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Li W, Zhang M, Hu Y, Shen P, Bai Z, Huangfu C, Ni Z, Sun D, Wang N, Zhang P, Tong L, Gao Y, Zhou W. Acute mountain sickness prediction: a concerto of multidimensional phenotypic data and machine learning strategies in the framework of predictive, preventive, and personalized medicine. EPMA J 2025; 16:265-284. [PMID: 40438497 PMCID: PMC12106293 DOI: 10.1007/s13167-025-00404-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/10/2025] [Indexed: 06/01/2025]
Abstract
Background Acute mountain sickness (AMS) is a self-limiting illness, involving a complex series of physiological responses to rapid ascent to high altitudes, where the body is exposed to lower oxygen levels (hypoxia) and changes in atmospheric pressure. AMS is the mildest and most common form of altitude sickness; however, without adequate preparation and adherence to ascent guidelines, it can progress to life-threatening conditions. Aims Due to the multi-factorial predisposition of AMS among individuals, identifying AMS biomarkers before high altitude exposure from multiple dimensions (e.g., clinical, metabolic, and proteomic markers) and integrating them to build an AMS predictive model enables early diagnosis and personalized interventions, which allows targeted allocation of medical resources, such as prophylactic medications (e.g., acetazolamide) and supplemental oxygen, to those who need them most and prevention of unnecessary complications. Consequently, predicting AMS utilizing biomarkers from multidimensional phenotypic data before high-altitude exposure is essential for the paradigm change in high-altitude medical research from currently applied reactive services to the cost-effective predictive, preventive, and personalized medicine (PPPM/3PM) in primary (reversible damage to health and targeted protection against health-to-disease transition) and secondary (personalized protection against disease progression) care. Methods To this end, this study recruited 83 Han Chinese male volunteers and obtained clinical, proteomic, and metabolomic profiles for analysis before they ascended to high altitudes. The Mann-Whitney U test was used to identify clinical features distinguishing AMS from non-AMS. The proteomic and metabolomic features were concatenated and clustered to find co-expression modules associated with AMS. A machine learning model, Mutual Information-radial kernel-based Support Vector Machine-Recursive Feature Elimination (MI-radialSVM-RFE) was employed for biomarkers selection and AMS prediction. A molecular docking technique was used to select molecular biomarkers that can bind with Traditional Chinese Medicine (TCM) ingredients. Results Among 83 participants, 66 were selected for detailed analysis after quality control steps. Six protein-metabolite co-expression modules were identified as significantly associated with AMS. The MI-radialSVM-RFE model selected 12 biomarkers (two clinical features: systolic blood pressure (SBP) and peak expiratory flow (PEF); six proteins: Acyl-CoA synthetase long-chain family member 4 (ACSL4), immunoglobulin kappa variable 1D-16 (IGKV1D-16), coagulation factor XIII B subunit (F13B), prosaposin (PSAP), poliovirus receptor (PVR), and multimerin-2 (MMRN2); and four metabolites: 2-Methyl-1,3-cyclohexadiene, calcitriol, 4-Acetamido-2-amino-6-nitrotoluene, and 20-Hydroxy-PGE2) for the AMS prediction model. The model exhibited excellent predictive performance in both training (n = 66) and validating cohorts (n = 24) with AUCs of 0.97 and 0.94, respectively. Additionally, molecular docking analysis suggested PSAP and ACSL4 proteins as potential molecular targets for AMS prevention. Conclusion and expert recommendations This study advances high-altitude medicine by developing a predictive model for AMS using clinical, proteomic, and metabolomic data. The identified biomarkers linked to energy metabolism, immune response, and vascular regulation offer insights into AMS mechanisms. High-altitude predictive approaches should focus on implementing biomarker-driven risk screening using clinical, proteomic, and metabolomic data to identify high-risk individuals before high-altitude exposure. Preventive measures should prioritize pre-acclimatization protocols, tailored nutritional strategies and interventions guided by biomarker profiles, and lifestyle adjustments, such as maintaining mitochondrial health through proper nutritional strategies. Supplementary Information The online version contains supplementary material available at 10.1007/s13167-025-00404-9.
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Affiliation(s)
- Wenhui Li
- Research Center for High Altitude Medicine, Qinghai Provincial Key Laboratory of Plateau Medical Application, Key Laboratory of Ministry of Education, Qinghai-Utah Joint Research Key Laboratory for High Altitude Medicine, Qinghai University, Xining, 810000 China
- The Fifth People’s Hospital of Qinghai Province, Xining, 810000 China
| | - Meng Zhang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
| | - Yangyi Hu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
| | - Pan Shen
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
| | - Zhijie Bai
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
| | - Chaoji Huangfu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
| | - Zhexin Ni
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
| | - Dezhi Sun
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
| | - Ningning Wang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
| | - Pengfei Zhang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
| | - Li Tong
- Qinghai Provincial Key Laboratory of Traditional Chinese Medicine Research for Glucolipid Metabolic Diseases, Qinghai University, Xining, 810000 China
| | - Yue Gao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, 100853 China
| | - Wei Zhou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850 China
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Cheng EY, Mirzaei A. Differential risk of autoimmune disorders in non-traumatic osteonecrosis: clue to pathogenesis. Expert Rev Clin Immunol 2025; 21:413-424. [PMID: 40035487 DOI: 10.1080/1744666x.2025.2475982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 02/11/2025] [Accepted: 03/03/2025] [Indexed: 03/05/2025]
Abstract
INTRODUCTION Non-traumatic osteonecrosis is a frequent complication in patients with autoimmune disorders, though its prevalence varies markedly depending upon the type of disorder. Understanding the causes of this difference can help uncover the underlying pathophysiology of osteonecrosis and guide the development of effective preventive and therapeutic strategies. AREAS COVERED In this perspective study, we reviewed available databases, including PubMed, Cochrane Library, Scopus, and Web of Science, to explore why the risk of osteonecrosis varies among different autoimmune disorders. Is this variation primarily due to the disease's pathophysiology, the use of medications such as corticosteroids, or a combination of both? If both factors are involved, what is the extent of each contribution in this context? EXPERT OPINION Non-traumatic osteonecrosis is often induced by an interaction between disease pathophysiology and corticosteroid use. In patients with different autoimmune disorders but an identical history of corticosteroid use, the risk of osteonecrosis is influenced by how the underlying pathophysiology compromises bone health. In autoimmune disorders with multiple adverse effects on bone, such as SLE (systemic lupus erythematosus), there is a much higher risk of osteonecrosis compared to disorders with minimal impact on bone health, such as celiac disease and MS (multiple sclerosis).
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Affiliation(s)
- Edward Y Cheng
- Department of Orthopedic Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Alireza Mirzaei
- Department of Orthopedic Surgery, University of Minnesota, Minneapolis, MN, USA
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Guan G, Zhuoga S, Zheng S, Xu K, Weng T, Qian W, Ji D, Yu X. A New Risk Prediction Model for Detecting Endoscopic Activity of Ulcerative Colitis. Gut Liver 2024; 18:834-844. [PMID: 38623059 PMCID: PMC11391131 DOI: 10.5009/gnl230370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 12/13/2023] [Accepted: 01/11/2024] [Indexed: 04/17/2024] Open
Abstract
Background/Aims Ulcerative colitis (UC) is an incurable, relapsing-remitting inflammatory disease that increases steadily. Mucosal healing has become the primary therapeutic objective for UC. Nevertheless, endoscopic assessments are invasive, expensive, time-consuming, and inconvenient. Therefore, it is crucial to develop a noninvasive predictive model to monitor endoscopic activity in patients with UC. Methods Clinical data of 198 adult patients with UC were collected from January 2016 to August 2022 at Huadong Hospital, China. Results Patients with UC were randomly divided into the training cohort (70%, n=138) and the validation cohort (30%, n=60). The receiver operating characteristic curve value for the training group was 0.858 (95% confidence interval [CI], 0.781 to 0.936), whereas it was 0.845 (95% CI, 0.731 to 0.960) for the validation group. The calibration curve employed the Hosmer-Lemeshow test (p>0.05) to demonstrate the consistency between the predicted and the actual probabilities in the nomogram of these two groups. The decision curve analysis validated that the nomogram had clinical usefulness. Conclusions The nomogram, which incorporated activated partial thromboplastin time, fecal occult blood test, β2-globulin level, and fibrinogen degradation products, served as a prospective tool for evaluating UC activity in clinical practices.
