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Aim: To investigate the role of endothelial PV-1 in patients with untreated celiac disease (CD)-associated liver injury. Materials & methods: PV-1 and PV-1 mRNA were measured in intestinal biopsies from untreated CD patients with elevated or normal alanine transaminase levels, controls, patients with inflammatory bowel disease and patients with toxic liver injury. Circulating PV-1 levels were also evaluated. Results: Circulating PV-1 levels were significantly increased in the serum of patients with CD-associated liver injury and reverted to normal following a gluten-free diet. Mucosal PV-1 and PV-1 mRNA were no different in patients with CD-associated liver injury. Conclusion: Serum but not mucosal PV-1 represents a marker of gluten-dependent liver injury and response to a gluten-free diet in patients with untreated CD.
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Enfermedad Celíaca/sangre , Hepatopatías/sangre , Proteínas de la Membrana/sangre , Adolescente , Adulto , Biomarcadores/sangre , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/dietoterapia , Enfermedad Celíaca/patología , Niño , Preescolar , Dieta Sin Gluten/métodos , Femenino , Glútenes/metabolismo , Humanos , Lactante , Hígado/patología , Hepatopatías/complicaciones , Hepatopatías/patología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
OBJECTIVE: Causes of small-bowel villous atrophy (VA) include coeliac disease (CD), its complications and other rare non-coeliac enteropathies. However, forms of VA of unknown aetiology may also exist. We defined them as idiopathic VA (IVA). To retrospectively classify the largest cohort of IVA patients and compare their natural history with CD. METHODS: Notes of 76 IVA patients attending two tertiary centres between January 2000 and March 2019 were retrospectively reviewed. CD, its complications and all the known causes of VA were excluded in all of them. Persistence of VA during follow-up and lymphoproliferative features were used to retrospectively classify IVA, as follows. Group 1: IVA with spontaneous histological recovery (50 patients). Group 2: persistent IVA without lymphoproliferative features (14 patients). Group 3: persistent IVA with lymphoproliferative features (12 patients). Survival was compared between IVA groups and 1114 coeliac patients. HLA was compared between IVA patients, coeliac patients and appropriate controls. RESULTS: Five-year survival was 96% in IVA group 1, 100% in IVA group 2, 27% in IVA group 3 and 97% in CD. On a multivariate analysis hypoalbuminemia (P = 0.002) and age at diagnosis (P = 0.04) predicted mortality in IVA. Group 2 showed association with HLA DQB1*0301 and DQB1*06. CONCLUSION: IVA consists of three groups of enteropathies with distinct clinical phenotypes and prognoses. Mortality in IVA is higher than in CD and mainly due to lymphoproliferative conditions necessitating more aggressive therapies.
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Enfermedad Celíaca , Atrofia , Enfermedad Celíaca/diagnóstico , Estudios de Cohortes , Humanos , Fenotipo , Estudios RetrospectivosRESUMEN
We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD40L (Spearman's rank correlation coefficient [rs ], -0.33; P < 0.001), sNox2-dp (rs , -0.57; P < 0.0001), and urinary excretion of isoprostanes (rs, -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2α-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation.
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BACKGROUND: A clinically meaningful impairment of bone mass secondary to malabsorption is frequent in untreated celiac disease. In adult patients, a rigorous gluten-free diet (GFD) significantly improves, but does not always normalize, bone mineral density (BMD). The reason for this marginal response is unclear. Accordingly, we evaluated the role of both local and systemic factors for bone loss in celiac patients on long-term GFD. STUDY: In a prospective cohort, 22 patients with low lumbar and/or femoral BMD and 22 with normal BMD underwent bone and mineral metabolism evaluation: we tested calcium, phosphate, parathyroid hormone, and vitamin D; telopeptide of type I collagen, a bone resorption index; propeptide of type I procollagen, a bone neoformation index; receptor antagonist of NF-kB ligand, an osteoclast-stimulating factor; osteoprotegerin (OPG), a decoy receptor for RANKL. Sunlight exposure and physical exercise were measured. RESULTS: Patients with bone loss showed prevalently osteopenia, severe osteoporosis was rare. In comparison with normal BMD patients, they showed higher serum OPG, telopeptide, and lower serum propeptide, suggesting an increased bone turnover. Lumbar T-score was negatively correlated with OPG, telopeptide and RANKL and positively with propeptide. Propeptide was negatively correlated with OPG and telopeptide. OPG was positively correlated with telopeptide. CONCLUSIONS: The persistent activation of inflammation should be considered the main pathophysiological mechanism for bone defect in celiac disease patients with bone loss on long-term GFD. High levels of OPG, an attempt at protective mechanism, and low levels of propeptide of type I procollagen, reflecting an insufficient matrix production, characterize this subgroup of patients.
