Anemia In Inflammatory Bowel Disease Research Articles

Myeloid Ptpn2 Deficiency in Mice Causes Functional Iron Deficiency

Background: Anemia is the most prevalent extraintestinal complication of inflammatory bowel disease (IBD) and is associated with the manifestation of Crohn’s disease. Anemia significantly reduces the quality of life, increases hospitalization visits, and increases medical care expenses of IBD patients. Iron deficiency is the leading cause of anemia in IBD; however, the physiological mechanisms involved are still poorly understood. Macrophages significantly contribute to iron homeostasis by mechanisms including iron recycling by phagocytosing senescent erythrocytes and damaged cells, and nurturing erythropoiesis in the bone marrow. In this study, we investigated the role of the IBD candidate gene, protein tyrosine phosphatase non-receptor type 2 ( PTPN2), in regulating macrophage iron homeostasis. Methods: Myeloid cell-specific knockout mice ( Ptpn2LysMCre) and control littermates ( Ptpn2fl/fl) were analyzed for serum iron content and liver and spleen non-heme iron. Duodenal epithelial cell (DEC) proteins were assayed by Western blotting. Localization of the brush border ferrous iron transporter, DMT1, and the coupled ferrous iron absorption driver, NHE3, in duodenal tissue was determined by immunohistochemistry (IHC). Gene expression profiles of macrophages were analyzed by Nanostring. Results: Ptpn2LysMCre mice had reduced serum iron ( p<0.0001; n=12) and reduced spleen non-heme iron (p=0.0017; n=6), whereas liver non-heme iron was unaltered (n=6), indicating iron deficiency in select tissues. DMT1 (n=8) and NHE3 (n=5) protein expression in DECs was unaltered and IHC confirmed the unaltered localization of DMT1 and NHE3 (n=6) in the duodenal epithelium of Ptpn2LysMCre mice, suggesting the reduction in serum iron was not due to an impairment in intestinal non-heme iron uptake. Nanostring analyses revealed that the gene expression of the iron transporter Dmt1, iron exporter Fpn, and iron importer Tfr1 were significantly downregulated (p<0.05; n=5) in macrophages from Ptpn2LysMCre mice, indicating an iron sequestering phenotype. Conclusions: Loss of myeloid Ptpn2 in mice causes functional iron deficiency. These findings indicate a major role of myeloid PTPN2 in regulating systemic iron homeostasis. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

INDOLENT SYSTEMIC MASTOCYTOSIS MASQUERADING AS CHRONIC ANEMIA IN ULCERATIVE COLITIS: A CASE STUDY

Abstract BACKGROUND Anemia is a frequent systemic/extra-intestinal manifestation of inflammatory bowel disease (IBD). It has a complex multifactorial etiology which suppresses erythropoiesis due to pro-inflammatory mediators, myelosuppression, iron and micronutrient deficiency. It significantly impacts quality of life (QoL) and increases hospitalizations, length of hospital stays and mortality rates. It Is commonly thought to arise as a consequence of IBD or it’s related therapy. Current strategies are aimed at correction of anemia with low priority towards identifying a specific cause. Here, we represent a case of UC with chronic anemia secondary to systemic mastocytosis (SM). CASE A 41 y/o female with UC presents to the outpatient clinic with complaints of fatigue. Further questioning revealed a baseline of 1-2 formed bowel movements per day. She did not report any hematochezia or weight loss. She was managed on 300 mg of vedolizumab every 4 weeks. Prior failure to medications includes anti-tumor necrosis factor inhibitors and tofacitinib. Labs were consistent with albumin 4.5 mg/dL and CRP < 1 mg/dL. Iron studies revealed low iron, TIBC and ferritin levels. Fecal calprotectin measurements were not available due to patient non-compliance. Patient (Pt) was thought to have experienced a UC flare and colonoscopy was recommended. Colonoscopy was unrevealing with no sign of active disease on examination (Mayo Endo 0). Pt was referred to hematology where she underwent a bone marrow biopsy revealing multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) expressing CD2+ and CD 25+ with 25% showing atypical morphology in bone marrow biopsies. KIT D816V mutation was also positive. The serum tryptase level in this pt was 47.1ug/L. She was then placed on anti-histamines, proton pump inhibitors and steroid therapy. CONCLUSION SM is a clonal disorder of MC that infiltrates one or more organs. It almost always involves the bone marrow. Gastrointestinal (GI) symptoms are present in up to 80% patients. These symptoms are secondary to systemic effects of MC mediators. Incidence of SM in UC has never been established. SM has been shown to mimic Crohn’s disease and is difficult to differentiate based on clinical and endoscopic features. Furthermore, little is known regarding histopathological features of GI involvement in SM. The presence of chronic anemia despite adequate therapy in a clinically/endoscopically inactive UC patient should raise suspicion of other pathologic causes of anemia. Our case highlights the importance of diagnosing the specific cause of anemia in IBD as it may lead to inaccurate clinical judgements of disease flares leading to undue alteration in therapy.

