bluuebunny/crossref_metadata_2025 huggingface dataset:
A148 DESMOID FIBROMATOSIS DIAGNOSED IN A 27-YEAR-OLD MALE AFTER BEING MISTAKEN FOR A GASTRIC GIST
Authors: Albino L G , Guo Y , Dieleman L A
Published: March 2021

Background

The gastrointestinal tract can be affected by both epithelial and non-epithelial tumors. When considering non-epithelial tumors, gastrointestinal stromal tumors (GISTs) are the most common with an incidence of 7–15 cases per million per year. Fibroblastic desmoid tumors, originating from mesenchymal cells, are rarer with an incidence of 2–4 cases per million per year. Despite being distinct lesions, these tumors may appear similar on imaging when they involve the stomach wall or bowel. As a result, they may be confused with one another when initially diagnosed.

Aims

This report aims to present a case where a desmoid tumor was mistaken for a gastric GIST despite extensive investigation prior to laparotomy.

Methods

Retrospective review of one patient.

Results

A 27-year-old gentleman presented with acute left-sided abdominal pain and postprandial fullness that began 2 days prior. A CT-abdomen/pelvis demonstrated a large exophytic mass arising from the lesser sac of the stomach, in keeping with an aggressive gastrointestinal stromal tumor (GIST). He was admitted and was further investigated with an endoscopic ultrasound, which demonstrated an exophytic hemorrhagic mass arising from the muscularis propria of the gastric wall. Again, this was most consistent with a GIST and urgent surgical resection was recommended. An exploratory laparotomy was organized the following day. There were no signs of a GIST intraoperatively, but rather a soft tissue tumor of the left mesentery of the transverse colon. This mass was resected, and a biopsy of the peritoneum was collected. Pathology identified a low-grade spindle cell tumor, CD117/CD34 negative with patchy cytoplasmic and nuclear β-catenin staining, in keeping with desmoid fibromatosis.

Conclusions

This case illustrates how GISTs and desmoid tumors are often mistaken for one another when associated with the stomach wall or bowel. Despite morphologic features of both tumors outlined in the literature, pathology, with focus on specific staining patterns, is necessary in many cases to distinguish the two. This distinction is paramount for appropriate prognostication and management, including timely investigation for associated diseases such as Familial Adenomatous Polyposis in patients with desmoid tumors.

Funding Agencies

None
A149
TRP53 LOSS IN KRT15+ INTESTINAL STEM CELLS SEVERELY AFFECTS SECRETORY CELL FATE AND SELF-RENEWAL
Authors: Dubey A , Gonneaud A , Giroux V
Published: March 2021

Background

Intestinal epithelium homeostasis is maintained by two main populations of stem cells: Lgr5+ and reserve stem cells. Under injury, cell plasticity has been observed in progenitor and differentiated cells. We recently reported that Krt15+ cells are present in small intestinal and colon epithelia, and harbor self-renewal, multipotent and regenerative capacities. As in Lgr5+and reserve stem cells, hyperactivation of Wnt/b-catenin pathway in Krt15+ stem cells lead to tumor formation in the intestinal epithelium. While these intestinal stem cell populations can act as tumor-initiating cells in sporadic colon cancer, little is known about the cell-of-origin of colitis-associated colon cancer (CAC). TP53 alteration is reported as an early event in CAC. Therefore, we hypothesize that Trp53 loss specifically in Krt15+ stem cells will perturb the epithelial homeostasis and lead to tumor formation.

Aims

Identify if Krt15+ cells may act as the cell-of-origin in colitis-associated colorectal cancer

Methods

To induce Trp53 loss specifically in Krt15+ cells, we generated Krt15-CrePR1;Trp53fl/fl (Krt15△Trp53) mice, induced Cre recombination by injecting RU486 (PR agonist) and euthanized the mice at different time points following recombination.

Results

Results

Twelve-month following Cre recombination, adenoma formation was observed in a small proportion of Krt15△Trp53 mice. Though, Trp53 loss in Krt15+ cells severely perturbed the small intestinal morphology in every mouse studied. Increased crypt length and villi width was observed in Krt15△Trp53 vs control mice without any changes in cell proliferation. We also observed an increased number of Tuft cells and goblet cells in the villi of experimental mice. In the crypt, higher number of Paneth cells and aberrant presence of goblet cells were noted in Krt15△Trp53mice. Interestingly, we also observed crypt cells expressing goblet and Paneth cell markers and decreased Notch pathway activation suggesting dysregulation of secretory cell fate. Krt15△Trp53 mice display higher number of fibroblasts in the villi and the submucosa, as well as thickening of the muscularis layer. Interestingly, similar observations (accumulation of secretory cells and fibrosis) have been reported in IBD patients, supporting the possible role of Krt15+ cells in CAC. Furthermore, crypts isolated from Krt15△Trp53 mice rapidly die when seeded as organoids vs crypts from control mice, suggesting that the alterations observed in vivo in Paneth cells might interfere with the stem cell niche and therefore reduce self-renewal of Krt15+ cells.

Conclusions

Trp53 loss specifically in Krt15+ cells impaired cell fate decision, induced secretory cell hyperplasia, affected self-renewal ability, and initiated adenoma formation supporting the possible role of Krt15+ cells in gut inflammation and cancer.

Funding Agencies

Canada Research Chair, Cancer Research Society, CFI
A151 COMPARABLE NEONATAL AND PREGNANCY-RELATED OUTCOMES BETWEEN EARLY AND LATE DISCONTINUATION OF BIOLOGICS IN PREGNANT WOMEN WITH INFLAMMATORY BOWEL DISEASE
Authors: Tao J J , Tandon P , Huang V W
Published: March 2021

Background

Inflammatory bowel disease (IBD) disease activity during pregnancy is related to adverse neonatal and pregnancy-related outcomes. Biologics are used to suppress disease activity, however, since there is known transplacental passage, the American Gastroenterology Association (AGA) recommends timing the final dose with drug-specific half-lives although there is little evidence demonstrating adverse outcomes.