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Affiliation(s)
- Guoyu Guan
- Department of Gastroenterology, Huadong Hospital, Shanghai Medical College Fudan University, Shanghai, China
| | - Sangdan Zhuoga
- Department of Gastroenterology, Huadong Hospital, Shanghai Medical College Fudan University, Shanghai, China
| | - Songbai Zheng
- Department of Gastroenterology, Huadong Hospital, Shanghai Medical College Fudan University, Shanghai, China
| | - Kangqiao Xu
- Department of Respiration, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tingwen Weng
- Department of Cardiology, Huadong Hospital, Shanghai Medical College Fudan University, Shanghai, China
| | - Wensi Qian
- Department of Hematology, Huadong Hospital, Shanghai Medical College Fudan University, Shanghai, China
| | - Danian Ji
- Department of Endoscopy Center, Huadong Hospital, Shanghai Medical College Fudan University, Shanghai, China
| | - Xiaofeng Yu
- Department of General Practice, Huadong Hospital, Shanghai Medical College Fudan University, Shanghai, China
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Hou JJ, Ding L, Yang T, Yang YF, Jin YP, Zhang XP, Ma AH, Qin YH. The proteolytic activity in inflammatory bowel disease: insight from gut microbiota. Microb Pathog 2024; 188:106560. [PMID: 38272327 DOI: 10.1016/j.micpath.2024.106560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 01/20/2024] [Accepted: 01/22/2024] [Indexed: 01/27/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease caused by the destruction of the intestinal mucosal epithelium that affects a growing number of people worldwide. Although the etiology of IBD is complex and still elucidated, the role of dysbiosis and dysregulated proteolysis is well recognized. Various studies observed altered composition and diversity of gut microbiota, as well as increased proteolytic activity (PA) in serum, plasma, colonic mucosa, and fecal supernatant of IBD compared to healthy individuals. The imbalance of intestinal microecology and intestinal protein hydrolysis were gradually considered to be closely related to IBD. Notably, the pivotal role of intestinal microbiota in maintaining proteolytic balance received increasing attention. In summary, we have speculated a mesmerizing story, regarding the hidden role of PA and microbiota-derived PA hidden in IBD. Most importantly, we provided the diagnosis and therapeutic targets for IBD as well as the formulation of new treatment strategies for other digestive diseases and protease-related diseases.
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Affiliation(s)
- Jun-Jie Hou
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Liang Ding
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Tao Yang
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Yan-Fei Yang
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Yue-Ping Jin
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Xiao-Ping Zhang
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - A-Huo Ma
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China
| | - Yue-Hua Qin
- Department of Gastroenterology, Shaoxing People's Hospital, Shaoxing, PR China.
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Yan P, Sun Y, Luo J, Liu X, Wu J, Miao Y. Integrating the serum proteomic and fecal metaproteomic to analyze the impacts of overweight/obesity on IBD: a pilot investigation. Clin Proteomics 2023; 20:6. [PMID: 36759757 PMCID: PMC9909917 DOI: 10.1186/s12014-023-09396-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 02/02/2023] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) encompasses a group of chronic relapsing disorders which include ulcerative colitis (UC) and Crohn's disease (CD). The incidences of IBD and overweight/obesity are increasing in parallel. Here, we investigated alterations in proteomic in serum and metaproteomic in feces of IBD patients with overweight/obesity and aimed to explore the effect of overweight/ obesity on IBD and the underlying mechanism. METHODS This prospective observational study (n = 64) comprised 26 health control subjects (HC, 13 with overweight/obesity) and 38 IBD patients (19 with overweight/obesity) at a tertiary hospital. Overweight/obesity was evaluated by body mass index (BMI) and defined as a BMI greater than 24 kg/m2. The comprehensive serum proteomic and fecal metaproteomic analyses were conducted by ultra-performance liquid chromatography-Orbitrap Exploris 480 mass spectrometry. RESULTS UC and CD presented similar serum molecular profiles but distinct gut microbiota. UC and CD serum exhibited higher levels of cytoskeleton organization- associated and inflammatory response-related proteins than the HC serum. Compared the serum proteome of UC and CD without overweight/obesity, inflammatory response-associated proteins were dramatically decreased in UC and CD with overweight/obesity. Fecal metaproteome identified 66 species in the feces. Among them, Parasutterella excrementihominis was increased in CD compared with that in HC. UC group had a significant enrichment of Moniliophthora roreri, but had dramatically decreased abundances of Alistipes indistinctus, Clostridium methylpentosum, Bacteroides vulgatus, and Schizochytrium aggregatum. In addition, overweight/obesity could improve the microbial diversity of UC. Specifically, the UC patients with overweight/obesity had increased abundance of some probiotics in contrast to those without overweight/obesity, including Parabacteroides distasonis, Alistipes indistincus, and Ruminococcus bromii. CONCLUSION This study provided high-quality multi-omics data of IBD serum and fecal samples, which enabled deciphering the molecular bases of clinical phenotypes of IBD, revealing the impacts of microbiota on IBD, and emphasizing the important role of overweight/obesity in IBD.
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Affiliation(s)
- Ping Yan
- grid.285847.40000 0000 9588 0960Kunming Medical University, Kunming, China ,grid.440682.c0000 0001 1866 919XDepartment of Gastroenterology, First Affiliated Hospital of Dali University, Dali, China ,Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Yang Sun
- grid.414902.a0000 0004 1771 3912Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Kunming, China ,Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Juan Luo
- grid.414902.a0000 0004 1771 3912Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Kunming, China ,Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Xiaolin Liu
- grid.414902.a0000 0004 1771 3912Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Kunming, China ,Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Jing Wu
- grid.414902.a0000 0004 1771 3912Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Kunming, China ,Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Yinglei Miao
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Kunming, China. .,Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China.
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Xie X, Wu Z, Wu Y, Liu J, Chen X, Shi X, Wei C, Li J, Lv J, Li Q, Tang L, He S, Zhan T, Tang Z. Cysteine protease of Clonorchis sinensis alleviates DSS-induced colitis in mice. PLoS Negl Trop Dis 2022; 16:e0010774. [PMID: 36084127 PMCID: PMC9491586 DOI: 10.1371/journal.pntd.0010774] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 09/21/2022] [Accepted: 08/29/2022] [Indexed: 11/19/2022] Open
Abstract
Background
Currently, inflammatory bowel disease (IBD) has become a global chronic idiopathic disease with ever-rising morbidity and prevalence. Accumulating evidence supports the IBD-hygiene hypothesis that helminths and their derivatives have potential therapeutic value for IBD. Clonorchis sinensis (C. sinensis) mainly elicit Th2/Treg-dominated immune responses to maintain long-term parasitism in the host. This study aimed to evaluate the therapeutic effects of cysteine protease (CsCP) and adult crude antigen (CsCA) of C. sinensis, and C. sinensis (Cs) infection on DSS-induced colitis mice.
Methods
BALB/c mice were given 5% DSS daily for 7 days to induce colitis. During this period, mice were treated with rCsCP, CsCA or dexamethasone (DXM) every day, or Cs infection which was established in advance. Changes in body weight, disease activity index (DAI), colon lengths, macroscopic scores, histopathological findings, myeloperoxidase (MPO) activity levels, regulatory T cell (Treg) subset levels, colon gene expression levels, serum cytokine levels, and biochemical indexes were measured.
Results
Compared with Cs infection, rCsCP and CsCA alleviated the disease activity of acute colitis more significant without causing abnormal blood biochemical indexes. In comparison, rCsCP was superior to CsCA in attenuating colonic pathological symptoms, enhancing the proportion of Treg cells in spleens and mesenteric lymph nodes, and improving the secretion of inflammatory-related cytokines (e.g., IL-2, IL-4, IL-10 and IL-13) in serum. Combined with RNA-seq data, it was revealed that CsCA might up-regulate the genes related to C-type lectin receptor and intestinal mucosal repair related signal pathways (e.g., Cd209d, F13a1 and Cckbr) to reduce colon inflammation and benefit intestinal mucosal repair. Dissimilarly, rCsCP ameliorated colitis mainly through stimulating innate immunity, such as Toll like receptor (TLR) signaling pathway, down-regulating the expression of inflammatory cytokines (e.g., IL-12b, IL-23r and IL-7), thereby restraining the differentiation of Th1/Th17 cells.
Conclusions
Both rCsCP and CsCA showed good therapeutic effects on the treatment of acute colitis, but rCsCP is a better choice. rCsCP is a safe, effective, readily available and promising therapeutic agent against IBD mainly by activating innate immunity and regulating the IL-12/IL-23r axis.