Follow-up evaluation and management of anemia in inflammatory bowel disease: A study by the Italian Group for Inflammatory Bowel Diseases (IG-IBD)

BackgroundThe RIDART I study found a 13.6% prevalence of anemia in Italian patients with inflammatory bowel disease (IBD); most cases were due to iron-deficiency anemia (IDA). AimsTo evaluate changes in hemoglobin concentration during a 24-week follow-up of anemic patients with IBD. MethodsFollow-up laboratory and clinical data were obtained from RIDART I study patients with anemia. Factors affecting hemoglobin concentration, the impact of anemia on fatigue and quality of life (QoL), and its relationship with treatment, disease activity and disease complications were investigated. ResultsHemoglobin was 108 g/L at baseline, increased to 121 g/L at follow-up week 12 (p < 0.001) and then stabilized until week 24, but most patients remained anemic, with IDA, throughout the study. Hemoglobin improvement was greater in patients receiving either oral or parenteral iron supplementation. Following hemoglobin normalization, anemia relapse rate during follow-up was 30%. Oral iron did not cause disease reactivation. Lower follow-up hemoglobin was associated with a higher probability of having active disease, clinical complications, increased fatigue and reduced QoL. ConclusionsIn anemic patients with IBD, anemia represents a long-lasting problem, in most cases persisting for up to 24 weeks, with high relapse rate and a negative impact on fatigue and QoL.

Clinical Significance of Erythroferrone and Bone Morphogenetic Protein-6 in Patients with Anemia in the Course of Inflammatory Bowel Disease.

In recent years, a steady increase in the incidence of inflammatory bowel diseases (IBD) has been observed with anemia as their most common extraintestinal symptom. Erythroferrone and Bone Morphogenetic Protein 6 (BMP-6) are recently identified cytokines involved in the process of increased erythropoiesis in anemia of various pathomechanisms. The aim of this study was to analyze the concentration of erythroferrone and BMP-6 in IBD patients in relation to clinical and laboratory data. The study comprised 148 patients: 118 with IBD, including 73 (61.85%) diagnosed with anemia (42 with Crohn's disease (CD) (66.7%) and 31 (56.4%) with ulcerative colitis (UC)) and 30 as a control group. The erythroferrone concentration was significantly higher in IBD patients with anemia (p = 0.009) and higher in UC patients both with and without anemia (p = 0.018), compared to the control group. In CD, no similar difference was observed between patients with and without anemia. Regarding BMP-6, higher levels were found in CD patients with anemia compared to the control group (p = 0.021). The positive correlation between BMP-6 and iron concentration in UC was also noticed. In conclusion, we confirm an increase in erythroferrone concentration in the entire group of IBD patients with anemia, while BMP-6 levels were higher only in anemic CD patients. Due to the clinical importance of anemia in IBD, this problem is worth further analysis and research projects.

Adherence to ECCO Guidelines for Management of Iron Deficiency and Anemia in Inflammatory Bowel Diseases Among Israeli Adult and Pediatric Gastroenterologists.

The consensus guidelines of the European Crohn's and Colitis Organization (ECCO) for the diagnosis and treatment of iron deficiency anemia (IDA) were published in 2015. We examined the management practices of both adult gastroenterologists (AGs) and pediatric gastroenterologists (PGs) in Israel in treating ID among patients with inflammatory bowel disease (IBD). An 18-question multiple-choice anonymous questionnaire was electronically delivered to AGs and PGs. Questions explored 3 areas of interest: physician demographics, adherence to ECCO guidelines, and management practices of IDA in patients with IBD. Completed questionnaires were returned by 72 AGs and 89 PGs. Practice setting and years of practice were similar. A large majority of AGs and PGs (89% and 92%, respectively) measure complete blood count (CBC) and serum ferritin (S-Fr) at least every 3 months in outpatients with active IBD, as recommended by the ECCO guidelines. In contrast, in IBD patients in remission, only 53% and 26% of AGs and PGs, respectively ( P < 0.001), reported adherence to ECCO guidelines, measuring CBC and S-Fr every 6 months. The ECCO treatment guidelines recommend that intravenous (IV) iron should be considered the first-line treatment in patients with clinically active IBD, with previous oral iron intolerance and those with a hemoglobin level <10 g/dL. Study results indicate that only 43% of AGs recommend IV iron for these indications, compared to 54% of PGs ( P > 0.1). In this study we have demonstrated a relatively low level of adherence to ECCO guideline recommendations among both AGs and PGs, regarding the management of IDA in patients with IBD.

Prevalence and Risk Factors of Anemia in Inflammatory Bowel Diseases: A Case-Control Study.

