RESUMEN
OBJECTIVE: Persistent villous atrophy (pVA) in coeliac disease (CD) despite a gluten-free diet (GFD) has unclear meaning. We aimed to (i) study the relationship between pVA and long-term outcomes and (ii) develop a score to identify patients at risk of pVA. DESIGN: This is a multicentre retrospective-prospective study consisting of a study cohort (cohort 1) and an external validation cohort (cohort 2) of patients with biopsy-proven CD diagnosed between 2000 and 2021. Cohort 1 was used to (i) compare long-term outcomes between patients with and without pVA (Marsh ≥3a) at follow-up biopsy and (ii) to develop a score to evaluate the risk of pVA, which was validated in cohort 2. RESULTS: Of 2211 patients, 694 (31%) underwent follow-up duodenal biopsy and were included in the study cohort (491F, 44±16 years). 157/694 (23%) had pVA. Risk of complications (HR 9.53, 95% CI 4.77 to 19.04, p<0.001) and mortality (HR 2.93, 95% CI 1.43 to 6.02, p<0.01) were increased in patients with pVA. A 5-point score was developed and externally validated (receiver operating characteristic area under the curve 0.78, 95% CI 0.68 to 0.89) to stratify patients by risk of pVA: low (0-1 points, 5% pVA), intermediate (2 points, 16% pVA) and high (3-5 points, 73% pVA). Predictors for pVA used in the score were age at diagnosis ≥45 years (OR 2.01, 95% CI 1.21 to 3.34, p<0.01), classical pattern of CD (OR 2.14, 95% CI 1.28 to 3.58, p<0.01), lack of clinical response to GFD (OR 2.40, 95% CI 1.43 to 4.01, p<0.001) and poor GFD adherence (OR 48.9, 95% CI 26.1 to 91.8, p<0.001). CONCLUSIONS: Risk of complications and mortality were increased in patients with pVA. We developed a score to identify patients at risk of pVA and in need of histological reassessment and closer follow-up.
Asunto(s)
Enfermedad Celíaca , Humanos , Adulto , Persona de Mediana Edad , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/diagnóstico , Estudios Retrospectivos , Estudios Prospectivos , Estudios Longitudinales , Mucosa Intestinal/patología , Atrofia/patología , Dieta Sin Gluten , BiopsiaRESUMEN
Our understanding of the pathophysiology of celiac disease has progressed greatly over the past 25 years; however, some fallacies about the clinical characteristics and management persist. Worldwide epidemiologic data are now available showing that celiac disease is ubiquitous. An elevated body mass index is common at the time of the diagnosis. The gluten-free diet (GFD) is an imperfect treatment for celiac disease; not all individuals show a response. This diet is widely used by people without celiac disease, and symptomatic improvement on a GFD is not sufficient for diagnosis. Finally, the GFD is burdensome, difficult to achieve, and thus has an incomplete efficacy, opening exciting opportunities for novel, nondietary treatments.
Asunto(s)
Enfermedad Celíaca , Índice de Masa Corporal , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/etnología , Enfermedad Celíaca/fisiopatología , Enfermedad Celíaca/terapia , Diagnóstico Diferencial , Dieta Sin Gluten , Grano Comestible/efectos adversos , Medicina Basada en la Evidencia , Predisposición Genética a la Enfermedad , HumanosRESUMEN
BACKGROUND: Non-responsive celiac disease (NRCD) has many aetiologies, including gluten exposure. Budesonide may be used for refractory celiac disease (RCD) and celiac crisis. AIMS: We reviewed the effectiveness of budesonide to induce clinical and histologic response in NRCD with villous atrophy (VA). METHODS: Case series of adult cases with NRCD and VA prescribed budesonide at two celiac centers. Clinical variables and mucosal recovery (i.e., normal villous architecture within 1 year of treatment) were evaluated. RESULTS: Forty-two cases [77% female, median age 45.0 (IQR 28.3-60.0) years] were included. Most common symptoms were diarrhea (64%) and abdominal pain (62%). Budesonide was initiated at 9 mg (83%) for a median duration of 16.0 weeks (IQR 6.8-25.0 weeks). In total, 57% exhibited a clinical response, positively associated with diarrhea (adjusted OR 6.08 95% CI 1.04-35.47) and negatively with fatigue (adjusted OR 0.18 95% CI 0.03-0.98). Clinical response was higher among those with dietitian counseling prior to budesonide (n = 29, 70 vs. 23%, p < 0.01). Mucosal recovery was observed in 11/24 with follow-up duodenal biopsies. There was no association between clinical response and mucosal recovery, and 79% of clinical responders had a symptomatic relapse. RCD (48%) and chronic gluten exposure (24%) were the main suspected aetiologies of NRCD. Most individuals without a clinical response subsequently received an IBS-related diagnosis. CONCLUSIONS: Budesonide may be effective to induce clinical response in NRCD presenting with diarrhea and VA, but clinical recurrence and lack of mucosal recovery are frequent after tapering. Other diagnoses, including coexisting IBS, may be considered in non-responders to budesonide therapy.