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Affiliation(s)
- Xiaoying Xie
- School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
| | - Zhanshuai Wu
- Department of Immunology, Guangxi University of Chinese Medicine, Nanning, China
- GuangXi Medical Transformational Key Laboratory of Combine Traditional Chinese and Western Medicine and High Incidence of Infectious Diseases, Nanning, China
| | - Yuhong Wu
- School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
- Department of Cell Biology and Genetics, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
| | - Jing Liu
- School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
| | - Xinyuan Chen
- School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
| | - Xiaoqian Shi
- School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
| | - Caiheng Wei
- School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
| | - Jiasheng Li
- School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
| | - Jiahui Lv
- School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
- Department of Parasitology, Guangxi Medical University, Nanning, China
| | - Qing Li
- Department of Cell Biology and Genetics, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
| | - Lili Tang
- Department of Parasitology, Guangxi Medical University, Nanning, China
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
| | - Shanshan He
- Department of Parasitology, Guangxi Medical University, Nanning, China
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
| | - Tingzheng Zhan
- Department of Parasitology, Guangxi Medical University, Nanning, China
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
- * E-mail: (TZ); (ZT)
| | - Zeli Tang
- Department of Cell Biology and Genetics, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, China
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
- * E-mail: (TZ); (ZT)
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Li Y, Lee AQ, Lu Z, Sun Y, Lu JW, Ren Z, Zhang N, Liu D, Gong Z. Systematic Characterization of the Disruption of Intestine during Liver Tumor Progression in the xmrk Oncogene Transgenic Zebrafish Model. Cells 2022; 11:cells11111810. [PMID: 35681505 PMCID: PMC9180660 DOI: 10.3390/cells11111810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/29/2022] [Accepted: 05/30/2022] [Indexed: 01/27/2023] Open
Abstract
The crosstalk between tumors and their local microenvironment has been well studied, whereas the effect of tumors on distant tissues remains understudied. Studying how tumors affect other tissues is important for understanding the systemic effect of tumors and for improving the overall health of cancer patients. In this study, we focused on the changes in the intestine during liver tumor progression, using a previously established liver tumor model through inducible expression of the oncogene xmrk in zebrafish. Progressive disruption of intestinal structure was found in the tumor fish, displaying villus damage, thinning of bowel wall, increase in goblet cell number, decrease in goblet cell size and infiltration of eosinophils, most of which were observed phenotypes of an inflammatory intestine. Intestinal epithelial cell renewal was also disrupted, with decreased cell proliferation and increased cell death. Analysis of intestinal gene expression through RNA-seq suggested deregulation of genes related to intestinal function, epithelial barrier and homeostasis and activation of pathways in inflammation, epithelial mesenchymal transition, extracellular matrix organization, as well as hemostasis. Gene set enrichment analysis showed common gene signatures between the intestine of liver tumor fish and human inflammatory bowel disease, the association of which with cancer has been recently noticed. Overall, this study represented the first systematic characterization of the disruption of intestine under the liver tumor condition and suggested targeting intestinal inflammation as a potential approach for managing cancer cachexia.
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Affiliation(s)
- Yan Li
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (A.Q.L.); (Z.L.); (Y.S.); (J.-W.L.); (Z.R.); (N.Z.)
- Correspondence: (Y.L.); (Z.G.)
| | - Ai Qi Lee
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (A.Q.L.); (Z.L.); (Y.S.); (J.-W.L.); (Z.R.); (N.Z.)
| | - Zhiyuan Lu
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (A.Q.L.); (Z.L.); (Y.S.); (J.-W.L.); (Z.R.); (N.Z.)
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China
| | - Yuxi Sun
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (A.Q.L.); (Z.L.); (Y.S.); (J.-W.L.); (Z.R.); (N.Z.)
- Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China;
| | - Jeng-Wei Lu
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (A.Q.L.); (Z.L.); (Y.S.); (J.-W.L.); (Z.R.); (N.Z.)
| | - Ziheng Ren
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (A.Q.L.); (Z.L.); (Y.S.); (J.-W.L.); (Z.R.); (N.Z.)
| | - Na Zhang
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (A.Q.L.); (Z.L.); (Y.S.); (J.-W.L.); (Z.R.); (N.Z.)
- Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China;
| | - Dong Liu
- Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China;
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (A.Q.L.); (Z.L.); (Y.S.); (J.-W.L.); (Z.R.); (N.Z.)
- Correspondence: (Y.L.); (Z.G.)
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Cerebral Venous Thrombosis as an Initial Presentation of Ulcerative Colitis. Case Rep Gastrointest Med 2022; 2022:9438757. [PMID: 35388355 PMCID: PMC8977341 DOI: 10.1155/2022/9438757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 03/12/2022] [Indexed: 12/04/2022] Open
Abstract
Cerebral venous thrombosis (CVT) is a rare complication of ulcerative colitis (UC) that is potentially fatal once it occurs. This report describes a case of CVT that led to a diagnosis of UC. A 48-year-old woman was diagnosed with CVT due to paresthesia and weakness and was hospitalized for treatment. She developed bloody diarrhea on admission and was further diagnosed with UC based on endoscopic and pathologic findings. Treatment of UC with steroids and sulfasalazine was administered immediately. Her condition improved significantly within several days following treatment. After discharge, the patient experienced no recurrence of either CVT or UC flare-up over the last five years. This report describes CVT as an initial presentation of UC. This is also the first report of a long-term follow-up following successful treatment of CVT with concomitant UC.
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The versatile role of the contact system in cardiovascular disease, inflammation, sepsis and cancer. Biomed Pharmacother 2021; 145:112429. [PMID: 34801854 DOI: 10.1016/j.biopha.2021.112429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/09/2021] [Accepted: 11/12/2021] [Indexed: 11/24/2022] Open
Abstract
The human contact system consists of plasma proteins, which - after contact to foreign surfaces - are bound to them, thereby activating the zymogens of the system into enzymes. This activation mechanism gave the system its name - contact system. It is considered as a procoagulant and proinflammatory response mechanism, as activation finally leads to the generation of fibrin and bradykinin. To date, no physiological processes have been described that are mediated by contact activation. However, contact system factors play a pathophysiological role in numerous diseases, such as cardiovascular diseases, arthritis, colitis, sepsis, and cancer. Contact system factors are therefore an interesting target for new therapeutic options in different clinical conditions.
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Stadnicki A, Stadnicka I. Venous and arterial thromboembolism in patients with inflammatory bowel diseases. World J Gastroenterol 2021; 27:6757-6774. [PMID: 34790006 PMCID: PMC8567469 DOI: 10.3748/wjg.v27.i40.6757] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/22/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023] Open
Abstract
The risk of thromboembolism (TE) is increased in patients with inflammatory bowel disease (IBD), mainly due to an increased risk of venous TE (VTE). The risk of arterial TE (ATE) is less pronounced, but an increased risk of cardiovascular diseases needs to be addressed in IBD patients. IBD predisposes to arterial and venous thrombosis through similar prothrombotic mechanisms, including triggering activation of coagulation, in part mediated by impairment of the intestinal barrier and released bacterial components. VTE in IBD has clinical specificities, i.e., an earlier first episode in life, high rates during both active and remission stages, higher recurrence rates, and poor prognosis. The increased likelihood of VTE in IBD patients may be related to surgery, the use of medications such as corticosteroids or tofacitinib, whereas infliximab is antithrombotic. Long-term complications of VTE can include post-thrombotic syndrome and high recurrence rate during post-hospital discharge. A global clot lysis assay may be useful in identifying patients with IBD who are at risk for TE. Many VTEs occur in IBD outpatients; therefore, outpatient prophylaxis in high-risk patients is recommended. It is crucial to continue focusing on prevention and adequate treatment of VTE in patients with IBD.