Introduction Inflammatory bowel diseases (IBDs) including Crohn's disease and ulcerative colitis may induce anemia, ranging from 25% to 75% depending on the study population and diagnostic criteria. It might negatively impact their health and quality of life. Objectives The aim of this work is to study the effectiveness and safety of treatments for anemia in patients with IBD. Methodology This case-control study compared patients with IBD who have anemia (cases; n=60) with patients who have IBD but do not have anemia (controls; n=60) from June 2019 to August 2021 in Hayatabad Medical Complex, Peshawar, Pakistan. Data were collected through interviews, from patients` medical records, and from lab test reports. Statistical analysis was performed using SPSS, Version 23.0 (IBM Corp., Armonk, NY). Results Cases had a greater mean age (45.2 years) than controls (42.8 years). Cases included 60% females and controls 45%. Also, cases earned less (p = 0.019). Anemic patients (group 1) had lower mean hemoglobin (10.2 g/dL) and iron than non-anemic controls (group 2) (p = 0.042 and 0.009, respectively). Anemia increased Crohn's Disease Activity Index and Mayo Score. Group 1 has iron deficiency anemia, whereas group 2 has chronic disease. Group 1 reacts rapidly, but gastrointestinal side effects, allergies, and iron overload are more prevalent. Conclusion IBD patients exhibited low hemoglobin and iron, suggesting anemia. Anemia increased disease activity, but not statistically. IBD patients need iron and anemia treatment. Comparing groups demonstrates differences in anemia types, iron replacement history, treatment response, and bad effects, proposing targeted iron supplementation for deficiency anemia and managing chronic illness factors for chronic disease anemia. IBD anemia treatment involves individualization.

Constitutive Loss of Ptpn2 in Mice Causes Features of Anemia Including Iron Deficiency

Background: Anemia is the most frequent extraintestinal manifestation of inflammatory bowel disease (IBD) and is associated with the risk of Crohn’s disease. Anemia significantly impairs quality of life, increases hospitalization rates, and increases medical care costs of IBD patients. Iron deficiency is the most frequent cause of anemia in IBD; however, the mechanisms involved are still poorly understood. Here, we investigated the role of the IBD risk gene, protein tyrosine phosphatase non-receptor type 2 ( PTPN2), in regulating iron homeostasis. Methods: Constitutive Ptpn2 wild type (WT), heterozygous (Het), and knockout (KO) 3-week-old mice were analyzed for serum iron content, complete blood count parameters, and intestinal and extraintestinal non-heme iron. Protein and RNA from duodenal epithelial cells (DECs) were assayed by western blotting and qPCR. Localization of the brush border ferrous iron transporter, DMT1, and the ferrous iron absorption driver, NHE3, in duodenal tissue was determined by immunohistochemistry (IHC). Results: Ptpn2-KO mice had reduced i) serum iron ( p=0.0007; n=10); ii) serum iron carrier transferrin saturation ( p=0.0077; n=8); iii) hemoglobin ( p=0.0002; n=5); iv) hematocrit ( p=0.0023; n=5); v) intestinal non-heme iron: duodenum ( p=0.0128; n=10) and jejunum ( p=0.0006; n=8); and vi) extraintestinal tissue non-heme iron: liver ( p=0.0014; n=10), spleen ( p=0.04; n=10), kidney ( p=0.0004; n=7), and gastrocnemius muscle ( p=0.0436; n=9) vs. Ptpn2-WT and Het mice. This indicated that loss of Ptpn2 causes characteristics of anemia including decreased serum iron and tissue iron storage and impaired intestinal iron homeostasis. DEC gene expression of the intracellular iron storage molecule ferritin ( Fth1) was reduced ( p=0.048; n=4) while the basolateral cellular iron importer transferrin receptor 1 ( Tfrc1) was significantly increased ( p=0.0048; n=5) in Ptpn2-KO mice. Reduced FTH1 protein expression ( p=0.007; n=12) and increased TFRC1 protein expression ( p=0.0021; n=8) in DECs of Ptpn2-KO mice was confirmed by western blot, indicating cellular iron deficiency. DMT1 (n=6) and NHE3 (n=8) protein expression in DECs was unaltered, whereas IHC showed reduced apical membrane DMT1 and NHE3 in the duodenal epithelium of Ptpn2-KO mice (n=6), suggesting a possible mechanism of impaired intestinal non-heme iron uptake. Conclusions: Loss of Ptpn2 in mice causes features of anemia including iron deficiency associated with mislocalization of DMT1 and reduced apical membrane expression of NHE3. These findings identify a critical role for PTPN2 in regulating systemic iron homeostasis. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Prevalence of Anemia in Chronic Inflammatory Bowel Disease during COVID-19: Experience of the Gastroenterology Department of the Moulay Ismail Meknes Military Hospital: About 70 Cases

Inflammatory bowel diseases (IBD) include Crohn's disease and ulcerative colitis. IBD represents a pathology that evolves through relapses interspersed with remission. Anemia is the most common extra-intestinal complication in inflammatory bowel disease (IBD). Depending on the hemoglobin level, the anemia is mild, moderate or severe. It can affect quality of life and increase the hospitalization rate of patients. The reported prevalence of anemia in patients with IBD ranges from 6% to 74%. Although the causes of anemia in IBD are multifactorial, iron deficiency anemia remains the most common. Management is based on treating the disease and correcting the anemia with injectable iron. The aim of the work is to take stock of the prevalence and treatment of chronic anemia during IBD, as well as the impact of the covid19 period on the monitoring of this chronic pathology in our structure.