Asunto(s)
Antiinflamatorios/administración & dosificación , Budesonida/administración & dosificación , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/tratamiento farmacológico , Manejo de la Enfermedad , Adulto , Antiinflamatorios/metabolismo , Budesonida/metabolismo , Enfermedad Celíaca/metabolismo , Estudios de Cohortes , Dieta Sin Gluten/métodos , Dieta Sin Gluten/tendencias , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Celiac disease (CeD) is a common gluten-responsive T cell-mediated enteropathy. The only current treatment is gluten avoidance; however, even when attempting to adhere to a gluten-free diet (GFD), symptomatic gluten exposures are frequent.1.
Asunto(s)
Antiinflamatorios/administración & dosificación , Budesonida/administración & dosificación , Enfermedad Celíaca/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Glútenes/efectos adversos , Administración Oral , Adolescente , Adulto , Anciano , Enfermedad Celíaca/dietoterapia , Dieta Sin Gluten , Femenino , Glucocorticoides/administración & dosificación , Humanos , Intestino Delgado/efectos de los fármacos , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Brote de los Síntomas , Comprimidos Recubiertos/administración & dosificación , Resultado del TratamientoRESUMEN
Celiac disease is a common form of enteropathy with frequent extraintestinal manifestations (EIM). Misrecognition of these presentations may lead to significant delays in diagnosis. Any organ may be involved, either through an immune/inflammatory phenomenon, or nutritional deficiencies. Some EIM, such as gluten ataxia, may be irreversible if left untreated, but most will improve with a gluten-free diet. Knowledge of the various EIM, as well as the associated conditions which do not improve on a gluten-free diet, will avoid delays in the diagnosis and management of celiac disease and associated manifestations.
Asunto(s)
Enfermedad Celíaca/diagnóstico , Diagnóstico Tardío , Evaluación de Síntomas , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/dietoterapia , Dieta Sin Gluten , Oftalmopatías/diagnóstico , Oftalmopatías/etiología , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/etiología , Humanos , Desnutrición/diagnóstico , Desnutrición/etiología , Trastornos Mentales/diagnóstico , Trastornos Mentales/etiología , Enfermedades de la Boca/diagnóstico , Enfermedades de la Boca/etiología , Enfermedades Musculoesqueléticas/diagnóstico , Enfermedades Musculoesqueléticas/etiología , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/etiología , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/etiologíaRESUMEN
PURPOSE: We describe an exceptional case of Langerhans cell histiocytosis (LCH) that presented as Crohn's disease and primary sclerosing cholangitis. METHODS: The patient's clinical, endoscopic, and histologic data from the Centre Hospitalier de l'Universite de Montreal were reviewed, as well as the literature on LCH involving the digestive tract and the liver, with a focus on the similarities with Crohn's disease and primary sclerosing cholangitis. RESULTS: A 39 years-old man first presented with anal fissures and deep punctiform colonic ulcers. Histologic assessment of colon biopsies showed chronic active colitis, consistent with Crohn's disease. Mild cholestasis and endoscopic retrograde cholangiopancreatography (ERCP) showing multiple intra and extrahepatic biliary tract strictures also led to a diagnosis of sclerosing cholangitis. Perianal disease progressed despite conventional treatment with antibiotics and infliximab. Subsequent discovery of non-Langerhans cutaneous xanthogranulomas and panhypopituitarism raised the suspicion of LCH, and a second review of colon biopsies ultimately led to the diagnosis, with the identification of Langerhans cells depicting elongated, irregular nuclei with nuclear grooves as well as immunohistochemical reactivity for S100, CD1a and vimentin. BRAF V600E mutation was detected afterwards by DNA sequencing of a bile duct sample. CONCLUSION: LCH may mimic inflammatory bowel disease (IBD) and must be suspected in the presence of other suggestive clinical signs, or when there is failure of conventional IBD treatment.
