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Bass JA, Friesen CA, Deacy AD, Neilan NA, Bracken JM, Shakhnovich V, Singh V. Investigation of potential early Histologic markers of pediatric inflammatory bowel disease. BMC Gastroenterol 2015; 15:129. [PMID: 26463759 PMCID: PMC4604710 DOI: 10.1186/s12876-015-0359-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 09/25/2015] [Indexed: 12/30/2022] Open
Abstract
Background Early manifestations of pediatric inflammatory bowel disease (IBD) can be relatively nonspecific. Initial mucosal biopsies may not be conclusive, delaying the diagnosis until subsequent biopsies demonstrate typical histologic features of IBD. We hypothesized that certain inflammatory cell types may be utilized as early histologic indicators of IBD in children. Methods A retrospective analysis compared histologic findings from initially inconclusive or negative endoscopic studies in 22 patients who were subsequently diagnosed with IBD (after diagnostic endoscopy) to those of 20 comparison patients with functional abdominal pain matched for age, gender, and study type. A pediatric pathologist, blinded to study group, reviewed biopsies for histologic abnormalities. Eosinophil densities were obtained from the stomach, duodenum, and rectosigmoid areas. Immunohistochemistry (IHC) staining for tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP-9) was performed on the stomach and rectosigmoid areas. Results Gastritis and colonic crypt distortion were present in the IBD group at a greater rate (61 % vs. 22 %, p = 0.020; 34 % vs. 4 %, p = 0.008, respectively). Peak and mean eosinophil densities in the rectosigmoid area were greater in the IBD group (17.0/hpf vs. 5.0/hpf, p = 0.0063; 12.3/hpf vs. 4.2/hpf, p = 0.0106, respectively). TNF-α and MMP-9 staining did not reveal any significant differences. Conclusions Our data suggests that significantly greater inflammation in the stomach, crypt distortion in the colon, and eosinophilia in the rectosigmoid distinguished the IBD group from the comparison group at the time of the initial endoscopic evaluation.
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Affiliation(s)
- Julie A Bass
- Division of Gastroenterology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Craig A Friesen
- Division of Gastroenterology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Amanda D Deacy
- Division of Gastroenterology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA. .,Division of Developmental and Behavioral Sciences, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Nancy A Neilan
- Division of Infectious Disease, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Julia M Bracken
- Division of Gastroenterology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Valentina Shakhnovich
- Division of Gastroenterology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA. .,Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Vivekanand Singh
- Department of Pathology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
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Albenberg LG, Mamula P, Brown K, Baldassano RN, Russo P. Colitis in Infancy and Childhood. PATHOLOGY OF PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2014:197-248. [DOI: 10.1007/978-3-642-54053-0_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Müller KE, Lakatos PL, Papp M, Veres G. [Frequency and characteristics of granulomas in 368 pediatric patients with Crohn's disease]. Orv Hetil 2013; 154:1702-1708. [PMID: 24140509 DOI: 10.1556/oh.2013.29725] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2024]
Abstract
INTRODUCTION Epitheloid granulomas are one of the best histological criteria for distinguishing Crohn's disease from other inflammatory bowel diseases. However, the role of granuloma in the pathogenesis and clinical characteristics of Crohn's disease is unclear. AIM The aim of the present study was to evaluate the frequency of granulomas and their association with clinical characteristics using the database of the Hungarian Pediatric Inflammatory Bowel Disease Registry. METHOD Three hundred and sixty-eight children with Crohn's disease were registered between January 1st, 2007 and December 31st, 2010. RESULTS The frequency of granulomas was 31.4% (111/353) at diagnosis. Isolated granuloma in the upper gastrointestinal tract was detected in 2.5% of patients, while those in the terminal ileum was found in 5% of patients. There was no difference in location, behavior and disease activity indexes between patients with and without granulomas. Need for immunomodulators and biological therapy was similar in the two groups in the first year of diagnosis. CONCLUSIONS The frequency of granulomas in this cohort was comparable to the frequency reported in other studies. Interestingly, granulomas in the terminal ileum or upper gastrointestinal tract contributed to the diagnosis of Crohn's disease in one of 13 children. These data indicate that multiple biopsies from multiple sites are essential for the diagnosis of pediatric Crohn's disease.