Clinical and Laboratory Characteristics of Anaemia in Hospitalized Patients with Inflammatory Bowel Disease.

Anaemia is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). Due to its multifactorial etiopathogenesis, the differential diagnosis and treatment of anaemia in IBD is a significant clinical problem. The main aim of our study was to assess the usefulness of laboratory parameters, including hepcidin, in differential diagnoses of anaemia in hospitalized IBD patients. This study also estimated the impact of anaemia on the length of hospitalization and its relationship with clinical data of analyzed patients. The study included 118 adult patients diagnosed with IBD-55 with ulcerative colitis (UC) and 63 with Crohn's disease (CD). Anaemia was significantly more frequent in patients with CD-42 (66.7%)-compared to 31 (56.4%) patients with UC (p = 0.033). The prevalence of anaemia increased significantly with the severity of IBD and the extent of inflammatory changes in the endoscopic examination. Hospitalization time was significantly longer in patients with anaemia, especially in the group with UC. Ferritin concentrations < 30 ng/mL were found only in 15 (20.55%) IBD patients (9 with UC and 6 with CD), and ferritin < 100 ng/mL was observed in 22 (30.14%) patients, equally frequent with UC and CD (p > 0.05). Significantly higher concentrations of transferrin were observed in patients with anaemia in the course of UC compared to CD (2.58 ± 0.90 g/L vs. 2.15 ± 0.82 g/L; p = 0.037). On the other hand, saturation of transferrin < 16% was equally common in UC and CD patients. In our study, hepcidin levels in anaemic UC patients were significantly lower compared to UC without anaemia (p = 0.042), with no similar differences in CD independently of anaemia presence (p = 0.565). To conclude, we observed a high incidence of anaemia in patients with IBD and its significant impact on the length of hospitalization in UC. Routinely determined single laboratory parameters are not sufficient for the differential diagnosis of anaemia, and a complex laboratory assessment, including of hepcidin levels, is necessary for the full picture of anaemia in the course of IBD.

Human-Centered Design of a Clinical Decision Support for Anemia Screening in Children with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) commonly leads to iron deficiency anemia (IDA). Rates of screening and treatment of IDA are often low. A clinical decision support system (CDSS) embedded in an electronic health record could improve adherence to evidence-based care. Rates of CDSS adoption are often low due to poor usability and fit with work processes. One solution is to use human-centered design (HCD), which designs CDSS based on identified user needs and context of use and evaluates prototypes for usefulness and usability. this study aimed to use HCD to design a CDSS tool called the IBD Anemia Diagnosis Tool, IADx. Interviews with IBD practitioners informed creation of a process map of anemia care that was used by an interdisciplinary team that used HCD principles to create a prototype CDSS. The prototype was iteratively tested with "Think Aloud" usability evaluation with clinicians as well as semi-structured interviews, a survey, and observations. Feedback was coded and informed redesign. Process mapping showed that IADx should function at in-person encounters and asynchronous laboratory review. Clinicians desired full automation of clinical information acquisition such as laboratory trends and analysis such as calculation of iron deficit, less automation of clinical decision selection such as laboratory ordering, and no automation of action implementation such as signing medication orders. Providers preferred an interruptive alert over a noninterruptive reminder. Providers preferred an interruptive alert, perhaps due to the low likelihood of noticing a noninterruptive advisory. High levels of desire for automation of information acquisition and analysis with less automation of decision selection and action may be generalizable to other CDSSs designed for chronic disease management. This underlines the ways in which CDSSs have the potential to augment rather than replace provider cognitive work.

Autoimmune Hemolytic Anemia in Inflammatory Bowel Disease-Report of a Case and Review of the Literature.

A wide spectrum of extraintestinal manifestations (EIMs) can burden patients with inflammatory bowel disease (IBD). EIMs contribute fairly to morbidity and mortality rates in IBD patients. Moreover, EIMs in IBD patients are so frequent that some suggest that IBD should be approached as a systemic disorder. Anemia is very common in IBD patients. The two most common types of anemia in IBD, iron deficiency anemia and anemia of chronic disease, are extraintestinal complications. Autoimmune hemolytic anemia (AIHA) is a rare extraintestinal manifestation of IBD, more frequent in ulcerative colitis (UC) than in Crohn's disease (CD). In this case-based review of the literature, we present a 36-year-old female patient diagnosed with Crohn's disease (CD) and Coombs positive AIHA, complicated by pulmonary thromboembolism and successfully treated with anti-tumor necrosis factor (anti-TNF) therapy. The underlying pathophysiological mechanism of AIHA in IBD is unclear. Treatment options for AIHA in IBD patients before biologic therapy included corticosteroids alone or in combination with azathioprine (AZA), methotrexate, and surgical treatment (colectomy and/or splenectomy). Currently, biologic therapy is a promising therapeutic option, especially in corticosteroid refractory or corticosteroid-dependent IBD patients with AIHA.

