Diagnostic Testing in IBD //
In 1997 we reported in Gastroenterology that patients with Crohn’s disease who are being evaluated for disease extent or recurrence could undergo a routine small bowel barium study and get at least as good results as when a small bowel barium study using a nasogastric tube (known as a small bowel enema or small bowel enteroclysis). However, small bowel barium studies can sometimes be insensitive at picking up Crohn’s disease. Hence, we were looking for other imaging techniques to help us evaluate patients with Crohn’s disease.
For a review on imaging tests in IBD see: Mackalski BA, Bernstein CN. New diagnostic imaging tools for inflammatory bowel disease. Gut 2006 May; 55(5):733-41.
Endoscopy remains the main method of diagnosing IBD, particularly if there is colonic involvement (all those with ulcerative colitis and the 50-60% of persons with Crohn’s disease who have colonic disease as well). An important aspect of endoscopy is taking biopsies. The review of the biopsies (snips of tissue) by the pathologist can help distinguish Crohn’s disease from ulcerative colitis some of the time. Biopsies are also important when looking for pre-cancer type changes (dysplasia).
In the past 15 years capsule endoscopy has become an important diagnostic tool that can assess an area of the small bowel, not seen with routine upper or lower endoscopy. Capsule endoscopy entails swallowing a video camera, small enough to be placed within a capsule that can be easily swallowed. The video camera can take 8-14 hours of images and transmits them to a receiver worn on the patient’s belt. Then the person goes about his/her day and then brings the receiver back to our offices where the information gets downloaded onto a computer and then Dr. Bernstein reads the study off the computer. While capsule endoscopy offers the advantage of visualizing the entire length of the small bowel, it is limited in its ability to accurately determine where in the small bowel an identified lesion is located, and there is no capacity to biopsy a lesion once identified. Another newer endoscopic tool is called single balloon or double balloon endoscopy. With the help of a balloon system the endoscope is able to be maneuvered through the curvy small bowel and get all the way to the end. These balloon endoscopy systems have the advantage that one can biopsy lesions that are seen through the scope. However, a disadvantage is that they are tedious and long procedures. Dr Singh perfoms single ballon endoscopy at our centre.
El Zimaity H, Shaffer S, Riddell RH, Pai R, Bernstein CN. Beyond Neutrophils for predicting relapse and remission in ulcerative colitis. Journal of Crohn’s and Colitis 2023; 17:767-776.
This study examines colonic histologic features in ulcerative colitis in endoscopic remission to determine which cell types and biopsy sites best predict a patient's likelihood of remaining in remission. This is a retrospective chart, endoscopy and histology review of 166 persons with ulcerative colitis in endoscopic remission followed in a single IBD practice over a median of 6 years (range, 2-11 years). Clinical remission was based on global physician assessment and colonoscopy reports, and clinical relapse on chart review. Histologic features of previous injury and also number and location of plasma cells and eosinophils were assessed. We evaluated all semi-quantitatively using a standard set of illustrations for the grade to maintain consistency. Multiple logistic regression analysis and survival analysis were used to identify features associated with relapse. Results: Clinical relapse occurred in 44 persons. Ulceration, especially in the left colon. was highly predictive of relapse. In the absence of acute inflammation of ulceration, the variables most predictive of relapse were increased plasma cells in the basal 20% of the lamina propria, and eosinophils in the left colon. The variable most predictive of persistent remission was the presence of intraepithelial eosinophils whether in the surface epithelium or within crypts, especially in the right colon. Lamina propria eosinophils (grade>2) throughout the colon predicted relapse. Conclusion: In the absence of neutrophils or ulceration, left-sided plasmacytosis in the basal 20% of the lamina propria and increased lamina propria eosinophils provide the best indicators of relapse in UC in clinical and endoscopic remission.
Shaffer SR, Nugent Z, Yu BN, Lix LM, Bernstein CN, Walkty A, Singh H. Effect of clinical vs. administrative data definitions on the epidemiology of C. difficile among hospitalized individuals with IBD: A population-based cohort study. BMC Gastroenterology 2022; Mar 26; 22(1):140.
Hospitalization admissions and discharge databases using the International Classification of Diseases (ICD) codes are often used to describe the epidemiology of Clostridioides difficile infections among those with IBD, even though discharge databases Clostridioides difficile infections definition can miss many cases of Clostridioides difficile infections. There are no data comparing the assessment of the epidemiology of Clostridioides difficile infections among those with IBD by discharge databases versus laboratory diagnosis. We used a population-based dataset to determine the effect of using discharge databases versus laboratory Clostridioides difficile infections diagnosis on Clostridioides difficile infections assessment among those with IBD. We linked the University of Manitoba IBD Epidemiology Database to the provincial Clostridioides difficile infections laboratory dataset for the years 2005-2014. Time trends of Clostridioides difficile infections were assessed using joinpoint analyses. We used stratified logistic regression analysis to assess factors associated with Clostridioides difficile infections among individuals with IBD. Results: Time trends of Clostridioides difficile infections among hospitalized individuals with IBD were similar when using discharge databases or the laboratory Clostridioides difficile infections diagnosis. Prior hospital admission and antibiotic exposure were associated with Clostridioides difficile infections using either of the Clostridioides difficile infections definitions, 5-ASA use was associated with Clostridioides difficile infections using discharge databases but not laboratory diagnosis, whereas corticosteroid exposure was associated with laboratory-based Clostridioides difficile infections diagnosis. Using laboratory results as gold standard, discharge databases had a sensitivity and specificity of 75.4% and 99.6% for Clostridioides difficile infections among those with IBD. Conclusions: Using ICD codes in the discharge databases for Clostridioides difficile infections provides similar epidemiological time trend patterns as identifying Clostridioides difficile infections in the laboratory dataset. Hence, ICD codes are reliable to determine Clostridioides difficile infections epidemiology among hospitalized individuals with IBD.
Shaffer SR, Nugent Z, Yu BN, Lix LM, Bernstein CN, Walkty A, Singh H. Time trends and predictors of laboratory-confirmed recurrent and severe Clostridioides difficile infections in Manitoba: a population-based study. CMAJ Open 2020 Nov 16;8(4):E737-E746.
