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IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.
Cananzi, M, Wohler, E, Marzollo, A, Colavito, D, You, J, Jing, H, Bresolin, S, Gaio, P, Martin, R, Mescoli, C, et al
Human genetics. 2021;(9):1299-1312
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Abstract
Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.
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Treatment of iron deficiency anemia with liposomal iron in inflammatory bowel disease: efficacy and impact on quality of life.
de Alvarenga Antunes, CV, de Alvarenga Nascimento, CR, Campanha da Rocha Ribeiro, T, de Alvarenga Antunes, P, de Andrade Chebli, L, Martins Gonçalves Fava, L, Malaguti, C, Maria Fonseca Chebli, J
International journal of clinical pharmacy. 2020;(3):895-902
Abstract
Background Anemia is a clinical condition frequently seen in patients with inflammatory bowel disease, which is responsible for a significant loss of quality of life. Objective To assess the efficacy and safety of using oral liposomal iron to treat iron deficiency anemia in inflammatory bowel disease patients, as well as assess the impact of this treatment on psychometric scores. Methods Patients with inactive/mildly active inflammatory bowel disease were screened for anemia in this interventional pilot study conducted from November 2016 to March 2018. Patients with mild anemia were treated with oral liposomal iron for 8 weeks. Main outcome measure The primary endpoint of the study was the response to liposomal oral iron therapy. Treatment response was defined as patients who achieved a hemoglobin increase of ≥ 1 g/dL and/or hemoglobin normalization by the 8th week of treatment. Results Out of 200 screened patients, 40 (20%) had anemia. Of the 21 patients who completed treatment, 13 (62%) responded to oral liposomal iron replacement therapy (mean increases of hemoglobin from 11.4 to 12.6 g/dL). The transferrin saturation index increased by an average of 10.2 (p = 0.006) and the quality of life by 26.3 (p < 0.0001). There was also a mean reduction of 9.2 in the perception of fatigue (p < 0.0001). Conclusion Treatment with oral liposomal iron is effective in improving mild iron deficiency anemia and quality of life, as well as in decreasing fatigue in patients with inactive or mildly active inflammatory bowel disease.
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Serum Hepcidin Levels Predict Intestinal Iron Absorption in Patients with Inflammatory Bowel Disease.
Aksan, A, Wohlrath, M, Iqbal, TH, Farrag, K, Dignass, A, Stein, J
Clinical laboratory. 2019;(3)
Abstract
BACKGROUND Hepcidin has been shown to be inversely associated with iron absorption and the expression of iron transport proteins in healthy females and patients with iron deficiency. Data describing the relationship between hepcidin expression and iron absorption in patients with inflammatory bowel disease (IBD) are lacking. The objective of this study was to assess the relationship between serum concentrations of hepcidin and iron absorption in patients with IBD and iron deficiency by means of an oral iron absorption test. METHODS This study was conducted as a comparative, single-centered, open clinical trial. After overnight fasting, an oral iron absorption test was performed, serum iron concentrations were measured 60, 90, 120, 180, and 240 minutes. Changes in iron levels between baseline and the 2-hour timepoint were calculated and recorded. RESULTS Both ferritin and serum hepcidin levels are found to be good predictors of iron malabsorption, with sensitivity and specificity both at levels > 95%. When the two markers are compared, in our analysis, serum hepcidin levels (AUC: 0.817) tended to predict iron malabsorption slightly better than serum ferritin (AUC: 0.788). CONCLUSIONS The evidence from our study suggests that serum hepcidin levels are a promising predictor of absorptive capacity in patients treated with oral iron compounds.
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Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population.
Ostrowski, J, Paziewska, A, Lazowska, I, Ambrozkiewicz, F, Goryca, K, Kulecka, M, Rawa, T, Karczmarski, J, Dabrowska, M, Zeber-Lubecka, N, et al
Scientific reports. 2016;:39831
Abstract
Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn's disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping. Whole exome sequencing (WES) was performed on 44 IBD patients diagnosed before 6 years of age, 45 patients diagnosed after 40 years of age, and 18 healthy controls. Altogether, out of 88 selected SNPs, 31 SNPs were replicated for association with IBD. A novel BRD2 (rs1049526) association reached significance of P = 5.2 × 10-11 and odds ratio (OR) = 2.43. Twenty SNPs were shared between pediatric and adult patients; 1 and 7 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare and potentially deleterious variants in IBD-associated or innate immunity-associated genes. Deleterious alleles in both groups were over-represented among rare variants in affected children. Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare and deleterious variants in affected children suggests a contribution by yet unexplained genetic components.