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Densidad Ósea/fisiología , Enfermedad Celíaca/fisiopatología , Dieta Sin Gluten , Inflamación/fisiopatología , Adulto , Enfermedades Óseas Metabólicas/epidemiología , Enfermedad Celíaca/dietoterapia , Estudios de Cohortes , Femenino , Humanos , Osteoporosis/epidemiología , Osteoprotegerina/metabolismo , Fragmentos de Péptidos/metabolismo , Procolágeno/metabolismo , Estudios ProspectivosRESUMEN
Autoimmune and allergic disorders are highly prevalent conditions in which an altered or abnormal immune response is mounted against self- or environmental antigens, respectively. Antigen-based immunotherapy is a therapeutic option aimed at restoring the specific immune tolerance toward pathogenic antigens while leaving the rest of the immune system unaffected. This strategy proved efficacy especially in allergic diseases, including asthma, allergic rhinitis, and food allergies, but still has shortcomings for the treatment of autoimmune diseases. However, there are no available therapies, currently, in clinical practice for restoring the physiological tolerance that is typically lost in autoimmune diseases. In celiac disease, which is a common immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals, antigen-based immunotherapy could be a feasible option thanks to our deep understanding of the pathogenic mechanisms underpinning this condition. In fact, the immunodominant gluten epitopes are well-characterized and are recognized by pathogenic CD4+ T-cells that could be desensitized with immunotherapy. Moreover, the intestinal damage occurring in celiac disease (i.e., villous atrophy) is reversible upon gluten withdrawal. Only recently the results of a phase I trial of an intradermal, adjuvant-free, formulation of three specific gluten peptides (Nexvax2) showed a good safety profile, albeit its efficacy still needs to be demonstrated. More results are awaited, as they may radically change patients' quality of life that is constrained by the lifelong gluten-free diet and by the potential onset of life-threatening complications.
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Celiac disease (CD), the most common chronic enteropathy worldwide, is triggered and sustained by a dysregulated immune response to dietary gluten in genetically susceptible individuals. Up to date either the role of environmental factors and the pathways leading to mucosal damage have been only partially unraveled. Therefore, we seized the unique opportunity to study a naturally-occurring experimental model of a family composed of both parents suffering from CD (one on a gluten-free diet) and two non-celiac daughters. The control group consisted in four unrelated cases, two celiac and two non-celiac subjects, all matching with family members for both disease status and genetic susceptibility. In this privileged setting, we sought to investigate gene expression in peripheral blood mononuclear cells (PBMCs), a population known to mirror the immune response state within the gut. To this purpose, PBMCs were obtained from the four biopsied-proven CD patients and the four non-celiac cases. Each group included two family members and two unrelated control subjects. After RNA purification and cDNA synthesis, each sample underwent a microarray screen on a whole-transcriptome scale, and the hybridization results were visualized by hierarchical clustering. Differentially expressed genes (DEG) were partitioned into clusters displaying comparable regulations among samples. These clusters were subjected to both functional and pathway analysis by using the Kyoto Encyclopedia of Genes and Genomes. Interestingly, on a global gene expression level, the family members clustered together, regardless of their disease status. A relevant fraction of DEG belonged to a limited number of pathways, and could be differentiated based on disease status: active CD vs. treated CD and CD vs. controls. These pathways were mainly involved in immune function regulation, cell-cell junctions, protein targeting and degradation, exosome trafficking, and signal transduction. Worth of noting, a small group of genes mapping on the male-specific region of the Y chromosome, and previously linked to cardiovascular risk, was found to be strongly upregulated in the active CD case belonging to the family, who suddenly died of a heart attack. Our results provide novel information on CD pathogenesis and may be useful in identifying new therapeutic tools and risk factors associated with this condition.
