Long-standing Ulcerative Colitis Research Articles

Hypermethylation of Corticotropin Releasing Hormone Receptor-2 Gene in Ulcerative Colitis Associated Colorectal Cancer.

The difficulty of early diagnosis of colitis associated colorectal cancer (CACRC) due to colonic mucosal changes in long-standing ulcerative colitis (UC) patients is often experienced in daily clinical practice. Noninvasive objective monitoring for cancer development is advantageous for optimizing treatment strategies in UC patients. We aimed to examine the epigenetic alterations occurring in CACRC, focusing on DNA hypermethylation of CpG islands. The level of DNA methylation in CpG cites was compared between CACRC and the counterpart non-tumorous mucosa using Infinium HumanMethylation 450K BeadChip. Our subjects included 3 males and 3 females (median age, 49.5 years). The 450K CpG site DNA methylation microarray revealed that the difference in β value (level of hypermethylation) was the highest for corcicotropin releasing hormone receptor 2 (CRHR2) between CACRC and counterpart non-tumorous mucosa. Detection of hypermethylation of CRHR2 may be promising for cancer screening in UC patients.

Malignant Perforation of Sigmoid Colon in Long-standing Ulcerative Colitis

Malignant Perforation of Sigmoid Colon in Long-standing Ulcerative Colitis

Diagnostic Accuracy of Endoscopic Trimodal Imaging and Chromoendoscopy for Lesion Characterization in Ulcerative Colitis.

Background During surveillance colonoscopy of patients with long-standing ulcerative colitis [UC], a variety of dysplastic and non-dysplastic lesions are detected. The aim of this study was to address the diagnostic accuracy of endoscopic characterization of endoscopic trimodal imaging [ETMI] and chromoendoscopy [CE]. ETMI includes the combination of autofluorescence imaging [AFI], narrow band imaging [NBI] and white light endoscopy [WLE]. Methods This is a pre-specified additional analysis of a multi-centre, randomized controlled trial that compared AFI with CE for dysplasia detection in 210 patients with long-standing UC [FIND-UC trial]. In the AFI arm, endoscopists used the ETMI system to record AFI colour, Kudo pit pattern using NBI and WLE for lesion characterization. For AFI, purple colour and ambiguous colour combined with pit pattern type III-V on NBI was considered dysplastic. Kudo pit pattern was described in the CE arm. For pit pattern description using NBI and CE, type III-V was considered dysplastic. Histology was the reference standard. Results In total, 52 dysplastic and 255 non-dysplastic lesions were detected. Overall sensitivity for real-time prediction of dysplasia was 76.9% (95% confidence interval [CI] 46.2-95.0) for ETMI, and 81.6% [95% CI 65.7-92.3] for CE. Overall negative predictive value [NPV] for ETMI was 96.9% [95% CI 92.0-98.8] and 94.7% [90.2-97.2] for CE. Conclusions Sensitivity for endoscopic differentiation of dysplastic lesions detected during surveillance of patients with long-standing UC seems limited using ETMI and CE. Future research is warranted as the high NPV indicates that these techniques are valuable for the exclusion of dysplastic lesions [NTR4062].

Virtual Chromoendoscopy With FICE for the Classification of Polypoid and Nonpolypoid Raised Lesions in Ulcerative Colitis.

The aim of this study was to analyze the performance of Fuji Intelligent Color Enhancement (FICE) using the classification of Kudo in the differentiation of neoplastic and non-neoplastic raised lesions in ulcerative colitis (UC). The Kudo classification of mucosal pit patterns is an aid for the differential diagnosis of colorectal polyps in the general population, but no systematic studies are available for all forms of raised lesions in UC. All raised, polypoid and nonpolypoid, lesions found during consecutive surveillance colonoscopies with FICE for long-standing UC were included. In the primary prospective analysis, the Kudo classification was used to predict the histology by FICE. In a post hoc analysis, further endoscopic markers were also explored. Two hundred and five lesions (mean size, 8 mm; range, 2 to 30 mm) from 59 patients (mean age, 56 y; range, 21 to 79 y) were analyzed. Twenty-three neoplastic (11%), 18 hyperplastic (9%), and 164 inflammatory (80%) lesions were found. Thirty-one lesions (15%), none of which were neoplastic, were unclassifiable according to Kudo. After logistic regression, a strong negative association resulted between endoscopic activity and neoplasia, whereas the presence of a fibrin cap was significantly associated with endoscopic activity. Using FICE, the sensitivity, specificity, and positive and negative likelihood ratios of the Kudo classification were 91%, 76%, 3.8, and 0.12, respectively. The corresponding values by adding the fibrin cap as a marker of inflammation were 91%, 93%, 13, and 0.10, respectively. FICE can help to predict the histology of raised lesions in UC. A new classification of pit patterns, based on inflammatory markers, should be developed in the setting of UC to improve the diagnostic performance.