Aims

We aim to assess the safety of early versus late discontinuation of biologics according to drug-specific half-lives by comparing various neonatal and pregnancy-related outcomes.

Methods

This is a REB approved single-center retrospective cohort study on all patients with IBD ≥18 years of age on a biologic agent prior to conception, have a documented final dose during pregnancy, and were seen at Mount Sinai Hospital from 2016–2019. Neonate and pregnancy-related outcomes were compared amongst the two groups (Table 1) using the student’s t-test (birthweight, gestational age, Apgar scores) and Fischer’s exact test (NICU admission, congenital anomalies, GBS, chorioamnionitis) analyzed in SPSS Version 27. The level of significance was set at p<0.05.

Results

We identified 53 patients on biologics pre-conception. 26 patients had a documented final dose (19 early cohort, 7 late cohort) and were included in the analysis. Aside from mean birthweight (3014 vs 3561 g, p=0.036), there were no statistically significant differences between the early and late cohorts for gestational age (37.4 vs 39.0 weeks, p=0.20), 1- and 5-min Apgar scores (7.8 vs 8.8, p=0.37 and 8.5 vs 9.0, p=0.49), NICU admissions (p=0.54), congenital anomalies (p=1.00), GBS (p=0.55), and chorioamnionitis (p=1.00).

Conclusions

Overall, our study suggests that early and late discontinuation of biologics have comparable safety profiles based on various neonatal and pregnancy-related outcomes. In fact, we see significantly higher birthweights in the late cohort along with a consistent (non-statistically significant) trend of later gestational ages, and higher Apgar scores. Further, no cases involving NICU admissions, congenital abnormalities, GBS, or chorioamnionitis were seen in the late cohort. Next, we hope to verify our findings by conducting a prospective cohort study with a larger study population and more comprehensive data collection. This will provide higher statistical power and allow for additional subgroup analyses based on objective disease activity (FCP levels) and therapeutic drug monitoring (serum drug levels).

Funding Agencies

None
A152 INVESTIGATING THE ROLE OF NOVEL NUDT15 VARIANT IN AZATHIOPRINE-RELATED MYELOTOXICITY
Authors: Wang Q , Wilson A
Published: March 2021

Background

Azathioprine (AZA), an immunosuppressant, has classically been used to treat patients with inflammatory bowel disease (IBD). AZA inhibits purine synthesis, and its metabolism occurs via a pathway involving thiopurine methyltransferase (TPMT). While standard TPMT genetic screening is conducted for IBD patients initiating AZA treatment to minimize adverse drug effects (ADE), a majority of patients experiencing ADE have wildtype TPMT. Another gene, NUDT15, has been found to be associated with AZA-related myelotoxicity

Aims

In this study we report two novel variants in NUDT15 and aim to evaluate the impact of NUDT15 variation on its gene expression. We hypothesize that the mutations found within novel NUDT15 variant are detrimental either to the gene’s expression levels or its translation process, resulting in a lower amount of NUDT15 product present and hence translating to AZA-related myelotoxicity observed clinically.

Methods

IBD patients experiencing AZA-related myelotoxicity were recruited for this study. Patients were then genotyped and the NUDT15 variants were replicated through site-directed mutagenesis. The NUDT15 variants were subsequently transformed into mammalian cell lines then E. coli cells. DNA products were isolated, and transcription levels were assessed through RT-PCR.

Results

Patient cohort consisted of 27 AZA-exposed IBD patients who developed myelotoxicity despite their TPMT wildtype genotype. Two novel NUDT15 variants were found. The mutation in one of the variants was placed in 3’ UTR, and hence further research was not pursued. Further analysis was conducted for the variant with mutation in coding region. RT-PCR was conducted to assess and compare gene transcription levels between wildtype and variant NUDT15. Wildtype NUDT15 had a relative gene expression level of 0.8x107, whereas variant NUDT15’s relative gene expression level was at 1.1x107. The two groups were not significantly different in terms of gene expression.

Conclusions

Contrary to our initial hypothesis, it appears that the mutation in the start codon for variant NUDT15 gene does not significantly impact its gene expression as compared to the wildtype gene. We are currently pursuing protein expression analysis studies to assess for translational deficits possibly present in the novel NUDT15 variant.

Funding Agencies

SRTP - Schulich School of Medicine
A154 PROTEOMIC IDENTIFICATION OF INFLAMMATORY AND FIBROSTENOTIC BLOOD SERUM BIOMARKERS IN CROHN’S DISEASE
Authors: Mainoli B , Filyk A K , Lu C , Dufour A
Published: March 2021

Background

Crohn’s disease (CD) is an incurable relapsing-remitting inflammatory bowel disease (IBD) where patients may experience bowel damage with symptoms such as abdominal pain, chronic diarrhea, extraintestinal manifestations and life-long disability. CD is heterogeneous with three distinct phenotypes including a stricturing phenotype marked by intestinal fibrosis. This fibrotic morphology is generally more unresponsive to drug treatment; delaying a patient’s remission, control of the disease and often requiring surgical intervention. Thus, early and accurate identification of fibrostenosis in CD is important to optimize patient treatment and predict response to therapy.

Aims

The aim of our study is to distinguish inflammatory and intestinal fibrostenosis in CD patients using serum protein biomarkers.