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High-dose fast infusion of parenteral iron isomaltoside is efficacious in inflammatory bowel disease patients with iron-deficiency anaemia without profound changes in phosphate or fibroblast growth factor 23.
Dahlerup, JF, Jacobsen, BA, van der Woude, J, Bark, LÅ, Thomsen, LL, Lindgren, S
Scandinavian journal of gastroenterology. 2016;(11):1332-8
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Abstract
OBJECTIVE Iron isomaltoside (Monofer(®)) is a high-dose intravenous iron preparation with good tolerability and efficacy in inflammatory bowel disease (IBD) patients with iron deficiency anaemia (IDA). This trial evaluates the safety and efficacy, including effect on intact fibroblast growth factor 23 (iFGF23) of a high single dose and cumulative doses of iron isomaltoside in IBD patients with IDA. MATERIALS AND METHODS The trial was a prospective, open-label, multi-centre trial conducted in IBD patients with IDA. Based upon haemoglobin (Hb) levels at baseline and weight, the patients received 1500, 2000, 2500 or 3000 mg of iron isomaltoside infused in single doses up to 2000 mg. The outcome measurements included adverse drug reactions (ADRs) and changes in haematology and biochemistry parameters. RESULTS Twenty-one IBD patients with IDA were enrolled, receiving 1500 (seven patients), 2000 (eight patients), 2500 mg (four patients) or 3000 (two patients) mg of iron. No serious ADRs were observed. Four patients experienced nine mild to moderate ADRs (hypersensitivity, pyrexia, vomiting, constipation, abdominal pain, dyspepsia (two events) and eye allergy (two events)). In total, 15 (75%) patients had an increase in Hb of ≥2.0 g/dL during the trial, with normalisation of ferritin. No changes in iFGF23 or clinically significant hypophosphataemia were found. CONCLUSION Rapid infusions of high-dose iron isomaltoside, administered as single doses up to 2000 mg and cumulative doses up to 3000 mg, were without safety concerns and were efficacious in increasing Hb levels in IBD patients. Iron isomaltoside did not induce profound phosphate wasting via increased iFGF23 levels.
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Effects of Probiotics on Gut Microbiota in Patients with Inflammatory Bowel Disease: A Double-blind, Placebo-controlled Clinical Trial.
Shadnoush, M, Hosseini, RS, Khalilnezhad, A, Navai, L, Goudarzi, H, Vaezjalali, M
The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi. 2015;(4):215-21
Abstract
BACKGROUND/AIMS: Several clinical trials have revealed various advantages for probiotics in inflammatory bowel disease (IBD). The aim of this study was to further investigate the effects of probiotic yogurt consumption on gut microbiota in patients with this disease. METHODS A total of 305 participants were divided into three groups; group A (IBD patients receiving probiotic yogurt; n=105), group B (IBD patients receiving placebo; n=105), and control group (healthy individuals receiving probiotic yogurt; n=95). Stool samples were collected both before and after 8 weeks of intervention; and population of Lactobacillus, Bifidobacterium and Bacteroides in the stool specimens was measured by Taqman real-time PCR method. RESULTS By the end of the intervention, no significant variations in the mean weight and body mass index were observed between three groups (p>0.05). However, the mean numbers of Lactobacillus, Bifidobacterium, and Bacteroides in group A were significantly increased compared to group B (p<0.001, p<0.001, and p< 0.01, respectively). There were also significant differences in the mean numbers of either of three bacteria between group A and the healthy control group; however, these differences between two groups were observed both at baseline and the end of the intervention. CONCLUSIONS Consumption of probiotic yogurt by patients with IBD may help to improve intestinal function by increasing the number of probiotic bacteria in the intestine and colon. However, many more studies are required in order to prove the concept.