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Immune-mediated disorders affecting the gastrointestinal (GI) tract may compromise GI integrity, interfere with the absorption of nutrients and cause bleeding and inflammation. All these features contribute to the pathogenesis of anaemia, the most prevalent extra-intestinal manifestation of immune-mediated GI disorders. Anaemia is most commonly due to iron deficiency and/or inflammation, but vitamin deficiencies and, more infrequently, autoimmune haemolysis or drug-induced myelosuppression can be involved. Here we address several issues related to the differential diagnosis and treatment of anaemia in immune-mediated GI disorders, giving particular relevance to the problem of iron deficiency anaemia associated with inflammation. It is emphasized how, in most cases, anaemias due to iron or vitamin deficiencies are best treated by parenteral administration of the deficient factor(s), and how the available high dose intravenous (IV) iron formulations can reduce ambulatory and social costs of IV iron supplementation, while improving patient's compliance to treatment. Actual and future treatment possibilities for anaemia of inflammation, involving the use of erythropoiesis stimulating agents, biologicals and hepcidin inhibitors are discussed.
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Anemia/etiología , Enfermedades Autoinmunes/complicaciones , Enfermedades Gastrointestinales/complicaciones , Anemia/diagnóstico , Anemia/terapia , Enfermedad Celíaca/complicaciones , Diagnóstico Diferencial , Gastritis Atrófica/complicaciones , Humanos , Enfermedades Inflamatorias del Intestino/complicacionesRESUMEN
Enteropathy-associated T-cell lymphoma is regarded as a dismal, late complication of coeliac disease, though a single case of T-cell lymphoma with such features arising in the setting of autoimmune enteropathy of the adult has been reported to date. We aim to describe the case of a 41-year-old woman complaining of severe malabsorption syndrome, who was diagnosed with autoimmune enteropathy based on the presence of flat intestinal mucosa unresponsive to any dietary restriction and positivity for enterocyte autoantibodies. Steroid therapy led to a complete recovery of both mucosal and clinical findings over 12 years, when disease relapse was accompanied by the appearance of monoclonal rearrangement of T-cell receptor-γ and peculiar T-cell phenotypic abnormalities, leading to a rapid transition to an overt T-cell lymphoma with features of the enteropathy-associated subtype. Despite intensive treatment, the patient developed cerebral metastasis and died 9 months later. Our case enhances the concept of enteropathy-associated T-cell lymphoma as a disease that may arise in the setting of enteropathies other than coeliac disease, thus representing a heterogeneous entity. Moreover, our observations support the need of a close follow-up of these patients, coupled with comprehensive characterization of mucosal biopsies.
