The effect of iron therapy on oxidative stress and intestinal microbiota in inflammatory bowel diseases: A review on the conundrum.

One in five patients with Inflammatory Bowel Disease (IBD) suffers from anemia, most frequently caused by iron deficiency. Anemia and iron deficiency are associated with worse disease outcomes, reduced quality of life, decreased economic participation, and increased healthcare costs. International guidelines and consensus-based recommendations have emphasized the importance of treating anemia and iron deficiency. In this review, we draw attention to the rarely discussed effects of iron deficiency and iron therapy on the redox status, the intestinal microbiota, and the potential interplay between them, focusing on the clinical implications for patients with IBD. Current data are scarce, inconsistent, and do not provide definitive answers. Nevertheless, it is imperative to rule out infections and discern iron deficiency anemia from other types of anemia to prevent untargeted oral or intravenous iron supplementation and potential side effects, including oxidative stress. Further research is necessary to establish the clinical significance of changes in the redox status and the intestinal microbiota following iron supplementation.

Disease activity in inflammatory bowel disease patients is associated with increased liver fat content and liver fibrosis during follow-up.

PURPOSE: Liver steatosis is a frequently reported condition in patients with inflammatory bowel disease (IBD). Different factors, both metabolic and IBD-associated, are believed to contribute to the pathogenesis. The aim of our study was to calculate the prevalence of liver steatosis and fibrosis in IBD patients and to evaluate which factors influence changes in steatosis and fibrosis during follow-up. METHODS: From June 2017 to February 2018, demographic and biochemical data was collected at baseline and after 6-12 months. Measured by transient elastography (FibroScan), liver steatosis was defined as Controlled Attenuation Parameter (CAP) ≥248 and fibrosis as liver stiffness value (Emed) ≥7.3 kPa. IBD disease activity was defined as C-reactive protein (CRP) ≥10 mg/l and/or fecal calprotectin (FCP) ≥150 µg/g. Univariate and multivariate regression analysis was performed; a p-value of ≤0.05 was considered significant. RESULTS: Eighty-two out of 112 patients were seen for follow-up; 56% were male. The mean age was 43 ± 16.0 years, and mean BMI was 25.1 ± 4.7 kg/m2. The prevalence of liver steatosis was 40% and of fibrosis was 20%. At baseline, 26 patients (32%) had an active episode of IBD. Using a multivariate analysis, disease activity at baseline was associated with an increase in liver steatosis (B = 37, 95% CI 4.31-69.35, p = 0.027) and liver fibrosis (B = 1.2, 95% CI 0.27-2.14, p = 0.016) during follow-up. CONCLUSIONS: This study confirms the relatively high prevalence of liver steatosis and fibrosis in IBD patients. We demonstrate that active IBD at baseline is associated with both an increase in liver steatosis and fibrosis during follow-up.

The Pathogenesis of Extraintestinal Manifestations: Implications for IBD Research, Diagnosis, and Therapy.

This article reports on the sixth scientific workshop of the European Crohn's and Colitis Organisation [ECCO] on the pathogenesis of extraintestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. This paper has been drafted by 15 ECCO members and 6 external experts [in rheumatology, dermatology, ophthalmology, and immunology] from 10 European countries and the USA. Within the workshop, contributors formed subgroups to address specific areas. Following a comprehensive literature search, the supporting text was finalized under the leadership of the heads of the working groups before being integrated by the group consensus leaders.

The Impact of Ethnicity and Country of Birth on Inflammatory Bowel Disease Phenotype: a Prospective Cohort Study.

BACKGROUND AND AIMS: The number of patients with inflammatory bowel disease [IBD], of non-Caucasian descent in Western Europe, is increasing. We aimed to explore the impact of ethnicity and country of birth on IBD phenotype. METHODS: IBD patients treated in the eight University Medical Centers in The Netherlands [Dutch IBD Biobank] were divided into two groups according to their ethnicity: 1] Caucasian patients of Western and Central European descent [CEU]; and 2] patients of non-Caucasian descent [non-CEU]. The non-CEU group was subdivided according to country of birth, into: born in The Netherlands or Western Europe [non-CEU European born]; or born outside Western-Europe who migrated to The Netherlands [non-CEU non-European born]. Both comparisons were analysed for phenotype differences [by chi-square test]. RESULTS: The Dutch IBD Biobank included 2921 CEU patients and 233 non-CEU patients. Non-CEU Crohn's disease [CD] patients more often had upper gastro-intestinal disease [16% vs 8%, p = 0.001] and anal stenosis [10% vs 4%, p = 0.002] than CEU CD patients. The use of anti-tumour necrosis factor [TNF] agents and immunomodulators was higher in non-CEU IBD patients than in CEU IBD patients [45% vs 38%, p = 0.042] and [77% vs 66%, p = 0.001], respectively. Non-CEU IBD patients born in Europe [n = 116] were diagnosed at a lower age than non-CEU IBD patients born outside Europe [n = 115] [at 22.7 vs 28.9 years old, p < 0.001]. CONCLUSION: Non-Caucasians had more severe disease behaviour than Caucasians. Non-CEU patients born in Europe were diagnosed at a lower age with IBD than those born outside Europe who migrated to The Netherlands.