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Iron deficiency generates secondary thrombocytosis and platelet activation in IBD: the randomized, controlled thromboVIT trial.
Kulnigg-Dabsch, S, Schmid, W, Howaldt, S, Stein, J, Mickisch, O, Waldhör, T, Evstatiev, R, Kamali, H, Volf, I, Gasche, C
Inflammatory bowel diseases. 2013;(8):1609-16
Abstract
BACKGROUND Secondary thrombocytosis is a common clinical feature. In patients with cancer, it is a risk factor for venous thromboembolic events. In inflammatory bowel disease (IBD), thrombocytosis is so far considered a marker of active disease and may contribute to the increased thromboembolic risk in this population. Observed effects of iron therapy on normalization of platelet counts led us to hypothesize that iron itself may regulate megakaryopoiesis. Here, we want to test the effect of iron replacement on platelet count and activity in IBD-associated thrombocytosis. METHODS We performed a randomized, single-blinded placebo-controlled trial testing the effect of ferric carboxymaltose (FCM) in patients with IBD with secondary thrombocytosis (platelets > 450 G/L). Changes in platelet counts, hemoglobin, iron parameters, disease activity, megakaryopoietic growth factors, erythropoietin, and platelet activity were assessed. Patients received placebo or up to 1500 mg iron as FCM. Endpoints were evaluated at week 6. RESULTS A total of 26 patients were included in the study, 15 patients were available for the per protocol analysis. A drop in platelets >25% (primary endpoint) was observed in 4 of 8 (50%, iron group) and 1 of 7 patients (14%, placebo group, P = 0.143). Mean platelet counts dropped on FCM but not on placebo (536 G/L to 411 G/L versus 580 G/L to 559 G/L; P = 0.002). Disease activity and megakaryopoietic growth factors remained unchanged and hemoglobin and iron parameters increased on FCM. The normalization of platelet counts was associated with a decrease in platelet aggregation and P-selectin expression. CONCLUSION FCM lowers platelet counts and platelet activation in patients with IBD-associated secondary thrombocytosis.
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Laparoendoscopic single-site surgery is feasible in complex colorectal resections and could enable day case colectomy.
Gash, KJ, Goede, AC, Chambers, W, Greenslade, GL, Dixon, AR
Surgical endoscopy. 2011;(3):835-40
Abstract
BACKGROUND Fast-track surgery accelerates recovery, reduces morbidity, and shortens hospital stay. However, the benefits of laparoscopic versus open surgery remain unproven within a fast-track program. Case reports of laparoendoscopic single-site (LESS) colectomies are appearing with claims of cosmetic advantage and decreased parietal trauma. This report describes the largest case series of LESS colorectal surgery and its effects on recovery. METHODS In this series, 20 consecutive unselected patients underwent LESS colorectal surgery including right hemicolectomy (n = 3), extended right hemicolectomy, high anterior resection (n = 2), low anterior resection involving total mesorectal excision (TME; n = 3), ileocolic anastomosis (n = 2, including 1 redo surgery), colectomy and ileorectal anastomosis (n = 4, including 1 with ventral mesh rectopexy), panproctocolectomy (n = 2), proctocolectomy and ileoanal pouch (n = 2) and an abdominoperineal excision of rectum. Single-port conventional instrumentation and transversus abdominus plane (TAP) block analgesia were used. The indications included cancer (n = 8), Crohn's disease (n = 4), ulcerative colitis (n = 3) complicated diverticulosis (n = 2), and slow-transit constipation (n = 3). Eight of the patients had undergone previous surgery. RESULTS Most of the cases (90%) were managed successfully using the LESS technique and conventional instrumentation. Two operations (10%) were converted to standard laparoscopy, due to insufficient theater time and an unstable port. The operative time ranged from 45 to 240 min (median, 110 min). A normal diet was tolerated within 6 h by 7 patients and in 12 to 16 h (overnight) by 11 patients. Complications included anastomotic bleed (n = 1), ileus (n = 2), acute renal failure secondary to hyperphosphatemia and hypocalcemia (n = 1), urine retention (n = 1), and wound infection (n = 1). The median hospital stay was 46 h (range, 7-384 h). Eight patients were discharged within 24 h. There was one readmission (5%). CONCLUSION Laparoendoscopic single-site colorectal resection using conventional instrumentation is feasible and safe when performed by an experienced team. The LESS approach may have advantages in terms of minimal pain, cosmesis, lower costs, and faster recovery. A randomized trial is required to confirm whether LESS offers a true patient benefit over standard laparoscopic resection.