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Linfoma de Células T Asociado a Enteropatía/etiología , Neoplasias Intestinales/etiología , Linfoma de Células T/etiología , Poliendocrinopatías Autoinmunes/complicaciones , Adulto , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/etiología , Diagnóstico Diferencial , Linfoma de Células T Asociado a Enteropatía/diagnóstico , Femenino , Humanos , Neoplasias Intestinales/diagnóstico , Linfoma de Células T/diagnóstico , Síndromes de Malabsorción/diagnóstico , Síndromes de Malabsorción/etiologíaRESUMEN
OBJECTIVES: Some evidence suggests that prevalence of celiac disease in the general population is increasing over time. Because the prognosis of celiac disease was a dismal one before discovering the role of gluten, our aim was to investigate a possible relationship between children under-5 mortality rates and prevalence rates of celiac disease. METHODS: Thanks to a literature review, we found 27 studies performed in 17 different countries describing the prevalence of celiac disease in schoolchildren; between 1995 and 2011, 4 studies were performed in Italy. A meta-analysis of prevalence rates was performed. Prevalence was compared between specific country under-5 mortality groups, publication year, and age. RESULTS: In the last decades, under-5 mortality rates have been decreasing all over the world. This reduction is paralleled by an increase of the prevalence of celiac disease. The Spearman correlation coefficient was -63%, 95% confidence interval -82% to -33% (Pâ<â0.001). So, the higher the mortality rate, the lower the prevalence of CD. This finding is confirmed by the meta-analysis of the 4 studies conducted in Italy over time. CONCLUSIONS: The under-5 mortality rate seems to influence the prevalence of celiac disease in the general population. In the near future, the number of patients with celiac disease will increase, thanks to the better environmental conditions that nowadays allow a better survival of children with celiac disease.
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Enfermedad Celíaca/epidemiología , Mortalidad del Niño , Enfermedad Celíaca/mortalidad , Niño , Preescolar , Dieta Sin Gluten , Humanos , Lactante , PrevalenciaRESUMEN
BACKGROUND: Coeliac disease is characterised by an increased mortality mostly due to its complications. AIMS: To study the risk of developing complications according to clinical presentation and age at diagnosis, a combined retrospective-prospective longitudinal study was performed in three Italian centres. METHODS: Incidence of complications and mortality rates were calculated using type and age at diagnosis of coeliac disease, sex, and centre of diagnosis as predictors. Patients referred after being found to suffer from coeliac disease elsewhere were excluded. RESULTS: Between 01/1999 and 06/2015, 2225 adult coeliac patients were directly diagnosed in our centres. 17 of them developed a complication and 29 died. In patients older than 60 years at diagnosis of coeliac disease, the risk of complication is 18 times higher than in patients diagnosed at 18-40 years and 9 times higher than in patients diagnosed at 40-60 years. Classical presentation increases the risk of complications by 7 times compared to non-classical presentation; in asymptomatic patients the risk of complication is virtually absent. CONCLUSIONS: The risk of developing complications in coeliac patients is linked to age at diagnosis of coeliac disease and type of clinical presentation. Follow-up methods of coeliac patients should be tailored according to these parameters.
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Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Italia/epidemiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (ß-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage- and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear ß-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat ß-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis.
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Carcinoma/patología , Enfermedad Celíaca/complicaciones , Enfermedad de Crohn/complicaciones , Neoplasias Intestinales/patología , Adulto , Carcinoma/etiología , Carcinoma/mortalidad , Femenino , Humanos , Neoplasias Intestinales/etiología , Neoplasias Intestinales/mortalidad , Intestino Delgado/patología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
OBJECTIVE: Villous atrophy (VA) of the small bowel is mainly related to coeliac disease (CD), whose diagnosis is made on the basis of positive endomysial/tissue transglutaminase antibodies while on a gluten-containing diet in the vast majority of patients. However, VA can also occur in other conditions whose epidemiology is little known. Our aim was to study the epidemiology and clinical features of these rare enteropathies. PATIENTS AND METHODS: Clinical and laboratory data of all the patients with VA directly diagnosed in our centre in the last 15 years were collected and statistically analysed. RESULTS: Between September 1999 and June 2015, 274 patients were diagnosed with VA. A total of 260 patients were also positive to coeliac antibodies; the other 14 had VA, but no IgA endomysial antibodies: five had common variable immunodeficiency, three had dermatitis herpetiformis, two had IgA deficiency associated with CD, one had abdominal lymphoma, one had unclassified sprue, one had olmesartan-associated enteropathy and one had seronegative CD. Mortality was 6.0 deaths per 100 person years (95% confidence interval: 2.2-16) in patients with VA but negative coeliac antibodies, whereas only 0.2 deaths per 100 person years (95% confidence interval: 0.1-0.6) occurred in coeliac patients. CONCLUSION: Patients with VA and negative endomysial antibodies are rare. However, these forms of VA identify specific causes that can be diagnosed. These patients are affected by a very high mortality.