Many previous studies of Clostridioides difficile infection epidemiology have used hospital discharge data codes, which can have limited accuracy. We used a data set of laboratory-confirmed cases of Clostridioides difficile in the province of Manitoba, Canada, to describe the epidemiology of Clostridioides difficile over a decade. We conducted a population-based historical cohort study using Manitoba Health's population-wide laboratory-based Clostridioides difficile data set linked to administrative health databases. All individuals living in Manitoba and experiencing a Clostridioides difficile episode between 2005 and 2015 were included (n = 8471) and followed up from Clostridioides difficile diagnosis. We assessed time trends of Clostridioides difficile, incidence and predictors of recurrence and severe outcomes, and health care encounters after Clostridioides difficile diagnosis. Clostridioides difficile episodes were stratified by community versus hospital site of acquiring Clostridioides difficile. Results: Between 2005 and 2009, overall Clostridioides difficile diagnoses decreased by an average of 12.6% per year (95% confidence interval [CI] -4.4 to -20.0), with no statistically significant change from 2010 to 2015. In stratified analysis, incident and recurrent Clostridioides difficile had a similar decrease in the initial study time period and then stabilized. The proportion of community-associated Clostridioides difficile cases increased by an average of 4.8% per year (95% CI 2.8 to 6.8) during the study period. Clostridioides difficile acquired in a health care facility had a higher recurrence rate and more severe outcomes. Recurrence of Clostridioides difficile increased the likelihood of admission to hospital. Conclusion: Between 2005 and 2015, the rates of overall laboratory-confirmed Clostridioides difficile, incident Clostridioides difficile, recurrent Clostridioides difficile and severe outcomes following Clostridioides difficile initially decreased before stabilizing, and an increasing proportion of Clostridioides difficile cases were community-associated. There is an increasing need to test for Clostridioides difficile among outpatients with diarrhea and to increase efforts to prevent recurrent Clostridioides difficile.
Wang H, Labus JS, Griffin F, Gupta A, Bhatt RR, Sauk JS , Turkiewicz J, Bernstein CN, Kornelsen J, Mayer EA. Functional Brain Rewiring and Altered Cortical Stability in Ulcerative Colitis. Molecular Psychiatry 2022; in press.
Despite recent advances, there is still a major need to better understand the interactions between brain function and chronic gut inflammation and its clinical implications. Alterations in executive function have previously been identified in several chronic inflammatory conditions, including inflammatory bowel diseases. Inflammation-associated brain alterations can be captured by connectome analysis. Here, we used the resting-state fMRI data from 222 participants comprising three groups (ulcerative colitis (UC), irritable bowel syndrome (IBS), and healthy controls (HC), N = 74 each) to investigate the alterations in functional brain wiring and cortical stability in UC compared to the two control groups and identify possible correlations of these alterations with clinical parameters. Globally, UC participants showed increased functional connectivity and decreased modularity compared to IBS and HC groups. Regionally, UC showed decreased eigenvector centrality in the executive control network (UC < IBS < HC) and increased eigenvector centrality in the visual network (UC > IBS > HC). UC also showed increased connectivity in dorsal attention, somatomotor network, and visual networks, and these enhanced subnetwork connectivities were able to distinguish UC participants from HCs and IBS with high accuracy. Dynamic functional connectome analysis revealed that UC showed enhanced cortical stability in the medial prefrontal cortex (mPFC), which correlated with severe depression and anxiety-related measures. None of the observed brain changes were correlated with disease duration. Together, these findings are consistent with compromised functioning of networks involved in executive function and sensory integration in UC.
Kornelsen J, Witges K, Labus J, Mayer EA, Bernstein CN. Brain structure and function changes in ulcerative colitis. Neuroimage Reports 2021: in press.
As the importance of the brain-gut axis in the pathobiology of inflammatory bowel disease continues to evolve, a greater understanding of brain structure and functional connectivity in diseases such as ulcerative colitis are necessary. In this magnetic resonance imaging (MRI) study, we investigated differences in brain structure and in functional connectivity of brain regions in 76 participants with ulcerative colitis and 74 healthy controls. Voxel based morphometry analysis indicate greater grey matter volume in multiple brain regions in ulcerative colitis as compared to healthy controls. Differences in functional connectivity between groups were identified in the cerebellar, default mode, visual, and dorsal attention networks. functional connectivity differed by sex for the visual and dorsal attention networks. These differences warrant further investigation to determine if they help direct the evolution of ulcerative colitis or if they evolve in response to the presence of ulcerative colitis. These differences provide further evidence that the brain-gut axis is altered in ulcerative colitis.
Shen B, Kochhar GS, Navaneethan U, Cross RK, Farraye FA, Iacucci M, Schwartz DA, Gonzalez-Lama Y, Schairer J, Kiran RP, Kotze PG, Kobayashi T, Bortlik M, Liu X, Levy AN, González Suárez B, Tang SJ, Coelho-Prabhu N, Lukas M, Bruining DH, El-Hachem S, Charles RJ, Chen Y, Sood A, Mao R, Loras C, Dulai PS, Picoraro JA, Chiorean M, Lukas M, Shergill A, Silverberg MS, Sandborn WJ, Bernstein CN. Endoscopic evaluation of surgically altered bowel in inflammatory bowel disease: a consensus guideline from the Global Interventional Inflammatory Bowel Disease Group. Lancet Gastroenterology and Hepatology 2021; 6; 482-487.
The majority of patients with Crohn's disease and a proportion of patients with ulcerative colitis will ultimately require surgical treatment despite advances in diagnosis, therapy, and endoscopic interventions. The surgical procedures that are most commonly done include bowel resection with anastomosis, strictureplasty, faecal diversion, and ileal pouch. These surgical treatment modalities result in substantial alterations in bowel anatomy. In patients with inflammatory bowel disease, endoscopy plays a key role in the assessment of disease activity, disease recurrence, treatment response, dysplasia surveillance, and delivery of endoscopic therapy. Endoscopic evaluation and management of surgically altered bowel can be challenging. This consensus guideline delineates anatomical landmarks and endoscopic assessment of these landmarks in diseased and surgically altered bowel.
Shen B, Kochar G, Kariv R, Liu X, Navaneethan U, Rubin DT, Cross R, Sugita A, D’Hoore A, Schairer J, Farraye FA, Kiran RP, Fleshner P, Rosh J, Shah S, Chang S, Scherl E, Pardi D, Schwartz DA, Kotze PG, Bruining DH, Kane S, Philpott J, Abraham B, Segal J, Sedano R, Kayal M, Bentley-Hibbert S, Tarabar D, El-Hachem S, Sehgal P, McCormck JT, Picoraro JA, Silverberg MS, Bernstein CN, Sandborn WJ, Vermeire S. Diagnosis and Classification of Ileal Pouch Disorders: Consensus Guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterology and Hepatology 2021; 6; 826-849.