Adenocarcinoma is not always the diagnosis – colon neoplasia in patient with long-standing ulcerative colitis under long-term prednisone maintenance therapy

Adenocarcinoma is not always the diagnosis – colon neoplasia in patient with long-standing ulcerative colitis under long-term prednisone maintenance therapy

Screening and surveillance methods for dysplasia in inflammatory bowel disease patients: Where do we stand?

Patients with long-standing ulcerative colitis (UC) and extensive Crohn’s colitis (CC) are at increased risk for dysplasia and colorectal cancer (CRC). Several studies have shown that UC extending proximal to the rectum, CC involving at least 1/3 of the colon, co-existence of primary sclerosing cholangitis, undetermined or unclassified colitis, family history of CRC and young age at diagnosis appear to be independent risk factors for inflammatory bowel disease (IBD) - related CRC. Therefore, screening and surveillance for CRC in IBD patients is highly recommended by international and national guidelines, whilst colonoscopy remains the unequivocal tool in order to detect potentially resectable dysplastic lesions or CRC at an early stage. Although the importance of screening and surveillance is widely proven, there is a controversy regarding the time of the first colonoscopy and the criteria of who should undergo surveillance. In addition, there are different recommendations among scientific societies concerning which endoscopic method is more efficient to detect dysplasia early, as well as the terminology for reporting visible lesions and the management of those lesions. This article concisely presents the main endoscopic methods and techniques performed for detecting dysplasia and CRC surveillance in patients with IBD focusing on their evidence-based accuracy and efficiency, as well as their cost-effectiveness. Finally, newer methods are mentioned, highlighting their applicability in daily endoscopic practice.

Diagnostic Accuracy of Endoscopic Trimodal Imaging and Chromoendoscopy for Lesion Characterization in Ulcerative Colitis.

During surveillance colonoscopy of patients with long-standing ulcerative colitis [UC], a variety of dysplastic and non-dysplastic lesions are detected. The aim of this study was to address the diagnostic accuracy of endoscopic characterization of endoscopic trimodal imaging [ETMI] and chromoendoscopy [CE]. ETMI includes the combination of autofluorescence imaging [AFI], narrow band imaging [NBI] and white light endoscopy [WLE]. This is a pre-specified additional analysis of a multi-centre, randomized controlled trial that compared AFI with CE for dysplasia detection in 210 patients with long-standing UC [FIND-UC trial]. In the AFI arm, endoscopists used the ETMI system to record AFI colour, Kudo pit pattern using NBI and WLE for lesion characterization. For AFI, purple colour and ambiguous colour combined with pit pattern type III-V on NBI was considered dysplastic. Kudo pit pattern was described in the CE arm. For pit pattern description using NBI and CE, type III-V was considered dysplastic. Histology was the reference standard. In total, 52 dysplastic and 255 non-dysplastic lesions were detected. Overall sensitivity for real-time prediction of dysplasia was 76.9% (95% confidence interval [CI] 46.2-95.0) for ETMI, and 81.6% [95% CI 65.7-92.3] for CE. Overall negative predictive value [NPV] for ETMI was 96.9% [95% CI 92.0-98.8] and 94.7% [90.2-97.2] for CE. Sensitivity for endoscopic differentiation of dysplastic lesions detected during surveillance of patients with long-standing UC seems limited using ETMI and CE. Future research is warranted as the high NPV indicates that these techniques are valuable for the exclusion of dysplastic lesions [NTR4062].

