk factors, and prevention of post-ERCP pancreatitis. Gastroenterol Clin North Am 2007; 36:259-76, vii-viii. [PMID: 17533078 DOI: 10.1016/j.gtc.2007.03.006] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Because of the potential risks and consequences of post-ERCP pancreatitis, considerable efforts have been made to define patient- and procedure-related factors that may be associated with an increased risk of this complication, along with determining interventions that can be done to reduce post-ERCP pancreatitis.
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Affiliation(s)
- Scott T Cooper
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Presbyterian University Hospital, 200 Lothrop Street, M Level, C Wing, Pittsburgh, PA 15213, USA
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Abstract
Pancreatitis is the most common complication after endoscopic retrograde cholangio-pancreatography (ERCP); the reported incidence of this complication varies from less than 1% to 40%, but a rate of 4%-8% is reported in most prospective studies involving non-selected patients. Differences in criteria for defining pancreatitis, methods of data collection, and patient populations (i.e. number of high-risk patients included in the published series) are factors that are likely to affect the varying rates of post-ERCP pancreatitis. The severity of post-ERCP pancreatitis (PEP) can range from a minor inconvenience with one or two days of added hospitalization with full recovery to a devastating illness with pancreatic necrosis, multiorgan failure, permanent disability, and even death. Although, most episodes of PEP are mild (about 90%), a small percentage of patients (about 10%) develop moderate or severe pancreatitis. In the past, PEP was often viewed as an unpredictable and unavoidable complication, with no realistic strategy for its avoidance. New data have aided in stratification of patients into PEP risk categories and new measures have been introduced to decrease the risk of PEP. As most ERCPs are performed on an outpatient basis, the majority of patients will not develop PEP and can be discharged. Alternatively, early detection of those patients who will go on to develop PEP can guide decisions regarding hospital admission and aggressive management. In the last decade, great efforts have been addressed toward prevention of this complication. Points of emphasis have included technical measures, pharmacological prophylaxis, and patient selection. This review provides a comprehensive, evidence-based assessment of published data on PEP and current suggestions for its avoidance.
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Affiliation(s)
- Ayman M Abdel Aziz
- Division of Gastroenterology and Hepatology, Indiana University Medical Center, Indianapolis, IN 46202, USA
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Abstract
Post-ERCP pancreatitis (PEP) is a potential complication of ERCP. Pharmacotherapy for prevention of PEP aims at reducing basal sphincter pressure and contractility or a decrease in pancreatic secretion to reduce intraductal pressure. Timing and route of administration of drugs are critical to ensure maximum benefits from medications. Pancreatic stenting offers an alternative to decompress the pancreas and is effective in reducing PEP in high-risk patients.
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Rochester JS, Jaffe DL. Minimizing complications in endoscopic retrograde cholangiopancreatography and sphincterotomy. Gastrointest Endosc Clin N Am 2007; 17:105-27, vii. [PMID: 17397779 DOI: 10.1016/j.giec.2006.11.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Endoscopic retrograde cholangiopancreatography (ERCP) is a major tool in the diagnosis and management of numerous biliary and pancreatic conditions, including choledocholithiasis as well as benign and malignant pancreatic diseases, especially those causing biliary obstruction. Since the procedure's inception, the techniques and indications have evolved along with advances in technology and an improved understanding of risks associated with ERCP. The trend has been away from purely diagnostic procedures; most ERCPs are now therapeutic in intent. ERCP remains among the more invasive of endoscopic procedures, with significant rates of complications that can be major. As advances are made in less invasive technology, it is important to understand the complications of ERCP and how best to avoid them.