Investigation of the effects of anti-TNF agents on hemoglobin levels in patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by many clinical features. Anemia is 1 of the most frequent complications and/or extraintestinal manifestations of IBD. There are conflicting data regarding the relationship between changes in hemoglobin levels and disease prevalence in IBD patients with and without antitumor necrosis factor (antiTNF) therapy. In our study, we aimed to investigate the long-term effect of antiTNF agents on anemia in IBD.The records of IBD patients followed-up in our hospital between January 2011 and January 2021 were reviewed retrospectively. Demographic, clinical, endoscopic, radiological and medical treatment data of the patients were recorded. Complete blood count and laboratory markers of inflammation and disease activation, were recorded at the beginning and at the first year of treatment in all patients. The data of patients with and without antiTNF therapy were analyzed statistically. A total of 240 IBD patients who met the inclusion criteria were enrolled in the study. The number of patients with and without antiTNF therapy was 102 (42.5%) and 138 (57.5%), respectively. The change in all laboratory parameters between the beginning and the first year of treatment was statistically significant (P < .001) in all IBD patients with and without antiTNF therapy. The change in Hb level after 1 year of treatment was significantly different in patients with antiTNF therapy compared to those without therapy (3.00 ± 1.78 g/dL vs 1.19 ± 1.38 g/dL, P < .001). In the multiple regression analysis, male gender, antiTNF therapy, baseline Hb level and iron therapy were independent significant variables of hematopoietic response. This study showed that with appropriate treatment, hemoglobin levels of IBD patients with and without antiTNF therapy increased within 1 year, and the use of antiTNF agents in the treatment of IBD was an independent variable in correcting anemia.

Anemia in inflammatory bowel disease

Anemia is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). Although there are several causes of anemia in IBD, the two most frequent etiologies are iron deficiency anemia and anemia of chronic disease. Despite the high prevalence of anemia in IBD and its significant impact on patient's quality of life, this complication is still underdiagnosed and undertreated by providers. Active screening for anemia, structured assessment, comprehensive management, and multidisciplinary collaboration are needed in IBD patients. The cornerstone of anemia management depends on the underlying etiology along with normalization of inflammatory activity. Although, oral iron is effective for the treatment of mild iron deficiency-related anemia, intravenous iron formulations have a good safety profile and can be used as first-line therapy in patients with active IBD, severe anemia and previous intolerance prior to oral iron. After proper treatment of anemia, careful monitoring is necessary to prevent its recurrence. Herein, we discuss the etiology, screening, diagnosis, therapy selection, and follow-up for anemia in IBD.

Loss of PTPN2 Activity Alters Iron Handling Protein Expression in IBD Patients and Causes Iron Deficiency in Mice

BackgroundAnemia is the most common extraintestinal complication of inflammatory bowel disease (IBD) and is a risk factor for Crohn’s disease (CD) onset. Iron deficiency is the most common cause of anemia in IBD; however, the mechanisms involved are poorly understood. Here, we investigated the role of the IBD risk gene, protein tyrosine phosphatase non‐receptor type 2 (PTPN2), in regulating iron homeostasis.MethodsProteomic analyses were performed on serum from IBD patients genotyped for the IBD‐associated loss‐of‐function rs1893217 PTPN2variant (n=10/genotype). Constitutive Ptpn2 wild type (WT), heterozygous (Het), and knockout (KO) 3‐week‐old mice were analyzed for serum iron content, liver non‐heme iron and liver expression of the iron regulatory hormone, hepcidin (Hamp1). Protein and RNA from duodenal epithelial cells (DECs) were assayed by western blotting and qPCR. Localization of the brush border ferrous iron transporter, DMT1, in duodenal tissue was determined by immunohistochemistry (IHC).ResultsIron homeostasis genes, the iron carrier transferrin (TF) and the transferrin receptor (TFRC), were reduced (‐log p‐value = 10.7) in CD patients with the PTPN2 risk variant. Ptpn2‐KO mice had reduced i) serum iron (p&lt;0.001; n=11); ii) serum TF saturation (p&lt;0.01; n=9); and iii) liver non‐heme iron levels (p&lt;0.01; n=10), vs. Ptpn2‐WT and Het mice. This indicated that PTPN2 loss decreased serum and liver iron storage. Moreover, Ptpn2‐KO mice had reduced liver expression of Hamp1 (p&lt;0.01; n=7), likely suppressed by low serum iron. DEC gene expression of ferritin (Fth1), an intracellular iron storage molecule, was reduced (p=0.048; n=5) while Tfrc1, a mediator of basolateral cellular iron uptake, was significantly increased (p=0.0048; n=6) in Ptpn2‐KO mice. Reduced FTH1 expression (p=0.007; n=12) in DECs of Ptpn2‐KO mice was confirmed by western blot, indicating reduced intracellular iron storage. DMT1 expression was unchanged (n=6), whereas IHC showed reduced apical membrane DMT1 in duodenal epithelium of Ptpn2‐KO mice (n=6), suggesting a possible mechanism of impaired intestinal non‐heme iron uptake.ConclusionsCD patients with the PTPN2 loss‐of‐function rs1893217 SNP display alterations in serum iron handling proteins. Loss of PTPN2 activity in mice causes features of anemia including iron deficiency associated with mislocalization of the duodenal transporter DMT1. These findings identify a major role for PTPN2 in regulating iron homeostasis.