Methods

Blood sera from 17 inflammatory and 17 fibrostenotic CD patients were collected. The phenotypic classification was confirmed by intestinal ultrasound and endoscopy. Samples were subjected to Shotgun Proteomics, an unbiased proteomics approach that allows for relative protein quantification. Proteins from each condition were isotopically labelled with formaldehyde (light +28 Da and heavy +34 Da), pooled and digested with trypsin. Following liquid chromatography and tandem mass spectrometry, peptides were then identified by MaxQuant software with a false discovery rate of 1%. Excel (Microsoft), Prism (Graphpad) and Metascape software were used for data filtering and analysis.

Results

Proteomic processing allowed for the identification of novel protein biomarkers in the inflammatory and stricture CD phenotypes. Inflammation was correlated with activation of the complement pathway and fatty acid metabolism; marked by increased levels of immunoglobulin gamma 4 chain (IGHG4), mitochondrial creatinine kinase (CKMT1), apolipoprotein A (LPA) and glutathione peroxidase 3 (GPX3) proteins. Fibrostenosis showed no distinct metabolic pathway, but an elevated expression of SWI/SNF-related matric associated actin (SMARCA5), haptoglobin related protein (HPR), immunoglobulin kappa and immunoglobulin heavy constant proteins.

Conclusions

Our data indicate that inflammation and strictures in CD may be driven by distinct signaling pathways. We identified specific protein signatures for the two phenotypes, which may aid in predicting those who are at risk of developing strictures and in the development of phenotype-specific treatment for CD patients. Future validation of these proteins will be performed to assess this unique protein profile.

Funding Agencies

McCaig Institute for Bone and Joint Health
A160 PREVALENCE OF OUTCOME SWITCHING AMONG PUBLISHED PHASE 3 INTERVENTIONAL TRIALS FOR INFLAMMATORY BOWEL DISEASE THERAPEUTICS
Authors: Bansal R , Khan R , Gimpaya N , Scaffidi M A , Elsolh K , Verma Y , Li J , Grover S C
Published: March 2021

Background

Outcome switching is a well-described form of inconsistent reporting in randomized clinical trials (RCTs), wherein pre-specified primary and/or secondary outcomes are changed between trial registration and the publication of results without explanation. This is of particular concern, as the selective publication of results that are favorable will insert bias into the trial’s results and may cast doubt on the veracity of its findings. While it has been investigated in other disciplines, the prevalence of outcome switching has yet to be described among RCTs for inflammatory bowel disease (IBD).

Aims

To determine the prevalence of correctly reported pre-specified primary and secondary outcomes in published phase 3 interventional RCTs for IBD.

Methods

We identified all phase 3 interventional trials for IBD with published results using clinicaltrials.gov. We included all results with an associated publication that detailed the results of the trial. We excluded registrations if: only an abstract of the results was available; trial results were only published as a pooled analysis; multiple trial segments were reported collectively; or a publication of the results could not be identified through clinicaltrials.gov or a custom search.

Two reviewers extracted all pre-specified primary and secondary outcomes for each trial using the clinical trial registration page that was dated before the commencement of the trial. These outcomes were compared to the outcomes reported in the corresponding journal articles. Any discrepancies were noted, and additional outcomes were extracted.

Results

We identified a total of 88 phase 3 interventional RCTs for IBD, of which 57 were matched to independent publications of their results. All trials pre-specified a primary outcome, and 50 (87.7%) pre-specified secondary outcomes. 10 (17.5%) of trials did not report some or all primary outcomes, and 19 (33.3%) trials had a change or alteration to the primary outcome. Of the trials that pre-specified secondary outcomes, 16 (28.1%) did not report all pre-specified secondary outcomes. 49 (86.0%) trials added 6 (IQR: 2–8) unspecified secondary outcomes on average.

Conclusions

Many phase 3 interventional RCTs in IBD either did not report some or all primary outcomes, or altered the primary outcome. Trials routinely reported additional outcomes that were not pre-specified and failed to note that they were added post hoc. Based on these results, we recommend improvements in the reporting of pre-specified outcomes and higher fidelity in order to maintain confidence in trial results.

Funding Agencies

None
A161 PREVALENCE OF FINANCIAL CONFLICTS OF INTEREST (FCOI) AMONG PROPENSITY-SCORE MATCHED RETROSPECTIVE STUDIES EVALUATING BIOLOGIC THERAPEUTICS FOR IBD
Authors: Elsolh K , Tham D , Scaffidi M A , Bansal R , Li J , Verma Y , Gimpaya N , Khan R , Grover S C
Published: March 2021

Background

Inflammatory Bowel Disease (IBD) studies have commonly relied on real-world evidence to evaluate different therapies. An emerging idea has been the use of propensity score matching as a statistical method to account for baseline characteristics in IBD patients. In retrospective studies, propensity score matching of patients helps reduce treatment assignment bias and mimic the effects of randomization. Recently, propensity-score matching has become an important tool in IBD studies comparing biologic therapeutics. Biologic medications are among the highest-grossing drugs worldwide, and their pharmaceutical producers make considerable payments to physicians to market them. In spite of this, there is a lack of evidence examining the role of undue industry influence among propensity-score matched comparative studies evaluating biologic therapeutics for IBD.

Aims

Given the documented association between IBD biologics and FCOI, we hypothesize a high burden of FCOI in propensity-score matched studies. The aim of this study was to evaluate the prevalence of disclosed & undisclosed financial conflicts of Interest (FCOI) in propensity-score matched comparison studies evaluating biologics for IBD.