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Affiliation(s)
- Katalin Eszter Müller
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest Bókay u. 53. 1083
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Sura R, Colombel JF, Van Kruiningen HJ. Lymphatics, tertiary lymphoid organs and the granulomas of Crohn's disease: an immunohistochemical study. Aliment Pharmacol Ther 2011; 33:930-9. [PMID: 21366631 DOI: 10.1111/j.1365-2036.2011.04605.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Case studies in the past repeatedly suggested that the fundamental alteration in Crohn's disease occurs in the regional lymphatics of the intestine. AIM To evaluate the lymphatic inflammation in Crohn's disease, and to characterise lymphoid aggregates and granulomas in and surrounding lymphatics and blood vasculature. METHODS Forty-eight tissue blocks from 24 Crohn's disease patients and 23 tissue blocks from 23 control patients were selected. Tissue sections were immunostained with a lymphatic endothelial cell marker (D2-40), a marker for blood vasculature (FVIII), and markers for T cells (CD3), B cells (CD20) and macrophages (CD68). RESULTS Lymphangiectasia and lymphocytic perilymphangitis were demonstrated in all 24 patients, lymphocyte-obstructed lymphatics in seven patients, granuloma-obstructed lymphatics in nine patients and inflammatory lymphoid follicles in all 24 patients. Free-standing granulomas occurred in 19 patients, and in three further patients granulomas were in or attached to blood vascular units. CONCLUSIONS This study, employing immunohistochemistry, revealed, better than standard microscopy, the association of inflammation, granulomas and tertiary lymphoid follicles or organs with the lymphatic vasculature in Crohn's disease. Disease in some patients was characterised by perilymphangitis and lymphoid follicular inflammation and in others by granulomas, some of which totally obstructed lymphatics. These findings have aetiological, therapeutic and prognostic implications.
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Affiliation(s)
- R Sura
- Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT, USA.
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New pathophysiological insights and modern treatment of IBD. J Gastroenterol 2010; 45:571-83. [PMID: 20213337 DOI: 10.1007/s00535-010-0219-3] [Citation(s) in RCA: 142] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2010] [Accepted: 02/03/2010] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD), which comprises two main types, namely, Crohn's disease and ulcerative colitis, affects approximately 3.6 million people in the USA and Europe, and an alarming rise in low-incidence areas, such as Asia, is currently being observed. In the last decade, spontaneous mutations in a diversity of genes have been identified, and these have helped to elucidate pathways that can lead to IBD. Animal studies have also increased our knowledge of the pathological dialogue between the intestinal microbiota and components of the innate and adaptive immune systems misdirecting the immune system to attack the colon. Present-day medical therapy of IBD consists of salicylates, corticosteroids, immunosuppressants and immunomodulators. However, their use may result in severe side effects and complications, such as an increased rate of malignancies or infectious diseases. In clinical practice, there is still a high frequency of incomplete or absent response to medical therapy, indicating a compelling need for new therapeutic strategies. This review summarizes current epidemiology, pathogenesis and diagnostic strategies in IBD. It also provides insight in today's differentiated clinical therapy and describes mechanisms of promising future medicinal approaches.
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Simpson P, Papadakis KA. Endoscopic evaluation of patients with inflammatory bowel disease. Inflamm Bowel Dis 2008; 14:1287-97. [PMID: 18300282 DOI: 10.1002/ibd.20398] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Endoscopy plays a critical role in the diagnosis and management of inflammatory bowel disease (IBD). This article reviews the utility of endoscopy in the diagnosis of ulcerative colitis (UC) and Crohn's disease (CD), recommendations for cancer surveillance, and the use of newer techniques for the enhanced detection of dysplasia in chronic UC. Finally, the use of endoscopy for the management of certain complications of IBD is also discussed.