Prevalence, Pathogenesis and Management of Anemia in Inflammatory Bowel Disease: An IG-IBD Multicenter, Prospective, and Observational Study.

Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD), with a 6% to 74% prevalence and a negative impact on patient survival and quality of life, although the prevalence is apparently declining due to improved disease treatment. We aimed to investigate the prevalence, pathogenesis, and clinical correlates of anemia in Italian patients with IBD. A multicenter, prospective, observational study, involving 28 Italian gastroenterology centers, was conducted to investigate the epidemiology and consequences of IBD-associated anemia. Clinical and laboratory data of anemic patients were obtained at study enrolment. Anemia was diagnosed in 737 of 5416 adult IBD outpatients (prevalence 13.6%); females were more commonly affected than males (odds ratio, 1.5; 95% confidence interval [CI], 1.2-1.7) and had more severe anemia. In the majority of cases, anemia was due to iron deficiency (62.5% of cases; 95% CI, 58.3%-66.6%), either isolated or in association with inflammation and/or vitamin deficiencies; anemia of inflammation accounted for only 8.3% of cases. More severe anemia was associated with increasing fatigue and worse quality of life. Only 68.9% of anemic patients with iron deficiency (95% CI, 63.4%-73.8%) and 34.6% of those with vitamin deficiencies (95% CI, 26.2%-44.2%) were properly treated with supplementation therapy. In Italy, the prevalence of IBD-associated anemia is lower than previously reported. Anemia of IBD is most commonly due to iron deficiency and contributes to fatigue and poor quality of life, but remains untreated in a large proportion of patients with iron and/or vitamin deficiencies. This study is registered at clinicaltrials.gov as NCT02872376.

P038 Targeting the hepcidin-ferroportin axis with Nrf2 agonists to treat iron deficiency anaemia in Inflammatory Bowel Disease

Abstract Background Anaemia of inflammation is a common extraintestinal manifestation of IBD, impacting patient quality of life and hospitalisation rates. High circulating levels of proinflammatory cytokines induce hepatic production of the iron-regulatory peptide hormone hepcidin. By binding to the iron exporter ferroportin, hepcidin induces its internalisation and degradation, restricting the bioavailability and absorption of iron. This study aimed to test the effect of dimethyl fumarate (DMF) and sulforaphane (SFN), known activators of the transcription factor Nrf2, on the hepcidin-ferroportin (hep-fer) axis. Methods HepG2 cells were cultivated under standard conditions and treated with DMF or SFN for 16h. For reporter gene assays, plasmids were transfected by lipofection; luciferase activity was measured luminometrically. Quantitative real-time PCR was performed to determine mRNA expression. Proteins were detected by Western blot or LC-MS/MS. For gene knockdown, HepG2 cells were transfected with targeting or nontargeting siRNA duplexes. Graph Pad Prism v.7.00 and IBM SPSS 25 were used for statistical analysis. Results Both DMF and SFN reduced basic hepcidin expression and counteracted cytokine-induced hepcidin expression at promoter, mRNA and protein levels in HepG2 cells, independent of Nrf2 activation. Furthermore, DMF caused upregulation of ferroportin and ferritin at mRNA level, dependent on induction of Nrf2 and its downstream target haem oxygenase-1 (HO-1). Conclusion The Nrf2 agonists DMF and SFN might ameliorate anaemia of inflammation by disrupting the hep-fer axis by Nrf2-dependent and -independent mechanisms, and may be a promising therapeutic option for anaemia of inflammation for patients with IBD.