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Affiliation(s)
- Antoni Stadnicki
- Department of Physiology, Faculty of Medicine, University of Technology, Katowice 41-209, Poland
| | - Izabela Stadnicka
- Department of Molecular Medicine, Medical University of Silesia, Faculty of Pharmacy, Sosnowiec 41-200, Poland
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11
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Motta JP, Palese S, Giorgio C, Chapman K, Denadai-Souza A, Rousset P, Sagnat D, Guiraud L, Edir A, Seguy C, Alric L, Bonnet D, Bournet B, Buscail L, Gilletta C, Buret AG, Wallace JL, Hollenberg MD, Oswald E, Barocelli E, Le Grand S, Le Grand B, Deraison C, Vergnolle N. Increased Mucosal Thrombin is Associated with Crohn's Disease and Causes Inflammatory Damage through Protease-activated Receptors Activation. J Crohns Colitis 2020; 15:787-799. [PMID: 33201214 PMCID: PMC8095389 DOI: 10.1093/ecco-jcc/jjaa229] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Thrombin levels in the colon of Crohn's disease patients have recently been found to be elevated 100-fold compared with healthy controls. Our aim was to determine whether and how dysregulated thrombin activity could contribute to local tissue malfunctions associated with Crohn's disease. METHODS Thrombin activity was studied in tissues from Crohn's disease patients and healthy controls. Intracolonic administration of thrombin to wild-type or protease-activated receptor-deficient mice was used to assess the effects and mechanisms of local thrombin upregulation. Colitis was induced in rats and mice by the intracolonic administration of trinitrobenzene sulphonic acid. RESULTS Active forms of thrombin were increased in Crohn's disease patient tissues. Elevated thrombin expression and activity were associated with intestinal epithelial cells. Increased thrombin activity and expression were also a feature of experimental colitis in rats. Colonic exposure to doses of active thrombin comparable to what is found in inflammatory bowel disease tissues caused mucosal damage and tissue dysfunctions in mice, through a mechanism involving both protease-activated receptors -1 and -4. Intracolonic administration of the thrombin inhibitor dabigatran, as well as inhibition of protease-activated receptor-1, prevented trinitrobenzene sulphonic acid-induced colitis in rodent models. CONCLUSIONS Our data demonstrated that increased local thrombin activity, as it occurs in the colon of patients with inflammatory bowel disease, causes mucosal damage and inflammation. Colonic thrombin and protease-activated receptor-1 appear as possible mechanisms involved in mucosal damage and loss of function and therefore represent potential therapeutic targets for treating inflammatory bowel disease.
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Affiliation(s)
- Jean-Paul Motta
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France,CVasThera, Arobase Castres-Mazamet, Castres, France
| | - Simone Palese
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France,Università di Parma, Dipartimento di Scienze degli Alimenti e del Farmaco, Parma, Italia
| | - Carmine Giorgio
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France,Università di Parma, Dipartimento di Scienze degli Alimenti e del Farmaco, Parma, Italia
| | - Kevin Chapman
- Department of Physiology & Pharmacology, and Medicine, University of Calgary Cumming School of Medicine, Calgary, AB, Canada
| | | | - Perrine Rousset
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - David Sagnat
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Laura Guiraud
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Anissa Edir
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Carine Seguy
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Laurent Alric
- Department of Internal Medicine and Digestive Diseases, CHU Toulouse, Toulouse, France,Pole Digestif, CHU Toulouse, Toulouse, France,Faculty of Medicine, Paul Sabatier University, Toulouse, France
| | - Delphine Bonnet
- Department of Internal Medicine and Digestive Diseases, CHU Toulouse, Toulouse, France,Pole Digestif, CHU Toulouse, Toulouse, France
| | - Barbara Bournet
- Pole Digestif, CHU Toulouse, Toulouse, France,Faculty of Medicine, Paul Sabatier University, Toulouse, France
| | - Louis Buscail
- Pole Digestif, CHU Toulouse, Toulouse, France,Faculty of Medicine, Paul Sabatier University, Toulouse, France
| | | | - Andre G Buret
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - John L Wallace
- Department of Physiology & Pharmacology, and Medicine, University of Calgary Cumming School of Medicine, Calgary, AB, Canada
| | - Morley D Hollenberg
- Department of Physiology & Pharmacology, and Medicine, University of Calgary Cumming School of Medicine, Calgary, AB, Canada
| | - Eric Oswald
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Elisabetta Barocelli
- Università di Parma, Dipartimento di Scienze degli Alimenti e del Farmaco, Parma, Italia
| | | | | | - Celine Deraison
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France,Department of Physiology & Pharmacology, and Medicine, University of Calgary Cumming School of Medicine, Calgary, AB, Canada,Corresponding author: Dr Nathalie Vergnolle, PhD, Institut de Recherche en Santé Digestive [IRSD], INSERM UMR-1220, Purpan Hospital, CS60039, 31024 Toulouse cedex 03, France. Tel.: 33-5-62-74-45-00; fax: 33-5-62-74-45-58;
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12
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Ferreira-Duarte M, Sousa JB, Diniz C, Sousa T, Duarte-Araújo M, Morato M. Experimental and Clinical Evidence of Endothelial Dysfunction in Inflammatory Bowel Disease. Curr Pharm Des 2020; 26:3733-3747. [PMID: 32611296 DOI: 10.2174/1381612826666200701212414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
The endothelium has a crucial role in proper hemodynamics. Inflammatory bowel disease (IBD) is mainly a chronic inflammatory condition of the gastrointestinal tract. However, considerable evidence points to high cardiovascular risk in patients with IBD. This review positions the basic mechanisms of endothelial dysfunction in the IBD setting (both clinical and experimental). Furthermore, we review the main effects of drugs used to treat IBD in endothelial (dys)function. Moreover, we leave challenging points for enlarging the therapeutic arsenal for IBD with new or repurposed drugs that target endothelial dysfunction besides inflammation.
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Affiliation(s)
| | | | - Carmen Diniz
- LAQV@REQUIMTE, University of Porto, Porto, Portugal
| | - Teresa Sousa
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
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13
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Tian Y, Zheng Y, Dong J, Zhang J, Wang H. Papaverine adjuvant therapy for microcirculatory disturbance in severe ulcerative colitis complicated with CMV infection: a case report. Clin J Gastroenterol 2019; 12:407-413. [PMID: 30945123 PMCID: PMC6763508 DOI: 10.1007/s12328-019-00974-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 03/26/2019] [Indexed: 12/21/2022]
Abstract
Ulcerative colitis has hypercoagulable state and high risk of thrombosis; so mucosal disturbance of microcirculation may be mediate and amplify the inflammation of ulcerative colitis. A 56-year-old female patient was admitted in hospital for discontinuously mucous bloody stool for more than 1 year. Ulcerative colitis was determined after colonoscopy and pathologic examination. Mesalazine was effective during the year, but her symptoms recurred three times due to her bad compliance. One month before admission, the patient had severe recurrence after mesalazine withdrawal. At this time, the result of quantitative fluorescence PCR of colonic histic CMV-DNA was 1.6 × 104 copies/mL positive, CMV colitis was accompanied. After 4 weeks of ganciclovir and 6 weeks of mesalazine usage and nutrition support, the symptoms of diarrhea and abdominal cramp did not improve; stool frequency was more than twenty times a day. Probe-based confocal laser endomicroscopy revealed local microcirculation disturbance. Papaverine 90-mg slow drip for at least 10 h a day was added. The symptoms dramatically disappeared after 3 days of papaverine treatment. The patient had yellow mushy stool 2–3 times a day. Pathological findings showed diffuse submucosal hemorrhage and transparent thrombosis in capillaries. Treatment of microcirculatory disturbance in severe UC is a promising adjuvant therapy. Confocal laser endomicroscopy may be an effective method for microcirculation judgment.
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Affiliation(s)
- Yu Tian
- Gastroenterology Department of Peking, University First Hospital, Beijing, China
| | - Yue Zheng
- Gastroenterology Department of Peking, University First Hospital, Beijing, China
| | - Jinpei Dong
- Gastroenterology Department of Peking, University First Hospital, Beijing, China
| | - Jixin Zhang
- Pathology Department of Peking, University First Hospital, Beijing, China
| | - Huahong Wang
- Gastroenterology Department of Peking, University First Hospital, Beijing, China.