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Enfermedad Celíaca/diagnóstico , Mucosa Intestinal/patología , Intestino Delgado/patología , Adolescente , Adulto , Anciano , Atrofia/etiología , Atrofia/mortalidad , Atrofia/patología , Autoanticuerpos/sangre , Biomarcadores/sangre , Biopsia , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/mortalidad , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/mortalidad , Diagnóstico Diferencial , Reacciones Falso Negativas , Femenino , Proteínas de Unión al GTP/inmunología , Humanos , Inmunoglobulina A/sangre , Italia/epidemiología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Proteína Glutamina Gamma Glutamiltransferasa 2 , Estudios Retrospectivos , Transglutaminasas/inmunología , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Vascular disease (VD), as assessed by history of myocardial infarction or peripheral artery disease or aortic plaque, increases stroke risk in atrial fibrillation (AF), and is a component of risk assessment using the CHA2DS2-VASc score. We investigated if systemic atherosclerosis as detected by ultrasound carotid plaque (CP) could improve the predictive value of the CHA2DS2-VASc score. METHODS: We analysed data from the ARAPACIS study, an observational study including 2027 Italian patients with non-valvular AF, in whom CP was detected using Doppler Ultrasonography. RESULTS: VD was reported in 351 (17.3%) patients while CP was detected in 16.6% patients. Adding CP to the VD definition leaded to higher VD prevalence (30.9%). During a median [IQR] follow-up time of 36months, 56 (2.8%) stroke/TIA events were recorded. Survival analysis showed that conventional VD alone did not increase the risk of stroke (Log-Rank: 0.009, p=0.924), while addition of CP to conventional VD was significantly associated to an increased risk of stroke (LR: 5.730, p=0.017). Cox regression analysis showed that VD+CP was independently associated with stroke (HR: 1.78, 95% CI: 1.05-3.01, p=0.0318). Reclassification analysis showed that VD+CP allowed a significant risk reclassification when compared to VD alone in predicting stroke at 36months (NRI: 0.192, 95% CI: 0.028-0.323, p=0.032). CONCLUSIONS: In non-valvular AF patients the addition of ultrasound detection of carotid plaque to conventional VD significantly increases the predictive value of CHA2DS2-VASc score for stroke.
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Fibrilación Atrial/complicaciones , Enfermedades de las Arterias Carótidas/diagnóstico , Placa Aterosclerótica/diagnóstico , Medición de Riesgo , Ultrasonografía Doppler/métodos , Anciano , Anciano de 80 o más Años , Índice Tobillo Braquial , Fibrilación Atrial/diagnóstico , Enfermedades de las Arterias Carótidas/epidemiología , Enfermedades de las Arterias Carótidas/etiología , Femenino , Humanos , Incidencia , Italia/epidemiología , Masculino , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia/tendenciasRESUMEN
BACKGROUND & AIMS: Through inhibition of iron absorption and iron mobilization from tissue stores, hepcidin exerts a negative control on iron homeostasis. Hepcidin, in fact, promotes the degradation of ferroportin (Fpn1), the iron exporter molecule expressed on the membrane of hepatocytes and macrophages, thus preventing iron release from cells to plasma. Hepcidin effects on enterocytes, however, are less clear. Aim of the present study was to further investigate the regulation of iron absorption by hepcidin. METHODS: The transcriptional response of human duodenal mucosa to hepcidin was investigated using organ cultures of duodenal biopsies perendoscopically collected from healthy controls. Biopsies were cultured for 4 h with or without hepcidin-25 and were then assayed for the expression of iron-related genes. RESULTS: In samples that had not been exposed to hepcidin, correlations were found between the expression of genes involved in iron absorption: DMT1, Fpn1, Dcytb and HCP1. In ex vivo experiments hepcidin down-regulated mRNA levels of the iron transporters Fpn1, and DMT1, of the ferric reductase Dcytb, of the ferroxidase hephaestin, and of the putative heme carrier protein HCP1. CONCLUSIONS: Through the reported transcriptional changes hepcidin can modulate several steps of the iron absorption process, including the reduction of dietary iron by Dcytb, its uptake by enterocytes through DMT1, the mucosal uptake of heme iron by HCP1, and enterocyte iron release to plasma by Fpn1 in conjunction with hephaestin.