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Affiliation(s)
- Jeremy S Rochester
- Division of Gastroenterology, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467-2490, USA
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Abstract
Acute pancreatitis has an incidence of approximately 40 cases per year per 100,000 adults. Although usually self-limiting, 10% to 20% of afflicted patients will progress to severe pancreatitis. The mortality rate among patients with severe pancreatitis may approach 30% when they progress to multisystem organ failure. The development of acute pancreatitis illustrates the requirement for understanding the basic mechanisms of disease progression to drive the exploration of therapeutic options. The pathogenesis of acute pancreatitis involves the interplay of local and systemic immune responses that are often difficult to characterize, particularly when results from animal models are used as a foundation for human trials. Experimental studies suggest that the prognosis for acute pancreatitis depends upon the degree of pancreatic necrosis and the intensity of multisystem organ failure generated by the systemic inflammatory response. This suggests an intricate balance between localized tissue damage with proinflammatory cytokine production and a systemic, anti-inflammatory response that restricts the inappropriate movement of proinflammatory agents into the circulation. The critical players of this interaction include the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, IL-8, and platelet activating factor (PAF). The anti-inflammatory cytokines IL-10, as well as TNF-soluble receptors and IL-1 receptor antagonist, have also been shown to be intimately involved in the inflammatory response to acute pancreatitis. Other compounds implicated in disease pathogenesis in experimental models include complement, bradykinin, nitric oxide, reactive oxygen intermediates, substance P, and higher polyamines. Several of these mediators have been documented to be present at increased concentrations in the plasma of patients with severe, acute pancreatitis. Preclinical work has shown that some of these mediators are markers for disease activity, whereas other inflammatory components may actually drive the disease process as important mediators. Implication of such mediators suggests that interruption or blunting of an inappropriate immune response has the potential to improve outcome. Although the manipulations of specific mediators in animal models may be promising, they may not transition well to the human clinical setting. However, continued reliance on experimental animal models of acute pancreatitis may be necessary to determine the underlying causes of disease. Full understanding of these basic mechanisms involves determining not only which mediators are present, but also closely documenting the kinetics of their appearance. Measurement of the inflammatory response may also serve to identify diagnostic markers for the presence of acute pancreatitis and provide insight into prognosis. Understanding the models, documenting the markers, and deciphering the mediators have the potential to improve treatment of acute pancreatitis.
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Affiliation(s)
- Jill Granger
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109-0602, USA
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Frank CD, Adler DG. Post-ERCP pancreatitis and its prevention. ACTA ACUST UNITED AC 2006; 3:680-8. [PMID: 17130878 DOI: 10.1038/ncpgasthep0654] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2006] [Accepted: 09/01/2006] [Indexed: 12/14/2022]
Abstract
Pancreatitis remains the most common severe complication of endoscopic retrograde cholangiopancreatography (ERCP), and typically develops in 5-7% of patients. Although most post-ERCP pancreatitis (PEP) is mild, severe pancreatitis and its complications (including a systemic inflammatory response or the development of pseudocysts or pancreatic necrosis) can occur, and in rare cases death can result. A means of preventing PEP in all patients who undergo the procedure remains elusive. Proper patient selection for ERCP is critical to avoid unnecessary risk. Pharmacologic attempts to prevent PEP have been largely unsuccessful; encouraging results have been difficult to validate. Prophylactic stenting of the pancreatic duct and minimally traumatic cannulation techniques offer the most promise as a means of preventing PEP. This manuscript reviews risk factors for PEP as well as pharmacologic and procedural means that can be used to reduce its incidence.
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Affiliation(s)
- Carl D Frank
- University of Texas-Houston Medical School, Houston, Texas, USA
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Milewski J, Rydzewska G, Degowska M, Kierzkiewicz M, Rydzewski A. N-acetylcysteine does not prevent post-endoscopic retrograde cholangiopancreatography hyperamylasemia and acute pancreatitis. World J Gastroenterol 2006; 12:3751-5. [PMID: 16773694 PMCID: PMC4087470 DOI: 10.3748/wjg.v12.i23.3751] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Acute pancreatitis (AP) is the most common and often severe complication of endoscopic retrograde cholangiopancreatography (ERCP). The early step in the pathogenesis of acute pancreatitis is probably the capillary endothelial injury mediated by oxygen-derived free radicals. N-acetylcysteine - a free radical scavenger may be potentially effective in preventing post-ERCP acute pancreatitis and it is also known that N-acetylcysteine (ACC) can reduce the severity of disease in experimental model of AP.
METHODS: One hundred and six patients were randomly allocated to two groups. Fifty-five patients were given N-acetylcysteine (two 600 mg doses orally 24 and 12 h before ERCP and 600 mg was given iv, twice a day for two days after the ERCP). The control group consisted of 51 patients who were given iv. isotonic saline twice a day for two days after the ERCP. Serum and urine amylase activities were measured before ERCP and 8 and 24 h after the procedure. The primary outcome parameter was post-ERCP acute pancreatitis and the secondary outcome parameters were differences between groups in serum and urine amylase activity.
RESULTS: There were no significant differences in the rate of post-ERCP pancreatitis between two groups (10 patients overall, 4 in the ACC group and 6 in the control group). There were also no significant differences in baseline and post-ERCP serum and urine amylase activity between ACC group and control group.