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Affiliation(s)
- Peter Simpson
- Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology 2007; 133:1670-89. [PMID: 17983810 DOI: 10.1053/j.gastro.2007.09.001] [Citation(s) in RCA: 277] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2007] [Accepted: 08/30/2007] [Indexed: 02/06/2023]
Abstract
The diagnosis of inflammatory bowel disease (IBD) with its 2 main subforms, Crohn's disease and ulcerative colitis, is based on clinical, endoscopic, radiologic, and histologic criteria. This paradigm remains unchanged despite the advent of new molecular technologies for the examination of serum proteins and genetic sequences, respectively. The main innovations in diagnostic technologies include the development of more sophisticated endoscopic and noninvasive imaging techniques with the aim of improving the identification of complications, in particular malignant diseases associated with IBD. The future will see further progress in the identification of genetic susceptibility factors and of protein biomarkers and their use to describe the molecular epidemiology of IBD. It can be expected that future diagnostic algorithms will include molecular parameters to detect early disease or guide therapies by predicting the individual course of disease.
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Affiliation(s)
- Susanna Nikolaus
- Department of General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
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Rubio CA, Orrego A, Nesi G, Finkel Y. Frequency of epithelioid granulomas in colonoscopic biopsy specimens from paediatric and adult patients with Crohn's colitis. J Clin Pathol 2007; 60:1268-72. [PMID: 17293387 PMCID: PMC2095463 DOI: 10.1136/jcp.2006.045336] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2007] [Indexed: 12/28/2022]
Abstract
AIMS To test the assumption that epithelioid granulomas found in colonoscopic biopsy specimens in patients with Crohn's colitis are markers of a different clinical behaviour. METHODS Sections from colonoscopic biopsy specimens from 352 consecutive patients (119 children and 233 adults) were investigated. RESULTS A total of 1117 colonoscopies were performed: 293 in children (mean 2.46 per patient) and 824 in adults (mean 3.53 per patient) (p<0.05). Granulomas at initial colonoscopy were recorded in 67.2% (43/64) of children and 65.9% (27/41) of adults (p>0.6), and at subsequent colonoscopies in 53.8% (64/119) of children and 17.6% (41/233) of adults (p<0.05). Surgical intervention was required in 6.3% (4/64) of the children having previous granuloma, but also in 14.5% (8/55) of those without previous granuloma, the rate for operated adults being 26.8% (11/41) and 24.5% (47/192), respectively (p>0.6). CONCLUSIONS Granulomas in entry and/or in subsequent colonoscopic biopsy specimens in patients with Crohn's colitis did not predict the need for subsequent surgical intervention. The fact that the frequency of granulomas was significantly higher in children than in adults with Crohn's colitis (despite a higher mean number of colonoscopic biopsies in adults), and that granulomas were present in colonoscopic biopsy specimens but not in the subsequent surgical specimens from 50% of the paediatric and 36% of the adult patients strengthen the conviction that granulomas in Crohn's colitis might evolve or regress at different time intervals during the course of the disease. This behaviour would reflect a particular immunological reaction, an epiphenomenon from immature tissues-as in children-when challenged by the so far elusive aetiological agent responsible for Crohn's disease.
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Affiliation(s)
- C A Rubio
- Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
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Abstract
AIM: Granuloma is considered the hallmark of microscopic diagnosis in Crohn’s disease (CD), but granulomas can be detected in only 21-60% of CD patients. The aim of this study was to evaluate the frequency of granulomas by multiple endoscopic biopsies in patients with CD and to examine whether group of patients with or without granuloma exhibit a different clinical course.
METHODS: Fifty-six patients with newly diagnosed CD were included in the study. Jejunoscopy, enteroclysis and ileo-colonoscopy were performed in all patients. At least two biopsy specimens from each examined gastrointestinal segment were examined microscopically searching granuloma. The clinical course was followed in all patients, and extraintestinal manifestations as well as details of any immunosuppressive therapy and surgical intervention were noted.