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Hepcidinas/sangre , Hepcidinas/genética , Absorción Intestinal/efectos de los fármacos , Intestinos/efectos de los fármacos , Hierro/farmacocinética , Adulto , Células CACO-2 , Proteínas de Transporte de Catión/sangre , Proteínas de Transporte de Catión/genética , Grupo Citocromo b/genética , Grupo Citocromo b/metabolismo , Enterocitos/efectos de los fármacos , Enterocitos/metabolismo , Femenino , Regulación de la Expresión Génica , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Hierro/sangre , Masculino , Persona de Mediana Edad , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Refractory coeliac disease (RCD) is a form of coeliac disease (CD) resistant to gluten-free diet and associated with elevated risk of complications. Many effector cytokines over-produced in the gut of patients with RCD are supposed to amplify the tissue-destructive immune response, but it remains unclear if the RCD-associated mucosal inflammation is sustained by defects in counter-regulatory mechanisms. The aim of the present study was to determine whether RCD-related inflammation is marked by high Smad7, an intracellular inhibitor of transforming growth factor-ß1 (TGF-ß1 ) activity. Smad7 was evaluated in duodenal biopsy samples of patients with RCD, patients with active CD, patients with inactive CD and healthy controls by Western blotting, immunohistochemistry and real-time PCR. In the same samples, TGF-ß1 and phosphorylated (p)-Smad2/3 were evaluated by ELISA and immunohistochemistry, respectively. Pro-inflammatory cytokine expression was evaluated in RCD samples cultured with Smad7 sense or antisense oligonucleotide. Smad7 protein, but not RNA, expression was increased in RCD compared with active and inactive CD patients and healthy controls and this was associated with defective TGF-ß1 signalling, as marked by diminished p-Smad2/3 expression. TGF-ß1 protein content did not differ among groups. Knockdown of Smad7 in RCD biopsy samples reduced interleukin-6 and tumour necrosis factor-α expression. In conclusion, in RCD, high Smad7 associates with defective TGF-ß1 signalling and sustains inflammatory cytokine production. These results indicate a novel mechanism by which the mucosal cytokine response is amplified in RCD and suggest that targeting Smad7 can be therapeutically useful in RCD.
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Enfermedad Celíaca/inmunología , Duodeno/inmunología , Inflamación/inmunología , Mucosa Intestinal/inmunología , Proteína smad7/metabolismo , Biopsia , Enfermedad Celíaca/terapia , Dieta Sin Gluten , Humanos , Interleucina-6/metabolismo , Terapia Molecular Dirigida , ARN Interferente Pequeño/genética , Recurrencia , Transducción de Señal , Proteína smad7/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoAsunto(s)
Enteritis/diagnóstico , Eosinofilia/diagnóstico , Gastritis/diagnóstico , Bazo/patología , Recuento de Células Sanguíneas , Eosinófilos/patología , Humanos , Biopsia Guiada por Imagen , Inmunohistoquímica , Mucosa Intestinal/patología , Masculino , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Intestinal fibrosis, caused by an excessive deposition of extracellular matrix components, and subsequent stricture development are a common complication of inflammatory bowel disease. However, currently there are no biomarkers which reliably predict the risk of developing intestinal strictures or identify early stages of fibrosis prior to clinical symptoms. Candidate biomarkers of intestinal fibrosis, including gene variants (i.e. nucleotide-binding oligomerization domain-2 gene), serum microRNAs (miR-19, miR-29), serum extracellular matrix proteins (i.e. collagen, fibronectin) or enzymes (i.e. tissue inhibitor of matrix metalloproteinase-1), serum growth factors (i.e. basic fibroblast growth factor, YKL-40), serum anti-microbial antibodies (i.e. anti-Saccharomyces cerevisiae) and circulating cells (i.e. fibrocytes) have shown conflicting results on relatively heterogeneous patients' cohorts, and none of them was proven to be strictly specific for fibrostenosis, but rather predictive of a disease disabling course. In this review we critically reassess the diagnostic and prognostic value of serum biomarkers of intestinal fibrosis in inflammatory bowel disease.
