RESUMEN
Iron is an essential cellular metal that is important for many physiological functions including erythropoiesis and host defense. It is absorbed from the diet in the duodenum and loaded onto transferrin (Tf), the main iron transport protein. Inefficient dietary iron uptake promotes many diseases, but mechanisms regulating iron absorption remain poorly understood. By assessing mice that harbor a macrophage-specific deletion of the tuberous sclerosis complex 2 (Tsc2), a negative regulator of mechanistic target of rapamycin complex 1 (mTORC1), we found that these mice possessed various defects in iron metabolism, including defective steady-state erythropoiesis and a reduced saturation of Tf with iron. This iron deficiency phenotype was associated with an iron import block from the duodenal epithelial cells into the circulation. Activation of mTORC1 in villous duodenal CD68+ macrophages induced serine protease expression and promoted local degradation of Tf, whereas the depletion of macrophages in mice increased Tf levels. Inhibition of mTORC1 with everolimus or serine protease activity with nafamostat restored Tf levels and Tf saturation in the Tsc2-deficient mice. Physiologically, Tf levels were regulated in the duodenum during the prandial process and Citrobacter rodentium infection. These data suggest that duodenal macrophages determine iron transfer to the circulation by controlling Tf availability in the lamina propria villi.
Asunto(s)
Hierro de la Dieta , Transferrina , Ratones , Animales , Transferrina/metabolismo , Hierro de la Dieta/metabolismo , Hierro/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Dieta , Duodeno/metabolismo , Receptores de Transferrina/metabolismoRESUMEN
With increasing urbanization and industrialization, the prevalence of inflammatory bowel diseases (IBDs) has steadily been rising over the past two decades. IBD involves flares of gastrointestinal (GI) inflammation accompanied by microbiota perturbations. However, microbial mechanisms that trigger such flares remain elusive. Here, we analyzed the association of the emerging pathogen atypical enteropathogenic E. coli (aEPEC) with IBD disease activity. The presence of diarrheagenic E. coli was assessed in stool samples from 630 IBD patients and 234 age- and sex-matched controls without GI symptoms. Microbiota was analyzed with 16S ribosomal RNA gene amplicon sequencing, and 57 clinical aEPEC isolates were subjected to whole-genome sequencing and in vitro pathogenicity experiments including biofilm formation, epithelial barrier function and the ability to induce pro-inflammatory signaling. The presence of aEPEC correlated with laboratory, clinical and endoscopic disease activity in ulcerative colitis (UC), as well as microbiota dysbiosis. In vitro, aEPEC strains induce epithelial p21-activated kinases, disrupt the epithelial barrier and display potent biofilm formation. The effector proteins espV and espG2 distinguish aEPEC cultured from UC and Crohn's disease patients, respectively. EspV-positive aEPEC harbor more virulence factors and have a higher pro-inflammatory potential, which is counteracted by 5-ASA. aEPEC may tip a fragile immune-microbiota homeostasis and thereby contribute to flares in UC. aEPEC isolates from UC patients display properties to disrupt the epithelial barrier and to induce pro-inflammatory signaling in vitro.
Asunto(s)
Colitis Ulcerosa , Escherichia coli Enteropatógena , Infecciones por Escherichia coli , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Humanos , Escherichia coli Enteropatógena/genéticaRESUMEN
Iron deficiency (ID) workup is a common challenge for gastrointestinal endoscopy. In premenopausal women current guidelines recommend serologic evaluation of coeliac disease only. Here we systematically tested serologic screening for autoimmune gastritis (AIG) in a large cohort of patients with ID. This is a retrospective analysis of patients who attended an out-patient clinic specialized for ID. Patients with ferritin <50 µg/L or transferrin saturation <15% were included. Laboratory workup included endomysial antibodies and parietal-cell antibodies (PCA). Upper gastrointestinal endoscopy with pH-measurement of gastric juice and histology was performed to confirm positive serologic results. Three hundred seventy-three patients with ID were included, about half of whom were anemic. Patients were predominately female with a median age of 40 (confidence interval 11). Positive endomysial antibodies were found in 4 (1%) patients, elevated levels of PCA (>20 U/mL) were found in 69 (18.5%) patients, PCA >100 U/mL in 23 (6.2%). Twenty-six were followed up by gastroscopy; in 12 of 26 patients the diagnosis of AIG was confirmed by histology with 2 additional patients diagnosed as early and/or questionable AIG. A sensitivity of 93% and a specificity of 98% were estimated for a PCA cut-off of 100 U/mL. In 20 patients gastric pH was measured. Achlorhydria was found in 7 patients all diagnosed with AIG. In this ID cohort AIG is by far more common than coeliac disease. PCA above 100 U/mL are a sensitive and specific cut-off for workup of patients with ID prior to endoscopy. Serologic suspicion of AIG helps preselection of patients for endoscopic workup for ID.