Smoking is Associated with Higher Disease-related Costs and Lower Health-related Quality of Life in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Smoking affects the course of inflammatory bowel disease [IBD]. We aimed to study the impact of smoking on IBD-specific costs and health-related quality-of-life [HrQoL] among adults with Crohn's disease [CD] and ulcerative colitis [UC]. METHODS: A large cohort of IBD patients was prospectively followed during 1 year using 3-monthly questionnaires on smoking status, health resources, disease activity and HrQoL. Costs were calculated by multiplying used resources with corresponding unit prices. Healthcare costs, patient costs, productivity losses, disease course items and HrQoL were compared between smokers, never-smokers and ex-smokers, adjusted for potential confounders. RESULTS: In total, 3030 patients [1558 CD, 1054 UC, 418 IBD-unknown] were enrolled; 16% smoked at baseline. In CD, disease course was more severe among smokers. Smoking was associated with > 30% higher annual societal costs in IBD (€7,905 [95% confidence interval €6,234 - €9,864] vs €6,017 [€5,186 - €6,946] in never-smokers and €5,710 [€4,687 - €6,878] in ex-smokers, p = 0.06 and p = 0.04, respectively). In CD, smoking patients generated the highest societal costs, primarily driven by the use of anti-tumour necrosis factor compounds. In UC, societal costs of smoking patients were comparable to those of non-smokers. Societal costs of IBD patients who quitted smoking > 5 years before inclusion were lower than in patients who quitted within the past 5 years (€ 5,135 [95% CI €4,122 - €6,303] vs €9,342 [€6,010 - €12,788], p = 0.01). In both CD and UC, smoking was associated with a lower HrQoL. CONCLUSIONS: Smoking is associated with higher societal costs and lower HrQoL in IBD patients. Smoking cessation may result in considerably lower societal costs.

Smoking is Associated With Extra-intestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Smoking affects the course of disease in patients with ulcerative colitis (UC) and Crohn's disease (CD). We aimed to study the association between smoking and extra-intestinal manifestations (EIMs) in inflammatory bowel disease (IBD). METHODS: We cross-sectionally explored the association between smoking and EIMs in IBD in three cohort studies: (1) the COIN study, designed to estimate healthcare expenditures in IBD; (2) the Groningen study, focused on cigarette smoke exposure and disease behaviour in IBD; and (3) the JOINT study, evaluating joint and back manifestations in IBD. RESULTS: In the COIN, Groningen and JOINT cohorts, 3030, 797 and 225 patients were enrolled, of whom 16, 24 and 23.5% were current smokers, respectively. Chronic skin disorders and joint manifestations were more prevalent in smoking IBD patients than in non-smokers (COIN, 39.1 vs 29.8%, p <0.01; Groningen, 41.7 vs 30.0%, p <0.01) in both CD and UC. In the JOINT cohort, smoking was more prevalent in IBD patients with joint manifestations than in those without (30.3 vs 13.0%, p <0.01). EIMs appeared to be more prevalent in high- than in low-exposure smokers (56.0 vs 37.1%, p = 0.10). After smoking cessation, the prevalence of EIMs in IBD patients rapidly decreased towards levels found in never smokers (lag time: COIN cohort, 1-2 years; Groningen cohort, within 1 year). CONCLUSIONS: There is a robust dose-dependent association between active smoking and EIMs in both CD and UC patients. Smoking cessation was found to result in a rapid reduction of EIM prevalence to levels encountered in never smokers.

Classifying Back Pain and Peripheral Joint Complaints in Inflammatory Bowel Disease Patients: A Prospective Longitudinal Follow-up Study.

BACKGROUND AND AIMS: Peripheral joint complaints [pJTC] and chronic back pain [CBP] are the most common extra-intestinal manifestations in patients with inflammatory bowel disease [IBD]. This prospective study evaluates variables associated with joint/back pain, including IBD disease activity. METHODS: IBD patients with back pain ≥ 3 months and/or peripheral joint pain/swelling [n = 155], and IBD patients without joint complaints [n = 100; controls], were followed for a period of 1 year. Patients were classified as having SpondyloArthritis [SpA] according to several sets of criteria. Statistical analysis included logistic regression models and linear mixed model analysis. RESULTS: Of the 155 patients with joint/back pain, 13 had chronic back pain, 80 peripheral joint complaints, and 62 axial and peripheral joint complaints. Smoking, female gender, and IBD disease activity were independently associated with IBD joint/back pain. The Assessment in Spondyloarthritis International Society criteria for axial and peripheral SpA were fulfilled in 12.3% of patients, with 9.7% [n = 15] receiving a rheumatological diagnosis of arthritis. During the 12-month follow-up, the majority of the patients reporting joint/back pain remained stable. CONCLUSIONS: In our cohort, the majority of IBD patients reported joint/back pain and SpA was relatively common. To facilitate effective care, gastroenterologists should be aware of the various features of SpA to classify joint complaints and, by making use of an efficient referral algorithm, to refer CBP patients to the rheumatologist.