Restorative proctocolectomy with ileal pouch-anal anastomosis is an option for most patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although the construction of an ileal pouch substantially improves patients' health-related quality of life, the surgery is, directly or indirectly, associated with various structural, inflammatory, and functional adverse sequelae. Furthermore, the surgical procedure does not completely abolish the risk for neoplasia. Patients with ileal pouches often present with extraintestinal, systemic inflammatory conditions. The International Ileal Pouch Consortium was established to create this consensus document on the diagnosis and classification of ileal pouch disorders using available evidence and the panellists' expertise. In a given individual, the condition of the pouch can change over time. Therefore, close monitoring of the activity and progression of the disease is essential to make accurate modifications in the diagnosis and classification in a timely manner.
Marrie RA, Walld R, Bolton J, Sareen J, Patten SB, Singer A, Lix L, Hitchon C Marriott JJ, El-Gabalawy R, Katz A, Fisk JD, Bernstein CN. Effect of comorbid mood and anxiety disorders on breast and cervical cancer screening in immune-mediated inflammatory disease. PLOS One 2021; Aug 5;16(8):e0249809.
We aimed to examine rates of breast and cervical cancer screening in women with immune-mediated inflammatory diseases, IBD, multiple sclerosis (MS) and rheumatoid arthritis versus a matched cohort with immune-mediated inflammatory diseases; and examine the association of psychiatric comorbidity with screening in these populations. We conducted a retrospective cohort study in Manitoba, Canada using administrative data. We identified women with IBD, MS and rheumatoid arthritis, and controls without these immune-mediated inflammatory diseases matched on age and region. Annually, we identified individuals with any active mood/anxiety disorder. Using physician claims, we determined the proportion of each cohort who had cervical cancer screening within three-year intervals, and mammography screening within two-year intervals. We modeled the difference in the proportion of the immune-mediated inflammatory diseases and matched cohorts who underwent mammography; and pap tests using log-binomial regression with generalized estimating equations, adjusting for sociodemographics, comorbidity and immune therapy use. We tested for additive interactions between cohort and mood/anxiety disorder status. During 2006-2016, we identified 17,230 women with immune-mediated inflammatory diseases (4,623 with IBD, 3,399 with MS, and 9,458 with rheumatoid arthritis) and 85,349 matched controls. Having an IMID was associated with lower (-1%) use of mammography; however, this reflected a mixture of more mammography in the IBD cohort (+2.9%) and less mammography in the MS (-4.8 to -5.2%) and RA (-1.5%) cohorts. Within the IBD, MS and rheumatoid arthritis cohorts, having an active mood/anxiety disorder was associated with more mammography use than having an inactive mood/anxiety disorder. The MS and rheumatoid arthritis cohorts were less likely to undergo Pap testing than their matched cohorts. In the absence of an active mood/anxiety disorder, the IBD cohort was more likely to undergo Pap testing than its matched cohort; the opposite was true when an active mood/anxiety disorder was present. Among women with an immune-mediated inflammatory diseases, mood/anxiety disorder influence participation in cancer screening.
Turkiewicz J, Bhatt RR, Wang H, Vora P, Krause B, Sauk JS, Jacobs JP, Bernstein CN, Kornelsen J, Labus JS, Gupta A, Mayer EA. Altered brain structural connectivity in patients with longstanding gut inflammation is correlated with psychological symptoms and disease duration. NeuroImage Clinical 2021; 30:102613.
We aimed to identify differences in network properties of white matter microstructure between asymptomatic ulcerative colitis participants who had a history of chronic gut inflammation, healthy controls and a disease control group without gut inflammation (irritable bowel syndrome; IBS). Diffusion weighted imaging was conducted in age and sex-matched participants with ulcerative colitis, IBS, and healthy controls (N = 74 each), together with measures of gastrointestinal and psychological symptom severity. Using streamline connectivity matrices and graph theory, we aimed to quantify group differences in brain network connectivity. Regions showing group connectivity differences were correlated with measures showing group behavioral and clinical differences. Ulcerative colitis participants exhibited greater centrality in regions of the somatosensory network and default mode network, but lower centrality in the posterior insula and globus pallidus compared to healthy controls s (q < 0.05). Hub analyses revealed compromised hubness of the pallidus in ulcerative colitis and IBS compared to healthy controls which was replaced by increased hubness of the postcentral sulcus. Surprisingly, few differences in network matrices between ulcerative colitis and IBS were identified. In ulcerative colitis, centrality measures in the secondary somatosensory cortex were associated with depression (q < 0.03), symptom related anxiety (q < 0.04), trait anxiety (q < 0.03), and symptom duration (q < 0.05).
A history of ulcerative colitis is associated with neuroplastic changes in several brain networks, which are associated with symptoms of depression, trait and symptom-related anxiety, as well as symptom duration. When viewed together with the results from IBS subjects, these findings suggest that chronic gut inflammation as well as abdominal pain have a lasting impact on brain network organization, which may play a role in symptoms reported by ulcerative colitis patients, even when gut inflammation has subsided.
Stone J, Grover K, Bernstein CN. The use of capsule endoscopy for diagnosis of iron deficiency anemia: A retrospective analysis. Journal of Clinical Gastroenterology 2020; 54(5): 452-458.
There was some ambiguity in the recent guidelines on the use of capsule endoscopy in cases of iron deficiency anemia (IDA). We aimed to examine the yield of capsule endoscopy in diagnosing the cause of IDA and to define clinical parameters that predict higher diagnostic yields. A total of 1351 individuals underwent capsule endoscopy in Winnipeg between 2005 and 2016. All studies were reported by 1 reading physician. Data included demographics and requested information on medication use, prior imaging studies, and hemoglobin and ferritin levels. In a total of 620 (46%) patients, capsule endoscopy was indicated for occult gastrointestinal bleeding or IDA. Positive findings on capsule endoscopy were separated into "definite" and "possible." Multinomial regression analysis was used to determine the variables correlated with definite capsule endoscopy findings. A survey analysis was then used to assess how the study results impacted further management. With regard to the 620 patients, the mean age was 62.9 years, mean hemoglobin level was 89 g/L, and median ferritin level was 9 μg/L. A total of 210 (33.9%) patients had positive findings (definite: 23%, possible: 10.8%). Vascular ectasias were the majority of definite findings (47.5%). Predictors of definite findings were age (relative risk ratio: 1.04; 95% confidence interval: 1.02-1.06) and male sex (relative risk ratio: 1.88; 95% confidence interval: 1.25-2.83). An overall 12.7% of positive studies required therapeutic intervention, with 65.8% undergoing further workup. We report a 33.9% positive yield, with 65.8% of patients undergoing further workup as a result of capsule endoscopy and 12.7% requiring therapeutic intervention. We conclude that capsule endoscopy plays an important role in the investigation of IDA and occult gastrointestinal bleeding and has important implications on further management.