P687 Prevalence of iron deficiency and anaemia in the outpatient Inflammatory Bowel Disease population: a Dutch national cross-sectional study

Abstract Background Iron deficiency (ID) and anaemia in Inflammatory Bowel Disease (IBD) are associated with reduced quality of life, worse disease outcomes, and an increase in healthcare costs. In the European guidelines, anaemia is listed as one of the treatment goals. The data on the prevalence of anaemia and ID are inconsistent. Therefore, we evaluated the prevalence of ID, anaemia, and potential risk factors in a large Dutch outpatient population. Methods Between January and November 2021, consecutive adult outpatients with IBD, who did not have significant comorbidities associated with anaemia, were included in this study across 16 general, teaching, and academic hospitals within the Netherlands. Besides demographic and clinical data, relevant biochemical parameters such as haemoglobin (Hb), Mean Corpuscular Volume (MCV), iron indices, and inflammatory markers (e.g., C-reactive protein (CRP) and faecal calprotectin (FCP)) were extracted from medical records. Active IBD was defined by either CRP &amp;gt;5mg/L or FCP &amp;gt;150mg/g. ID was defined by ferritin &amp;lt;100µg/L in case of inflammation and &amp;lt;30µg/L in quiescent IBD, or transferrin saturation &amp;lt;20%. The Dutch national reference range was used to define anaemia: Hb &amp;lt;7.5mmol/L or &amp;lt;8.5mmol/L for females and males, respectively. The data were analysed by stratifying patients into Crohn’s Disease (CD) and Ulcerative Colitis (UC) groups, with the latter also including patients with IBD-unclassified (IBDU). Results In total, 2197 patients (1271 CD, 849 UC, and 77 IBDU) were included in the study. The overall prevalence of anaemia, iron-deficiency anaemia (IDA), and ID was: 18.0%, 12.2%, and 43.4%, respectively. The prevalence of all three conditions did not differ between the CD and UC groups (P&amp;gt;0.05). Severe anaemia (Hb&amp;lt;6.2 mmol/L) was observed only in 28 patients. ID was more frequently observed in biochemically active IBD compared with quiescent IBD (70.8% versus 23.9%; P&amp;lt;0.001). Female gender, younger age, low MCV, and a twofold increase in biochemical inflammation were associated with ID development in multivariable analysis: Log2FCP [OR 1.39; 95% CI: 1.29–1.50; P&amp;lt;0.001] and Log2platelets [OR 1.85; 95% CI: 1.16–2.95; P&amp;lt;0.01]. In multivariable analysis, low ferritin and MCV, inflammation, older age, and male gender were associated with a higher risk of anaemia; however, disease location or behaviour did not affect the risk of developing anaemia or ID. Conclusion One in five ambulatory IBD patients presents with anaemia that is primarily caused by ID. Inflammation increases the risk of ID and anaemia regardless of IBD type or disease location. High ID prevalence suggests the need for screening and treatment optimisation.

P432 Relationship between haemoglobin status and utility in patients with iron deficiency anaemia in inflammatory bowel disease: A post-hoc analysis of a phase, 3 clinical trial

Abstract Background Iron deficiency anaemia (IDA) can significantly impair the health-related quality of life of patients with inflammatory bowel disease (IBD), but there is little evidence demonstrating a relationship between haemoglobin (Hb) and utility values. This study aimed to estimate preference-based health state utility values from Short-Form Health Survey (SF-36) data, stratifying by treatment received, and to investigate the relationship between Hb status and health-related quality of life. Methods A randomised phase, 3b clinical trial compared oral ferric maltol (FM) vs intravenous (IV) iron (ferric carboxymaltose (FCM)) in patients with IBD and IDA who were eligible for IV iron. This post-hoc analysis used patient-level data on SF-36 responses to generate Short-Form Six-Dimension (SF-6D) and EuroQol-5 Dimension (EQ-5D) health-state utility values using published algorithms. Utility values were further stratified by the proportion of patients achieving normalisation of Hb levels (Hb &amp;gt;, 13g/dL for men and &amp;gt;, 12g/dL for women). Results In the overall study population, mean (SD) SF-6D values were, 0.67 (±0.12) at baseline and, 0.70 (±0.13) at, 52 weeks. Mapped mean EQ-5D values were, 0.77 (±0.17) at baseline and, 0.78 (±0.19) at, 52 weeks. There were no significant differences in the mean utility estimates for patients receiving FM and FCM at any assessment point (Table, 1). Of note, 45.38% of patients randomised to the FCM arm received repeat treatments after the initial course administered at baseline. In the overall study population, mean utility estimates for patients in a normalised state were significantly greater than those estimated for patients in a non-normalised state (pooled analysis of all time points): SF-6D, 0.724 (95% CI:, 0.717–0.731) vs, 0.690 (95% CI:, 0.683–0.697), respectively, Pr (|T|&amp;gt;|t|):, 0.001; EQ-5D, 0.834 (95% CI:, 0.826–0.842) vs, 0.792 (95% CI:, 0.782–0.802), Pr (|T|&amp;gt;|t|):, 0.001. No statistically significant differences were observed between treatments in the normalised or non-normalised groups. Conclusion Oral ferric maltol results in similar utility scores to IV iron therapy with ferric carboxymaltose in patients with IBD eligible for intravenous iron therapy. Normalised Hb was associated with significantly better utility than non-normalised, demonstrating the value to patients of treating IDA in IBD. A cost-effectiveness analysis should be conducted to examine the incremental benefit of IV iron considering the large cost of treatment.