Asunto(s)
Enfermedad de Crohn/diagnóstico , Histiocitosis de Células de Langerhans/diagnóstico , Adulto , Colangiopancreatografia Retrógrada Endoscópica , Colangitis Esclerosante , Colitis , Enfermedad de Crohn/etiología , Histiocitosis de Células de Langerhans/complicaciones , Humanos , MasculinoAsunto(s)
Enfermedad Celíaca/epidemiología , Cardiopatías Congénitas/epidemiología , Anomalías Urogenitales/epidemiología , Enfermedad Celíaca/diagnóstico , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Periodo Posparto , Embarazo , Complicaciones del Embarazo/epidemiología , Diagnóstico Prenatal , Quebec/epidemiología , Factores de Riesgo , Sistema Urinario/anomalíasRESUMEN
Classically considered a disease of early childhood characterised by malabsorption and failure to thrive, coeliac disease is now recognised to arise in genetically susceptible individuals at any age. Although permissive HLA genotypes are the strongest predictor of coeliac disease, they are not sufficient. Several prospective cohort studies enrolling genetically at-risk infants have investigated the role of potential triggers of coeliac disease autoimmunity, such as timing of gluten introduction, viral infections and dietary patterns. Much less is known about triggers of coeliac disease in adulthood. Better understanding of factors leading to coeliac disease may be helpful in the management of those with potential coeliac disease (elevated serum celiac antibodies without villous atrophy in the small intestine), many of whom initiate a gluten-free diet without demonstration of villous atrophy. There are a range of clinical presentations of celiac disease in childhood and patterns of coeliac serology, including fluctuation and spontaneous reversion on a gluten-containing diet, vary. There is a current debate over best strategies to manage adults and children with potential coeliac disease to avoid over-treatment and under-treatment. Childhood and adolescence carry unique issues pertaining to the diagnosis and management of coeliac disease, and include nutrition and growth, rescreening, repeat biopsy, dietary adherence concerns and transition to adult care. In conclusion, while coeliac disease has similar pathogenesis and general clinical manifestations in paediatric and adult populations, diagnostic and management approaches need to adapt to the developmental stages.
Asunto(s)
Enfermedad Celíaca , Adolescente , Adulto , Atrofia/patología , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/terapia , Niño , Preescolar , Dieta Sin Gluten , Glútenes , Humanos , Lactante , Mucosa Intestinal/patología , Estudios ProspectivosRESUMEN
Background: Pancreatic Exocrine Insufficiency (PEI) is a possible cause of recurrent/persistent symptoms in celiac disease. Although pancreatic enzyme supplementation may be used to treat non-responsive celiac disease (NRCD) in clinical practice, clinical outcomes are variable and there is limited and low quality evidence to support this practice. The aim of this study was to assess the efficacy of pancreatic enzyme supplements (PES) for improvement of gastrointestinal symptoms in NRCD. Methods: Prospective, randomized, placebo-controlled, double-blind, cross-over trial in adults with NRCD examining Celiac Disease-Gastrointestinal Symptom Rating Scale (CeD-GSRS) scores on PES (pancrelipase co-administered with omeprazole) versus placebo (omeprazole only) during a 10-day treatment period. The study was registered under the clinical trials registry (https://clinicaltrials.gov/ number, NCT02475369) on 18 Jun 2015. Results: Twelve participants (nine female) were included in the per-protocol analysis; one participant had low fecal elastase-1. Pancrelipase was not associated with significant change in CeD-GSRS compared to placebo (-0.03 versus -0.26; P = 0.366). There was a significant decrease in mean values of total CeD-GSRS scores (3.58 versus 2.90, P = 0.004), abdominal pain (2.92 versus 2.42, P = 0.009), and diarrhea sub-scores (3.44 versus 2.92, P = 0.037) during the run-in period with omeprazole. Conclusion: In this prospective, cross-over randomized, placebo-controlled study, PES did not improve symptoms in patients with NRCD. It is unclear whether this is a trial effect or related to administration of omeprazole.