Chromoendoscopy for Surveillance in Inflammatory Bowel Disease Does Not Increase Neoplasia Detection Compared With Conventional Colonoscopy With Random Biopsies: Results From a Large Retrospective Study.

OBJECTIVES: Randomized trials demonstrated that chromoendoscopy is superior to white light endoscopy with random biopsy sampling (WLE) for the detection of dysplasia in patients with inflammatory bowel disease (IBD). Whether implementing chromoendoscopy can increase the detection of dysplasia in clinical practice is unknown. METHODS: Patients with ulcerative colitis (UC) and Crohn's disease (CD) undergoing colonoscopic surveillance between January 2000 and November 2013 in three referral centers were identified using the patients' medical records. In recent years, the use of high-definition chromoendoscopy was adopted in all three centers using segmental pancolonic spraying of 0.1% methylene blue or 0.3% indigo carmine (chromoendoscopy group). Previously, surveillance was performed employing WLE with random biopsies every 10 cm (WLE group). The percentage of colonoscopies with dysplasia was compared between both groups. RESULTS: A total of 440 colonoscopies in 401 patients were performed using chromoendoscopy and 1,802 colonoscopies in 772 patients using WLE. Except for a higher number of CD patients with extensive disease and more patients with a first-degree relative with colorectal cancer (CRC) in the chromoendoscopy group, the known risk factors for IBD-associated CRC were comparable between both groups. Dysplasia was detected during 48 surveillance procedures (11%) in the chromoendoscopy group as compared with 189 procedures (10%) in the WLE group (P=0.80). Targeted biopsies yielded 59 dysplastic lesions in the chromoendoscopy group, comparable to the 211 dysplastic lesions detected in the WLE group (P=0.30). CONCLUSIONS: Despite compelling evidence from randomized trials, implementation of chromoendoscopy for IBD surveillance did not increase dysplasia detection compared with WLE with targeted and random biopsies.

A thirty-year follow-up surveillance study for neoplasia of a dutch ulcerative colitis cohort.

BACKGROUND: Patients with ulcerative colitis have an increased risk of developing colorectal cancer (CRC). The aim of this study is to assess the yield of surveillance colonoscopies in a tertiary referral cohort of ulcerative colitis patients and to identify different risk groups for dysplasia. METHODS: A cohort of 293 patients (148 males, mean age 33.8 years at diagnosis) was built up at our center and started the surveillance program 8-12 years after start of symptoms. They underwent colonoscopies every one to three years. Endpoints were dysplasia or a (sub)total colectomy. RESULTS: After a follow-up period of 10 years, the cumulative incidence of any dysplasia was 23.5%, and of CRC 4.0%. After 15 years these percentages were 33.3% and 6.8%. Patients with pancolitis (n = 178) had a significantly higher cumulative risk of dysplasia than patients with distal disease, HR 1.9 (95%CI 1.1-3.3). Patients who started surveillance at an older age are at increased risk for any dysplasia, HR 1.03 (95%CI 1.01-1.05). CONCLUSIONS: This prospective surveillance study shows a high yield of dysplasia in ulcerative colitis patients. We recommend developing separate surveillance programs for different risk groups. In our opinion patients with distal colitis can follow the general population surveillance program.

High detection rate of adenomas in familial colorectal cancer.

BACKGROUND AND AIMS: Subjects with one first-degree relative (FDR) with colorectal cancer (CRC) <50 years old or two FDRs with CRC have an increased risk for CRC (RR 4-6). Current guidelines recommend colonoscopic surveillance of such families. However, information about the yield of surveillance is limited. The aim of the present study was to evaluate the outcome of surveillance and to identify risk factors for the development of adenomas. PATIENTS AND METHODS: Subjects were included if they fulfilled the following criteria: asymptomatic subjects aged between 45 and 65 years, with one FDR with CRC <50 years old (group A) or two FDRs with CRC diagnosed at any age (group B). Subjects with a personal history of inflammatory bowel disease or colorectal surgery were excluded. RESULTS: A total of 551 subjects (242 male) met the selection criteria. Ninety-five subjects with a previous colonoscopy were excluded. Two of 456 remaining subjects (0.4%) were found to have a colorectal tumour (one CRC and one carcinoid). Adenomas were detected in 85 (18.6%) and adenomas with advanced pathology in 37 subjects (8.1%). 30 subjects (6.6%) had multiple (>1) adenomas. Men were more often found to have an adenoma than women (24% vs 14.3%; p=0.01). Adenomas were more frequent in group B compared with group A (22.0% vs 15.6%; p=0.09). CONCLUSION: The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population.