Dietary intake of patients with inflammatory bowel disease: A comparison with individuals from a general population and associations with relapse

Individuals with inflammatory bowel disease (IBD) often hold strong beliefs on how diet impacts their disease. This study aimed to compare dietary intakes between IBD patients and individuals from the general population and to assess associations of dietary factors with relapse in patients with IBD. Patients with longstanding Crohn's disease and ulcerative colitis (n=165) filled out food frequency questionnaires, as did individuals participating in a Dutch population-based study (controls) (n=1469). Multivariable regression analyses were used to assess differences in habitual dietary intake between IBD patients and controls, and to estimate associations of dietary factors in patients in remission with the development of disease relapse at follow-up. IBD patients had higher intakes of animal protein (3.50g/d, 95% confidence interval (CI) 1.67-5.34) and carbohydrate (10.1g/d, 95% CI 5.23-14.9) than controls and lower intakes of (unsaturated) fat (-3.53g/d, 95% CI-5.57- -1.50), dietary fiber (-2.19g/d, 95% CI-3.05- -1.32) and alcohol (-0.84g/d, 95% CI-1.46- -0.22). This was explained by a higher consumption of carbonated beverages, meat and poultry and lower consumption of fruit, vegetables and dairy products (except cheese) by IBD patients compared with controls. Several dietary factors, particularly (saturated) fat and fiber, appeared to be associated with risk of relapse. IBD patients had higher dietary intakes of (animal) protein and carbohydrate and lower intakes of (unsaturated) fat, dietary fiber and alcohol compared with a general Dutch population. The results further underscore that dietary factors may have a role in disease course.

Updates in colorectal cancer screening in inflammatory bowel disease.

This review article will discuss the risk of colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD), as well as the current recommendations for CRC screening and surveillance in patients with ulcerative colitis or Crohn's colitis involving one-third of the colon. Given that most cases of CRC are thought to arise from dysplasia, previous guidelines have recommended endoscopic surveillance with random biopsies obtained from all segments of the colon. However, recent evidence has suggested that the majority of dysplastic lesions in patients with IBD are visible, and data have been supportive of chromoendoscopy with targeted biopsies of visible lesions rather than traditional random biopsies. There have also been efforts to endoscopically remove resectable visible dysplasia and only recommend surgery when this is not possible. Patients with long-standing ulcerative colitis or Crohn's colitis involving at least one-third of the colon are at increased risk for developing CRC and should undergo surveillance colonoscopy using new approaches and techniques.

Comparison of Endoscopic Dysplasia Detection Techniques in Patients With Ulcerative Colitis: A Systematic Review and Network Meta-analysis.

We assessed the comparative efficacy of different dysplasia detection techniques in patients with ulcerative colitis (UC) through a network meta-analysis and rated the quality of evidence using GRADE approach. Through a systematic literature review of multiple databases through June 30, 2017, we identified parallel-group randomized controlled trials (RCTs) in adults with long-standing UC undergoing surveillance colonoscopy with standard definition-white light endoscopy (SD-WLE), high-definition WLE (HD-WLE), narrow band imaging (NBI), or dye-based chromoendoscopy. The primary outcome was the total number of dysplastic lesions. Pairwise and network meta-analysis was performed; ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities. Based on 8 parallel-group RCTs (924 patients), low-quality evidence supports chromoendoscopy over SD-WLE (odds ratio [OR], 2.37; 95% credible interval [CrI], 0.81-6.94) for any dysplasia detection, whereas very low-quality evidence supports using HD-WLE or NBI over SD-WLE (HD-WLE [vs SD-WLE]: OR, 1.21; 95% CrI, 0.30-4.85; NBI: OR, 1.68; 95% CrI, 0.54-5.22). Very low-quality evidence from indirect comparative analysis supports the use of chromoendoscopy over HD-WLE (OR, 1.96; 95% CrI, 0.72-5.34) or NBI (OR, 1.41; 95% CrI, 0.70-2.84) for any dysplasia detection. The number of patients with advanced neoplasia was very small, precluding meaningful analysis. Although we did not find any single technique to be superior, chromoendoscopy is probably more effective than SD-WLE for detecting any dysplasia, and there is low confidence in estimates supporting its use over HD-WLE or NBI. There is very low-quality evidence to inform the comparative efficacy of these interventions in detecting advanced neoplasia or preventing future colorectal cancer. Pragmatic, parallel-group RCTs with longitudinal follow-up are warranted to inform optimal dysplasia surveillance techniques. 10.1093/ibd/izy188_video1izy188.video15789702674001.