Asunto(s)
Anemia Ferropénica/complicaciones , Autoanticuerpos/metabolismo , Gastritis/etiología , Células Parietales Gástricas/patología , Adulto , Anemia Ferropénica/patología , Femenino , Gastritis/patología , Humanos , Incidencia , Masculino , Estudios RetrospectivosRESUMEN
Autoimmune gastritis is a chronic inflammatory disease with destruction of parietal cells of the corpus and fundus of the stomach. The known consequence is vitamin B12 deficiency and, consequently, pernicious anemia. However, loss of parietal cells reduces secretion of gastric acid which is also required for absorption of inorganic iron; thus, iron deficiency is commonly found in patients with autoimmune gastritis. This usually precedes vitamin B12 deficiency and is found mainly in young women. Patients with chronic iron deficiency, especially those refractory to oral iron therapy, should therefore be evaluated for the presence of autoimmune gastritis.
Asunto(s)
Anemia Ferropénica/inmunología , Enfermedades Autoinmunes/inmunología , Gastritis/inmunología , Células Parietales Gástricas/inmunología , Adulto , Enfermedad Crónica , Femenino , Ácido Gástrico/metabolismo , Gastritis Atrófica/inmunología , Humanos , Masculino , Deficiencia de Vitamina B 12/inmunologíaRESUMEN
Anemia affects one-fourth of the world's population, and iron deficiency is the predominant cause. Anemia is associated with chronic fatigue, impaired cognitive function, and diminished well-being. Patients with iron deficiency anemia of unknown etiology are frequently referred to a gastroenterologist because in the majority of cases the condition has a gastrointestinal origin. Proper management improves quality of life, alleviates the symptoms of iron deficiency, and reduces the need for blood transfusions. Treatment options include oral and intravenous iron therapy; however, the efficacy of oral iron is limited in certain gastrointestinal conditions, such as inflammatory bowel disease, celiac disease, and autoimmune gastritis. This article provides a critical summary of the diagnosis and treatment of iron deficiency anemia. In addition, it includes a management algorithm that can help the clinician determine which patients are in need of further gastrointestinal evaluation. This facilitates the identification and treatment of the underlying condition and avoids the unnecessary use of invasive methods and their associated risks.
RESUMEN
BACKGROUND: Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD). In clinical practice, many patients receive initial treatment with iron tablets although intravenous (i.v.) iron supplementation is often preferable. AIM: This study investigated whether systemic inflammation at initiation of treatment (assessed by C-reactive protein [CRP] and interleukin-6 [IL-6] measurements) predicts response to iron therapy. METHODS: Data from a previously published phase III trial were retrospectively analyzed after stratification of patients according to baseline CRP (> 4 vs. ≤ 4 mg/L) and IL-6 (> 6 vs. ≤ 6 pg/mL) levels. The study population consisted of patients with Crohn's disease or ulcerative colitis and IDA (Hb ≤ 110 g/L and TSAT < 20 % or serum ferritin < 100 ng/mL), randomized to either oral (ferrous sulfate) or i.v. iron (ferric carboxymaltose). RESULTS: A total of 196 patients were evaluated (oral iron: n = 60; i.v. iron: n = 136). Baseline CRP and IL-6 levels were independent of patients' initial Hb levels and iron status (serum ferritin and TSAT; all p > 0.05). Among iron tablet-treated patients, Hb increase was significantly smaller in the high- versus low-CRP subgroup (1.1 vs. 2.0, 2.3 vs. 3.1, and 3.0 vs. 4.0 g/dL at weeks 2, 4, and 8, respectively; all p < 0.05). Differences were less pronounced with stratification according to baseline IL-6. Response to i.v. iron was mainly independent of inflammation. CONCLUSIONS: Patients with high baseline CRP achieved a lower Hb response with oral iron therapy. Our results suggest that CRP may be useful to identify IBD patients who can benefit from first-line treatment with i.v. iron to improve their IDA.
Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Proteína C-Reactiva/análisis , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Compuestos Férricos/administración & dosificación , Compuestos Ferrosos/administración & dosificación , Hematínicos/administración & dosificación , Mediadores de Inflamación/sangre , Maltosa/análogos & derivados , Administración Intravenosa , Administración Oral , Anemia Ferropénica/sangre , Anemia Ferropénica/diagnóstico , Anemia Ferropénica/inmunología , Biomarcadores/sangre , Ensayos Clínicos Fase III como Asunto , Colitis Ulcerosa/sangre , Colitis Ulcerosa/diagnóstico , Enfermedad de Crohn/sangre , Enfermedad de Crohn/diagnóstico , Hemoglobinas/metabolismo , Humanos , Interleucina-6/sangre , Maltosa/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Iron deficiency is a common cause of reactive thrombocytosis, however, the exact pathways have not been revealed. Here we aimed to study the mechanisms behind iron deficiency-induced thrombocytosis. Within few weeks, iron-depleted diet caused iron deficiency in young Sprague-Dawley rats, as reflected by a drop in hemoglobin, mean corpuscular volume, hepatic iron content and hepcidin mRNA in the liver. Thrombocytosis established in parallel. Moreover, platelets produced in iron deficient animals displayed a higher mean platelet volume and increased aggregation. Bone marrow studies revealed subtle alterations that are suggestive of expansion of megakaryocyte progenitors, an increase in megakaryocyte ploidy and accelerated megakaryocyte differentiation. Iron deficiency did not alter the production of hematopoietic growth factors such as thrombopoietin, interleukin 6 or interleukin 11. Megakaryocytic cell lines grown in iron-depleted conditions exhibited reduced proliferation but increased ploidy and cell size. Our data suggest that iron deficiency increases megakaryopoietic differentiation and alters platelet phenotype without changes in megakaryocyte growth factors, specifically TPO. Iron deficiency-induced thrombocytosis may have evolved to maintain or increase the coagulation capacity in conditions with chronic bleeding.