CONCLUSION: N-acetylcysteine fails to demonstrate any significant preventive effect on post-ERCP pancreatitis, as well as on serum and urine amylase activity.
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Affiliation(s)
- Janusz Milewski
- Department of Internal Medicine and Gastroenterology, Central Clinical Hospital of Ministry of Internal Affairs, Warsaw, Poland
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Ho YP, Sheen IS, Chiu CT, Wu CS, Lin CY. A strong association between down-regulation of HLA-DR expression and the late mortality in patients with severe acute pancreatitis. Am J Gastroenterol 2006; 101:1117-24. [PMID: 16606350 DOI: 10.1111/j.1572-0241.2006.00495.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES There is no reliable parameter to predict the late mortality of patients with severe acute pancreatitis though it is an important issue. Recently a proposed parameter for "immunoparalysis," a down-regulation of Human Leukocytes Antigens-DR (HLA-DR) expression on monocytes, had been detected in patients with severe but not mild acute pancreatitis. However, the relationship between this parameter and late mortality of acute pancreatitis is still unclear. Therefore, we conducted this study in order to elucidate this issue. METHODS Twenty-five patients of severe acute pancreatitis admitted to Chang-Gung Memorial Hospital were successively enrolled during the period of 1999-2002. The HLA-DR expression, and serum levels of interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-alpha) at different time points were measured. The HLA-DR expression was evaluated by flow cytometry and the levels of IL-10 and TNF-alpha were measured by ELISA. RESULTS In our series, there were 7 (28%) late mortality cases out of 25 patients with severe acute pancreatitis. When analyzing the serial change of HLA-DR expression, it is clear that in survival group the HLA-DR expression was gradually up-regulated and in late mortality group it was persistently down-regulated (p < 0.001). When comparing with other parameters like Acute Physiological and Chronic Health Evaluation II and Ranson's score by Cox hazards model, the HLA-DR expression on 10th day (HLA-DR-10) gave the only statistically significant correlation with late mortality (p = 0.001). Furthermore, HLA-DR10 is also a good predictor for late mortality when analyzed by receiver-operating characteristics (ROC) curves with 0.944 area under ROC (AUROC) value. The optimal cutoff value of HLA-DR on 10th day for predicting late mortality was 52.3% with 94.4% sensitivity and 85.7% specificity. As for the serum levels of TNF-alpha and IL-10, there were significant persistently higher levels in late mortality group than in survival group (p < 0.05). Furthermore, these monocytes from severe acute pancreatitis were with partial restoration of HLA-DR expression but with normal TNF-alpha and IL-10 secretion ability when stimulated in vitro with LPS. CONCLUSIONS In severe acute pancreatitis, there was a strong association between the persistent down-regulation of HLA-DR expression and the late mortality. Furthermore, a cutoff value of 52.3% of HLA-DR expressed monocytes on the 10th hospitalization day is a good predictor for late mortality in patients with severe acute pancreatitis.
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Affiliation(s)
- Yu-Pin Ho
- Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan
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Shi C, Zhao X, Lagergren A, Sigvardsson M, Wang X, Andersson R. Immune status and inflammatory response differ locally and systemically in severe acute pancreatitis. Scand J Gastroenterol 2006; 41:472-480. [PMID: 16635917 DOI: 10.1080/00365520500318965] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Acute pancreatitis (AP) is an inflammatory disorder that develops a complex cascade of immunological events. The local and systemic immune status and inflammatory response might contribute to the understanding of underlying pathophysiological mechanisms and potential treatment. MATERIAL AND METHODS Severe AP was induced by intraductal perfusion of 5% sodium taurodeoxycholate in rats. mRNA expression of cytokines and chemokines was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and NF-kappaB activation was assessed by electrophoretic mobility shift assay in fresh pancreatic acini and circulating monocytes 1, 3, 6 or 9 h after sham operation, induction of AP or N-acetylcysteine (NAC) pretreatment. Flow cytometry was performed on cells obtained from the peripheral blood. RESULTS An inverse relationship in pancreatic and circulating monocytic NF-kappaB activation was detected 6 and 9 h after induction of AP. NAC further suppressed monocytic NF-kappaB activation induced by AP as seen 9 h after induction of AP. A marked constitutive increase in the expression of IL-6, CINC and MCP-1 was seen in pancreatic acini, whereas no change in mRNA expression of inflammatory mediators was observed in circulating monocytes 6 h after induction of AP. Flow cytometry further confirmed the altered function of circulating monocytes. CONCLUSIONS The different immune status and inflammatory response in the pancreas and circulating monocytes improve the understanding of the mechanisms by which systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) develop in severe AP. A potential therapeutic approach could be to restore the functional capacity of the immune system in AP. The use of an NF-kappaB inhibitor, preferentially reaching the local inflammatory foci, could be a potential future way of intervention.