RESULTS: Granuloma was found in 44.6% of the cases (25 patients). Patients with granuloma had higher activity parameters at the time of the biopsies. Extraintestinal manifestations were observed and surgical interventions were performed more often in the granuloma group. The need of immunosuppressive therapy was significantly more frequent in the patients with granuloma. Granuloma formation is more often seen in younger patients, and mainly in the severe, active penetrating disease.
CONCLUSION: The significantly higher frequency of surgical interventions and immunosuppressive therapy suggests that granuloma formation is associated with a more severe disease course during the first years of CD.
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Affiliation(s)
- Tamas Molnár
- First Department of Medicine, Faculty of Medicine, University of Szeged, H-6720 Szeged, Korányi fasor 8., Hungary.
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Castellaneta SP, Afzal NA, Greenberg M, Deere H, Davies S, Murch SH, Walker-Smith JA, Thomson M, Srivistrava A. Diagnostic role of upper gastrointestinal endoscopy in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2004; 39:257-61. [PMID: 15319625 DOI: 10.1097/00005176-200409000-00006] [Citation(s) in RCA: 110] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Discrimination between ulcerative colitis (UC) and Crohn disease (CD) may be difficult on ileo-colonoscopy alone because of a lack of definitive lesions. Retrospective studies show upper gastrointestinal endoscopy may be helpful in confirming diagnosis in such cases. AIMS To prospectively determine importance of upper gastrointestinal endoscopy in diagnosis of inflammatory bowel disease (IBD) and assess factors predictive of upper gastrointestinal involvement in IBD. METHODS All pediatric patients were enrolled prospectively and consecutively over a 2-year period and investigated with an ileo-colonoscopy and barium meal follow-through. Children with procto-sigmoiditis, later confirmed histologically to be typical of UC, were excluded from the study. The remainder underwent upper gastrointestinal endoscopy. The protocol and methodology were determined a priori. RESULTS 65 children suspected of IBD underwent colonoscopy. Of the total, 11 had recto-sigmoiditis with typical macroscopic appearances of UC; once this was confirmed on histology these patients were excluded from the study. Of the 54 children (males, 31; median age, 11.1 years) remaining, 23 were initially diagnosed with CD on ileo-colonoscopy and 18 (33%) were diagnosed with UC. The diagnosis remained ambiguous in 13 (six colonic, four ileo-colonic, three normal colon) on clinical, radiologic and histologic grounds. Upper GI endoscopy helped to confirm CD in a further 11 (20.4%). Two patients were diagnosed with indeterminate colitis. Upper gastrointestinal inflammation was seen in 29 of 54 (22 CD; 7 UC ). Epigastric and abdominal pain, nausea and vomiting, weight loss and pan-ileocolitis were predictive of upper gastrointestinal involvement (P < 0.05). However, 9 children with upper gastrointestinal involvement were asymptomatic at presentation (31%). Overall upper gastrointestinal tract inflammation was most common in the stomach (67%), followed by the esophagus (54%) and duodenum (22%). CONCLUSIONS Upper gastrointestinal tract endoscopy should be part of the first-line investigation in all new cases suspected of IBD. Absence of specific upper gastrointestinal symptoms do not preclude presence of upper gastrointestinal inflammation.
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Affiliation(s)
- S P Castellaneta
- University Department of Paediatric Gastroenterology, Department of Histopathology, Royal Free Hospital, London, UK
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Abstract
Crohn's disease (CD) is diagnosed from information obtained clinically, pathologically, and radiologically. One important pathologic finding is a granuloma, which is helpful when a positive diagnosis of CD will affect treatment. Whether the presence of a granuloma has any clinical implication is not clear. We conducted a retrospective study to determine whether a granuloma found on a biopsy sample is associated with disease severity, fistulizing or perianal disease, frequent relapses, and extraintestinal manifestations. Eighty-two patients were identified who had a biopsy or bowel resection for CD between 1990 and 1994 at a tertiary referral center; 21 (25.6%) had a granuloma. This group was compared with a group of 61 patients without a granuloma. Forty-five percent were male (n = 37), mean age at diagnosis was 42.6 years (median, 39.5 years), mean disease duration at presentation was 8.8 years (median, 4.8 years), and mean follow-up duration was 2 years (range, 1 day to 10.2 years). No significant differences were demonstrated between the two groups by the Fisher exact test with regard to fistulizing or perianal disease, oral aphthous ulcers, disease severity, axial or peripheral arthralgia, episcleritis, anterior uveitis, erythema nodosum, or pyoderma gangrenosum.