Methods

We developed & ran a librarian-reviewed systematic search on EMBASE, MEDLINE, and Cochrane Library databases for all propensity-score matched retrospective studies comparing biologics for the treatment of IBD. Full-text retrieval & screening was performed on all studies in duplicate. 16 articles were identified. Industry payments to authors were only considered FCOI if they were made by a company producing a biologic that was included in the comparison study. Disclosed FCOI were identified by authors’ interests disclosures in full-texts. Any undisclosed FCOI among US authors were identified using the Centre for Medicare and Medicaid Services (CMS) Open Payments Database, which collects industry payments to physicians.

Results

Based on a preliminary analysis of 16 studies, there was at least one author with a relevant FCOI in 14 (88%) of the 16 studies. 14 studies (88%) had at least one disclosed FCOI, while 6 studies (37.5%) had at least one undisclosed FCOI. Among studies with disclosed FCOI, a mean of 40.2% (SD = 23.4%) of authors/study reported FCOI. Among studies with undisclosed FCOI, a mean of 18.8% (SD = 7.0%) of authors/study reported FCOI. The total dollar value of FCOIs was $1,974,328.3. The median conflict dollar value was $5,576.6 (IQR: $321.6 to $36,394.9).

Conclusions

We found a high burden of undisclosed FCOI (37.5%) among authors of propensity-score matched studies evaluating IBD biologics. Given the potential for undue industry influence stemming from such payments, authors should ensure better transparency with industry relationships.

Funding Agencies

None
A163 MAJORITY OF INFLAMMATORY BOWEL DISEASE PATIENTS WITH RECURRENT CLOSTRIDIOIDES INFECTION DO NOT REQUIRE FECAL MICROBIOTA TRANSPLANTATION
Authors: Balram B , winczura n , Kao D H , Dieleman L A , Halloran B , Kroeker K , Peerani F , Huang V , Wong K
Published: March 2021

Background

Patients with inflammatory bowel disease (IBD) are at increased risk of developing Clostridioides difficile infection (CDI) and have worse outcomes including higher rates of colectomy and death, and experience higher rates of recurrent CDI (rCDI). However, it is still not clear whether rCDI is a cause of refractory IBD or a consequence of the inflammatory state in the colon.

Aims

We aimed to assess the outcomes of rCDI in patients with active IBD compared to inactive IBD in the era of fecal microbiota transplantation (FMT)

Methods

This is a retrospective cohort of adult IBD patients with rCDI at the IBD centre at the University of Alberta hospital between 2014–2017. rCDI was defined as a recurrent episode occurring within 60 days of the prior after successful treatment with antibiotics. We collected demographic and clinical characteristics, along with the rCDI-related and FMT outcomes in patients with active and inactive IBD. Active IBD was based on clinical assessment using a combination of disease severity scores (Harvey Bradshaw Index, partial Mayo scores), presence of active disease on colonoscopy, clinical symptoms and/or treatment escalation or change in the month leading up to rCDI diagnosis.

Results

Over the study period, 56 IBD patients (50% ulcerative colitis, 28/56) had a total of 85 rCDI episodes. Thirty-four percent (19/56) of patients had two or more rCDI episodes. Forty-one percent (35/85) of rCDI episodes were toxin positive while the remainder were only PCR positive. Thirty-nine percent (33/85) had active IBD at the time of CDI diagnosis. Patients with active IBD were more likely to have rCDI (1.7 rCDI episodes vs. 1.5, p=0.018). IBD treatment escalation was also more likely in the active IBD cases (79% vs. 44%, p = 0.002) with the use of steroids (27% vs 2%, p = 0.001) and addition of biologics (18% vs. 2%, p = 0.013). Active IBD cases were also more likely to be hospitalized (30% vs. 10%, p = 0.02) and were more likely to receive FMT (27% vs. 4%, p = 0.003). There was no difference in the time between rCDI episodes, antibiotic exposure or colectomy rates between the two groups.

Conclusions

Compared to IBD patients in remission, patients with active IBD are more likely to experience rCDI, IBD treatment escalation and FMT. It is interesting to note that only 27% of patients with recurrent CDI required FMT suggesting CDI may be a marker of active or refractory disease rather than a cause. Larger, prospective studies are needed to help clarify this association.

Funding Agencies

None
A165 DOES APPENDECTOMY PREVENT THE SUBSEQUENT DEVELOPMENT OF ULCERATIVE COLITIS?: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Abdali D , Narula N
Published: March 2021

Background

Ulcerative colitis (UC) is a disease with a heavy burden of morbidity, for which we do not fully understand its etiology. Researchers have anecdotally observed a preventative effect of appendectomy on the risk of developing UC, with multiple studies exploring this relationship.

Aims

We aimed to complete a systematic review and meta-analysis, the largest of its kind, to determine with more certainty the effect of appendectomy on the subsequent development of UC.

Methods

A literature search and a review of reference lists of previously published articles was done to identify studies exploring the association between appendectomy and the subsequent development of UC. Our primary endpoint was the diagnosis of UC. Other variables of interest were geographical region, publication date, and age at time of appendectomy. Odds ratios with 95% confidence intervals (CI) are reported.

Results

Fifty-one studies (49 case-controls studies and 2 cohort studies) were included with a total of 1,270,332 participants. The pooled OR showed that appendectomy decreases the odds of developing UC (Figure 1; OR 0.37, 95% CI, 0.29–0.46, I2 = 89%). A similar pattern was seen for individuals who received an appendectomy before the age of 20 (Figure 2; OR 0.35, 95% CI, 0.21–0.61, I2 0%). The protective effect was seen again when including only high quality methodological studies with Newcastle-Ottawa scale ≥ 7 (Figure 3; OR 0.47, 95% CI, 0.34–0.65, I2 56%).