Issue Highlights

Issue Highlights

1000 - Chronic Fatigue is not Associated with Ongoing Inflammation in Patients with Longstanding Ulcerative Colitis

1000 - Chronic Fatigue is not Associated with Ongoing Inflammation in Patients with Longstanding Ulcerative Colitis

Early detection of ulcerative colitis-associated colorectal cancer.

Colitis-associated colorectal cancer (CACC) is one of the most serious complications of inflammatory bowel disease (IBD), particularly in ulcerative colitis (UC); it accounts for approximately 15% of all-causes mortality among IBD patients. Because CACC shows a worse prognosis and higher mortality than sporadic colorectal cancer, early detection is critical. Colonoscopy is primarily recommended for surveillance and several advanced endoscopic imaging techniques are emerging. In addition, recent studies have reported on attempts to develop clinically relevant biomarkers for surveillance using various biosamples, which may become high-performance screening tools in the future, so the best approach and technique for cancer surveillance in long-standing UC patients remain under debate. This review gives a comprehensive description and summary about what progress has been made in terms of early CACC detection.

Increased mucosal expression of miR-215 precedes the development of neoplasia in patients with long-standing ulcerative colitis.

Identification of biological markers predicting the onset of neoplasia in patients with long-standing ulcerative colitis (UC) could allow for risk stratification in this population. In this study, we retrospectively identified subjects with chronic UC who developed colon neoplasia (n = 16) matched to UC patients who never developed neoplasia. RNA was extracted from archived colonic biopsies obtained at an interval of 1–2 years prior and 3–5 years prior to the onset of neoplasia. miRNA expression was assessed using Nanostring arrays in 12 subjects, and significantly up-regulated miRNAs were evaluated by real time pcr in the entire cohort of patients. Expression of miR-215 was also assessed in UC-associated colon cancers and compared to p53 expression. By array analysis, there were 17 significantly down-regulated and 7 significantly up-regulated miRNAs in subjects who later developed neoplasia. miR-215 was significantly up-regulated both 1–2 years prior to the onset of neoplasia (3.5-fold, p < 0.001) and 3–5 years prior to the onset of neoplasia (5.4-fold, p = 0.007). miR-215 expression was also increased in UC-associated colon cancers (5.3-fold, p = 0.03) and adjacent non-dysplastic UC tissue (6.2-fold, p = 0.02). p53 was expressed in 20% of patients prior to the onset of neoplasia and in 67% of UC-associated colon cancers, although was not correlated with miR-215 expression. Our data demonstrates that expression of miR-215 can discriminate patients who progressed to neoplasia from non-progressors as early as 5 years prior to the diagnosis of neoplasia, supporting that this and perhaps other miRNAs could serve as predictive biomarkers to risk stratify patients with chronic UC.

Chromoendoscopy for Dysplasia Surveillance in Inflammatory Bowel Disease.

Long-standing ulcerative colitis (UC) and extensive Crohn's colitis confer increased risk for development of colorectal cancer. Screening and surveillance colonoscopy programs aim to identify, resect, or detect dysplasia or colorectal cancer. Dysplastic lesions can be removed by endoscopic resection and patients with unresectable lesions can be referred for colectomy at an earlier stage, with the goal of reducing overall morbidity and mortality from colorectal cancer. Surveillance colonoscopy for patients with inflammatory bowel disease (IBD) is endorsed by multiple specialty societies. High-definition endoscopy systems provide improved image resolution, and application of dilute indigo carmine or methylene blue for chromoendoscopy can provide increased contrast. International specialty society guidelines differ in their recommendations regarding use of chromoendoscopy for dysplasia surveillance, with some guidelines advocating a risk-stratified surveillance strategy. In this review, we discuss chromoendoscopy technique, training, implementation, yield as compared with standard-definition and high-definition white light colonoscopy, and positioning of this technique in clinical practice.