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14
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Xu F, Liu Y, Wheaton AG, Rabarison KM, Croft JB. Trends and Factors Associated with Hospitalization Costs for Inflammatory Bowel Disease in the United States. APPLIED HEALTH ECONOMICS AND HEALTH POLICY 2019; 17:77-91. [PMID: 30259396 PMCID: PMC10498392 DOI: 10.1007/s40258-018-0432-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
BACKGROUND Few studies have addressed recent trends in hospitalization costs for inflammatory bowel disease (IBD). OBJECTIVE We explored trends and described patient and hospital factors associated with hospitalization costs for IBD. METHODS Using data from the 2003-2014 National Inpatient Sample for adults aged ≥ 18 years, we estimated costs using multivariable linear models and assessed linear trends by time periods using piecewise linear regressions. RESULTS In 2014, there were an estimated 56,290 hospitalizations for Crohn's disease (CD), with a mean cost of US$11,345 and median cost of US$7592; and 33,585 hospitalizations for ulcerative colitis (UC), with a mean cost of US$13,412 and median cost of US$8873. Higher costs were observed among Hispanic [adjusted cost ratio (ACR) = 1.07; 95% confidence interval (CI) = 1.00-1.14; p = 0.04] or other non-Hispanic (ACR = 1.09; 95% CI = 1.02-1.17; p = 0.01) CD patients than for non-Hispanic White CD patients. For UC patients, higher costs were observed among men (ACR = 1.09; 95% CI = 1.05-1.13; p < 0.001) compared with women and among patients aged 35-44 years, 45-54 years, and 55-64 years compared with those aged 18-24 years. Among all patients, factors associated with higher costs included higher household income, more comorbidities, and hospitals that were government nonfederal versus private, were large versus small, and were located in the West versus Northeast regions. From 2003 to 2008, total costs increased annually by 3% for CD (1.03; 95% CI = 1.02-1.05; p < 0.001) and 4% for UC (1.04; 95% CI = 1.02-1.06; p < 0.001), but remained unchanged from 2008 to 2014. CONCLUSIONS The findings are important to identify IBD patients with higher hospitalization costs and to inform policy plans on hospital resource allocation.
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Affiliation(s)
- Fang Xu
- Division of Population Health, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 4770 Buford Highway NE, Mailstop F-78, Atlanta, GA, 30341, USA.
| | - Yong Liu
- Division of Population Health, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 4770 Buford Highway NE, Mailstop F-78, Atlanta, GA, 30341, USA
| | - Anne G Wheaton
- Division of Population Health, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 4770 Buford Highway NE, Mailstop F-78, Atlanta, GA, 30341, USA
| | - Kristina M Rabarison
- Division of Population Health, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 4770 Buford Highway NE, Mailstop F-78, Atlanta, GA, 30341, USA
| | - Janet B Croft
- Division of Population Health, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 4770 Buford Highway NE, Mailstop F-78, Atlanta, GA, 30341, USA
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15
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Ando K, Fujiya M, Nomura Y, Inaba Y, Sugiyama Y, Iwama T, Ijiri M, Takahashi K, Tanaka K, Sakatani A, Ueno N, Kashima S, Moriichi K, Mizukami Y, Okumura T. The incidence and risk factors of venous thromboembolism in Japanese inpatients with inflammatory bowel disease: a retrospective cohort study. Intest Res 2018; 16:416-425. [PMID: 30090041 PMCID: PMC6077312 DOI: 10.5217/ir.2018.16.3.416] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Revised: 01/02/2018] [Accepted: 01/03/2018] [Indexed: 12/25/2022] Open
Abstract
Background/Aims Venous thromboembolism (VTE) is a major extraintestinal manifestation in inflammatory bowel disease (IBD), regarded as an independent risk factor for VTE according to reports from Western countries. However, the incidence and risk factors of VTE in Asian IBD patients are not fully understood. We aimed to reveal the incidence and risk factors of VTE in Japanese IBD inpatients. Methods The incidence of VTE in inpatients with IBD (n=340), gastrointestinal cancers (n=557), and other gastrointestinal diseases (n=569) treated at our hospital from 2009 to 2013 was retrospectively investigated. The characteristics and laboratory data of IBD inpatients with and without VTE were compared in univariate and multivariate analyses. Clinical courses of VTE in IBD were surveyed. Results VTE was detected in 7.1% of IBD inpatients, significantly higher than in gastrointestinal cancer inpatients (2.5%) and inpatients with other gastrointestinal diseases (0.88%). The incidence of VTE in ulcerative colitis (UC) patients (16.7%) was much higher than that in those with Crohn's disease (3.6%). In the univariate analysis, the risk factors were an older age, central venous catheter, prednisolone, surgery, low serum albumin, high serum C-reactive protein and D-dimer. According to a multivariate analysis, >50 years of age and surgery were the only risk factors. The in-hospital mortality rate of IBD inpatients with VTE was 4.2%. Conclusions The incidence of VTE with IBD, especially UC, was found to be high compared with other digestive disease, which was almost equivalent to that of Western countries. The efficacy of prophylaxis needs to be investigated in Asian IBD patients.
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Affiliation(s)
- Katsuyoshi Ando
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Mikihiro Fujiya
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yoshiki Nomura
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yuhei Inaba
- Department of Gastroenterology, Asahikawa City Hospital, Asahikawa, Japan
| | - Yuuya Sugiyama
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Takuya Iwama
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Masami Ijiri
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Keitaro Takahashi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Kazuyuki Tanaka
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Aki Sakatani
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Nobuhiro Ueno
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Shin Kashima
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Kentaro Moriichi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yusuke Mizukami
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Toshikatsu Okumura
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
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16
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Diagnostic Markers for Nonspecific Inflammatory Bowel Diseases. DISEASE MARKERS 2018; 2018:7451946. [PMID: 29991970 PMCID: PMC6016179 DOI: 10.1155/2018/7451946] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 04/18/2018] [Accepted: 05/16/2018] [Indexed: 12/13/2022]
Abstract
The nonspecific inflammatory bowel diseases (IBD) represent a heterogeneous group of chronic inflammatory disorders of the gastrointestinal tract, and Leśniowski-Crohn's disease (CD) and ulcerative colitis (UC) are among the two major clinical forms. Despite the great progress in understanding the pathogenesis of these diseases, their etiology remains unclear. Genetic, immune, and environmental factors are thought to play a key role. The correct diagnosis of nonspecific inflammatory bowel diseases as well as the determination of disease activity, risk stratification, and prediction of response to therapy still relies on a multidisciplinary approach based on clinical, laboratory, endoscopic, and histologic examination. However, considerable effort has been devoted to the development of an accurate panel of noninvasive biomarkers that have increased diagnostic sensitivity and specificity. Laboratory biomarkers useful in differentiating IBD with functional disorders and in evaluating disease activity, prognosis, and treatment selection for IBD are presented in this study.
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17
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Flick MJ, Palumbo JS. Platelets couple inflammation to tumorigenesis, a bridge too far. J Thromb Haemost 2018; 16:759-761. [PMID: 29418061 DOI: 10.1111/jth.13967] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Indexed: 12/16/2022]
Affiliation(s)
- M J Flick
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - J S Palumbo
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
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18
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Wang B, Yang A, Zhao Z, He C, Liu Y, Colman RW, Dai J, Wu Y. The Plasma Kallikrein-Kininogen Pathway Is Critical in the Pathogenesis of Colitis in Mice. Front Immunol 2018; 9:21. [PMID: 29467753 PMCID: PMC5808240 DOI: 10.3389/fimmu.2018.00021] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 01/04/2018] [Indexed: 12/17/2022] Open
Abstract
The kallikrein-kinin system (KKS) consists of two serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-molecular-weight kininogen (HK). Upon activation of the KKS, HK is cleaved to release bradykinin. Although the KKS is activated in humans and animals with inflammatory bowel disease (IBD), its role in the pathogenesis of IBD has not been characterized. In the present study, we determined the role of the KKS in the pathogenesis of IBD using mice that lack proteins involved in the KKS. In two colitis models, induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS), mice deficient in HK, pKal, or bradykinin receptors displayed attenuated phenotypes, including body weight loss, disease activity index, colon length shortening, histological scoring, and colonic production of cytokines. Infiltration of neutrophils and inflammatory monocytes in the colonic lamina propria was reduced in HK-deficient mice. Reconstitution of HK-deficient mice through intravenous injection of HK recovered their susceptibility to DSS-induced colitis, increased IL-1β levels in the colon tissue and bradykinin concentrations in plasma. In contrast to the phenotypes of other mice lacking other proteins involved in the KKS, mice lacking FXII had comparable colonic inflammation to that observed in wild-type mice. The concentration of bradykinin was significantly increased in the plasma of wild-type mice after DSS-induced colitis. In vitro analysis revealed that DSS-induced pKal activation, HK cleavage, and bradykinin plasma release were prevented by the absence of pKal or the inhibition of Kal. Unlike DSS, TNBS-induced colitis did not trigger HK cleavage. Collectively, our data strongly suggest that Kal, acting independently of FXII, contributes to experimental colitis by promoting bradykinin release from HK.