Conclusions

Appendectomy may be protective against subsequent development of UC. Future research should focus on the physiological explanation behind this association, and the practicality of using appendectomy as a primary prevention measure in patients at high-risk of developing ulcerative colitis.

Funding Agencies

None
A175 BEHAVIORAL INTERVENTIONS TO ADDRESS INFLAMMATORY BOWEL DISEASE-RELATED DISTRESS AND QUALITY OF LIFE: A SYSTEMATIC REVIEW AND META-ANALYSIS.
Authors: Reise-Filteau M , Heisler C , Shepherd T , Stewart M J , Jones J
Published: March 2021

Background

Inflammatory bowel disease-associated psychological distress (IBD-PD) (inclusive of anxiety, depression, and high levels of stress) is prevalent amongst persons living with IBD. IBD-PD impairs quality of life (QoL) and worsens disease outcomes. Research relating to the efficacy of behavioral interventions for IBD-PD has been limited.

Aims

This systematic review and meta-analysis was conducted to evaluate the efficacy of cognitive behavioral therapy (CBT)-based interventions for the management of IBD-PD and QoL in persons living with IBD.

Methods

Pre-defined criteria were used to identify randomized controlled studies reporting on the efficacy of CBT-based interventions for IBD-PD and QoL in adults living with IBD. Electronic databases including CINAHL, Cochrane Library, Embase, MEDLINE, PsycArticles, PsycInfo, Pubmed, and Web of Science were searched from inception to May 30, 2020. Studies published in English or French were included. Risk of bias was assessed using the Cochrane risk-of-bias tool by two independent reviewers (CH and MRF). Data was extracted and summarized qualitatively. A random-effects model was used to generate pooled estimates.

Results

Eight studies (922 participants) met criteria for inclusion in this review. The studies evaluated outcomes of quality of life and IBD-PD using the IBD Questionnaire (IBDQ), United Kingdom IBDQ, Short IBSQ, 36-Item Short Form Survey (SF-36), Short Health Scale, Perceived Stress Questionnaire (PSQ), Perceived Stress Scale (PSS-10), Hospital anxiety depression scale (HADS) and the Depression, Anxiety and Stress Scale-21 Items (DASS-21). Of the 8 studies, 2 were low, 2 high, and 4 at intermediate risk of bias. Interventions, duration, and outcome assessments differed across studies and observed attrition rates were high. The pooled odds ratio for the short-term impact of CBT on IBDQ (n=3) was 0.30 (95% CI 0.17- 0.44) favoring CBT. Perceived stress (PSQ and PSS-10) were only reported in 3 studies as secondary outcomes. Overall, CBT had no observed benefit for perceived stress. Measurement of anxiety and depression was inconsistent across studies. The impact of CBT on anxiety and depression varied with studies revealing both neutral and positive results.

Conclusions

In patients IBD-PD, CBT-based interventions were observed to lead to short-term improvements in disease-related QoL. The impact of CBT on IBD-PD remains unclear due to limitations in study quality and heterogeneity in study design. Further studies are needed to evaluate the efficacy of CBT-based interventions for IBD-PD and to define the role of behavioral interventions delivered within the context of collaborative, biopsychosocial models of care. Expert consensus on best practice for CBT-based interventions and IBD-PD evaluation are needed.

Funding Agencies

None
A182 INFLAMMATORY BOWEL DISEASE AMONG SENIORS IN SASKATCHEWAN
Authors: Shahmoradi A , Fowler S , Peña-Sánchez J
Published: March 2021

Background

Inflammatory bowel disease (IBD) is a chronic inflammatory condition comprised of two major disorders: ulcerative colitis (UC) and Crohn’s disease (CD).The age of onset for many patients with UC and CD is between 15 and 30 years, with a second peak between 50 and 80 years of age.

Aims

We aim to determine if there are differences in disease characteristics, outcomes, and IBD-related health care utilization between elderly patients with IBD diagnosed at a young age compared to those diagnosed later in life.

Methods

A retrospective chart review of elderly (age ≥ 60 years) patients with IBD was conducted.Patients aged ≥ 60 years who were seen at the Saskatchewan Multidisciplinary IBD Clinic at the Royal University Hospital from 2012 to 2020 were included. Information on demographics, disease characteristics, and access to IBD-related health care was collected. Patients were divided in two groups according to age of diagnosis: <60 and ≥ 60 years. Chi-squares were used to compare the groups. Charts with missing data were omitted in the final analysis. Three patients with indeterminant colitis were excluded from the analyses. Logistic regression models were built to obtain odds ratios (OR) with their corresponding 95% confidence intervals (95%CI) and considering potential confounders.

Results

In total, 264 patients were included in the study; 210(79.5%) diagnosed <60 and 54(20.5%) ≥ 60. The mean age of diagnosis was 47.21(SD=16.18), [<60=41.69(SD=13.25), ≥60=68.00(SD=6.264)].Cross tabulation (Table 2) of age of diagnosis and patient’s characteristics (sex, IBD type, and clinical remission at last visit, current use of biologics and steroids) confirmed lack of inter-variable significance. However, in the same analysis individuals diagnosed ≥ 60 were more likely to be on 5-ASA therapy compared to their counterparts diagnosed before the age of 60. Logistic regression model results demonstrated that: Patients diagnosed ≥ 60 years were 2.06 (1.12–3.80, 95% CI) times more likely to be using 5-ASA therapy.Patients in clinical remission were 3.04 (95% CI, 1.65–5.61) times more likely to be using biologic therapy.