Asunto(s)
Plaquetas/metabolismo , Deficiencias de Hierro , Hierro/sangre , Megacariocitos/metabolismo , Mielopoyesis/fisiología , Trombopoyetina/metabolismo , Animales , Plaquetas/citología , Hierro/metabolismo , Masculino , Megacariocitos/citología , Fenotipo , Agregación Plaquetaria/fisiología , Recuento de Plaquetas/métodos , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Anemia Ferropénica/fisiopatología , Compuestos Férricos/uso terapéutico , Enfermedades Inflamatorias del Intestino/complicaciones , Maltosa/análogos & derivados , Activación Plaquetaria , Trombocitosis/etiología , Adolescente , Adulto , Eritropoyetina/metabolismo , Femenino , Hepcidinas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Maltosa/uso terapéutico , Persona de Mediana Edad , Selectina-P/metabolismo , Agregación Plaquetaria , Recuento de Plaquetas , Pronóstico , Estudios Prospectivos , Trombocitosis/tratamiento farmacológico , Adulto JovenRESUMEN
OBJECTIVES: Gut-directed hypnotherapy (GHT) in individual sessions is highly effective in the treatment of irritable bowel syndrome (IBS). This study aimed to assess the long-term effect of GHT in group sessions for refractory IBS. METHODS: A total of 164 patients with IBS (Rome-III-criteria) were screened, and 100 refractory to usual treatment were randomized 1:1 either to supportive talks with medical treatment (SMT) or to SMT with GHT (10 weekly sessions within 12 weeks). The primary end point was a clinically important improvement on several dimensions of daily life (assessed by IBS impact scale) after treatment and 12-month follow-up. The secondary end point was improvement in general quality of life (QOL; Medical Outcome Study Short-Form-36), psychological status (Hospital Anxiety Depression Scale) and reduction of single IBS symptoms. Analysis was by intention to treat. RESULTS: A total of 90 patients received allocated intervention. After treatment, 28 (60.8%) out of 46 GHT patients and 18 (40.9%) out of 44 SMTs improved (absolute difference 20.0%; 95% confidence interval (CI): 0-40.2%; P=0.046); over 15 months, 54.3% of GHT patients and 25.0% of controls improved (absolute difference 29.4%; 95% CI 10.1-48.6%; P=0.004). GHT with SMT improved physical and psychological well being significantly more than SMT alone (P<0.001). Gender, age, disease duration and IBS type did not have an influence on the long-term success of GHT. CONCLUSIONS: GHT improves IBS-related QOL, is superior to SMT alone, and shows a long-term effect even in refractory IBS.
Asunto(s)
Hipnosis/métodos , Síndrome del Colon Irritable/terapia , Calidad de Vida , Índice de Severidad de la Enfermedad , Adulto , Ansiedad , Austria , Depresión , Femenino , Estudios de Seguimiento , Humanos , Síndrome del Colon Irritable/psicología , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Psicoterapia de Grupo , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Secondary thrombocytosis is a clinical feature of unknown significance. In inflammatory bowel disease (IBD), thrombocytosis is considered a marker of active disease; however, iron deficiency itself may trigger platelet generation. In this study we tested the effect of iron therapy on platelet counts in patients with IBD-associated anemia. METHODS: Platelet counts were analyzed before and after iron therapy from four prospective clinical trials. Further, changes in hemoglobin, transferrin saturation, ferritin, C-reactive protein, and leukocyte counts, before and after iron therapy were compared. In a subgroup the effect of erythropoietin treatment was tested. The results were confirmed in a large independent cohort (FERGIcor). RESULTS: A total of 308 patient records were available for the initial analysis. A dose-depended drop in platelet counts (mean 425 G/L to 320 G/L; p<0.001) was found regardless of the type of iron preparation (iron sulphate, iron sucrose, or ferric carboxymaltose). Concomitant erythropoietin therapy as well as parameters of inflammation (leukocyte counts, C-reactive protein) had no effect on the change in platelet counts. This effect of iron therapy on platelets was confirmed in the FERGIcor study cohort (n=448, mean platelet counts before iron therapy: 383 G/L, after: 310 G/L, p<0.001). CONCLUSION: Iron therapy normalizes elevated platelet counts in patients with IBD-associated anemia. Thus, iron deficiency is an important pathogenetic mechanism of secondary thrombocytosis in IBD.