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Affiliation(s)
- Bo Wang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Aizhen Yang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Zhenzhen Zhao
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Chao He
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yuanyuan Liu
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Robert W. Colman
- The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, United States
| | - Jihong Dai
- The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, United States
- Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, United States
| | - Yi Wu
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, United States
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19
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Hanke LI, Bartsch F, Försch S, Heid F, Lang H, Kneist W. Transanal total mesorectal excision for restorative coloproctectomy in an obese high-risk patient with colitis-associated carcinoma. MINIM INVASIV THER 2017; 26:188-191. [PMID: 27885870 DOI: 10.1080/13645706.2016.1264426] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Transanal total mesorectal excision (TaTME) offers great potential for the treatment of malign and benign diseases. However, laparoscopic-assisted TaTME in ulcerative colitis has not been described in more than a handful of patients. We present a 47-year-old highly comorbid female patient with an ulcerative colitis-associated carcinoma of the ascending colon and steroid- refractory pancolitis. A two-stage restorative coloproctectomy including right-sided complete mesocolic excision was conducted. The second step consisted of a successful nerve-sparing TaTME and a handsewn ileal pouch-anal anastomosis. TaTME may extend the possible treatment options in inflammatory bowel disease, especially for high-risk patients.
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Affiliation(s)
- Laura Isabel Hanke
- a Department of General, Visceral and Transplant Surgery , University Medical Center of the Johannes Gutenberg-University Mainz , Germany
| | - Fabian Bartsch
- a Department of General, Visceral and Transplant Surgery , University Medical Center of the Johannes Gutenberg-University Mainz , Germany
| | - Sebastian Försch
- b Institute of Pathology, University Medical Center of the Johannes Gutenberg-University , Mainz , Germany
| | - Florian Heid
- c Department of Anaesthesiology , University Medical Center of the Johannes Gutenberg-University , Mainz , Germany
| | - Hauke Lang
- a Department of General, Visceral and Transplant Surgery , University Medical Center of the Johannes Gutenberg-University Mainz , Germany
| | - Werner Kneist
- a Department of General, Visceral and Transplant Surgery , University Medical Center of the Johannes Gutenberg-University Mainz , Germany
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Meher LK, Dalai SP, Panda S, Hui PK, Nayak S. Unusual Case of Cerebral Venous Sinus Thrombosis in Patient with Ulcerative Colitis in Remission. J Clin Diagn Res 2016; 10:OD35-6. [PMID: 27437291 DOI: 10.7860/jcdr/2016/20105.7883] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Accepted: 04/19/2016] [Indexed: 01/14/2023]
Abstract
Ulcerative colitis (UC) is an idiopathic autoimmune inflammatory disease of the gastrointestinal tract. Cerebral venous sinus thrombosis along with deep vein thrombosis, pulmonary embolism and arterial thrombosis have occasionally been reported as a complication in the active phase of UC being attributed to its pro-thrombotic state. This paper depicts a 38-year-old female with a history of UC in remission who developed sudden onset headache, blurring of vision and seizures. Subsequent diagnosis of cerebral venous sinus thrombosis was made with MRI venography and treated with low molecular weight heparin with complete resolution of symptoms. The highlights of this case underscore the importance of evaluating cerebral venous sinus thrombosis as a cause of acute onset neurological deterioration in a setting of inflammatory bowel disease. It also emphasizes on the hypothesis that the risk of venous thrombosis or other hypercoagulable states have no direct relationship with the disease activity or flare-up.
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Affiliation(s)
- Lalit Kumar Meher
- Professor, Department of Medicine, MKCG Medical College , Brahmapur, Odisha, India
| | - Siba Prasad Dalai
- Junior Resident, Department of Medicine, MKCG Medical College , Brahmapur, Odisha, India
| | - Sameer Panda
- Junior Resident, Department of Medicine, MKCG Medical College , Brahmapur, Odisha, India
| | - Pankaj Kumar Hui
- Associate Professor, Department of Medicine, MKCG Medical College , Brahmapur, Odisha, India
| | - Sachidananda Nayak
- Assistant Professor, Department of Medicine, MKCG Medical College , Brahmapur, Odisha, India
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Di Sabatino A, Santilli F, Guerci M, Simeone P, Ardizzone S, Massari A, Giuffrida P, Tripaldi R, Malara A, Liani R, Gurini E, Aronico N, Balduini A, Corazza GR, Davì G. Oxidative stress and thromboxane-dependent platelet activation in inflammatory bowel disease: effects of anti-TNF-α treatment. Thromb Haemost 2016; 116:486-95. [PMID: 27305860 DOI: 10.1160/th16-02-0167] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/13/2016] [Indexed: 02/06/2023]
Abstract
Patients with inflammatory bowel disease (IBD) are at higher risk of venous thromboembolism and coronary artery disease despite having a lower burden of traditional risk factors. Platelets from IBD patients release more soluble CD40 ligand (CD40L), and this has been implicated in IBD platelet hyper-activation. We here measured the urinary F2-isoprostane 8-iso-prostaglandin (PG)2α (8-iso-PGF2α), urinary 11-dehydro-thromboxane (TX) B2 (11-dehydro-TXB2) and plasma CD40L in IBD patients, and explored the in vitro action of anti-tumour necrosis factor (TNF)-α antibody infliximab on IBD differentiating megakaryocytes. Urinary and blood samples were collected from 124 IBD patients and 37 healthy subjects. Thirteen IBD patients were also evaluated before and after 6-week infliximab treatment. The in vitro effect of infliximab on patient-derived megakaryocytes was evaluated by immunoflorescence microscopy and by flow cytometry. IBD patients had significantly (p<0.0001) higher urinary 8-iso-PGF2α and 11-dehydro-TXB2 as well as plasma CD40L levels than controls, with active IBD patients displaying higher urinary and plasma values when compared to inactive patients in remission. A 6-week treatment with infliximab was associated with a significant reduction of the urinary excretion of 8-iso-PGF2α and 11-dehydro-TXB2 (p=0.008) and plasma CD40L (p=0.001). Infliximab induced significantly rescued pro-platelet formation by megakaryocytes derived from IBD patients but not from healthy controls. Our findings provide evidence for enhanced in vivo TX-dependent platelet activation and lipid peroxidation in IBD patients. Anti-TNF-α therapy with infliximab down-regulates in vivo isoprostane generation and TX biosynthesis in responder IBD patients. Further studies are needed to clarify the implication of infliximab induced-proplatelet formation from IBD megakaryocytes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Giovanni Davì
- Prof. Giovanni Davì, Internal Medicine and Center of Excellence on Aging, "G. D'Annunzio" University Foundation, Via Colle dell'Ara, 66013 Chieti, Italy, E-mail:
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Kim I, Min KH, Yeo M, Kim JS, Lee SH, Lee SS, Shin KS, Youn SJ, Shin DI. Unusual Case of Cerebral Venous Thrombosis in Patient with Crohn's Disease. Case Rep Neurol 2015; 7:115-20. [PMID: 26078745 PMCID: PMC4463793 DOI: 10.1159/000430805] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The development of cerebral venous thrombosis (CVT) as a secondary complication of Crohn's disease (CD) seems to be rare, but it is generally accepted that the disease activity of CD contributes to the establishment of a hypercoagulable state. Here, we describe a case of CVT that developed outside the active phase of CD. A 17-year-old male visited the emergency room because of a sudden onset of right-sided weakness and right-sided hypesthesia. He had been diagnosed with CD 1 year before and was on a maintenance regimen of mesalazine and azathioprine. He did not exhibit any symptoms indicating a CD flare-up (bloody stools, abdominal pain, complications, or weight loss). A brain MRI scan revealed an acute infarction of the left frontal cortex and a cortical subarachnoid hemorrhage. Additionally, a magnetic resonance venography revealed a segmental filling defect in the superior sagittal sinus and also the non-visualizability of some bilateral cortical veins. The characteristics of the present case suggest that the risk of CVT is most likely related to CD per se rather than disease activity associated with CD.