Conclusions

Thus far, the results indicate significant correlation between use of 5-ASA in patients diagnosed age ≥60. In the same cohort, clinical remission was also linked to current use of biologics agents. On further analysis, with data stratification based on type of IBD, the same significance did not hold true, likely associated with low power within the stratified group. Clinical remission with those diagnosed ≥60 years while on biologics treatment, may reflect the specific disease type and inflammatory pathways responsible for second wave of IBD diagnosis in later ages.Patients diagnosed later in life were less likely to have IBD-related hospitalization or surgery, likely a reflection of shorted disease history.

Funding Agencies

NoneNone
A198 LEFLUNOMIDE-INDUCED COLITIS IN IMMUNOSUPPRESSED PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND RHEUMATOID ARTHRITIS
Authors: Chis R , Gladman D , Vajpeyi R , Cino M
Published: March 2021

Background

Leflunomide is an oral disease-modifying antirheumatic drug (DMARD), with anti-inflammatory and immunomodulatory properties that has been in use since 1998. Common leflunomide side-effects include gastrointestinal symptoms (nausea, abdominal pain and diarrhea), occurring in 10–20% of patients treated with leflunomide. Scarce evidence exists that leflunomide can cause colitis.

Aims

We present the case of a 61-year-old female, with Lupus Erythematosus who presented with colitis induced by long-term leflunomide treatment.

Methods

Case report and review of literature

Results

A 61-year-old female was seen by the gastroenterology team with complaints of diarrhea ongoing for 6 weeks associated with 10 lb weight loss. The patient had a complex medical history, including lupus, hypothyroidism, asthma, atrial fibrillation, recurrent C. difficile infection, Bell’s palsy and avascular necrosis secondary to long-term corticosteroid therapy. Previous immunosuppressive therapies included prednisone, mycophenolic acid (Myfortic), hydroxychloroquine, azathioprine, mycophenolate (CellCept) but due to multiple intolerances, she was initiated on leflunomide in 2014 and has been maintained on it since.

Stool analysis ruled out infectious causes. COVID-19 testing was also negative. A CT of the abdomen revealed pancolitis. This was confirmed on colonoscopy, which revealed mild, Mayo 1 pancolitis and normal terminal ileum. She was initiated on Mezavant as a treatment for possible ulcerative colitis. However, during the hospitalization her symptoms, worsened and bloody diarrhea was noted. She underwent a subsequent endoscopic evaluation which revealed more severe disease, Mayo 2–3 colitis, with mucosal hyperemia and ulcerations, as well as effacement of the vasculature. Initial pathology results revealed mild colitis, but repeat pathology results revealed moderate active colitis, with cryptitis, crypt abscesses and significant apoptosis consistent with drug-induced colitis. Given these findings, the diagnosis of leflunomide-induced colitis was made. Leflunomide was therefore discontinued, the patient was initiated on a higher dose of corticosteroids and cholestyramine was initiated. Following these measures, her diarrhea resolved.

Conclusions

Leflunomide may cause diarrhea in up to 33% of patients. Challenges related to the diagnosis of leflunomide-induced colitis exist, including the rarity of the diagnosis, a not completely understood mechanism for acute leflunomide-induced diarrhea, as well as variable endoscopic and histologic findings associated with the diagnosis. This report illustrates a case of leflunomide-induced colitis which should be considered in patients on leflunomide, who present with symptoms of abdominal pain and diarrhea, even years after medication initiation.

Funding Agencies

None
A202 ROLE OF EXTRACELLULAR VESICLES IN GIARDIA-MICROBIOTA INTERACTIONS.
Authors: Siddiq A , Allain T , Dong G , Olivier M , Buret A
Published: March 2021

Background

Extracellular vesicles (EVs) have emerged as important mediators of host-parasite interactions. Studies in various parasites have shown that EVs have important roles in pathogenesis. The protozoan parasite Giardia duodenalis, which causes diarrheal disease, produces EVs in response to changes in the environment. However, their exact role in the pathogenesis of giardiasis remains unclear. In this study, we investigate the effects of Giardia EVs on the gut commensal bacteria. EVs mediated disruption of the microbiota represents a novel mechanism that has not been investigated before.

Aims

We hypothesize that Giardia EVs contain virulence factors that will modify the growth and behavior of commensal bacteria. Based on our hypothesis, the study has three aims:

1. Quantify and characterize the EVs produced by Giardia under varying conditions.

2. Examine the effects of Giardia EVs on commensal bacteria.

3. Identify proteins and virulence factors in Giardia EVs using proteomics.

Methods

G. duodenalis (isolate NF) was exposed to bile or left untreated and the EVs were isolated using Exo-Easy Maxi Kit (Qiagen). The isolated EVs were characterized using Nanosight track analysis (NTA) and transmission electron microscopy. To examine the effects of EVs on bacteria, we used a lab strain E.coli HB101 and human isolate E. cloacae. The bacteria were incubated with Giardia EVs and their growth rate was monitored using a bacterial kinetics assay. The swimming motility of bacteria exposed to Giardia EVs was assessed on a 0.3% agar. Additionally, the ability of the EVs treated bacteria to adhere to epithelial cells was also examined. Proteomic analysis of EVs was conducted using liquid chromatography with tandem mass spectrometry.

Results

Results indicate that bile treated Giardia trophozoites produce more EVs as compared to untreated trophozoites. Giardia EVs exerted bacteriostatic effects on E.coli HB101 and E. cloacae. Additionally, Giardia EVs significantly increased the swimming motility of both E.coli HB101 and E. cloacae as well as their adhesion to the intestinal epithelial cells. Finally, proteomic analysis of EVs revealed the presence of well-characterized Giardia virulence factors such as cysteine proteases, tenascins, variant surface proteins as well as metabolic enzymes such as arginine deaminase and ornithine carbamoyltransferase.