RESUMEN
BACKGROUND: Primary biliary cholangitis (PBC) frequently coexists with other autoimmune diseases, including celiac disease (CeD). Although the prevalence of CeD is high among cohorts with PBC, few studies have directly compared this prevalence to those among individuals with other liver diseases (OLD). AIM: To compare the prevalence of CeD between a cohort with PBC and a cohort with OLD. METHODS: Retrospective study from January 2013 to December 2016. All consecutive patients with an anti-transglutaminase (tTG) assay requested by a hepatologist and a diagnosis of chronic liver disease were included. CeD diagnosis was confirmed by duodenal biopsies. RESULTS: We included 399 consecutive patients (53.1 years SD 14.0, 54.1% women), notably 51 individuals with PBC and 348 individuals with OLD. PBC group included significantly more women (90.2% versus 48.9% P < 0.0001). The prevalence of CeD was higher in the group with PBC compared to the group with OLD (11.8 versus 2.9%, P < 0.003). In the OLD group, the prevalence of CeD was comparable regardless of the etiologic subgroup (nonalcoholic steatohepatitis 2.7% versus alcoholic liver disease 4.3%, versus viral 1.5% versus other autoimmune liver diseases 3.3%, NS). The presence of gastrointestinal symptoms at the time of the tTG assay was comparable between PBC and OLD groups (31.4 versus 29.6%, NS). CONCLUSION: There is a higher prevalence of CeD in the PBC group compared to other liver diseases.
RESUMEN
BACKGROUND: Non-responsive celiac disease (NRCD) is defined as the persistence of symptoms in individuals with celiac disease (CeD) despite being on a gluten-free diet (GFD). There is scant literature about NRCD in the pediatric population. AIM: To determine the incidence, clinical characteristics and underlying causes of NRCD in children. METHODS: Retrospective cohort study performed at Boston Children's Hospital (BCH). Children < 18 years diagnosed with CeD by positive serology and duodenal biopsies compatible with Marsh III histology between 2008 and 2012 were identified in the BCH's Celiac Disease Program database. Medical records were longitudinally reviewed from the time of diagnosis through September 2015. NRCD was defined as persistent symptoms at 6 mo after the initiation of a GFD and causes of NRCD as well as symptom evolution were detailed. The children without symptoms at 6 mo (responders) were compared with the NRCD group. Additionally, presenting signs and symptoms at the time of diagnosis of CeD among the responders and NRCD patients were collected and compared to identify any potential predictors for NRCD at 6 mo of GFD therapy. RESULTS: Six hundred and sixteen children were included. Ninety-one (15%) met criteria for NRCD. Most were female (77%). Abdominal pain [odds ratio (OR) 1.8 95% confidence interval (CI) 1.1-2.9], constipation (OR 3.1 95%CI 1.9-4.9) and absence of abdominal distension (OR for abdominal distension 0.4 95%CI 0.1-0.98) at diagnosis were associated with NRCD. NRCD was attributed to a wide variety of diagnoses with gluten exposure (30%) and constipation (20%) being the most common causes. Other causes for NRCD included lactose intolerance (9%), gastroesophageal reflux (8%), functional abdominal pain (7%), irritable bowel syndrome (3%), depression/anxiety (3%), eosinophilic esophagitis (2%), food allergy (1%), eating disorder (1%), gastric ulcer with Helicobacter pylori (1%), lymphocytic colitis (1%), aerophagia (1%) and undetermined (13%). 64% of children with NRCD improved on follow-up. CONCLUSION: NRCD after ≥ 6 mo GFD is frequent among children, especially females, and is associated with initial presenting symptoms of constipation and/or abdominal pain. Gluten exposure is the most frequent cause.