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Affiliation(s)
- Changbin Shi
- Department of Surgery, Lund University Hospital, Lund, Sweden
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Matsuda K, Mikami Y, Takeda K, Fukuyama S, Egawa S, Sunamura M, Maruyama I, Matsuno S. The cannabinoid 1 receptor antagonist, AM251, prolongs the survival of rats with severe acute pancreatitis. TOHOKU J EXP MED 2005; 207:99-107. [PMID: 16141678 DOI: 10.1620/tjem.207.99] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
It has recently been recognized that anandamide (arachidonylethanolamide), which is an endogeneous-cannabinoid (endocannabinoid), mediates septic shock. Cannabinoid means a mind-active material in cannabis (marijuana). Anandamide is mainly produced by macrophages. Cannabinoid 1 (CB1) receptor, which is one of the cannabiniod receptors, is also known to mediate hypotensive shock. The role of endocannabinoids in the progression of acute pancreatitis is unclear. The aims of this study are to clarify their relationship and to find a new therapeutic strategy by regulating the endocannabinoid signaling in acute pancreatitis. Male Wistar rats were injected with caerulein intravenously to induce mild edematous pancreatitis or injected with 5% sodium taurocholate to the bilio-pancreatic duct to induce severe necrotizing pancreatitis. The animals in the latter group were also injected with a CB1 receptor antagonist, AM251, or vehicle solution to see if the inhibition of endocannabinoids improves their survival. Plasma anandamide level was measured by the liquid chromatography/tandem mass spectrometry method. In both models of acute pancreatitis, the plasma anandamide levels were increased, and the levels were significantly higher in rats with severe necrotizing pancreatitis than those in rats with mild edematous pancreatitis. The mean arterial pressure and survival rate were significantly improved by the treatment with AM251, despite that the local inflammatory changes in the pancreas and various parameters (white blood cells, hematocrit, serum amylase, and serum interleukin-6) were similar. This is the first report to show that endocannabinoids are involved in the deterioration of acute pancreatitis and that the down-regulation of endocannabinoid signaling may be a new therapeutic strategy for severe acute pancreatitis.
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MESH Headings
- Acute Disease
- Animals
- Arachidonic Acids/blood
- Blood Pressure/drug effects
- Disease Models, Animal
- Endocannabinoids
- Fluorescent Antibody Technique, Indirect
- Immunohistochemistry
- Male
- Pancreatitis, Acute Necrotizing/chemically induced
- Pancreatitis, Acute Necrotizing/drug therapy
- Pancreatitis, Acute Necrotizing/mortality
- Pancreatitis, Acute Necrotizing/pathology
- Pancreatitis, Acute Necrotizing/physiopathology
- Piperidines/metabolism
- Piperidines/pharmacology
- Polyunsaturated Alkamides
- Pyrazoles/metabolism
- Pyrazoles/pharmacology
- Random Allocation
- Rats
- Rats, Wistar
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Survival Rate
- Taurocholic Acid
- Time Factors
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Affiliation(s)
- Kazuhisa Matsuda
- Division of Gastroenterological Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai, Japan.
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Laveda R, Martinez J, Munoz C, Penalva JC, Saez J, Belda G, Navarro S, Feu F, Mas A, Palazon JM, Sanchez-Paya J, Such J, Perez-Mateo M. Different profile of cytokine synthesis according to the severity of acute pancreatitis. World J Gastroenterol 2005; 11:5309-13. [PMID: 16149137 PMCID: PMC4622800 DOI: 10.3748/wjg.v11.i34.5309] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the cellular synthetic ability of cytokines involved in pro- and anti-inflammatory reactions in patients with AP.
METHODS: Sixty-seven patients with AP (16 severe, 51 mild) and 10 controls were included in the study. Cultures of whole blood were performed in samples obtained within the first 72 h from the onset of pain. Serum levels of interleukins (IL) 6, 8, 10, and TNF-α were measured at baseline and in the supernatant of cultures with (functional reserve) or without stimulation with phytohemaglutinin.