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Affiliation(s)
- Inha Kim
- Neurology, Chungbuk National University Hospital, Cheongju, Korea
| | - Kyung-Hyun Min
- Neurology, Chungbuk National University Hospital, Cheongju, Korea
| | - Minju Yeo
- Neurology, Chungbuk National University Hospital, Cheongju, Korea
| | - Ji Seon Kim
- Department of Neurology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Sung Hyun Lee
- Department of Neurology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Sang Soo Lee
- Department of Neurology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Kyeong Seob Shin
- Department of Laboratory Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Sei Jin Youn
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Dong Ick Shin
- Department of Neurology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
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Mozaffari S, Nikfar S, Abdollahi M. Inflammatory bowel disease therapies discontinued between 2009 and 2014. Expert Opin Investig Drugs 2015; 24:949-956. [PMID: 25861835 DOI: 10.1517/13543784.2015.1035432] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION New therapeutic approaches are currently under development, which consider the fundamental mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD). The disease is associated with inflamed intestinal and colonic mucosa in response to the dysregulated immune system. AREAS COVERED The aim of this article is to review drugs that have been designed for the treatment of IBD and discontinued between 2009 and 2014. Herein, nine molecules with different mechanisms of action are under review. Brodalumab, daclizumab, elubrixin and vatelizumab were withdrawn from the Phase II trial due to the lack of efficacy. Abatacept was not significantly superior to the placebo in the rate of remission and its Phase III trials were stopped. CNDO-210 and Catridecacog were discontinued due to safety concerns and lack of efficacy, respectively. Finally, NU-206 and alkaline phosphatase also ceased in development during Phase I and II tests. EXPERT OPINION The development in our knowledge and understanding of the pathophysiology of IBD and the identification of key objectives for the future play significant roles in IBD therapeutic development. Furthermore, well-planned clinical trials with concise measures of efficacy and safety are required to better decide whether to extend or terminate the development process. Some anti-inflammatory cytokines such as IL-2, IL-12, IL-17, IL-18, IL-23 and INF-γ could garner more attention in the future.
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Affiliation(s)
- Shilan Mozaffari
- Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Toxicology and Pharmacology , Tehran , Iran ;
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24
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Koutroubakis IE. The relationship between coagulation state and inflammatory bowel disease: current understanding and clinical implications. Expert Rev Clin Immunol 2015; 11:479-88. [PMID: 25719625 DOI: 10.1586/1744666x.2015.1019475] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel disease (IBD) is associated with a hypercoagulable state and subsequently with an increased risk for venous thromboembolism (VTE). VTE in IBD is characterized by a high recurrence rate and is associated with the disease activity. Acquired endothelial dysfunction, abnormalities of platelets, activation of coagulation system and impaired fibrinolysis are the main changes in the coagulation state in IBD. The development of VTE in IBD has been considered to be the result of multiple interactions between acquired and inherited risk factors. The treatment of VTE in IBD patients is recommended to be similar and to follow the same protocols as for non-IBD patients. In the clinical practice, the management of IBD patients and especially the hospitalized patients should include thromboprophylaxis.
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Affiliation(s)
- Ioannis E Koutroubakis
- Department of Gastroenterology, University Hospital Heraklion, P.O. Box 1352, 71110 Heraklion, Crete, Greece
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25
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Nabatov AA. The vesicle-associated function of NOD2 as a link between Crohn's disease and mycobacterial infection. Gut Pathog 2015; 7:1. [PMID: 25653718 PMCID: PMC4316803 DOI: 10.1186/s13099-015-0049-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 01/03/2015] [Indexed: 12/18/2022] Open
Abstract
Although Crohn’s disease (CD) etiology remains unclear, a growing body of evidence suggests that CD may include an infectious component, with Mycobacterium avium subsp. paratuberculosis (MAP) being the most likely candidate for this role. However, the molecular mechanism of the MAP involvement in CD pathogenesis remains unclear. The polymorphism of the NOD2 gene, coding for an intracellular pattern recognition receptor, is a factor of predisposition to mycobacterial infections and CD. Recent findings on NOD2 interactions and functions provide the missing pieces in the puzzle of a NOD2-mediated mechanism common for mycobacterial infections and CD. Implications of these new findings for the development of a better understanding and treatments of CD and mycobacterial infections are discussed.
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Affiliation(s)
- Alexey A Nabatov
- Maastricht Radiation Oncology, MAASTRO/GROW Maastricht University Medical Center+, PO Box 616, 6200 MD Maastricht, The Netherlands ; Science Center, Volga Region State Academy of Physical Culture, Sport and Tourism, 33, Universiade Village, Kazan, 420138 Russia
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Kuy S, Dua A, Chappidi R, Seabrook G, Brown KR, Lewis B, Rossi PJ, Lee CJ. The increasing incidence of thromboembolic events among hospitalized patients with inflammatory bowel disease. Vascular 2014; 23:260-4. [PMID: 24986868 DOI: 10.1177/1708538114541799] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND We performed a national population-based study examining the incidence of both venous and arterial thromboembolic events in patients hospitalized with inflammatory bowel disease over the past decade. METHODS A retrospective cross-sectional analysis using the Nationwide Inpatient Sample Database was performed. Patients hospitalized with Crohn's disease and ulcerative colitis were identified using ICD-9 codes. The incidence of clinically relevant venous thromboembolic events and arterial thromboembolic events including myocardial infarction, visceral ischemia, cerebrovascular accidents, and peripheral arterial events was examined. RESULTS During the study period, 461,415 hospitalized inflammatory bowel disease patients were identified. Among these patients, 28,820 had a diagnosis of a thromboembolic event (overall prevalence of 6%). The incidence of thromboembolic events in patients with inflammatory bowel disease rose from 5.65% in 2000 to 7.17% by 2009. There were 18,270 (3.96%) patients who had an arterial thrombotic event, the most common being myocardial infarction (50%), followed by visceral ischemia (25%), and cerebrovascular incidents (22%). There were 11,083 (2.4%) patients identified to have had a venous thrombotic event, with the most common manifestation being deep vein thrombosis (77%), pulmonary embolism (32%), and portal vein thrombosis (3.9%). CONCLUSION An increasing incidence of thromboembolic event in patients with inflammatory bowel disease was observed over the past decade. Interestingly, there were more arterial thrombotic events in comparison to venous thrombotic events.
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Affiliation(s)
- SreyRam Kuy
- Overton Brooks Veterans Affairs Medical Center and Louisiana State University at Shreveport, USA
| | - Anahita Dua
- Division of Vascular Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA Center for Translational Injury Research (CeTIR), Department of Surgery, University of Texas-Houston, Houston, TX, USA
| | - Rohit Chappidi
- Department of Internal Medicine, Loyola University, Chicago, IL, USA
| | - Gary Seabrook
- Division of Vascular Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Kellie R Brown
- Division of Vascular Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Brian Lewis
- Division of Vascular Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Peter J Rossi
- Division of Vascular Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Cheong J Lee
- Division of Vascular Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
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Kohoutova D, Pecka M, Cihak M, Cyrany J, Maly J, Bures J. Prevalence of hypercoagulable disorders in inflammatory bowel disease. Scand J Gastroenterol 2014; 49:287-94. [PMID: 24328909 DOI: 10.3109/00365521.2013.870597] [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: 02/04/2023]
Abstract
OBJECTIVE. Inflammatory bowel disease (IBD) can be associated with hypercoagulable disorders. Aim of this single-center, prospective study was an in-depth evaluation of acquired hypercoagulable states in IBD patients. METHODS. A total of 110 patients with Crohn's disease (CD) (aged 19-69; mean 40.5, median 38.5 years), 43 with ulcerative colitis (UC) (aged 17-72; mean 42, median 36 years), and 30 controls were enrolled. Full blood count, serum C-reactive protein (CRP), proteins C and S, activated protein C (APC) resistance, thrombin-antithrombin complex (TAT), F1+F2 fragments, tissue factor pathway inhibitor (TFPI) total and truncated, TFPI-factor Xa, tissue plasminogen activator (tPA) and PAI-I antigen were investigated in peripheral blood samples. RESULTS. Only 18 of 153 (11.8%) IBD patients had hemocoagulation parameters within normal range. Significant difference between IBD patients and controls was found in thrombocyte volume (p < 0.001), protein C (p = 0.025), protein S (p = 0.003), APC resistance (p < 0.001), F1+F2 fragments (p < 0.001), and tPA (p = 0.002). In CD patients who were divided into two subgroups according to serum CRP values (non-active disease: <5 mg/L; active disease ≥5 mg/L), thrombocyte count was significantly lower (p = 0.001), thrombocyte volume was significantly higher (p = 0.002), F1+F2 fragments were significantly lower (p = 0.007) and tPA was significantly higher (p = 0.038) in the subgroup with CRP <5 mg/L. In UC patients, no significant difference depending on CRP was found. CONCLUSIONS. Acquired hypercoagulable abnormalities in IBD patients are frequent. Patients with active CD, but not UC, displayed significantly different hemocoagulable parameters, when compared to non-active CD/UC subjects. In patients with active CD (with increased serum CRP concentration) and patients with active extensive UC found at endoscopy (despite low CRP values), prophylactic anticoagulation therapy should be considered.