Bernstein CN. New biomarkers for Crohn’s disease. Gastroenterology 2020; 159(1):30-32.
Case control studies of patients with IBD may facilitate the identification of factors present to a greater extent in those with the disease compared with those without the disease. If these factors are present before disease expression, they might be considered as risk factors. This can lead to further exploration of the biology of the factor in relation to IBD pathogenesis, or alternatively, as a biomarker identifying that the disease may be diagnosed at some future time. It is more difficult to prove that an antedating factor is a true risk factor. One reason is that it is very difficult to determine exactly when IBD starts in an individual patient. The first clinical presentation of disease might in fact be long after the biology of the disease has been set in motion. Prediagnosis factors have not necessarily emerged before disease onset, but rather before clinical manifestation of disease. They may in fact be sequelae of the disease pathogenesis unfolding. Postoperative Crohn’s disease is a good model of preclinical disease. Asymptomatic endoscopic recurrences are quite common. Finding environmental risk factors that might unravel disease etiology in IBD has been the holy grail of IBD researchers for decades. Measurable factors strongly associated with a disease can serve as biomarkers which can aid in diagnosis regardless of the timing at which they are found in relation to disease presentation. Anti-Sacccharomyces cerivisiae (ASCA) is one such marker. ASCA is also underexplored; the antibody and its fungal antigen present interesting opportunities for etiologic hypotheses. Newly identified biomarkers may be valuable diagnostic aids, but can also represent an entrance to an important pathogenetic pathway; or alternatively, an off-ramp to a misleading coincidence. It is on this complex background that 2 studies published in Gastroenterology this month point us in different directions along the etiologic and diagnostic hunt. In the article by Nair et al (Nair N, Austin C, Curtin P. et al. Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth. Gastroenterology. 2020; 159: 383-385), the authors relate the presence of heavy metals in baby teeth to the later development of Crohn’s disease. They lead off their discussion by suggesting that this finding is a key link to urbanization associated with Crohn’s disease. Theirs is a fascinating finding, but recent data have suggested that the disease does not necessarily favor urban areas.
Wherever the metals are coming from, this study strengthens the connection of IBD risk with the mothers of affected individuals. The finding of metals that can be tracked to the in utero state suggests that the offspring who will ultimately present with IBD and have high values of these metals are likely acquiring these metals from their mothers. Mothers may have accessed these metals in their cookware, in their cosmetics, in the packaged food they have eaten, or in the homegrown food they have consumed that has been affected by the metal-laden soil in which it was grown. The authors propose that the metals found in increased amounts may be important for the development of IBD. However, having not reported any metals that were not in excess in the affected individuals’ baby teeth argues against the 4 specific metals having unique roles in IBD pathogenesis. Nonetheless, the authors have identified that persons with IBD have associated markers that can be traced to early in life. Whatever ultimately leads to IBD may be experienced in the developing child. Our mothers are even more important to our health than we even previously considered! What and when they feed us during early childhood, and even what mothers ingest themselves may impact our future health. Recently, our study from Manitoba, published in Gastroenterology, reported that the strongest risk factor for a child ultimately developing IBD was the presence of IBD in their mothers.
This factor may be genetic—the mother passing on genes that modulate how metals are handled, genes that modulate the developing gut microbiome, or both. Alternatively, this factor may be environmental—the mother passing on to the child what she is ingesting. In the Manitoba study, the second most significant risk factor for developing IBD was having an infection in the first year of life—an infection in the child independent of his or her mother. Hence, an infection that may alter a developing gut microbiome, an infection that may be treated with antibiotics which may alter the developing gut microbiome or an infection the response to which may be impacted by the presence of excess heavy metals may be a critical inciting event in the pathogenesis of IBD. In the study by Torres et al (Torres J. Petralia F. Sato T. et al. Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis. Gastroenterology. 2020; 159: 96-104), a serum bank of Department of Defense recruits was accessed to study for microbial antibodies and immune-inflammatory markers for ≤5 years antedating diagnoses of either Crohn’s disease or ulcerative colitis. Anti-Flagellin X and ASCA-IgA were predictive of Crohn’s disease. A Somologic panel of 1100 potential proteins led to a handful that collectively formed a moderately good predictive model of later diagnosis of Crohn’s disease. These included C-reactive protein, complement C5, PRSS2 (trypsin 2), serum amyloid-P, osteomodulin, and aggrecan core protein. Four additional factors, complement factor I, IL-11 receptor subunit alpha, macrophage mannose receptor 1, and protein SET II were commonly selected at timepoints 1–4 years before diagnosis. It is not surprising that anti-Flagellin X and ASCA-IgA were predictive of Crohn’s disease since they have been associated with it previously. In fact, ASCA IgA has also been a strong predictor of aggressive disease behavior in Crohn’s disease. The significantly associated proteins are all involved in immune response, cytokine-mediated signaling pathway and apoptosis. Again, not surprising. Flagellin X is a bacterial product and ASCA is a response to a yeast. ASCA has been popping up as a disease marker for 30 years.
Is this the Helicobacter pylori-equivalent that has been staring at researchers? Of note Saccharomyces cerivisae may have an important role to play in heavy metal biosorption. The authors have convincingly showed that these microbial antibodies and immune-inflammatory mediators are present years before the first clinical manifestation of Crohn’s disease. These phenomena very likely are early biological manifestations of Crohn’s disease. They may not be risk factors that Crohn’s disease is coming, but rather that it is already present. If the value in identifying these markers in asymptomatic persons is so that they can be acted upon to prevent Crohn’s disease, it may be an unfulfilled hope, analogous to identifying NOD2 mutations. There are more people in the general population who have NOD2 mutations who will never get Crohn’s disease, but without question, persons who have NOD2 mutations are more likely to get Crohn’s disease.