RESULTS: Basal levels of cytokines were significantly higher in patients with severe AP. A significant increase of all pro-inflammatory cytokines vs basal levels was observed in the supernatant after 24 h of whole blood cultures in patients, but not in controls. In contrast, IL-10 increased significantly in the supernatant of cultures only in patients with mild AP. Cells showed a statistically significant functional reserve for all IL in patients with mild, but only for pro-inflammatory cytokines in patients with severe AP.
CONCLUSION: A marked activation of immune system may be observed in patients with AP, being balanced between pro- and anti-inflammatory cytokines in patients with mild but not severe AP. A reduced functional reserve for the synthesis of IL-10 may be observed in patients with severe AP, which might lead to a worst prognosis.
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Affiliation(s)
- Raquel Laveda
- Department of Gastroenterology, Hospital General Universitario de Alicante, Pintor Baeza s/n, Alicante 03010, Spain
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Madanick RD, O'Loughlin CJ, Barkin JS. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography. Dig Dis Sci 2005; 50:879-81. [PMID: 15906762 DOI: 10.1007/s10620-005-2658-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Abstract
Acute pancreatitis is a common clinical condition. It is a disease of variable severity in which some patients experience mild, self-limited attacks while others manifest a severe, highly morbid, and frequently lethal attack. The exact mechanisms by which diverse etiological factors induce an attack are still unclear. It is generally believed that the earliest events in acute pancreatitis occur within acinar cells. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction. If this inflammatory reaction is marked, it leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS). MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. Recent studies have established the role played by inflammatory mediators in the pathogenesis of acute pancreatitis and the resultant MODS. At the same time, recent research has demonstrated the importance of acinar cell death in the form of apoptosis and necrosis as a determinant of pancreatitis severity. In this review, we will discuss about our current understanding of the pathophysiology of acute pancreatitis.
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Affiliation(s)
- Madhav Bhatia
- Department of Pharmacology, National University of Singapore, Singapore.
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50
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Andriulli A, Solmi L, Loperfido S, Leo P, Festa V, Belmonte A, Spirito F, Silla M, Forte G, Terruzzi V, Marenco G, Ciliberto E, Sabatino A, Monica F, Magnolia MR, Perri F. Prophylaxis of ERCP-related pancreatitis: a randomized, controlled trial of somatostatin and gabexate mesylate. Clin Gastroenterol Hepatol 2004; 2:713-8. [PMID: 15290665 DOI: 10.1016/s1542-3565(04)00295-2] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It still is debated whether post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis can be prevented by administering either somatostatin or gabexate mesylate. The aim of the study is to assess the efficacy of a 6.5-hour infusion of somatostatin or gabexate mesylate in preventing ERCP-related complications. METHODS In a double-blind multicenter trial, 1127 patients undergoing ERCP were randomly assigned to intravenous administration of somatostatin (750 microg; n = 351), gabexate mesylate (500 mg; n = 381), or placebo (saline; n = 395). The drug infusion started 30 minutes before and continued for 6 hours after endoscopy. Patients were evaluated clinically, and serum amylase levels were determined at 4, 24, and 48 hours after endoscopy. RESULTS No significant differences in incidences of pancreatitis, hyperamylasemia, or abdominal pain were observed among the placebo (4.8%, 32.6%, and 5.3%, respectively), somatostatin (6.3%, 26.8%, and 5.1%, respectively), and gabexate mesylate groups (5.8%, 31.5%, and 6.3%, respectively). Univariate analysis of patient characteristics and endoscopic maneuvers showed that a Freeman score >1 (P < 0.0001), >/=3 pancreatic injections (P < 0.00001), and precut sphincterotomy (P = 0.01) were significantly associated with post-ERCP pancreatitis. At multiple logistic regression analysis, >/=3 pancreatic injections (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.45-2.63) and a Freeman score >1 (OR, 1.47; 95% CI, 1.11-1.94) retained their predictive power. CONCLUSIONS Long-term (6.5-hr) administration of either somatostatin or gabexate mesylate is ineffective for the prevention of post-ERCP pancreatitis. Pancreatic injury seems to be related to difficulty in common bile duct access.
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Affiliation(s)
- Angelo Andriulli
- Division of Gatroenterology, Casa Sollievo della Sofferenza Hospital-Istituto Ricovero Cura Carattere Scientifico, San Giovanni Rotondo, Italy.
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