Conclusions

Our research highlights a novel mechanism of Giardia’s interaction with commensal bacteria. Our results indicate that Giardia can release EVs in response to changes in the environment. These EVs also contain virulence factors that can modify the growth and behavior of commensal bacteria. These effects may have significant implications in disease pathophysiology. The results of the study can also be applied to other parasitic diseases where the production of EVs has been shown to play a role in the pathogenesis process.

Funding Agencies

NSERC
A217 NONINVASIVE ASSESSMENTS TO IDENTIFY PATIENTS WITH ADVANCED FIBROSIS DUE TO NASH: SCREENED POPULATION FROM THE REGENERATE TRIAL
Authors: Montano-Loza A J , Boursier J , Sanyal A J , Ratziu V , Rinella M , Loomba R , Dufour J , Mozaffari E , Shringarpure R , MacConell L , Granston T , Zhou H , Trylesinski A , Harrison S A , Bedossa P , Goodman Z , Younossi Z , Noureddin M , Bugianesi E , Anstee Q M
Published: March 2021

Aims

We explored the ability of noninvasive tests (NITs) to identify patients (pts) with advanced fibrosis due to NASH.

Methods

All screened pts from the ongoing phase 3 REGENERATE with available histology data were included. Five NITs were evaluated using established literature cutoffs to identify or exclude advanced fibrosis (values between upper and lower thresholds were considered indeterminate): Aspartate Transaminase-to-Platelet Ratio Index (APRI; ≥0.57, ≤0.84), Enhanced Liver Fibrosis (ELF; ≥7.7, <9.8), Fibrosis-4 (FIB-4; ≥1.30, <2.67), NAFLD fibrosis score (NFS; ≥−1.455, <0.676), and Transient Elastography (TE; ≥7.9 kPa, <9.6 kPa). Three testing methods applied were single NIT, 2 simultaneous NITs weighted equally (NFS+ELF, FIB-4+ELF, NFS+TE, FIB-4+TE), and 2 sequential NITs with the second test performed only if the first test was indeterminate (NFS→ELF, FIB-4→ELF, NFS→TE, FIB-4→TE).

Results

4133 pts in the REGENERATE screened population had an available biopsy (baseline liver biopsy: F0, 15.5%; F1, 27.2%; F2, 21.2%; F3, 29.6%; F4, 6.5%). Of these, 96% had FIB-4, NFS, and APRI, 41% had TE, and 28% had ELF. Single NITs with upper thresholds demonstrating strong specificity for identification of advanced fibrosis were FIB-4 (97%), NFS (94%), and APRI (86%); NITs with lower thresholds demonstrating good sensitivity for identification of early fibrosis were ELF (100%) and TE (88%). Evaluation of 2 simultaneous NITs resulted in a greater percentage of pts in the indeterminate zone. Application of 2 sequential tests improved the accuracy of identification and reduced misclassification vs 2 simultaneous tests.

Conclusions

Sequential NIT strategies may decrease liver biopsy rates while maintaining the accuracy of noninvasive diagnosis in pts with advanced fibrosis due to NASH.

Funding Agencies

Intercept Pharmaceuticals
A218 A CASE REPORT OF PSEUDOHYPONATREMIA IN CHOLESTATIC LIVER DISEASE
Authors: Shpoliansky M , Kamath B
Published: March 2021

Background

True hyponatremia in the setting of cholestatic liver disease may signify cirrhosis with fluid overload, and is therefore an ominous sign of deteriorating liver function. In pediatric liver transplant candidates, it is associated with increased waitlist mortality. Pseudohyponatremia however, is a falsely low measurement of plasma sodium when measured by indirect potentiometry. Pseudohyponatremia secondary to hypercholesterolemia is a phenomenon that occurs due to a reduced aqueous fraction of the plasma when levels of cholesterol or triglycerides are greatly elevated. Severe hypercholesterolemia due to Lipoprotein X accumulation may be the cause of pseudohyponatremia in biliary obstruction or cholestasis.

Aims

To describe a case of pseudohyponatremia secondary to hypercholesterolemia in an infant with Alagille syndrome (ALGS) and cholestatic liver disease.

Methods

This 7 month-old male with ALGS (confirmed JAGGED1 mutation) and severe cholestasis, failure to thrive, and pruritus, developed new-onset progressive hyponatremia as low as 121 mmol/L at an outside institution. He was therefore transferred to our center for liver transplant assessment due to concerns of progressive liver dysfunction and for management of the hyponatremia.

Results

Upon admission, the patient was jaundiced but euvolemic, with no evidence of ascites or peripheral edema. Laboratory work drawn at our institution showed conjugated bilirubin of 180 mmol/L, ALT 300 U/L, AST 250 U/L, and GGT 1200 U/L. INR was 1.1 and albumin of 35 g/L. The cholesterol was elevated above 16.8 mmol/L, with high triglycerides 2.68 mmol/L, and the serum appeared visibly lipemic. The sodium level was 138 mmol/L as measured by direct potentiometry due to the visible lipemia. The osmolality of 288 mmol/kg was normal with a normal osmolar gap. Urine osmolality and sodium were also normal. He underwent routine evaluation and was listed for a liver transplant due to the profound cholestasis and growth failure.

Conclusions

Pseudohyponatremia is an important entity to recognize when caring for patients with cholestatic liver disease and hyponatremia. Both direct potentiometry and indirect potentiometry are currently used for sodium testing in blood in biochemistry laboratories. These measurement techniques show good agreement as long as protein and lipid concentrations in blood are normal, however, hyperlipidemia is a well-recognized cause for error in sodium estimation. It is therefore imperative to evaluate apparent hyponatremia correctly, especially when the patient appears euvolemic clinically and by normal serum osmolality. In this clinical setting, pseudohyponatremia is the likely cause and a workup should be carried out to identify possible underlying etiologies, the most probable being hypercholesterolemia. Failure to recognize this phenomenon may lead to unnecessary and potentially harmful treatments and interventions.