Will the predictive package reported by Torres et al be stronger than ASCA alone or NOD-2 mutations?
Regardless, there remains little to offer to avoid the full expression of Crohn’s disease, even when it is believed to be in the offing. Some might say knowledge of a biomarker antedating Crohn’s disease presentation could lead to advice, for example, against smoking, for example, because smoking is associated, with Crohn’s disease in Western populations. There are surely better reasons not to smoke. Regardless, smoking does not even seem to be associated with Crohn’s disease in China or India where IBD is on the rise, likely in the absence of NOD2 mutations.
Torres et al present the premise that “biomarkers are needed to identify persons at risk for developing inflammatory bowel diseases.” Until the tools are available to truly prevent Crohn’s disease evolution, at best we can say that biomarkers are needed to help expand our diagnostic armamentarium.
These 2 groups of investigators should be congratulated for harnessing extraordinary resources (long-held baby teeth and a long-held serum bank) and for challenging the research community to make sense of their findings. From many years (in utero) to a few years before being diagnosed with Crohn’s disease, affected individuals are harboring increased levels of heavy metals and subclinical inflammation and antibody responses to microbial proteins. These 2 studies may be linked through the gut microbiome (including the fungome); being altered early in its development by exposure to heavy metals and ultimately establishing a proinflammatory microbiome that stimulates inflammatory proteins and antibodies to its constituents. To understand the biology of Crohn’s disease rather than studying those newly diagnosed in search of clues, a concerted effort should be undertaken to study a large cohort of pregnant women and their children. An expanded version of the Canadian Healthy Infant Longitudinal Development (CHILD) study could facilitate an understanding of early life changes that lead to chronic immune diseases some time later.
Lee E, Shafer LA, Walker JR, Waldman C, Michaud V, Yang C, Bernstein CN, Park J, Sisler J, Wittmeier K, Hathout L, Restall G, Singh H. Information experiences, needs, and preferences of colonoscopy patients: A pre-colonoscopy survey. Medicine 2019; 98(2):e15738.
Inadequate preparation for colonoscopy is associated with missed diagnoses and avoidable repeat procedures. Better pre-colonoscopy education may lead to improved bowel preparation, decreased anxiety, and a willingness to go direct to colonoscopy. We assessed the experiences, needs and preferences for information of patients undergoing colonoscopy. A self-administered survey was distributed between 08/2015-06/2016 to patients in Winnipeg, Canada when they attended an outpatient colonoscopy. The amount, type, helpfulness, and satisfaction with information provided were analyzed. Predictors of overall satisfaction and amount of information received were determined. 1,580 respondents answered parts of or all of the survey questions. Only half of respondents coming for a repeat colonoscopy and 40-44% of those coming for first colonoscopy received just the right amount of information from their endoscopy doctor (directly or by brochure). One quarter or less of the respondents indicated that they had received just the right amount of information from any source other than their colonoscopy doctor, and many indicated that they had received no information from the sources. 38% coming for a first colonoscopy and 44% coming for a repeat colonoscopy indicated that they had received no information from their family physicians. Those coming for their first colonoscopy had a lower average score (9.7 vs 11.1, p<0.001) for amount of information received (scale 0-15)), were less likely to be satisfied or very satisfied with the information they received (p=0.005) and were less likely to have found the information clear or very clear (p=0.004). We concluded that patients going for colonoscopy are inadequately informed about the procedure and it is significantly worse for those going for first time rather than repeat colonoscopy.
Restall GA, Michaud V, Walker JR, Waldman C, Bernstein CN, Park J, Wittmeier K, Singh H. Patient experiences with colonoscopy: A qualitative study. Journal of Canadian Association of Gastroenterology 2019; 17; 3(6): 249-256.
Patient perspectives have important roles in improving the quality of colonoscopy services. The purpose of this qualitative study was to obtain the perspectives of patients who recently had undergone colonoscopy procedures, about their experiences with bowel preparation, the procedure itself, and communication of follow-up results and recommendations. We recruited adults who had undergone a colonoscopy, to participate in semi-structured interviews. Interviews were audiotaped, transcribed and analyzed using inductive qualitative methods. Twenty-four adults (58% female) with an average age of 53.8 years participated. Results were categorized within the themes of bowel preparation, the colonoscopy procedure and communication of the results. Participants appreciated having clear consistent plain language messages about bowel preparation. Some participants experienced additional challenges to understanding, and navigating, colonoscopy procedures. At the time of the procedure, positive and reassuring interactions with, and between, members of the health care team, in addition to management of physical pain and discomfort, were important. Participants wanted clear and timely information about the results of their test. In summary, understanding patients’ needs for information and support can promote higher quality colonoscopy services. Our findings suggest that quality indicators should include: patients’ perspectives of the clarity of bowel instructions; the need for supports that are not routinely provided; the extent to which concerns about the procedure are addressed; interactions with the endoscopy team; the endoscopy team’s interactions with each other; comfort during the procedure, and the timeliness and clarity of results and follow-up instructions. These indicators should be included in annual patient surveys.
ten Hove JR, Shah SC, Shaffer SR, Bernstein CN, Castaneda D, Palmela C, Mooiweer E, Elman J, Kumar A, Glass J, Ullman TA, Colombel JF, Torres J, van Bodegraven AA, Hoentjen F, Jansen JM, de Jong M, Mahmmod N, van der Meulen-de Jong AE, Ponsioen CY, van der Woude CJ, Itzkowitz SH, Oldenburg B. Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with longstanding colitis: results of a 15-year multicenter, multinational cohort study. Gut 2019 Apr;68(4): 615-622.
Surveillance colonoscopy is thought to prevent colorectal cancer in patients with long-standing colonic IBD, but data regarding the frequency of surveillance and the findings thereof are lacking. Our aim was to determine whether consecutive negative surveillance colonoscopies adequately predict low neoplastic risk. This was a multicentre, multinational database of patients with long-standing IBD colitis without high-risk features and undergoing regular CRC surveillance was constructed undertaken in Amsterdam, New York and Winnipeg. A 'negative' surveillance colonoscopy was predefined as a technically adequate procedure having no postinflammatory polyps, no strictures, no endoscopic disease activity and no evidence of neoplasia; a 'positive' colonoscopy was a technically adequate procedure that included at least one of these criteria. The primary endpoint was advanced colorectal neoplasia, defined as high-grade dysplasia or CRC. Of 775 patients with long-standing IBD colitis, 44% (n=340) had at least 1 negative colonoscopy. Patients with consecutive negative surveillance colonoscopies were compared with those who had at least one positive colonoscopy. Both groups had similar demographics, disease-related characteristics, number of surveillance colonoscopies and time intervals between colonoscopies. No advanced colorectal neoplasias occurred in those with consecutive negative surveillance, compared with an incidence rate of 0.29 to 0.76/100 patient-years (P=0.02) in those having at least 1 positive colonoscopy on follow-up of over 6 years after the initial procedure. We concluded that Within this large surveillance cohort of patients with colonic IBD and no additional high-risk features, having two consecutive negative colonoscopies predicted a very low risk of advanced colorectal neoplasia occurrence on follow-up. Our findings suggest that longer surveillance intervals in this selected population may be safe.