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Affiliation(s)
- Darina Kohoutova
- 2nd Department of Internal Medicine - Gastroenterology, Charles University in Praha, Faculty of Medicine at Hradec Kralove, University Teaching Hospital , Hradec Kralove , Czech Republic
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Zhu LP, Wang PJ, Liu J, Li LJ, Li ZG, Jiang HY, Feng BS. Galectin-9 and inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2014; 22:515-520. [DOI: 10.11569/wcjd.v22.i4.515] [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] [Indexed: 02/06/2023] Open
Abstract
Galectin-9 (Gal-9), a beta-galactoside binding lectin, is a tandem-repeat-type member of the galectin family which can specifically recognize and bind to galactosidase associated with diverse biological processes. Gal-9 is widely expressed in various tissues, plays a role in cell growth, polarization, adhesion, aggregation, and apoptosis, and has important functions in inflammatory diseases, autoimmune diseases, tumors, and infections. Our recent studies showed that Gal-9 is strongly associated with the genesis and development of inflammatory bowel disease. Here we will review the progress in understanding the role of Gal-9 in the pathogenesis of inflammatory bowel disease.
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Owczarek D, Cibor D, Głowacki MK, Rodacki T, Mach T. Inflammatory bowel disease: epidemiology, pathology and risk factors for hypercoagulability. World J Gastroenterol 2014; 20:53-63. [PMID: 24415858 PMCID: PMC3886032 DOI: 10.3748/wjg.v20.i1.53] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Revised: 11/19/2013] [Accepted: 12/05/2013] [Indexed: 02/06/2023] Open
Abstract
Hypercoagulability observed in patients with inflammatory bowel diseases (IBD) may lead to thromboembolic events (TE), which affect the venous and arterial systems alike and are an important factor in patients' morbidity and mortality. The risk of TE in IBD patients has been demonstrated to be approximately three-fold higher as compared to the general population. The pathogenesis of thrombosis in IBD patients is multifactorial and not fully explained. The most commonly listed factors include genetic and immune abnormalities, disequilibrium between procoagulant and anticoagulant factors, although recently, the role of endothelial damage as an IBD-triggering factor is underlined. Several studies report that the levels of some coagulation enzymes, including fibrinogen, factors V, VII, VIII, active factor XI, tissue factor, prothrombin fragment 1 + 2 and the thrombin-antithrombin complex, are altered in IBD patients. It has been demonstrated that there is a significant decrease of tissue plasminogen activator level, a marked increase of plasminogen activator inhibitor type 1 and thrombin-activable fibrinolysis inhibitor, a significantly lower level of antithrombin III and tissue factor pathway inhibitor. IBD patients have been also observed to produce an increased amount of various anticoagulant antibodies. Hyperhomocysteinemia, which is a potential risk factor for TE was also observed in some IBD patients. Further studies are necessary to assess the role of coagulation abnormalities in IBD etiology and to determine indications for thromboprophylactic treatment in patients at high risk of developing TE.
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Katsanos A, Asproudis I, Katsanos KH, Dastiridou AI, Aspiotis M, Tsianos EV. Orbital and optic nerve complications of inflammatory bowel disease. J Crohns Colitis 2013; 7:683-93. [PMID: 23083697 DOI: 10.1016/j.crohns.2012.09.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Revised: 09/11/2012] [Accepted: 09/27/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Extraintestinal manifestations of inflammatory bowel disease (IBD) can involve the orbit and the optic nerve. Although these manifestations are rare, they can be particularly serious as they can lead to permanent loss of vision. The aim of the review is to present the existing literature on IBD-related optic nerve and orbital complications. METHODS A literature search identified the publications reporting on incidence, clinical features and management of IBD patients with optic nerve and orbital manifestations. RESULTS Posterior scleritis and orbital inflammatory disease (orbital pseudotumor) are the most commonly encountered entities affecting the structures of the orbit. On the other hand, the optic nerve of IBD patients can be affected by conditions such as optic (demyelinating) neuritis ("retrobulbar" neuritis), or ischaemic optic neuropathy. Other neuro-ophthalmic manifestations that can be encountered in patients with IBD are related to increased intracranial pressure or toxicity secondary to anti tumour necrosis factor (anti-TNF) agents. CONCLUSIONS IBD-related optic nerve and orbital complications are rare but potentially vision-threatening. Heightened awareness and close cooperation between gastroenterologists and ophthalmologists are warranted.
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Affiliation(s)
- Andreas Katsanos
- Ophthalmology Department, University of Ioannina, Ioannina, Greece
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Katsanos AH, Katsanos KH, Kosmidou M, Giannopoulos S, Kyritsis AP, Tsianos EV. Cerebral sinus venous thrombosis in inflammatory bowel diseases. QJM 2013; 106:401-13. [PMID: 23243293 DOI: 10.1093/qjmed/hcs229] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND It has been estimated that 1.3-6.4% of patients with inflammatory bowel diseases (IBD) are complicated by cerebral venous thrombosis (CVT) at some point of time during the course of their disease. METHODS We retrospectively reviewed and subsequently analyzed data from 65 case reports of IBD patients with CVT. Our sources included MEDLINE and EMBASE, and the references of retrieved articles were also screened. RESULTS Patients with CVT and IBD were significantly younger than CVT patients without IBD. Female patients were complicated more frequently but at an older age when compared with males. The incidence of ulcerative colitis was almost double compared with Crohn's disease. Active disease was detected in 78.4% of the cases and the proportions of patients with active ulcerative colitis or active Crohn's disease were almost equal. The predominant neurological symptom in these patients was persistent headache (80%) and the most common site of CVT was the superior sagittal sinus (50.7%). Severe iron deficiency anemia was highlighted as a significant risk factor for thrombosis in nearly half of the patients. Transient coagulation abnormalities and hereditary thrombogenic mutations were identified in 23 and 20% of the case reports, respectively. CONCLUSION The overall outcome was very good, especially in those patients who were treated acutely with heparin or low molecular weight heparin, suggesting that heparin administration is related with improved neurological outcome and decreased mortality rates even in IBD patients complicated with CVT.
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Affiliation(s)
- A H Katsanos
- Department of Neurology, University of Ioannina School of Medicine, University Campus, 45110 Ioannina, Greece
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Lin H, Dong Y, Fei ZY, Chen XT, Wang RW, Chen QF, Xu Y. Therapeutic effect of salvianolate against ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2013; 21:936-939. [DOI: 10.11569/wcjd.v21.i10.936] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the correlation between changes in platelets and coagulation and disease severity in patients with ulcerative colitis (UC) and to investigate the therapeutic effect of salvianolate against UC.
METHODS: One hundred and ten patients with UC and 84 healthy controls were included in the study. Platelet count (PLT), mean platelet volume (MPV), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were compared between UC patients and healthy controls. UC patients were randomly divided into a control group and a treatment group. The control group received only routine treatment, while the treatment group received both salvianolate and routine treatment. PLT, MPV, ESR, and CRP were compared between the two groups. Stool characters and colonoscopy performance were also observed to evaluate the treatment effect.
RESULTS: PLT in UC patients was superior to that in normal controls (292.0 ± 104.8 vs 217.2 ± 45.6), while MPV in UC patients was inferior to that in normal controls (9.1 ± 0.8 vs 10.5 ± 1.1, P < 0.05). PLT was higher in patients with severe disease than in those with mild disease (292.0 ± 104.8 vs 244.2 ± 74.8, P < 0.05). There was no significant difference in PLT between patients with mild and those with moderate disease (244.2 ± 74.8 vs 255.0 ± 52.3, P > 0.05), or between those with moderate and severe disease (255.0 ± 52.3 vs 292.0 ± 104.8, P > 0.05). There were significant differences in MPV (9.5 ± 0.6 vs 9.2 ± 0.6 vs 8.5 ± 1.0), ESR (6.1 ± 4.5 vs 17.1 ± 9.0 vs 30.0 ± 19.7), CRP (9.3 ± 4.3 vs 14.7 ± 9.8 vs 31.2 ± 21.0) between patients with mild, moderate and severe disease (all P < 0.05). PLT (218.0 ± 34.8 vs 245.0 ± 45.3), ESR (7.3 ± 5.1 vs 14.7 ± 4.7) and CRP (8.3 ± 3.7 vs 11.6 ± 6.4) were lower, but the effective rate (93.8% vs 75.0%) and MPV(10.1±1.0 vs 9.7±0.8) were higher in the treatment group than in the control group after therapy (all P < 0.05).
CONCLUSION: PLT and MPV can be used as markers for assessing the severity of UC. Treatment with salvianolate can improve the treatment effect of UC by reducing PLT number and activation and activating blood circulation.
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