Asunto(s)
Enfermedad Celíaca , Dieta Sin Gluten , Boston , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/epidemiología , Niño , Femenino , Glútenes , Humanos , Masculino , Estudios RetrospectivosRESUMEN
Progress has been made in understanding coeliac disease, a relatively frequent and underappreciated immune-mediated condition that occurs in genetically predisposed individuals. However, several gaps remain in knowledge related to diagnosis and management. The gluten-free diet, currently the only available management, is not curative or universally effective (some adherent patients have ongoing duodenal injury). Unprecedented numbers of emerging therapies, including some with novel tolerogenic mechanisms, are currently being investigated in clinical trials. In March 2020, the Celiac Disease Foundation and the Society for the Study of Celiac Disease convened a consensus workshop to identify high-yield areas of research that should be prioritized. Workshop participants included leading experts in clinical practice, academia, government and pharmaceutical development, as well as representatives from patient support groups in North America. This Roadmap summarizes key advances in the field of coeliac disease and provides information on important discussions from the consensus approach to address gaps and opportunities related to the pathogenesis, diagnosis and management of coeliac disease. The morbidity of coeliac disease is often underestimated, which has led to an unmet need to improve the management of these patients. Expanded research funding is needed as coeliac disease is a potentially curable disease.
Asunto(s)
Investigación Biomédica , Enfermedad Celíaca , Animales , Investigación Biomédica/economía , Investigación Biomédica/métodos , Investigación Biomédica/tendencias , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/etiología , Enfermedad Celíaca/fisiopatología , Enfermedad Celíaca/terapia , Dieta Sin Gluten , Humanos , Ratones , Apoyo a la Investigación como Asunto , Sociedades Médicas , Estados UnidosRESUMEN
BACKGROUND: Seronegative coeliac disease is poorly defined. AIMS: To study clinical phenotypes and long-term outcomes of seronegative coeliac disease in a multicentre cohort over 20 years. METHODS: Seronegative coeliac disease was diagnosed in HLA-DQ2/DQ8-positive patients with villous atrophy (VA), negative IgA endomysial (EmA), tissue transglutaminase (tTG) and deamidated-gliadin antibodies (DGP), clinical and histological response to a gluten-free diet (GFD), and no alternative causes for VA. In patients with IgA deficiency, coeliac disease was diagnosed through VA, positive IgG EmA/tTG/DGP and clinical/histological response to a GFD (coeliac disease+IgAd). Patients with seropositive coeliac disease served as controls. RESULTS: Of 227 patients previously diagnosed with seronegative coeliac disease, true seronegative coeliac disease was confirmed in 84, coeliac disease+IgAd in 48, and excluded in 55. Lack of follow-up duodenal biopsy precluded diagnosing seronegative coeliac disease in 40 patients. 2084 patients with seropositive coeliac disease served as controls. True seronegative coeliac disease had more severe symptoms at diagnosis and a higher risk of complications (HR 10.87, 95% CI 6.11-19.33, P < 0.001) and mortality (HR 2.18, 95% CI 1.12-4.26, P < 0.01) than seropositive coeliac disease. There were no differences between true seronegative coeliac disease and coeliac disease+IgAd. On multivariate analysis, age at diagnosis, lack of clinical response to a GFD, true seronegative coeliac disease, coeliac disease+IgAd, and classical presentation predicted complications. Age at diagnosis, complications and absence of clinical response to a GFD predicted mortality. CONCLUSIONS: Seronegative coeliac disease has a more aggressive disease phenotype than seropositive coeliac disease. These data argue against over-reliance on serology for the diagnosis of coeliac disease and support a strict clinical and histologic follow-up in seronegative coeliac disease.