Shafer LA, Walker JR, Waldman C, Michaud V, Yang C, Bernstein CN, Hathout L, Park J, Sisler J, Wittmeier K, Restall G, Singh H. Predictors of patient reluctance to wake early in the morning for bowel preparation for colonoscopy: A precolonoscopy survey in city wide practice. Endoscopy International Open 2018; Jun;6(6):E706-E713.
Many endoscopists do not use split-dose bowel preparation (SDBP) for morning colonoscopies. Despite SDBP being recommended practice, they believe patients will not agree to take early morning bowel preparation. In this study we assessed patients' opinions about waking early for bowel prep. A self-administered survey was distributed between 08/2015 and 06/2016 to patients in Winnipeg when they attended an outpatient colonoscopy. Of the 1336 respondents (52 % female, median age 57 years), 33 % had used SDBP for their current colonoscopy. Of the 1336, 49 % were willing, 24 % neutral, and 27 % reluctant to do early morning BP. Predictors of reluctant versus willing were number of prior colonoscopies (OR 1.20; 95 %CI: 1.07 - 1.35), female gender (OR 1.65; 95 %CI: 1.19 - 2.29), unclear bowel prep information (OR 1.86; 95 %CI: 1.21 - 2.85), high BP anxiety (OR 2.02; 95 %CI: 1.35 - 3.02), purpose of current colonoscopy being bowel symptoms (OR 1.40; 95 %CI: 1.00 - 1.97), use of 4 L of polyethylene glycol laxative (OR 1.45; 95 %CI: 1.02 - 2.06), not having SDBP (OR 1.96; 95 %CI: 1.31 - 2.93), and not having finished the laxative for the current colonoscopy (OR 1.66; 95 %CI: 1.01 - 2.73). We concluded that almost three-quarters of patients do not express reluctance to get up early for BP. Among those who are reluctant, improving bowel prep information, allaying bowel prep-related anxiety, and use of low volume bowel prep may increase acceptance of SDBP.
Shafer LA, Walker JR, Yang C, Waldman C, Michaud V, Bernstein CN, Hathout L, Park J, Sisler J, Restall G, Wittmeier K, Singh H. Factors Associated with Anxiety about Colonoscopy: The Preparation, the Procedure, and the Anticipated Findings. Digestive Diseases and Sciences 2018; 63: 610-8.
Previous research has assessed anxiety around colonoscopy procedures, but has not considered anxiety related to different aspects related to the colonoscopy process. Before patients underwent colonoscopy, we assessed anxiety about: bowel preparation, the procedure, and the anticipated results. An anonymous survey was distributed to patients immediately prior to their outpatient colonoscopy in six hospitals and two ambulatory care centers in Winnipeg, Canada. Anxiety was assessed using a visual analog scale. A total of 1316 respondents completed the questions about anxiety (52% female, median age 56 years). Anxiety scores > 70 (high anxiety) were reported by 18% about bowel preparation, 29% about the procedure, and 28% about the procedure results. High anxiety about bowel preparation was associated with female sex, perceived unclear instructions, unfinished laxative, and no previous colonoscopies. High anxiety about the procedure was associated with female sex, no previous colonoscopies, and confusing instructions. High anxiety about the results was associated with symptoms as an indication for colonoscopy and instructions perceived as confusing. In summary, fewer people had high anxiety about preparation than about the procedure and findings of the procedure. There are unique predictors of anxiety about each colonoscopy aspect. Understanding the nuanced differences in aspects of anxiety may help to design strategies to reduce anxiety, leading to improved acceptance of the procedure, compliance with preparation instructions, and less discomfort with the procedure.
Siegel CA, Whitman CB, Spiegel BMR, Feagan B, Sands B, Loftus EV Jr, Remo Panaccione, D’Haens G, Bernstein CN, Gearry R, Ng S, Mantzaris GJ, Sartor B, Silverberg MS, Riddell R, Koutroubakis I, O’Morain C, Lakatos PL, McGovern DPB, Halfvarson J, Reinisch W, Rogler G, Kruis W, Tysk C, Schreiber S, Danese S, Sandborn W, Griffiths A, Moum B, Gasche C, Pallone F, Travis S, Panes J, Colombel JF, Hanauer S, Peyrin-Biroulet L. Development of an index to define overall disease severity in inflammatory bowel disease. Gut 2018; 67: 244-54.
Disease activity for Crohn's disease and ulcerative colitis is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both Crohn's disease and ulcerative colitis. 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise to create a relative ranking of these attributes. For Crohn’s disease, 16% of overall disease severity was attributed to the presence of mucosal lesions (lesions in the lining of the bowel), 11% to a history of a fistula, 10% to history of abscess and 7% to history of intestinal surgery. For ulcerative colitis, 18% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11% for C reactive protein (a blood measure of inflammation) and 10% for prior experience with biologics. Based on specialist opinion, overall Crohn’s disease severity was associated more with intestinal damage, in contrast to overall ulcerative colitis disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.
Enns RA, Hookey L, Armstrong D, Bernstein CN, Heitman SJ, Teshima C, Leontiadis GI, Tse F, Sadowski D. Clinical practice guidelines for the use of video capsule endoscopy. Gastroenterology 2017; 152:497-514
In this paper we report consensus guidelines using a Delphi technique and the GRADE scheme on use of capsule endoscopy. Much of the guidelines deal with capsule endoscopy in the setting of bleeding, the most common use fo capsule endoscopy. However, there is also discussion and recommendations for its use in Crohn’s disease and other conditions.
Singh H, Nugent Z, Yu BN, Lix LM, Targownik LE, Bernstein CN. Higher Incidence of Clostridium difficile Infection Among Individuals with Inflammatory Bowel Disease. Gastroenterology 2017 Aug; 153(2):430-438.