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BACKGROUND: In experimental models, thromboxane (Tx)A2 reduced renal perfusion and accelerated renal failure. The aim of the study was to investigate the association between the use of aspirin, which inhibits TxA2 production, and the incidence of an estimated Glomerular Filtration Rate (eGFR) <60 and <45ml/min/1.73m2 in patients with atrial fibrillation (AF) and chronic kidney disease (CKD). METHODS: Prospective multicentre observational cohort study including 800 anticoagulated AF patients; CKD was defined as an eGFR <90ml/min/1.73m2 by CKD-EPI formula; eGFR was measured at baseline and after a median of 28.0months. Urinary 11-dehydro-TxB2, was measured in 401 patients. The incidence of cardiovascular events (CVEs) was also registered. RESULTS: Baseline eGFR was 65.1ml/min/1.73m2; 147 and 91 patients had incident eGFR<60 and <45ml/min/1.73m2, respectively; 16.5% patients received a concomitant treatment with aspirin 100mg/day. Multivariate logistic regression analysis showed a direct association with incident eGFR<45ml/min/1.73m2 for female sex (odds ratio [OR]:1.910, p=0.005) and hypertension (OR: 7.589, p=0.047), while aspirin use was inversely associated (OR: 0.347, p=0.016). Propensity score adjustment confirmed this association (p=0.017). Patients with incident eGFR<45ml/min/1.73m2 had higher TxB2, compared to those without (123.0 vs. 90.0ng/mg creatinine, p=0.031); TxB2 was inversely associated with incident eGFR<45ml/min/1.73m2 (log TxB2 OR 2.239, p=0.036). Incident eGFR<45ml/min was associated with an increased rate of CVEs (HR: 2.211, p=0.01). CONCLUSION: Aspirin use was associated with a less decline in eGFR in our cohort of AF patients with CKD. Our findings suggest that TxA2 may be implicated in renal function deterioration in AF.
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Aspirina/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Progresión de la Enfermedad , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Estudios de Cohortes , Inhibidores de la Ciclooxigenasa/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/epidemiología , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiologíaRESUMEN
Type II refractory celiac disease (RCD), as defined according to the amount of aberrant intraepithelial lymphocytes, is a condition characterized by severe malabsorption syndrome and poor prognosis, with no effective treatment. Based on the regenerative and immunomodulatory properties of mesenchymal stem cells (MSCs), we investigated the feasibility, safety, and efficacy of serial infusions of autologous bone marrow-derived MSCs in a 51-year-old woman with type II RCD. Mesenchymal stem cells were isolated, expanded, and characterized following standard protocols. Monitoring of the patient's malabsorption indexes, mucosal architecture, and percentage of aberrant intraepithelial lymphocytes was scheduled for the time of enrollment, at each infusion, and after 6 months. Determination of mucosal expression of interleukin (IL)-15 and its receptor was also performed. Expansion of MSCs was feasible, and the patient underwent 4 systemic infusions of 2 × 10(6) MSCs/kg body weight 4 months apart, without adverse effects. During the treatment period, she experienced gradual and durable amelioration of her general condition, with normalization of stool frequency, body mass index, laboratory test results, and mucosal architecture. Remarkably, the expression of IL-15 and its receptor almost completely disappeared. Thus, treatment of RCD with serial MSC infusions seems promising, leading to recovery from the life-threatening condition while blocking the IL-15 pathogenic pathway.