Asunto(s)
Enfermedad Celíaca , Autoanticuerpos , Biopsia , Enfermedad Celíaca/diagnóstico , Dieta Sin Gluten , Estudios de Seguimiento , Gliadina , Humanos , Inmunoglobulina A , TransglutaminasasRESUMEN
Nodular regenerative hyperplasia (NRH) is one of the most frequent causes of noncirrhotic intrahepatic hypertension, but is a difficult histologic diagnosis. The expression of glutamine synthetase (GS) and cytokeratin 7 (CK7) has been reported to be increased in other regenerative/vascular conditions, while CK7 and BerEP4 are also markers of hepatic progenitor cells. The aims of this study were to investigate the use of GS, CK7, and BerEP4 as the potential markers for NRH. This is a retrospective case series of NRH at Centre Hospitalier de l'Universite de Montreal between 1993 and 2013. Normal liver from partial hepatectomies for tumors were used as controls. GS, CK7, CK19, and BerEP4 immunohistochemical stains were performed on all specimens. Immunohistochemical staining patterns were scored from 0 to 3+. NRH was identified in 46 samples obtained from 26 patients. Liver chemistry profile was cholestatic in 45% of the patients. In 93% of the NRH cases, there was abnormal zone 2 expression of GS. Weak panacinar GS staining was seen in all the NRH cases. Aberrant CK7 expression was present in all cases of NRH, but were not associated with cholestasis. BerEP4 was overexpressed in 47% of the NRH cases (P<0.05); all cases with diffuse BerEP4 staining also showed extensive CK7 expression (P<0.01). NRH showed increased immunohistochemical GS staining that may support its morphologic diagnosis. Our findings suggest that there is an activation of hepatic progenitor cells in NRH.
Asunto(s)
Regulación Enzimológica de la Expresión Génica , Glutamato-Amoníaco Ligasa/biosíntesis , Regeneración Hepática , Hígado/enzimología , Células Madre/inmunología , Femenino , Humanos , Hiperplasia , Hígado/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Células Madre/patologíaRESUMEN
BACKGROUND: Indications for a breath test (BT) are well established in the symptomatic patient with risk factors predisposing them to small intestinal bacterial overgrowth (SIBO). Characteristics and the profile of this population are not well known. Our objective was to study the characteristics of patients undergoing a BT for SIBO and to identify factors associated with a positive BT. METHODS: Retrospective study was conducted from 2012 to 2016 at the neurogastroenterology unit of the Centre Hospitalier de l'Universite de Montreal (CHUM). All patients who completed a BT (lactulose and/or glucose) were included. Demographics and clinical factors were analyzed to identify predictors of positive BT. Type of antibiotic treatment and clinical response were compiled. Groups of patients with (SIBO+) and without SIBO (SIBO-) were also compared. RESULTS: A total of 136 patients were included in the study (mean age 51.2, range 20 - 80 years; 63% women), and SIBO was detected in 33.8% (n = 46). Both groups were similar in terms of age, body mass index, and gender. SIBO was significantly associated with the presence of abdominal pain (odds ratio (OR) = 4.78; P < 0.05), bloating (OR = 5.39; P < 0.05), smoking (OR = 6.66; P < 0.05), and anemia (OR = 4.08; P < 0.05). No association was identified with gender, age, obesity, and risk factors for SIBO. Antibiotics were used in 43% of patients with a positive BT, but clinical response was not significantly different in the subgroup that received antibiotics versus the subgroup that did not. CONCLUSIONS: The prevalence of SIBO is high in symptomatic patients who underwent breath testing. Abdominal pain, bloating, smoking, and anemia are strongly associated with SIBO. Treatment of SIBO with antibiotics needs to be further investigated to better determine its efficacy on gastrointestinal symptoms.
RESUMEN
BACKGROUND: The liver and celiac disease (CeD) share a complex relationship. While in some patients, isolated hypertransaminasemia is the only manifestation of CeD, liver diseases (LD) may also be associated with the presence of isolated tissue transglutaminase antibodies IgA (tTG IgA) without histologic evidence of CeD. AIMS: To examine the yield of tTG IgA testing (a) in the workup for chronic liver disease (CLD) or cytolysis and (b) to identify biopsy-confirmed CeD (BxCeD) among patients with concomitant LD. METHODS: Retrospective study including two cohorts. Cohort 1 represented 444 consecutive individuals without known CeD for which liver specialists requested tTG IgA. Incidence of positive tTG and BxCeD was evaluated. Cohort 2 included 212 consecutive individuals with positive tTG IgA and subsequent duodenal biopsies. The frequency and clinical characteristics of individuals without BxCeD were examined, with and without concurrent LD. RESULTS: The rate of first time positive tTG IgA among the tests requested by a liver specialist (cohort 1) was 2.0% (n = 9). However, 33.0% (n = 3) of these patients did not have BxCeD. Cohort 2 included 33 individuals with coexisting LD, of which 42.4% did not have BxCeD, compared with 16.2% of the patients without LD (P < 0.001). The majority of the patients without BxCeD (65.1%) showed an increase < 3 times upper limit of normal of tTG IgA. CONCLUSIONS: Although there is clinical value in testing for CeD in the context of LD, there could be a high rate of positive CeD serology unaccompanied by histologic signs in patients with coexisting LD.