Chromoendoscopy versus autofluorescence imaging for neoplasia detection in patients with longstanding ulcerative colitis (FIND-UC): an international, multicentre, randomised controlled trial

Patients with longstanding ulcerative colitis undergo regular dysplasia surveillance because they have an increased colorectal cancer risk. Autofluorescence imaging and chromoendoscopy improve dysplasia detection. The aim of this study was to determine whether autofluorescence imaging should be further studied as an alternative method for dysplasia surveillance in patients with longstanding ulcerative colitis. This prospective, international, randomised controlled trial included patients from an ulcerative colitis-dysplasia surveillance cohort from five centres in the Netherlands and the UK. Eligible patients were aged 18 years or older who were undergoing dysplasia surveillance after being diagnosed with extensive colitis (Montreal E3) at least 8 years before study start or with left-sided colitis (Montreal E2) at least 15 years before study start. Randomisation (1:1) was minimised for a previous personal history of histologically proven dysplasia and concomitant primary sclerosing cholangitis. The coprimary outcomes were the proportion of patients in whom at least one dysplastic lesion was detected and the mean number of dysplastic lesions per patient. The relative dysplasia detection rate, calculated as the ratio of the detection rates by autofluorescence imaging and chromoendoscopy, needed to be more than 0·67 (using an 80% CI) for both primary outcomes to support a subsequent large non-inferiority trial. Outcomes were analysed on a per-protocol basis. The trial is registered at the Netherlands Trial Register, number NTR4062. Between Aug 1, 2013, and March 10, 2017, 210 patients undergoing colonoscopy surveillance for longstanding ulcerative colitis were randomised for inspection with either autofluorescence imaging (n=105) or chromoendoscopy (n=105). Dysplasia was detected in 13 (12%) patients by autofluorescence imaging and in 20 patients (19%) by chromoendoscopy. The relative dysplasia detection rate of autofluorescence imaging versus chromoendoscopy for the proportion of patients with ulcerative colitis with at least one dysplastic lesion was 0·65 (80% CI 0·43-0·99). The mean number of detected dysplastic lesions per patient was 0·13 (SD 0·37) for autofluorescence imaging and 0·37 (1·02) for chromoendoscopy (relative dysplasia detection rate 0·36, 80% CI 0·21-0·61). Adverse events were reported for two patients in the autofluorescence imaging group (one patient had intraprocedural mild bleeding, and one patient had abdominal pain) and for three patients in the chromoendoscopy group (two patients had intraprocedural mild bleeding, and one patient had perforation). Autofluorescence imaging did not meet criteria for proceeding to a large non-inferiority trial. Therefore, existing autofluorescence imaging technology should not be further investigated as an alternative dysplasia surveillance method. Olympus Europe and Olympus Keymed.

An Update on Surveillance in Ulcerative Colitis.

Patients with long-standing ulcerative colitis have an increased risk for the development of colorectal cancer (CRC). Colitis-related dysplasia appears to confer the greatest risk. Colonoscopic surveillance to detect dysplasia has been advocated by gastrointestinal societies. The aim of surveillance is the reduction of mortality and morbidity of CRC through detection and resection of dysplasia or detecting CRC at an earlier and potentially curable stage. Traditional surveillance has relied on mucosal assessment with targeted biopsy of visible lesions and random biopsy sampling on the premise that dysplasia was not visible at endoscopy. Advances in optical technology permitting increased detection of dysplasia and evidence that most dysplasia is visible has had practice-changing implications. Emerging evidence favours chromoendoscopy (CE) for dysplasia detection and is gaining wider acceptance through recent international (International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease (SCENIC)) recommendations and endorsed by many gastrointestinal societies. Adoption of CE as the gold standard of surveillance has been met with by scepticism, from conflicting data, operational barriers and the need to understand the true impact of increasingly higher dysplasia detection on overall CRC mortality. Valid debate notwithstanding, implementation of a risk stratification protocol that includes CE is an effective approach allowing earlier detection of dysplasia and colorectal neoplasia, determination of surveillance intervals with appropriate allocation of resources and limiting morbidity from CRC and colonoscopy itself. Further prospective data should define the true and long-term impact of dysplasia detection with modern techniques.