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Affiliation(s)
- Nizar N Ramzan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona 85259, USA
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Tanaka M, Masuda T, Yao T, Saito H, Kusumi T, Nagura H, Kudo H. Observer variation of diagnoses based on simple biopsy criteria differentiating among Crohn's disease, ulcerative colitis, and other forms of colitis. J Gastroenterol Hepatol 2001; 16:1368-72. [PMID: 11851834 DOI: 10.1046/j.1440-1746.2001.02638.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Simple mucosal biopsy criteria proposed by authors reliably differentiate idiopathic inflammatory bowel disease (IBD) from other forms of colitis (non-IBD) and Crohn's disease involving the colon (CD) from ulcerative colitis (UC). The aim of this study is to investigate the reproducibility of these criteria. METHODS Three established pathologists and two medical students blindly examined 20 sets of multiple biopsy slides from patients with CD, 20 from those with UC, and 20 from those with non-IBD. The students had been given instructions on histological definitions using another 15 sets previously. Each observer evaluated 10 histological items required in the criteria and determined categorical diagnoses such as definite IBD and probable UC. Interobserver agreement for the individual histological items was measured by using kappa analysis and Pearson's correlation, while it was measured for categorical diagnoses with the use of Spearman's rank correlation. RESULTS All of the individual histological items expressed excellent or fair-to-good agreement among the five observers, although two items associated with the criteria for CD and UC had poor agreements among the students. With regard to categorical diagnoses based on the criteria for IBD and non-IBD, and those for CD and UC, coefficients for Spearman's rank correlation exceeded 0.92 and 0.86 among the pathologists, and 0.76 and 0.74 among the students, respectively; all of the coefficients were statistically significant (P < 0.05). CONCLUSIONS The simple criteria were sufficiently reproducible and would help most pathologists to make an automated and objective diagnosis.
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Affiliation(s)
- M Tanaka
- Department of Pathology, Hirosaki University School of Medicine, Hirosaki, Japan
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Tanaka M, Saito H, Fukuda S, Sasaki Y, Munakata A, Kudo H. Simple mucosal biopsy criteria differentiating among Crohn disease, ulcerative colitis, and other forms of colitis: measurement of validity. Scand J Gastroenterol 2000; 35:281-6. [PMID: 10766322 DOI: 10.1080/003655200750024155] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recently established mucosal biopsy criteria reliably differentiate idiopathic inflammatory bowel disease (IBD) from other forms of colitis (non-IBD), and Crohn disease involving the colon (CD) from ulcerative colitis (UC) but were inconvenient in practical use because of the need for relatively complicated calculations. Our objectives were to establish simple criteria in which calculation could be done in the user's head and to measure their validity. METHODS On the basis of the above original criteria, we constructed two sets of criteria in which coefficients and constants were simplified to integral numbers. The first set of criteria consisted of the diagnostic categories 'definite IBD', 'probable IBD', 'unknown', 'probable non-IBD', and 'definite non-IBD'. Similarly, the second set had five categories from 'definite CD' to 'definite UC'. The validity of the criteria was evaluated in 117 patients with CD, 125 with UC, and 484 with non-IBD. RESULTS In categories of probable IBD and probable non-IBD both sensitivity and specificity exceeded 96.3%. Probable CD and probable UC showed sensitivities of 95.7% and 92.0% and specificities of 93.6% and 98.3%. CONCLUSIONS Despite simplified coefficients and constants, the validity appeared to be high enough to apply the present criteria to routine work.
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Affiliation(s)
- M Tanaka
- Dept. of Pathology, Hirosaki University School of Medicine, Japan
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