Studies of Clostridium difficile infections (CDIs) among individuals with IBD have used data from single centers or CDI administrative data codes of limited diagnostic accuracy. We determined the incidence, risk factors, and outcomes after CDI in a population-based cohort of patients with IBD and laboratory confirmation diagnoses of CDI. We searched the University of Manitoba IBD Epidemiology Database and Manitoba Health CDI databases to identify individuals with CDI, with or without IBD, from July 1, 2005 through March 31, 2014. Time trends of incidence were assessed using joinpoint regression. Multivariable Cox regression analyses were performed to assess differences in CDI incidence rates and mortality after CDI between individuals with and without IBD.
Individuals with IBD had a 4.8-fold increase in risk of CDI than individuals without IBD; we found no difference between individuals with ulcerative colitis vs Crohn's disease. There was no increase in CDI incidence over the study time period in either group. Among individuals with IBD, exposure to corticosteroids, infliximab or adalimumab, metronidazole, hospitalizations, higher ambulatory care visits, shorter duration of IBD, and higher comorbidities were associated with an increased risk of CDI. Although CDI increased mortality among individuals with and without IBD, there was lower mortality after CDI among individuals with IBD than without IBD by 35% We concluded that CDI incidence is no longer increasing among individuals with IBD. We identified unique risk factors for CDI in patients with IBD. CDI is associated with a greater increase in mortality among individuals without IBD than with IBD.
Singh H, Nugent Z, Yu N, Lix L, Targownik LE, Bernstein CN. Hospital discharge abstracts have limited accuracy in identifying occurrence of Clostridium difficile infections among hospitalized individuals with inflammatory bowel disease: a population-based study. PLOS One 2017; 2017 Feb 15; 12(2):e0171266.
Hospital discharge databases are used to study the epidemiology of Clostridium difficile infections (CDI) among hospitalized patients with IBD. CDI in IBD is increasingly important and accurately estimating its occurrence is critical in understanding its comorbidity. There are limited data on the reliability of the International Classification of Diseases 10th revision (ICD-10) (now widely used in North America) CDI code in determining occurrence of CDI among hospitalized patients. We compared the performance of ICD-10 CDI coding to laboratory confirmed CDI diagnoses.The University of Manitoba IBD Epidemiology Database was used to identify individuals with and without IBD discharged with CDI diagnoses between 07/01/2005 and 3/31/2014. There were 273 episodes of laboratory confirmed CDI (hospitalized and non-hospitalized) among 7396 individuals with IBD and 536 among 66,297 matched controls. The sensitivity, specificity, positive predictive value and negative predictive value of ICD-10 CDI code in discharge abstracts was 72.8%, 99.6%, 64.1% and 99.7% among those with IBD and 70.8%, 99.9%, 79.0% and 99.9% among those without IBD. Predictors of diagnostic inaccuracy included IBD, older age, increased co-morbidity and earlier years of hospitalization. We concluded that identification of CDI using ICD-10 CDI code in hospital discharge abstracts may not identify up to 30% of CDI cases, with worse performance among those with IBD.
El Matary W, Abej E, Deora V, Singh H, Bernstein CN. Impact of fecal calprotectin measurement on decision-making in children with inflammatory bowel disease. Frontiers in Pediatrics 2017; 25: 5-7.
The use of fecal calprotectin (FCal) as a marker of intestinal inflammation, in the management of IBD is increasing. The aim of this study was to examine the impact of FCal measurements on decision-making and clinical care of children with IBD. FCal, clinical activity indices, and blood markers were measured in children with established diagnoses of IBD. Decisions based on FCal measurements were prospectively documented and participants were evaluated 3-6 months later A total of 115 fecal samples were collected from 77 children with IBD [median age 14, 42 females, 37 with Crohn's disease]. FCal positively correlated with clinical activity indices and erythrocyte sedimentation rate and negatively correlated with hemoglobin Sixty four out of 74 (86%) positive FCal measurements (at least 250 μg/g of stools) resulted in treatment escalation with subsequent significant clinical improvement while in the FCal negative group, 34 out of 41 (83%) measurements resulted in no change in treatment and were associated with remission on follow-up. We concluded that based on high FCal, the majority of children had treatment escalation that resulted in clinical improvement. FCal measurements were useful and reliable in decision-making and clinical care of children with IBD.
Cloutier J, Wall D, Paulsen K, Bernstein CN. Upper versus lower endoscopy in the diagnosis of graft-versus-host disease. Journal of Clinical Gastroenterology 2017 Sep;51(8):7701-706.
The optimal endoscopic approach to patients with suspected gut graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT) is uncertain. We aimed to assess the diagnostic yield of upper and lower endoscopies performed in patients post-HSCT. We identified a cohort post-HSCT with acute and chronic GVHD who underwent gastrointestinal endoscopies for GVHD diagnosis. Hospital charts were reviewed and results were stratified according to patients' symptoms. From 1990 to 2013 433 HSCTs were performed. Fifty-six patients underwent 141 endoscopies, of which 117 were done to evaluate for GVHD or an alternative diagnosis. A total of 28/43 (65%) of the lower endoscopies and 41/74 (55%) of the upper endoscopies diagnosed GVHD or an alternative disease process on pathology. A total of 15/43 (35%) of lower endoscopies were flexible sigmoidoscopies, and 11/15 (73%) of these diagnosed GVHD or an alternative diagnosis. Upper endoscopy performed in patients with diarrhea as their only symptom diagnosed GVHD in 44% and an alternative diagnosis in 11%. In comparison, lower endoscopy in patients with only diarrhea diagnosed GVHD in 50%, and 18% offered an alternative diagnosis. Upper endoscopy provided a diagnosis of opportunistic viral and fungal infections of the upper gastrointestinal tract in 7 patients, while lower endoscopy diagnosed pseudomembranous colitis in 2. Upper and lower endoscopy had a similar diagnostic yield in patients with known or suspected GVHD involving the gut, even for patients presenting only with diarrhea. Because of its ease and safety upper endoscopy is the preferred initial endoscopic approach in patients with suspected gut GVHD, however flexible sigmoidoscopy is a reasonable other option.
Abej E, El Matary W, Singh H, Bernstein CN. The utility of fecal calprotectin in the real-world clinical care of patients with inflammatory bowel disease. Canadian Journal of Gastroenterology and Hepatology 2016; Article ID 2483261, 6 pages.