Screening by Chromo Endoscopy for Colorectal Cancer and Dysplasia in Ulcerative Colitis: An Algerian Prospective Cohort

Patients with longstanding extensive ulcerative colitis have an increased risk of colorectal cancer. Aims : To determine the incidence of dysplasia and colorectal cancer, in patients with longstanding ulcerative colitis. To evaluate prospectively, the proportion of dysplastic lesions detected by chromoendoscopy from targeted biopsies of macroscopically visible abnormalities, as opposed to random biopsies of colonic mucosa. Patients and methods : In this prospective study, consecutive patients with clinically inactive, longstanding UC (more than 8 years) were recruited from 4 centers; colonoscopy with chromoendoscopy using 0.1% methylene blue was performed for each patient. Four mucosal biopsy specimens were taken every 10 cm between the cecum and the rectum, with additional biopsies or removal of any mucosal abnormality. All the endoscopies were performed by a single specialist in gastroenterology. All the biopsies have been reviewed by a pathologist experienced in gastroenterology. Results: Two hundred and twenty four chromoendoscopies were performed in 106 patients. We diagnosed 49 neoplastic lesions in 31 patients; there were six adenocarcinomas, eight high grade dysplasia, 24 low grade dysplasia, and 11 lesions indefinite for dysplasia. We took 8035 random biopsies and found seven dysplastic lesions in six patients: one high grade dysplasia, two low grade dysplasia and four lesions indefinite for dysplasia. Random biopsies alone diagnosed dysplasia in two patients (1.8%), and had clinical impact only in one patient (0.9%). Conclusion : In our cohort, we experienced a high diagnostic yield of chromoendoscopy in the detection of neoplasia in high risk IBD patients. Random biopsies don’t have clinical impact and should be abandoned.

Peroxiredoxin 1 expression in active ulcerative colitis mucosa identified by proteome analysis and involvement of thioredoxin based on immunohistochemistry.

Ulcerative colitis (UC) is a chronic, relapsing, inflammatory bowel disease, and patients with long-standing UC are at high risk of developing colorectal cancer as a typical case of the organ-specific chronic inflammation-carcinoma sequence. Interactions between epithelial and stromal cells and alterations in a variety of stromal microenvironments have been demonstrated to have important roles in the carcinogenesis of UC-associated carcinoma. Therefore, the identification of proteins in the inflammatory microenvironment is important not only in the epithelium, however also in the stroma of UC inflammatory foci. To identify proteins associated with UC-associated carcinoma, the present study used proteomic analysis with two-dimensional electrophoresis and mass spectrometry. Differentially expressed proteins were assessed between active and inactive UC biopsy specimens. Results were verified by immunohistochemistry. Peroxiredoxin 1 (PRDX1) was among the proteins identified to have increased expression in active compared with inactive UC. Immunohistochemical analysis indicated that the expression of both PRDX1 and thioredoxin (TRX) increased with increasing inflammation grade in epithelial cells in UC mucosal crypts. PRDX1-positive stromal cells in the lower half of the lamina propria increased along with colitis severity. Furthermore, the expression of both PRDX1 and TRX proteins was increased in UC-associated neoplastic lesions compared with normal mucosa. A stepwise increase in PRDX1 expression was clear with increasing tumor progression in UC-associated tumorigenesis. Since PRDX1 and TRX overexpression was a unique characteristic of UC activity and UC-associated neoplastic lesions, PRDX1 and TRX expression may reflect oxidative stress along with the severity of colitis activity and UC-associated tumorigenesis in patients with UC.

Results of a 36-year surveillance program for ulcerative colitis-associated neoplasia in the Japanese population.

Surveillance colonoscopy has been carried out for patients with long-standing ulcerative colitis who have an increased risk for colorectal cancer. The aim of the present study was to determine the incidence of and the risk factors for neoplasia. We evaluated 289 ulcerative colitis patients who underwent surveillance colonoscopy between January1979 and December 2014. Cumulative incidence of neoplasia and its risk factors were investigated. Clinical stage and overall survival were compared between the surveillance and non-surveillance groups. Cumulative risk of dysplasia was 3.3%, 12.1%, 21.8%, and 29.1% at 10, 20, 30 and 40 years after the onset of ulcerative colitis, respectively. Cumulative risk of colorectal cancer was 0.7%, 3.2%, 5.2%, and 5.2% at 10, 20, 30 and 40 years from the onset of ulcerative colitis, respectively. Total colitis was a risk factor for neoplasia (P = 0.015; hazard ratio, 2.96). Our surveillance colonoscopy program revealed the incidence and risk factors of ulcerative colitis-associated neoplasias in the Japanese population. Total colitis is a risk factor for neoplasia.