Funding Agencies

None
A223 FRAILTY INCREASES THE RISK OF CIRRHOSIS DISEASE PROGRESSION, DEATH, AND HOSPITALIZATION IN CIRRHOSIS
Authors: Wang S , Xu C , Whitlock R , Taneja S , Singh S , Abraldes J , Lai J , Tandon P
Published: March 2021

Background

In cirrhosis, frailty is associated with increased risk of morbidity and mortality, including an increased risk of hospitalization. While frailty is established as a prognostic marker in cirrhosis, its impact on the progression of cirrhosis, especially in earlier stages of disease, remains unclear.

Aims

To determine the relationship between frailty and risk of cirrhosis progression, mortality, and unplanned hospitalizations in patients with cirrhosis across the spectrum of disease.

Methods

Adult patients with cirrhosis from two centers in North America and one in India were included in this retrospective review of prospectively collected data. Frailty was measured at baseline using the Liver Frailty Index (LFI), comprising grip strength, chair stands, and balance testing. Progression of cirrhosis was defined by an increase from one ordinal stage to the next using the D’Amico classification. Factors associated with progression, mortality, and hospitalizations were evaluated using multivariate competing risk regression models, with transplant as a competing risk.

Results

In total, 822 patients with cirrhosis were included. The median MELD score was 15.5 ± 6.0. Of these patients, 201 (24.5%), 488 (59.4%), and 133 (16.2%) were classified as frail, pre-frail, and robust, respectively. Over a median follow up time of 1.2 years, 60 (7.3%) patients developed progression of cirrhosis, 187 (22.7%) died, 233 (28.3%) underwent liver transplantation, and 342 (41.6%) were alive without cirrhosis progression or transplant. Adjusting for age, sex, and MELD at baseline, being frail was associated with an increased risk of progression to the next cirrhosis stage or to death as compared to being robust (HR 2.47, 95% CI 1.63–3.76, p<0.001). As a continuous variable, every increase in the LFI by 0.1 unit increased the risk of decompensation or death by 1.05-fold (95% CI 1.04–1.07, p<0.001). Similarly, patients who were frail were more likely to be hospitalized as compared to patients who were robust (HR 2.88, 95% CI 2.08–3.98, p<0.001).

Conclusions

Frailty was associated with an increased risk of cirrhosis progression or death, and hospitalization, independent of MELD at baseline. Future studies are needed to evaluate the possibility of slowing cirrhosis disease progression by reversing or preventing frailty.

Funding Agencies

None
A225 INFERIOR VENA CAVA STENOSIS AFTER HEPATIC LOBECTOMY: A RARE CAUSE OF PORTAL HYPERTENSION AND REFRACTORY ASCITES
Authors: Collins A W , Brahmania M , Tsoi K
Published: March 2021

Background

Inferior vena cava (IVC) stenosis is a rare occurrence in post-liver transplant patients, affecting less than 3% of recipients. IVC stenosis is rarely described in non-transplant patients or considered in the differential of portal hypertension and refractory ascites. Patients with IVC stenosis may experience lower extremity edema, dyspnea, ascites and other signs of portal hypertension.

Aims

We describe a case of portal hypertension and refractory ascites secondary to IVC stenosis following hepatic lobectomy.

Methods

Case report.

Results

We report a 61-year-old woman with a history of diabetes, obesity status post sleeve gastrectomy and solitary neuroendocrine tumor of the right hepatic lobe, adjacent to the porta hepatis with no evidence of metastasis. She underwent a laparoscopic right hepatectomy with wedge resection (<5 cm) in segment 4 to remove the neuroendocrine tumor in 2016. Surgery also included an intraoperative cholangiogram and placement of intra-ductal stent using endoscopic retrograde cholangiopancreatography (ERCP) technology as well as significant adhesiolysis along the IVC, right hepatic vein and biliary tract. In February 2020, the patient was referred to Hepatology for evaluation of new ascites. Imaging did not demonstrate evidence of tumor recurrence or features of cirrhosis but identified a new findings of portal hypertension and moderate ascites. Common causes of chronic liver disease were excluded and hepatic synthetic function was normal. Paracentesis revealed a high serum albumin ascites gradient (SAAG; 20 g/L) and a high ascitic fluid protein (34 g/L). Although these findings were suggestive of cardiac ascites, a 2D echocardiogram was normal. A trans-jugular liver biopsy was attempted in July 2020. The right atrial pressure was 8 mmHg and inferior vena cava (IVC) pressure was 22 mmHg at the level of the liver. Loss of pulsation suggested hemodynamically significant stenosis of the hepatic IVC. The wedged hepatic venous pressure was 3 mmHg and the calculated portal systemic gradient was 4 mmHg. A trans jugular biopsy failed due to unfavourable anatomy. These findings, taken in conjunction with previous results, suggested non-cirrhotic post-hepatic portal hypertension. Subsequent computed tomography imaging confirmed stenosis of the hepatic portion of the IVC and this was felt to be the ultimate cause of the portal hypertension. She has since been referred back to interventional radiology (IR) for consideration of balloon angioplasty dilation of the IVC stenosis as well as additional testing to determine if there is any underlying hepatic fibrosis related to congestive hepatopathy.

Conclusions

IVC stenosis post hepatic lobectomy is a rare phenomenon described in the literature but warrants high suspicion in cases of refractory ascites.

Funding Agencies

None