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Variable deficits of bone mineral despite chronic glucocorticoid therapy in pediatric patients with inflammatory diseases: a Glaser Pediatric Research Network study.
von Scheven, E, Gordon, CM, Wypij, D, Wertz, M, Gallagher, KT, Bachrach, L
Journal of pediatric endocrinology & metabolism : JPEM. 2006;(6):821-30
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Abstract
OBJECTIVE To evaluate the relationship between chronic glucocorticoid (GC) exposure and bone mineral density (BMD) in children with rheumatic diseases and inflammatory bowel disease. STUDY DESIGN Lumbar spine BMD was measured by DXA in 86 GC-treated children (66% female, age 8-20 years, mixed ethnicity) screened for a multi-center intervention trial. Predictors of spine BMD z-score and vitamin D [25(OH)D] were examined by multivariable linear regression. RESULTS Mean prior year and lifetime cumulative GC exposure was 77.8 mg/kg and 224.6 mg/kg, respectively. BMD z-scores ranged from -3.7 to 2.2 SD (-1.1 +/- 1.2, mean +/- SD). Lower BMD z-scores were associated with increased prior year average daily GC dose (p = 0.03), decreased height z-score (p = 0.003), and decreased 25(OH)D concentrations (p = 0.03), but explained only a small proportion of BMD variability (adjusted R2 = 0.29). The 25(OH)D levels were <20 ng/ml in 45% of patients, and low 25(OH)D was associated with non-Caucasian ethnicity (p <0.001), increased age (p = 0.004), increased parathyroid hormone (p = 0.03), and residing in the Boston area (p <0.001). CONCLUSIONS Although GC exposure is significantly associated with BMD z-score, the association is too variable to serve as a consistent predictor of reduced BMD in children. Vitamin D insufficiency is common and may contribute to skeletal deficits in this population.
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Modulation of nitric oxide and cytokines production by L-arginine in human gut mucosa.
Lecleire, S, Coeffier, M, Leblond, J, Hubert, A, Lemoulan, S, Petit, A, Ducrotte, P, Dechelotte, P, Marion, R
Clinical nutrition (Edinburgh, Scotland). 2005;(3):353-9
Abstract
BACKGROUND Arginine is a conditionally essential amino-acid with immuno-modulatory properties, mainly through the nitric oxide (NO) pathway. AIM: To assess the effects of arginine on intestinal production of pro- and anti-inflammatory cytokines and NO in human gut. METHODS An enteral solution of arginine or a control solution of amino-acids was administered to 8 healthy volunteers on a randomized cross-over design. Duodenal biopsies were taken. Pro- (IL-6, IL-8) and anti-inflammatory (IL-4, IL-10) cytokines mRNA expression was assessed by RT-PCR. Other biopsies were cultured with 0.1, 0.5 or 2 mM arginine or control amino-acids, under basal or IL-1beta-induced inflammatory conditions. Interleukin-4, IL-6, IL-8 and IL-10 production was measured in culture supernatant by ELISA and NO production by Griess reaction. RESULTS Arginine enhanced the production of NO under inflammatory conditions in a dose-dependent manner (P=0.03). IL-1beta increased the production of IL-8 and IL-6 (P<0.01). Arginine had no effect on pro- and anti-inflammatory cytokines production both under basal and inflammatory conditions. CONCLUSIONS Arginine enhanced the production of NO but did not affect that of cytokines in inflammatory human gut. Further clinical studies are required to assess whether arginine-enhanced NO production plays a beneficial or deleterious effect in intestinal inflammation.