RESUMEN
BACKGROUND AND AIMS: CD14+ mononuclear phagocytes [MNPs] and T cells infiltrate colon in ulcerative colitis [UC]. Here we investigated how CD14+ MNPs and the cytokines they produce shape the colonic effector T cell profile. METHODS: Colonic or mesenteric lymph node [mLNs] CD4+ T cells isolated from UC or Crohn's disease [CD] patients were stimulated with cytokines or autologous CD14+ MNPs. Cytokine expression was assessed by intracytoplasmic staining and multiplex ELISA. Unsupervised phenotypic multicolour analysis of colonic CD14+ MNPs was performed using the FlowSOM algorithm. RESULTS: Among CD14+CD64+HLA-DR+SIRPαâ+ MNPs, only the pro-inflammatory cytokine-producing CD163- subpopulation accumulated in inflamed UC colon and promoted mucosal IL-1ß-dependent Th17, Th17/Th1, Th17/Th22 but not Th1 responses. Unsupervised phenotypic analysis of CD14+CD64+ MNPs segregated CD163- monocyte-like cells and CD163+ macrophages. Unexpectedly, IL-12, IL-1ß and CD163-, but not CD163+, cells induced IL-8 expression in colonic CD4+ T cells, which co-expressed IFN-γ and/or IL-17 in UC and not CD. The CD163- monocyte-like cells increased the frequency of IL-8+IL-17+/-IFN-γâ+/- T cells through IL-1ß and IL-12. Finally, colonic IL-8+ T cells co-expressing GM-CSF, TNF-α and IL-6 were detected ex vivo and, promoted by IL-12 in the mucosa and mLNs in UC only. CONCLUSIONS: Our findings established a link between monocyte-like CD163- MNPs, IL-12, IL-1ß and the detection of colonic memory IL-8-producing CD4+ T cells, which might all contribute to the pathogenesis of UC.
Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/metabolismo , Interleucina-12/metabolismo , Interleucina-8/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Colitis Ulcerosa/patología , Enfermedad de Crohn/patología , Femenino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Inflammatory bowel diseases are associated with dysregulated immune responses in the intestinal tissue. Four molecularly identified macrophage subsets control immune homeostasis in healthy gut. However, the specific roles and transcriptomic profiles of the phenotypically heterogeneous CD14+ macrophage-like population in inflamed gut remain to be investigated in Crohn's disease (CD). Here we identified two phenotypically, morphologically and functionally distinct colonic HLADR+SIRPα+CD14+ subpopulations that were further characterized using single-cell RNA-sequencing (scRNAseq) in CD. Frequencies of CD64hiCD163-/dim cells selectively augmented in inflamed colon and correlated with endoscopic score of disease severity. IL-1ß and IL-23-producing CD64hiCD163-/dim cells predominated over TNF-α-producing CD64hiCD163hi cells in lesions. Purified "inflammatory monocyte-like" CD163-, but not "macrophage-like" CD163hi cells, through IL-1ß, promoted Th17/Th1 but not Th1 responses in tissue memory CD4+T cells. Unsupervised scRNAseq analysis that captures the entire HLADR+SIRPα+ population revealed six clusters, two of which were enriched in either CD163- or CD163hi cells, and best defined by TREM1/FCAR/FCN1/IL1RN or CD209/MERTK/MRCI/CD163L1 genes, respectively. Selected newly identified discriminating markers were used beyond CD163 to isolate cells that shared pro-Th17/Th1 function with CD163- cells. In conclusion, a molecularly distinct pro-inflammatory CD14+ subpopulation accumulates in inflamed colon, drives intestinal inflammatory T-cell responses, and thus, might contribute to CD disease severity.