Efficacy and Safety of Ferric Derisomaltose/Iron Isomaltoside in Patients with Inflammatory Bowel Disease: A Systematic Review

BackgroundAnemia in inflammatory bowel disease (IBD) presents as a common extraintestinal manifestation resulting in many complications. This condition is often missed or underrated, anemia is secondary to blood loss or defective absorption of iron which can result in a combination of iron deficiency anemia (IDA) or anemia of chronic disease (ACD). The management is iron replacement therapy which improves the quality of life in these patients. Due to the constraints in the use of oral iron, parenteral preparations are more used in IBD patients. Commonly used iron sucrose and ferric carboxymaltose are often associated with side effects leading to poor compliance. Our study explores data about ferric derisomaltose also known as iron isomaltoside (IIM), a recently approved IV iron preparation. The FDA approved this drug in 2020 for patients with poor compliance with other iron preparations. We explored the efficacy and safety data of ferric derisomaltose in adult patients with IBD.Material/MethodsA literature search was performed using the following databases: PubMed, Cochrane, Embase, Clinical trials.gov, and Web of Science. The search was completed without using any filter and we used the MeSH Terms for “anemia”, “iron deficiency anemia”, “inflammatory bowel disease”, and “ferric compounds”. A total of 1590 articles were screened, and we finally selected 2 trials and 2 observational studies. We followed the PRISMA guidelines for literature search and selection of studies. Case reports, preclinical trials, meta-analyses, and review articles were excluded. Trial and observational studies related to IBD were included.ResultsIn total, 294 patients with anemia in inflammatory bowel disease received ferric derisomaltose intravenously as a single dose between 500 mg to 2000 mg. All patients were >18 years of age. The mean pre-treatment hemoglobin (Hb) level varied from 10.0 g/dL to 12.3 g/dL. The mean serum ferritin ranged from 19.6 µg/L to 57 µg/L and the mean transferrin saturation (TSAT) ranged from 8.8% to 18.5%. J. Stein et al investigated the effectiveness and safety of IIM in routine practical care of IDA in IBD patients. Dahlerup et al (NCT01599702) compared single dose IIM with multiple dosages of IIM in IBD patients. The remaining two studies investigated the effectiveness and safety of high dose IIM in patients with IBD. Results are summarized in Table 1.Efficacy:The increase in hemoglobin ranged from 0.6 g/dl to 2.9 g/dl from baseline while the increase in serum ferritin ranged between 102 µg /L to 250 µg /L and transferrin saturation increased in the range of 15.0%-23.7% in 10 to 52 weeks post iron isomaltoside (IIM) therapy. All markers of iron deficiency anemia showed significant improvement. In the observational study by J. Stein et al, the hemoglobin increased from a mean of 10.7 g/dl to 13.1 g/dl, serum ferritin increased from 57 µg /L to 146 µg /L, and TSAT from 8.8% to 23.7% at 16 weeks. Dahlerup et al demonstrated a Hb increase of >2 g/dl in 75% of patients at 10 weeks. According to W. Reinisch et al (NCT 01410435), there was a mean increase in serum ferritin from 32 µg /L to 102 µg /L and a decrease in TSAT from the baseline, but this decrease was not statistically significant.Safety:Adverse events were noted in 8 (3.6%) patients. Out of the 8 patients, 4 (<2%) were serious adverse events such as perianal abscess, miliary tuberculosis, nephrolithiasis, and worsening of ulcerative colitis, which may not be related to the study drug. The other 4 (1.8%) had life-threatening events, anaphylaxis being the most common. All four patients recovered. The most common mild adverse events reported were hypersensitivity reaction (HSR) seen in 3 patients. 2 patients discontinued due to mild HSR. There were no reports of death due to side effects of the drug.ConclusionFerric derisomaltose has demonstrated a substantial increment in iron parameters in anemia in patients with IBD. This was measured in terms of hemoglobin response, serum ferritin, and transferrin saturation. Greater Hb response was achieved irrespective of concomitant treatment with steroids and anti-TGF-ß.The adverse events were mild, and patients recovered showing high compliance. Since the average duration of follow-up in our study was 21 weeks, long-term follow-up is limited for this drug, we need further studies to assess the need for maintenance therapy. [Display omitted] DisclosuresAnwer: GlaxoSmithKline: Research Funding; BMS / Celgene: Honoraria, Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; Allogene Therapeutics: Research Funding.

Hemolytic Anemia in Inflammatory Bowel Disease: Our "Gut" Tells Us to Blame the Drug.

Several studies determined that autoimmune hemolytic anemia (AIHA) is a rare extraintestinal IBD manifestation, related to the underlying disease activity. However, evidence linking biologic therapy to AIHA is sparse. This article reviews the evidence on the association of these clinical phenomena. There are two retrospective studies and a few case reports linking biologic therapies to AIHA. While some autoimmune phenomenon triggered by our biologic therapies have been well recognized, we do not find the evidence associating these therapies to AIHA sufficiently compelling.