We aimed to determine the relationship between fecal calprotectin (FCAL) and imaging studies and other biochemical inflammatory markers and the impact of FCAL measurements on decision-making in IBD patient management in usual clinical practice. 240 persons with IBD were enrolled. The correlation between FCAL values and other markers for disease activity such as serum albumin (alb), hemoglobin (Hg), and C-reactive protein (CRP) and diagnostic imaging or colonoscopy was examined. FCAL greater than 250 mcg/g of stool was considered a positive result indicating active IBD. 183 stool samples (76.3%) were returned. The return rate in the pediatric and adult cohorts was 91% (n = 82) and 67.3% (n = 101), respectively. Positive FCAL was associated with colonoscopy findings of active IBD, low albumin, anemia, and elevated CRP. There was no significant difference for FCAL results by outcomes on small bowel evaluation among the 21 persons with small bowel CD. Most persons (87.5%) with normal FCAL and no change in therapy remained in remission during subsequent 3 months. We concluded that FCAL is a useful marker of disease activity and a valuable tool in managing persons with IBD in clinical practice. Clinicians have to be cautious in interpreting FCAL results in small bowel.
Moffatt D, Yu BN, Yei W, Bernstein CN. Trends in utilization of diagnostic and therapeutic ERCP and cholecystectomy over the past 25 years: a population based study. Gastrointestinal Endoscopy 2014; 79: 615-622.
ERCP is a test used to determine if gallstones are causing problems in the bile duct leading from the liver or from the pancreas. In the context of persons with IBD it can be used to determine if there is a condition called primary sclerosing cholangitis or complications of that condition are present. We aimed to establish crude and age-adjusted population-based rates of ERCP, evaluate for changing indications for ERCP, and evaluate for interactions between cholecystectomy (gall bladder removal) technique and ERCP use from 1984 to 2009 In Manitoba The rate of ERCP/10,000 people increased from 7.70 (1984) to 13.86/10,000 (2009) (nearly doubled). Diagnostic ERCP declined from 7.28/10,000 (1984) to 1.11/10,000 (2009), and therapeutic ERCP increased from 0.42/10,000 (1984) to 12.75/10,000 (2009). ERCPs were more common in women (62%) and in older populations (60-79 years, >80 years), with rates of therapeutic ERCP reaching 62.58/10,000 in the elderly. The primary indication for ERCP has changed over time, with biliary indications increasing from 50.3% to 67.3% and pancreatic indications decreasing from 18.3% to 8.1%. The rate of therapeutic ERCP increased during the transition from open to laparoscopic cholecystectomy (1991-1994), whereas open bile duct exploration decreased from 2.0 to 0.18/10,000.We concluded that ERCP use increased steadily from 1984 to 2009, and changed from a diagnostic modality to a therapeutic one. Changes in cholecystectomy technique may have influenced therapeutic ERCP use and likewise, the availability of therapeutic ERCP has decreased the need for open bile duct exploration.
Israeli E, Ying S, Henderson B, Mottola JT, Strome T, Bernstein CN. The impact of abdominal computed tomography in a tertiary referral center emergency department on the management of patients with inflammatory bowel disease. Alimentary Pharmacology and Therapeutics 2013; 38: 513-21.
Although exposure to diagnostic radiation may be associated with increased risk of malignancy, the use of abdominal CT (ACT) in the last decade has increased for patients in the emergency department (ED).We aimed to examine the impact of ACT ordered in the ED on management of patients with IBD, as well as to quantify the cumulative effective dose (CED) of radiation received by these patients. A total of 152 patients with Crohn's disease and 130 patients with ulcerative colitis that presented to the ED in a tertiary centre between 2009 and 2011 were identified. For patients that had an ACT, chart review assessed if the ACT findings changed clinical management. CED of diagnostic radiation was calculated for all imaging studies between 1 January 2006 and 30 August 2012. Abdominal CT use was 49% for CD and 19% for UC. ACTs with findings of penetrating/obstructive disease were 35% for Crohn’s disease. Urgent non-IBD-related diagnoses were found in 13% for Crohn’s disease and 28% for ulcerative coltis (P < 0.05). ACT caused a change in management in 81% of Crohn’s disease and 69% of ulcerative colitis patients. Average CED from diagnostic radtation was 77.4 ± 63.0 mSv for Crohn’s disease and 67.2 ± 51.0 mSv for ulcerative coltis (P = 0.47). The CED for the 80-month period exceeded 75 mSv in 35% and 36% respectively. We concluded that Although abdominal CT often changes management of IBD patients in the ED, this population carries a very high-risk of radiation exposure. Efforts should be made to decrease this risk by development of low-radiation protocols, and wider use of MRI/ultrasound.
Chisick L, Oleschuk C, Bernstein CN. The utility of TPMT testing in inflammatory bowel disease. Canadian Journal of Gastroenterology 2013; 27: 39-43.
This study aimed to assess the levels of red blood cell thiopurine methyltransferase (TPMT) in subjects with IBD and to determine how these levels impacted thiopurine dosing and leukopenia over the first six months of therapy. A retrospective chart review was performed on all adult IBD patients (n=423, 88.2% Caucasian) who had TPMT levels measured by 11 participating gastroenterologists in Manitoba between 2008 and 2010. In addition to descriptive data, white blood cell count, dose and reason for discontinuation were analyzed for the first six months of therapy. Patients receiving at least 2.0 mg/kg of azathioprine (AZA) or at least 1.0 mg/kg of 6-mercapatopurine were considered to be 'substantially' dosed. Of the 423 patients, 8.3% had intermediate levels and 93.4% had normal levels of TPMT. Only one subject had a low level. A total of 216 patients had sufficient data to be included for full analysis. Patients with intermediate TPMT levels were generally started at lower doses of thiopurine than patients with normal TPMT levels (average 1.0 mg/kg versus 1.8 mg/kg). Of the subjects with normal TPMT levels, only 37.8% were dosed with at least 2.0 mg/kg of AZA. Each month, approximately 5% of subjects were leukopenic (had low white blood cell counts). These subjects received an average overall AZA dose of 1.9 mg/kg and had an average white blood cell count of 3.8 x10(9)/L. We concluded that normal TPMT levels did not prevent the development of leukopenia, although life-threatening leukopenia was rare. Physicians are not using TPMT levels to substantially dose thiopurines at the outset, which may limit the speed at which adequate doses are reached to facilitate remission.